bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Sleep Traits Have No Causal Effect on Inflammatory Bowel Diseases: A Mendelian Randomization Study
Authors: Chen Min , Peng Wen-Yan , Tang Tai-Chun , Zheng Hui
Published: December 2021

Background: Previous studies suggested an association of sleep disorders with inflammatory bowel disease (IBD) and indicated that using pharmacological treatments for the modulation of circadian rhythms might prevent IBD pathogenesis or aggravation, but whether the effect of sleep traits on IBD was causal is inconclusive and, therefore, prevents drug repurposing based on the previous studies. We aimed to examine the causal effect of different sleep traits on the pathogenesis of IBD.

Methods: Genetic instruments for sleep traits were selected from the largest GWAS studies available in the UK Biobank (n = 449,734) and the 23andMe Research (n = 541,333). A two-sample Mendelian randomization (MR) study was conducted to examine the association of the genetic instruments with IBD (12,882 cases and 21,770 controls), ulcerative colitis (6,968 cases, 20,464 controls), and Crohn’s disease (5,956 cases and 14,927 controls). We applied the inverse-variance weighted (IVW) method to estimate causal effects, and we used the weighted median and MR-Egger method for sensitivity analyses.

Results: We found that sleep duration (OR, 1.00, 95% CI 1.00–1.01), short sleep duration (OR, 1.07, 95% CI 0.41–2.83), morningness (OR, 1.05, 95% CI 0.87–1.27), daytime napping (OR, 1.64, 95% CI 0.62–4.4), frequent insomnia (OR, 1.17, 95% CI 0.8–1.72), any insomnia (OR, 1.17, 95% CI 0.69–1.97), and snoring (OR, 0.31, 95% CI 0.06–1.54) had no causal effect on IBD, and these sleep traits had no causal effect on ulcerative colitis and Crohn’s disease either. Most of the sensitivity analyses showed consistent results with those of the IVW method.

Conclusion: Our MR study did not support the causal effect of sleep traits on IBD. Pharmacological modulation of circadian rhythms for the prevention of IBD pathogenesis was unwarranted.
A Survey of Preclinical Studies Evaluating Nanoparticle-Based Vaccines Against Non-Viral Sexually Transmitted Infections
Authors: Abisoye-Ogunniyan Abisola , Carrano Isabella M. , Weilhammer Dina R. , Gilmore Sean F. , Fischer Nicholas O. , Pal Sukumar , de la Maza Luis M. , Coleman Matthew A. , Rasley Amy
Published: December 2021

A worldwide estimate of over one million STIs are acquired daily and there is a desperate need for effective preventive as well as therapeutic measures to curtail this global health burden. Vaccines have been the most effective means for the control and potential eradication of infectious diseases; however, the development of vaccines against STIs has been a daunting task requiring extensive research for the development of safe and efficacious formulations. Nanoparticle-based vaccines represent a promising platform as they offer benefits such as targeted antigen presentation and delivery, co-localized antigen-adjuvant combinations for enhanced immunogenicity, and can be designed to be biologically inert. Here we discuss promising types of nanoparticles along with outcomes from nanoparticle-based vaccine preclinical studies against non-viral STIs including chlamydia, syphilis, gonorrhea, and recommendations for future nanoparticle-based vaccines against STIs.
Fluoxetine Potentiates Phagocytosis and Autophagy in Microglia
Authors: Park Sung Hee , Lee Young-Sun , Yang Hyun-Jeong , Song Gyun Jee
Published: December 2021

Fluoxetine is a classic antidepressant drug, and its immunomodulatory effects have recently been reported in many disease models. In addition, it has strong antineuroinflammatory effects in stroke and neurodegenerative animal models. However, the effect of fluoxetine on microglia phagocytosis and its molecular mechanisms have not yet been studied. In this study, we investigated whether fluoxetine has a regulatory effect on microglial function. Microglia cell lines and primary mouse microglia were treated with fluoxetine, and the production of inflammatory cytokines and neurotrophic factors and the phagocytosis of amyloid β were measured. Fluoxetine significantly attenuated the production of lipopolysaccharide-induced proinflammatory cytokines and oxidative stress in microglia. Fluoxetine also significantly potentiated microglia phagocytosis and autophagy. In addition, autophagy flux inhibitors attenuated fluoxetine-induced phagocytosis. In conclusion, fluoxetine induces autophagy and potentiates phagocytosis in microglia, which can be a novel molecular mechanism of the neuroinflammatory and neuroprotective effects of fluoxetine.
Comparative Evidence for Intrahepatic Cholestasis of Pregnancy Treatment With Traditional Chinese Medicine Therapy: A Network Meta-Analysis
Authors: Jiang Yinxiao , Li Haotian , Song Dan , Ye Penghui , Xu Nuo , Chen Yuan , Zhang Wenwen , Hu Qichao , Ma Xiao , Wen Jianxia , Li Yeyu , Zhao Yanling
Published: December 2021

Background: Intrahepatic cholestasis of pregnancy (ICP) seriously threatens the health of pregnant women and newborns. A various number of Chinese prescriptions and patent medicines combined with ursodeoxycholic acid (UDCA) are used for treating ICP in China. However, there are still many doubts in choosing the suitable therapeutic drugs for the treatment of ICP in clinical practice.

Methods: Several electronic databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBM), Wanfang, and VIP, were comprehensively searched from the database inception to February 22, 2021. Randomized controlled trials (RCTs) reporting the use of UDCA only, Chinese prescriptions plus UDCA, and patent medicine plus UDCA for the treatment of ICP were collected according to their inclusion and exclusion criteria. Cochrane Reviewers’ Handbook version 5.2 was applied for the risk assessment of the included trials. STATA 16.0 software was used for network meta-analysis (NMA). The pruritus score and the serum levels of total bile acid (TBA), alanine aminotransferase (ALT), and aspartate transaminase (AST) in ICP patients served as the primary outcomes. Moreover, this study had been registered in PROSPERO (https://www.crd.york.ac.uk/PROSPERO/#joinuppage), and the registration number is CRD42020188831.

Results: Thirty-eight RCTs comprising 3,841 patients meeting the inclusion criteria were included in the network meta-analysis. The NMA results showed that compared with UDCA used alone, Yinchenhao decoction (seven different Chinese prescriptions or patent medicines) plus UDCA dramatically alleviated the primary outcomes of ICP, including the pruritus score, as well as the serum levels of TBA, ALT, and AST. The NMA results showed that the optimal drug ratio for the treatment of ICP was different from the dosage ratio of traditional Yinchenhao decoction. Significantly, the intervention plan f (IP-f) group [the similar prescription of Yinchenhao decoction 2 (Artemisia capillaris Thunb >15 g, Gardenia >9 g, and Rhubarb <5 g) + UDCA] was the best therapeutics among the eight therapies.

Conclusion: Overall, the combined use of Chinese prescriptions or patent medicine with UDCA was generally better than UDCA used alone. The dose of IP-f might be a beneficial therapeutic method for the clinical medication of ICP.

Clinical Trail Registration:https://www.crd.york.ac.uk/, identifier CRD42020188831.
Cinobufagin Is a Selective Anti-Cancer Agent against Tumors with EGFR Amplification and PTEN Deletion
Authors: He Kunyan , Wang Guang-Xing , Zhao Li-Nan , Cui Xiao-Fang , Su Xian-Bin , Shi Yi , Xie Tian-Pei , Hou Shang-Wei , Han Ze-Guang
Published: December 2021

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor, and almost half of the patients carrying EGFR-driven tumor with PTEN deficiency are resistant to EGFR-targeted therapy. EGFR amplification and/or mutation is reported in various epithelial tumors. This series of studies aimed to identify a potent compound against EGFR-driven tumor. We screened a chemical library containing over 600 individual compounds purified from Traditional Chinese Medicine against GBM cells with EGFR amplification and found that cinobufagin, the major active ingredient of Chansu, inhibited the proliferation of EGFR amplified GBM cells and PTEN deficiency enhanced its anti-proliferation effects. Cinobufagin also strongly inhibited the proliferation of carcinoma cell lines with wild-type or mutant EGFR expression. In contrast, the compound only weakly inhibited the proliferation of cancer cells with low or without EGFR expression. Cinobufagin blocked EGFR phosphorylation and its downstream signaling, which additionally induced apoptosis and cytotoxicity in EGFR amplified cancer cells. In vivo, cinobufagin blocked EGFR signaling, inhibited cell proliferation, and elicited apoptosis, thereby suppressing tumor growth in both subcutaneous and intracranial U87MG-EGFR xenograft mouse models and increasing the median survival of nude mice bearing intracranial U87MG-EGFR tumors. Cinobufagin is a potential therapeutic agent for treating malignant glioma and other human cancers expressing EGFR.
The Human SCN10AG1662S Point Mutation Established in Mice Impacts on Mechanical, Heat, and Cool Sensitivity
Authors: Chidiac Celeste , Xue Yaping , Muniz Moreno Maria del Mar , Bakr Rasheed Ameer Abu , Lorentz Romain , Birling Marie-Christine , Gaveriaux-Ruff Claire , Herault Yann
Published: December 2021

The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.
Impact of Dose Reduction of Afatinib Used in Patients With Non–Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Wang Ziyu , Du Xin , Chen Ken , Li Shanshan , Yu Zhiheng , Wu Ziyang , Yang Li , Chen Dingding , Liu Wei
Published: December 2021

Background and Aim: As one of the second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors, afatinib brings survival benefits to patients with common and rare EGFR mutations. This study aimed to compare the effectiveness and safety of 30 and 40 mg of afatinib in patients with non–small cell lung cancer (NSCLC) using qualitative and quantitative analysis methods so as to provide reference for clinical medication.

Methods: The PubMed, Embase, ClinicalTrials.gov, Cochrane Library, China National Knowledge Infrastructure, and WanFang databases were thoroughly searched from inception to February 26, 2021. Two researchers independently screened the literature, extracted data, and evaluated the quality. RevMan and Stata 15.0 were used for meta-analysis.

Results: Twelve cohort studies including 1290 patients for final analysis were selected; of which, 1129 patients were analyzed to measure the effectiveness outcomes and 470 patients were analyzed for safety outcomes. In patients with non-brain metastasis, the progression-free survival of the first- or second-line treatment with reduced-dose afatinib was equivalent to the conventional dose. In terms of safety, the reduced dose could significantly lower the incidence of severe diarrhea and severe rash, but not the total incidence of diarrhea, rash, and all levels of paronychia.

Conclusions: The incidence of common serious adverse reactions was significantly lower with 30 mg of afatinib than with 40 mg of afatinib in patients with NSCLC. The effectiveness appeared to be similar to that in patients with non-brain metastasis. This study provides a reference for clinical dose reduction of afatinib.

Systematic Review Registration: [PROSPERO], identifier [CRD42021238043]
Genetic Variation of G6PD and CYP2D6: Clinical Implications on the Use of Primaquine for Elimination of Plasmodium vivax
Authors: Stewart Alexandra G. A. , Zimmerman Peter A. , McCarthy James S.
Published: December 2021

Primaquine, an 8-aminoquinoline, is the only medication approved by the World Health Organization to treat the hypnozoite stage of Plasmodium vivax and P. ovale malaria. Relapse, triggered by activation of dormant hypnozoites in the liver, can occur weeks to years after primary infection, and provides the predominant source of transmission in endemic settings. Hence, primaquine is essential for individual treatment and P. vivax elimination efforts. However, primaquine use is limited by the risk of life-threatening acute hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. More recently, studies have demonstrated decreased efficacy of primaquine due to cytochrome P450 2D6 (CYP2D6) polymorphisms conferring an impaired metabolizer phenotype. Failure of standard primaquine therapy has occurred in individuals with decreased or absent CYP2D6 activity. Both G6PD and CYP2D6 are highly polymorphic genes, with considerable geographic and interethnic variability, adding complexity to primaquine use. Innovative strategies are required to overcome the dual challenge of G6PD deficiency and impaired primaquine metabolism. Further understanding of the pharmacogenetics of primaquine is key to utilizing its full potential. Accurate CYP2D6 genotype-phenotype translation may optimize primaquine dosing strategies for impaired metabolizers and expand its use in a safe, efficacious manner. At an individual level the current challenges with G6PD diagnostics and CYP2D6 testing limit clinical implementation of pharmacogenetics. However, further characterisation of the overlap and spectrum of G6PD and CYP2D6 activity may optimize primaquine use at a population level and facilitate region-specific dosing strategies for mass drug administration. This precision public health approach merits further investigation for P. vivax elimination.
Propolis in Oral Healthcare: Antibacterial Activity of a Composite Resin Enriched With Brazilian Red Propolis
Authors: Oliveira José Marcos dos Santos , Cavalcanti Théo Fortes Silveira , Leite Ingrid Ferreira , dos Santos Dávida Maria Ribeiro Cardoso , Porto Isabel Cristina Celerino de Moraes , de Aquino Fernanda Lima Torres , Sonsin Artur Falqueto , Lins Renata Matos Lamenha , Vitti Rafael Pino , de Freitas Johnnatan Duarte , Barreto Emiliano de Oliveira , de Souza Samuel Teixeira , Kamiya Regianne Umeko , do Nascimento Ticiano Gomes , Tonholo Josealdo
Published: December 2021

The aim of this study was to obtain a Brazilian red propolis (BRP) enriched composite resin and to perform the characterization of its antibacterial activity, mechanical, and physical-chemical properties. Brazilian red propolis ethyl acetate extract (EABRP) was characterized by LC-ESI-Orbitrap-FTMS, UPLC-DAD, antibacterial activity, total flavonoids content, and radical scavenging capacity. BRP was incorporated to a commercial composite resin (RC) to obtain BRP enriched composite at 0.1, 0.15 and 0.25% (RP10, RP15 and RP25, respectively). The antibacterial activity RPs was evaluated against Streptococcus mutans by contact direct test and expressed by antibacterial ratio. The RPs were characterized as its cytotoxicity against 3T3 fibroblasts, flexural strength (FS), Knoop microhardness (KHN), post-cure depth (CD), degree of conversion (DC%), water sorption (Wsp), water solubility (Wsl), average roughness (Ra), and thermal analysis. Were identified 50 chemical compounds from BRP extract by LC-ESI-Orbitrap-FTMS. EABRP was bacteriostatic and bactericide at 125 and 500 μg/ml, respectively. The RP25 exhibited antibacterial ratio of 90.76% after 1 h of direct contact with S. mutans (p < 0.0001) while RC no showed significative antibacterial activity (p = 0.1865), both compared with cell control group. RPs and RC no showed cytotoxicity. RPs exhibited CD from 2.74 to 4.48 mm, DC% from 80.70 to 83.96%, Wsp from 17.15 to 21.67 μg/mm3, Wsl from 3.66 to 4.20 μg/mm3, Ra from 14.48 to 20.76 nm. RPs showed thermal resistance between 448–455°C. The results support that propolis can be used on development of modified composite resins that show antibacterial activity and that have compatible mechanical and physical-chemical properties to the indicate for composite resins.
TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis
Authors: Liu Xin , Zheng Xinchuan , Lu Yongling , Chen Qian , Zheng Jiang , Zhou Hong
Published: December 2021

Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis.
Graph Embedding for Scholar Recommendation in Academic Social Networks
Authors: Yuan Chengzhe , He Yi , Lin Ronghua , Tang Yong
Published: December 2021

The academic social networks (ASNs) play an important role in promoting scientific collaboration and innovation in academic society. Accompanying the tremendous growth of scholarly big data, finding suitable scholars on ASNs for collaboration has become more difficult. Different from friend recommendation in conventional social networks, scholar recommendation in ASNs usually involves different academic entities (e.g., scholars, scientific publications, and status updates) and various relationships (e.g., collaboration relationship between team members, citations, and co-authorships), which forms a complex heterogeneous academic network. Our goal is to recommend potential similar scholars for users in ASNs. In this article, we propose to design a graph embedding-based scholar recommendation system by leveraging academic auxiliary information. First, we construct enhanced ASNs by integrating two types of academic features extracted from scholars’ academic information with original network topology. Then, the refined feature representations of the scholars are obtained by a graph embedding framework, which helps the system measure the similarity between scholars based on their representation vectors. Finally, the system generates potential similar scholars for users in ASNs for the final recommendation. We evaluate the effectiveness of our model on five real-world datasets: SCHOLAT, Zhihu, APS, Yelp and Gowalla. The experimental results demonstrate that our model is effective and achieves promising improvements than the other competitive baselines.
Silty Clay Stabilization Using Metakaolin-Based Geopolymer Binder
Authors: Wang Shengnian , Su Jun , Wu Zhijian , Ma Wei , Li Yue , Hui Honglei
Published: December 2021

Geopolymer binders are adjudged as the latest wave of sustainable alkali-activated materials for soil stabilization due to their excellent bonding properties. This study applied metakaolin as a precursor for synthesizing the geopolymer binder by employing the mixture of quicklime and sodium bicarbonate as an alkali activator. The optimal mass mixing ratio of the alkali activator, metakaolin, and silty clay was determined by unconfined compression tests. The stabilization mechanisms of the geopolymer binder were measured by x-ray diffraction and Fourier transform infrared spectroscopy. The microstructural characteristics of the geopolymer-stabilized silty clay were observed by scanning electron microscopy with an energy dispersive x-ray spectroscopy and mercury intrusion porosimetry test for understanding the strengthening mechanism of the silty clay after the treatment. Results indicate that the optimal mass mixing ratio of the alkali activator, metakaolin, and silty clay is 1:2:17, and the unconfined compressive strength of the geopolymer-stabilized silty clay reaches the maximum value of 0.85 MPa with adding 15 wt% of the geopolymer binder. Diffraction patterns show an insufficient polymerization of the geopolymer binder in the silty clay in the early days but a rapid synthesis of aluminosilicate gels after that. The new asymmetrical stretching vibration peaks signified the formation of aluminosilicate networks and are responsible for the strength improvement of the silty clay. Microstructural analyses further confirm the formation of aluminosilicate gels and their positive impacts on the structure of the silty clay over curing age.
Vibration Isolation of a Rubber-Concrete Alternating Superposition In-Filled Trench for Train-Induced Environmental Vibration Based on 2.5D Indirect Boundary Element Method
Authors: Jin Liguo , Wang Jingya , Liu Xujin , Li Qiangqiang , Zhou Zhenghua
Published: December 2021

A new train-induced vibration isolation measure of rubber-concrete alternating superposition in-filled trench is presented in this paper. For analyzing the vibration isolation effect of the new measure, this paper establishes a 2.5D train-track-layered foundation-filled trench model to analyze the dynamics of track and layered foundation with the in-filled trench. The correctness of the model is verified by using the measured data of the Sweden X-2000 high-speed train. The vibration isolation effect of the rubber-concrete alternating superposition in-filled trench is calculated by using the actual soft soil foundation parameters of the X-2000 high-speed train, and the vibration isolation effect is also compared with that of the empty trench, rubber in-filled trench, and concrete in-filled trench. The results show that the vibration isolation effect of the rubber-concrete alternating superposition in-filled trench proposed in this paper is better than that of the C30 concrete in-filled trench, especially the impact on displacement. Compared with low-frequency vibrations generated by the lower train speed, the rubber-concrete alternating superposition in-filled trench has a better vibration isolation effect on high-frequency vibrations caused by higher-speed trains. The rubber-concrete alternately superposition in-filled trench has the frequency band characteristics of elastic waves. Elastic waves in the passband frequency range can propagate without attenuation, while the elastic waves in the forbidden frequency range will be filtered out.
Predicting Central Serous Chorioretinopathy Recurrence Using Machine Learning
Authors: Xu Fabao , Wan Cheng , Zhao Lanqin , You Qijing , Xiang Yifan , Zhou Lijun , Li Zhongwen , Gong Songjian , Zhu Yi , Chen Chuan , Li Cong , Zhang Li , Guo Chong , Li Longhui , Gong Yajun , Zhang Xiayin , Lai Kunbei , Huang Chuangxin , Zhao Hongkun , Ting Daniel , Jin Chenjin , Lin Haotian
Published: December 2021

Purpose: To predict central serous chorioretinopathy (CSC) recurrence 3 and 6 months after laser treatment by using machine learning.

Methods: Clinical and imaging features of 461 patients (480 eyes) with CSC were collected at Zhongshan Ophthalmic Center (ZOC) and Xiamen Eye Center (XEC). The ZOC data (416 eyes of 401 patients) were used as the training dataset and the internal test dataset, while the XEC data (64 eyes of 60 patients) were used as the external test dataset. Six different machine learning algorithms and an ensemble model were trained to predict recurrence in patients with CSC. After completing the initial detailed investigation, we designed a simplified model using only clinical data and OCT features.

Results: The ensemble model exhibited the best performance among the six algorithms, with accuracies of 0.941 (internal test dataset) and 0.970 (external test dataset) at 3 months and 0.903 (internal test dataset) and 1.000 (external test dataset) at 6 months. The simplified model showed a comparable level of predictive power.

Conclusion: Machine learning achieves high accuracies in predicting the recurrence of CSC patients. The application of an intelligent recurrence prediction model for patients with CSC can potentially facilitate recurrence factor identification and precise individualized interventions.
Neurogenic Hypertension Mediated Mitochondrial Abnormality Leads to Cardiomyopathy: Contribution of UPRmt and Norepinephrine-miR- 18a-5p-HIF-1α Axis
Authors: Nandi Shyam S. , Katsurada Kenichi , Mahata Sushil K. , Patel Kaushik P.
Published: December 2021

Aims: Hypertension increases the risk of heart disease. Hallmark features of hypertensive heart disease is sympathoexcitation and cardiac mitochondrial abnormality. However, the molecular mechanisms for specifically neurally mediated mitochondrial abnormality and subsequent cardiac dysfunction are unclear. We hypothesized that enhanced sympatho-excitation to the heart elicits cardiac miR-18a-5p/HIF-1α and mitochondrial unfolded protein response (UPRmt) signaling that lead to mitochondrial abnormalities and consequent pathological cardiac remodeling.

Methods and Results: Using a model of neurogenic hypertension (NG-HTN), induced by intracerebroventricular (ICV) infusion of Ang II (NG-HTN; 20 ng/min, 14 days, 0.5 μl/h, or Saline; Control, 0.9%) through osmotic mini-pumps in Sprague-Dawley rats (250–300 g), we attempted to identify a link between sympathoexcitation (norepinephrine; NE), miRNA and HIF-1α signaling and UPRmt to produce mitochondrial abnormalities resulting in cardiomyopathy. Cardiac remodeling, mitochondrial abnormality, and miRNA/HIF-1α signaling were assessed using histology, immunocytochemistry, electron microscopy, Western blotting or RT-qPCR. NG-HTN demonstrated increased sympatho-excitation with concomitant reduction in UPRmt, miRNA-18a-5p and increased level of HIF-1α in the heart. Our in silico analysis indicated that miR-18a-5p targets HIF-1α. Direct effects of NE on miRNA/HIF-1α signaling and mitochondrial abnormality examined using H9c2 rat cardiomyocytes showed NE reduces miR-18a-5p but increases HIF-1α. Electron microscopy revealed cardiac mitochondrial abnormality in NG-HTN, linked with hypertrophic cardiomyopathy and fibrosis. Mitochondrial unfolded protein response was decreased in NG-HTN indicating mitochondrial proteinopathy and proteotoxic stress, associated with increased mito-ROS and decreased mitochondrial membrane potential (ΔΨm), and oxidative phosphorylation. Further, there was reduced cardiac mitochondrial biogenesis and fusion, but increased mitochondrial fission, coupled with mitochondrial impaired TIM-TOM transport and UPRmt. Direct effects of NE on H9c2 rat cardiomyocytes also showed cardiomyocyte hypertrophy, increased mitochondrial ROS generation, and UPRmt corroborating the in vivo data.

Conclusion: In conclusion, enhanced sympatho-excitation suppress miR-18a-5p/HIF-1α signaling and increased mitochondrial stress proteotoxicity, decreased UPRmt leading to decreased mitochondrial dynamics/OXPHOS/ΔΨm and ROS generation. Taken together, these results suggest that ROS induced mitochondrial transition pore opening activates pro-hypertrophy/fibrosis/inflammatory factors that induce pathological cardiac hypertrophy and fibrosis commonly observed in NG-HTN.
Sirtuins at the Service of Healthy Longevity
Authors: Watroba Mateusz , Szukiewicz Dariusz
Published: December 2021

Sirtuins may counteract at least six hallmarks of organismal aging: neurodegeneration, chronic but ineffective inflammatory response, metabolic syndrome, DNA damage, genome instability, and cancer incidence. Moreover, caloric restriction is believed to slow down aging by boosting the activity of some sirtuins through activating adenosine monophosphate-activated protein kinase (AMPK), thus raising the level of intracellular nicotinamide adenine dinucleotide (NAD+) by stimulating NAD+ biosynthesis. Sirtuins and their downstream effectors induce intracellular signaling pathways related to a moderate caloric restriction within cells, mitigating reactive oxygen species (ROS) production, cell senescence phenotype (CSP) induction, and apoptosis as forms of the cellular stress response. Instead, it can promote DNA damage repair and survival of cells with normal, completely functional phenotypes. In this review, we discuss mechanisms of sirtuins action toward cell-conserving phenotype associated with intracellular signaling pathways related to moderate caloric restriction, as well as some tissue-specific functions of sirtuins, especially in the central nervous system, heart muscle, skeletal muscles, liver, kidneys, white adipose tissue, hematopoietic system, and immune system. In this context, we discuss the possibility of new therapeutic approaches.
Intermittent Hypoxia Exposure Helps to Restore the Reduced Hemoglobin Concentration During Intense Exercise Training in Trained Swimmers
Authors: Weng Xiquan , Lin Jieru , Yuan Yu , Lin Baoxuan , Huang Weiwei , Tin Hiu Tung , Li Jia , Yan Xu , Lin Wentao , Chen Hao
Published: December 2021

In prolonged intense exercise training, the training load of athletes may be reduced once their hemoglobin concentrations ([Hb]s) are decreased dramatically. We previously reported that intermittent hypoxia exposure (IHE) could be used to alleviate the decrease of [Hb] and help to maintain the training load in rats. To further explore the feasibility of applying IHE intervention to athletes during prolonged intense exercise training, 6 trained swimmers were recruited to conduct a 4-week IHE intervention at the intervals after their [Hb] dropped for 10% or more during their training season. IHE intervention lasted 1 h and took place once a day and five times a week. Hematological and hormonal parameters, including [Hb], red blood cells (RBC), hematocrit (Hct), reticulocytes, serum erythropoietin (EPO), testosterone (T) and cortisol (C) were examined. After the IHE intervention was launched, [Hb], RBC and Hct of the subjects were increased progressively with their maximum levels (P < 0.01) showing at the third or fourth week, respectively. An increase in reticulocyte count (P < 0.01) suggests that IHE intervention promotes erythropoiesis to increase [Hb]. Besides, serum level of EPO, the hormone known to stimulate erythropoiesis, was overall higher than that before the IHE intervention, although it was statistically insignificant. Furthermore, the serum level of T, another hormone known to stimulate erythropoiesis, was increased progressively with the maximum level showing at the fourth week. Collectively, this study further confirms that IHE intervention may be used as a new strategy to prevent intense exercise training-induced reductions in [Hb].
A Role for Adipocytes and Adipose Stem Cells in the Breast Tumor Microenvironment and Regenerative Medicine
Authors: Brock Courtney K. , Hebert Katherine L. , Artiles Maria , Wright Maryl K. , Cheng Thomas , Windsor Gabrielle O. , Nguyen Khoa , Alzoubi Madlin S. , Collins-Burow Bridgette M. , Martin Elizabeth C. , Lau Frank H. , Bunnell Bruce A. , Burow Matthew E.
Published: December 2021

Obesity rates are climbing, representing a confounding and contributing factor to many disease states, including cancer. With respect to breast cancer, obesity plays a prominent role in the etiology of this disease, with certain subtypes such as triple-negative breast cancer having a strong correlation between obesity and poor outcomes. Therefore, it is critical to examine the obesity-related alterations to the normal stroma and the tumor microenvironment (TME). Adipocytes and adipose stem cells (ASCs) are major components of breast tissue stroma that have essential functions in both physiological and pathological states, including energy storage and metabolic homeostasis, physical support of breast epithelial cells, and directing inflammatory and wound healing responses through secreted factors. However, these processes can become dysregulated in both metabolic disorders, such as obesity and also in the context of breast cancer. Given the well-established obesity-neoplasia axis, it is critical to understand how interactions between different cell types in the tumor microenvironment, including adipocytes and ASCs, govern carcinogenesis, tumorigenesis, and ultimately metastasis. ASCs and adipocytes have multifactorial roles in cancer progression; however, due to the plastic nature of these cells, they also have a role in regenerative medicine, making them promising tools for tissue engineering. At the physiological level, the interactions between obesity and breast cancer have been examined; here, we will delineate the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment. We will define the current state of understanding of how adipocytes and ASCs contribute to tumor progression through their role in the tumor microenvironment and how this is altered in the context of obesity. We will also introduce recent developments in utilizing adipocytes and ASCs in novel approaches to breast reconstruction and regenerative medicine.
Eph-ephrin Signaling Affects Eye Lens Fiber Cell Intracellular Voltage and Membrane Conductance
Authors: Cheng Catherine , Gao Junyuan , Sun Xiurong , Mathias Richard T.
Published: December 2021

The avascular eye lens generates its own microcirculation that is required for maintaining lifelong lens transparency. The microcirculation relies on sodium ion flux, an extensive network of gap junction (GJ) plaques between lens fiber cells and transmembrane water channels. Disruption of connexin proteins, the building blocks of GJs, or aquaporins, which make up water and adhesion channels, lead to lens opacification or cataracts. Recent studies have revealed that disruption of Eph-ephrin signaling, in particular the receptor EphA2 and the ligand ephrin-A5, in humans and mice lead to congenital and age-related cataracts. We investigated whether changes in lens transparency in EphA2 or ephrin-A5 knockout (–/–) mice is related to changes in GJ coupling and lens fluid and ion homeostasis. Immunostaining revealed changes in connexin 50 (Cx50) subcellular localization in EphA2–/– peripheral lens fibers and alteration in aquaporin 0 (Aqp0) staining patterns in ephrin-A5–/– and EphA2–/– inner mature fiber cells. Surprisingly, there was no obvious change in GJ coupling in knockout lenses. However, there were changes in fiber cell membrane conductance and intracellular voltage in knockout lenses from 3-month-old mice. These knockout lenses displayed decreased conductance of mature fiber membranes and were hyperpolarized compared to control lenses. This is the first demonstration that the membrane conductance of lens fibers can be regulated. Together these data suggest that EphA2 may be needed for normal Cx50 localization to the cell membrane and that conductance of lens fiber cells requires normal Eph-ephrin signaling and water channel localization.
Lifestyle Modification Using a Wearable Biometric Ring and Guided Feedback Improve Sleep and Exercise Behaviors: A 12-Month Randomized, Placebo-Controlled Study
Authors: Browne Jonathan D. , Boland David M. , Baum Jaxon T. , Ikemiya Kayla , Harris Quincy , Phillips Marin , Neufeld Eric V. , Gomez David , Goldman Phillip , Dolezal Brett A.
Published: December 2021

Purpose: Wearable biometric monitoring devices (WBMD) show promise as a cutting edge means to improve health and prevent disease through increasing accountability. By regularly providing real-time quantitative data regarding activity, sleep quality, and recovery, users may become more aware of the impact that their lifestyle has on their health. The purpose of this study was to examine the efficacy of a biometric tracking ring on improving sleep quality and increasing physical fitness over a one-year period.

Methods: Fifty-six participants received a biometric tracking ring and were placed in one of two groups. One group received a 3-month interactive behavioral modification intervention (INT) that was delivered virtually via a smartphone app with guided text message feedback (GTF). The other received a 3-month non-directive wellness education control (CON). After three months, the INT group was divided into a long-term feedback group (LT-GTF) that continued to receive GTF for another nine months or short-term feedback group (ST-GTF) that stopped receiving GTF. Weight, body composition, and VO2max were assessed at baseline, 3months, and 12months for all participants and additionally at 6 and 9months for the ST-GTF and LT-GTF groups. To establish baseline measurements, sleep and physical activity data were collected daily over a 30-day period. Daily measurements were also conducted throughout the 12-month duration of the study.

Results: Over the first 3months, the INT group had significant (p<0.001) improvements in sleep onset latency, daily step count, % time jogging, VO2max, body fat percentage, and heart rate variability (rMSSD HRV) compared to the CON group. Over the next 9months, the LT-GTF group continued to improve significantly (p<0.001) in sleep onset latency, daily step count, % time jogging, VO2max, and rMSSD HRV. The ST-GTF group neither improved nor regressed over the latter 9months except for a small increase in sleep latency.

Conclusion: Using a WBMD concomitantly with personalized education, encouragement, and feedback, elicits greater change than using a WBMD alone. Additionally, the improvements achieved from a short duration of personalized coaching are largely maintained with the continued use of a WBMD.
In situ Metabolomics of Metabolic Reprogramming Involved in a Mouse Model of Type 2 Diabetic Kidney Disease
Authors: Linnan Bai , Yanzhe Wang , Ling Zhang , Yuyuan Liu , Sijia Chen , Xinmiao Xie , Fengqin Li , Xiaoxia Wang
Published: December 2021

The in situ metabolic profiling of the kidney is crucial to investigate the complex metabolic reprogramming underlying diabetic kidney disease (DKD) and to allow exploration of potential metabolic targets to improve kidney function. However, as the kidney is a highly heterogeneous organ, traditional metabolomic methods based on bulk analysis that produce an averaged measurement are inadequate. Herein, we employed an in situ metabolomics approach to discover alternations of DKD-associated metabolites and metabolic pathways. A series of histology-specific metabolic disturbances were discovered in situ using airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI–MSI). In combination with integrated metabolomics analysis, five dysfunctional metabolic pathways were identified and located in the kidneys of type-2 DKD mice simultaneously for the first time, including taurine metabolism, arginine and proline metabolism, histidine metabolism, biosynthesis of unsaturated fatty acids, and fatty acid degradation pathways. As crucial nodes of metabolic pathways, five dysregulated rate-limiting enzymes related to altered metabolic pathways were further identified. These findings reveal alternations from metabolites to enzymes at the molecular level in the progression of DKD and provide insights into DKD-associated metabolic reprogramming.
Cortisol and C-Reactive Protein Vary During Sleep Loss and Recovery but Are Not Markers of Neurobehavioral Resilience
Authors: Yamazaki Erika M. , Antler Caroline A. , Casale Courtney E. , MacMullen Laura E. , Ecker Adrian J. , Goel Namni
Published: December 2021

Cortisol and C-reactive protein (CRP) typically change during total sleep deprivation (TSD) and psychological stress; however, it remains unknown whether these biological markers can differentiate robust individual differences in neurobehavioral performance and self-rated sleepiness resulting from these stressors. Additionally, little is known about cortisol and CRP recovery after TSD. In our study, 32 healthy adults (ages 27–53; mean ± SD, 35.1 ± 7.1 years; 14 females) participated in a highly controlled 5-day experiment in the Human Exploration Research Analog (HERA), a high-fidelity National Aeronautics and Space Administration (NASA) space analog isolation facility, consisting of two baseline nights, 39 h TSD, and two recovery nights. Psychological stress was induced by a modified Trier Social Stress Test (TSST) on the afternoon of TSD. Salivary cortisol and plasma CRP were obtained at six time points, before (pre-study), during [baseline, the morning of TSD (TSD AM), the afternoon of TSD (TSD PM), and recovery], and after (post-study) the experiment. A neurobehavioral test battery, including measures of behavioral attention and cognitive throughput, and a self-report measure of sleepiness, was administered 11 times. Resilient and vulnerable groups were defined by a median split on the average TSD performance or sleepiness score. Low and high pre-study cortisol and CRP were defined by a median split on respective values at pre-study. Cortisol and CRP both changed significantly across the study, with cortisol, but not CRP, increasing during TSD. During recovery, cortisol levels did not return to pre-TSD levels, whereas CRP levels did not differ from baseline. When sex was added as a between-subject factor, the time × sex interaction was significant for cortisol. Resilient and vulnerable groups did not differ in cortisol and CRP, and low and high pre-study cortisol/CRP groups did not differ on performance tasks or self-reported sleepiness. Thus, both cortisol and CRP reliably changed in a normal, healthy population as a result of sleep loss; however, cortisol and CRP were not markers of neurobehavioral resilience to TSD and stress in this study.
Identification of Finely Mapped Quantitative Trait Locus and Candidate Gene Mining for the Three-Seeded Pod Trait in Soybean
Authors: Li Candong , Jiang Hongwei , Li Yingying , Liu Chunyan , Qi Zhaoming , Wu Xiaoxia , Zhang Zhanguo , Hu Zhenbang , Zhu Rongsheng , Guo Tai , Wang Zhixin , Zheng Wei , Zhang Zhenyu , Zhao Haihong , Wang Nannan , Shan Dapeng , Xin Dawei , Luan Feishi , Chen Qingshan
Published: December 2021

The three-seeded pod number is an important trait that positively influences soybean yield. Soybean variety with increased three-seeded pod number contributes to the seed number/plant and higher yield. The candidate genes of the three-seeded pod may be the key for improving soybean yield. In this study, identification and validation of candidate genes for three-seeded pod has been carried out. First, a total of 36 quantitative trait locus (QTL) were detected from the investigation of recombinant inbred lines including 147 individuals derived from a cross between Charleston and Dongning 594 cultivars. Five consensus QTLs were integrated. Second, an introgressed line CSSL-182 carrying the target segment for the trait from the donor parent was selected to verify the consensus QTL based on its phenotype. Third, a secondary group was constructed by backcrossing with CSSL-182, and two QTLs were confirmed. There were a total of 162 genes in the two QTLs. The mining of candidate genes resulted in the annotation of eight genes with functions related to pod and seed sets. Finally, haplotype analysis and quantitative reverse transcriptase real-time PCR were carried to verify the candidate genes. Four of these genes had different haplotypes in the resource group, and the differences in the phenotype were highly significant. Moreover, the differences in the expression of the four genes during pod and seed development were also significant. These four genes were probably related to the development process underlying the three-seeded pod in soybean. Herein, we discuss the past and present studies related to the three-seeded pod trait in soybean.
PocketMaize: An Android-Smartphone Application for Maize Plant Phenotyping
Authors: Liu Lingbo , Yu Lejun , Wu Dan , Ye Junli , Feng Hui , Liu Qian , Yang Wanneng
Published: December 2021

A low-cost portable wild phenotyping system is useful for breeders to obtain detailed phenotypic characterization to identify promising wild species. However, compared with the larger, faster, and more advanced in-laboratory phenotyping systems developed in recent years, the progress for smaller phenotyping systems, which provide fast deployment and potential for wide usage in rural and wild areas, is quite limited. In this study, we developed a portable whole-plant on-device phenotyping smartphone application running on Android that can measure up to 45 traits, including 15 plant traits, 25 leaf traits and 5 stem traits, based on images. To avoid the influence of outdoor environments, we trained a DeepLabV3+ model for segmentation. In addition, an angle calibration algorithm was also designed to reduce the error introduced by the different imaging angles. The average execution time for the analysis of a 20-million-pixel image is within 2,500 ms. The application is a portable on-device fast phenotyping platform providing methods for real-time trait measurement, which will facilitate maize phenotyping in field and benefit crop breeding in future.
Wheat Apoplast-Localized Lipid Transfer Protein TaLTP3 Enhances Defense Responses Against Puccinia triticina
Authors: Zhao Jiaojie , Bi Weishuai , Zhao Shuqing , Su Jun , Li Mengyu , Ma Lisong , Yu Xiumei , Wang Xiaodong
Published: December 2021

Plant apoplast serves as the frontier battlefield of plant defense in response to different types of pathogens. Many pathogenesis-related (PR) proteins are accumulated in apoplastic space during the onset of plant–pathogen interaction, where they act to suppress pathogen infection. In this study, we found the expression of Triticum aestivum lipid transfer protein 3 (TaLTP3) gene was unregulated during incompatible interaction mediated by leaf rust resistance genes Lr39/41 at the early infection stage. Stable transgenic wheat lines overexpressing TaLTP3 exhibited enhanced resistance to leaf rust pathogen Puccinia triticina. Transcriptome analysis revealed that overexpression of TaLTP3 specifically activated the transcription of pathogenesis-related protein 1a (TaPR1a) and multiple plant hormone pathways, including salicylic acid (SA), jasmonic acid (JA), and auxin, in response to the infection of the model bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Further investigation indicated that TaLTP3 physically associated with wheat TaPR1a protein in the apoplast. Transgenic wheat lines overexpressing TaLTP3 and TaPR1a showed higher accumulations of reactive oxygen species (ROS) during plant defense responses. All these findings suggested that TaLTP3 is involved in wheat resistance against leaf rust pathogen infection and forming a TaLTP3-TaPR1a complex in apoplast against this pathogen, which provides new insights into the functional roles of PR proteins.