bluuebunny/crossref_metadata_2025 huggingface dataset:
The Key Role of Exosomes on the Pre-metastatic Niche Formation in Tumors
Authors: Yang Xuyang , Zhang Yang , Zhang Yaguang , Zhang Su , Qiu Lei , Zhuang Zixuan , Wei Mingtian , Deng Xiangbing , Wang Ziqiang , Han Junhong
Published: September 2021

Exosomes or other extracellular vesicles released from cells play an important role in cell-to-cell communication by transferring bio-information (DNA, coding/non-coding RNA, and proteins), which indicates parental cell status to recipient cells in the extracellular environment. Increasingly, evidence shows that tumor-derived exosomes mediate tumor pre-metastatic niche (PMN) remodeling to establish a supportive and receptive niche to promote tumor cell colonization and metastasis. Uptake of genetic information by target cells in the extracellular environment triggers epigenetic changes that contribute to PMN formation. Here, we provide a comprehensive overview of the current understanding of exosomes-mediated reprogramming of cells in PMN formation.
Ophthalmic Biomarkers for Alzheimer’s Disease: A Review
Authors: Majeed Ayesha , Marwick Ben , Yu Haoqing , Fadavi Hassan , Tavakoli Mitra
Published: September 2021

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by neuronal loss, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tau tangles. A diagnosis is currently made from the presenting symptoms, and the only definitive diagnosis can be done post-mortem. Over recent years, significant advances have been made in using ocular biomarkers to diagnose various neurodegenerative diseases, including AD. As the eye is an extension of the central nervous system (CNS), reviewing changes in the eye’s biology could lead to developing a series of non-invasive, differential diagnostic tests for AD that could be further applied to other diseases. Significant changes have been identified in the retinal nerve fiber layer (RNFL), cornea, ocular vasculature, and retina. In the present paper, we review current research and assess some ocular biomarkers’ accuracy and reliability that could potentially be used for diagnostic purposes. Additionally, we review the various imaging techniques used in the measurement of these biomarkers.
Microglial Phenotypic Transition: Signaling Pathways and Influencing Modulators Involved in Regulation in Central Nervous System Diseases
Authors: Li Jiaxin , Shui Xinyu , Sun Ruizheng , Wan Lily , Zhang Boxin , Xiao Bo , Luo Zhaohui
Published: September 2021

Microglia are macrophages that reside in the central nervous system (CNS) and belong to the innate immune system. Moreover, they are crucially involved in CNS development, maturation, and aging; further, they are closely associated with neurons. In normal conditions, microglia remain in a static state. Upon trauma or lesion occurrence, microglia can be activated and subsequently polarized into the pro-inflammatory or anti-inflammatory phenotype. The phenotypic transition is regulated by numerous modulators. This review focus on the literature regarding the modulators and signaling pathways involved in regulating the microglial phenotypic transition, which are rarely mentioned in other reviews. Hence, this review provides molecular insights into the microglial phenotypic transition, which could be a potential therapeutic target for neuroinflammation.
Robotic Shoulder Rehabilitation With the Hybrid Assistive Limb in a Patient With Delayed Recovery After Postoperative C5 Palsy: A Case Report
Authors: Kubota Shigeki , Kadone Hideki , Shimizu Yukiyo , Takahashi Hiroshi , Koda Masao , Miura Kousei , Watanabe Hiroki , Suzuki Kenji , Hada Yasushi , Sankai Yoshiyuki , Yamazaki Masashi
Published: September 2021

C5 palsy is a serious complication that may occur after cervical spine surgery; however, standard procedures for shoulder rehabilitation for patients with postoperative C5 palsy have not yet been established. We used a wearable robot suit Hybrid Assistive Limb (HAL) in a patient with delayed recovery after postoperative C5 palsy and conducted shoulder abduction training with the HAL. A 62-year-old man presented with weakness in his left deltoid muscle 2 days after cervical spine surgery. He experienced great difficulty in elevating his left arm and was diagnosed with postoperative C5 palsy. Seven months after surgery, shoulder abduction training with a HAL was initiated. In total, 23 sessions of shoulder HAL rehabilitation were conducted until 26 months after surgery. His shoulder abduction angle and power improved at every HAL session, and he was able to fully elevate his arm without any compensatory movement after the 23rd session, suggesting that the HAL is a useful tool for shoulder rehabilitation in patients with postoperative C5 palsy. We employed shoulder HAL training for a patient with delayed recovery from postoperative C5 palsy and achieved complete restoration of shoulder function. We believe that the HAL-based training corrected the erroneous motion pattern of his paralyzed shoulder and promoted errorless motor learning for recovery. Our collective experience suggests that shoulder HAL training could be an effective therapeutic tool for patients with postoperative C5 palsy.
First Experience of Three Neurovascular Centers With the p64MW-HPC, a Low-Profile Flow Diverter Designed for Proximal Cerebral Vessels With Antithrombotic Coating
Authors: Winters Helge , Schüngel Marie-Sophie , Scherlach Cordula , Mucha Dirk , Thalwitzer Jörg , Härtig Wolfgang , Donitza Aneta , Bailis Nikolaos , Maybaum Jens , Hoffmann Karl Titus , Quäschling Ulf , Schob Stefan
Published: September 2021

Background: In the last decade, flow diversion (FD) has been established as hemodynamic treatment for cerebral aneurysms arising from proximal and distal cerebral arteries. However, two significant limitations remain—the need for 0.027” microcatheters required for delivery of most flow diverting stents (FDS), and long-term dual anti-platelet therapy (DAPT) in order to prevent FDS-associated thromboembolism, at the cost of increasing the risk for hemorrhage. This study reports the experience of three neurovascular centers with the p64MW-HPC, a FDS with anti-thrombotic coating that is implantable via a 0.021” microcatheter.

Materials and methods: Three neurovascular centers contributed to this retrospective analysis of patients that had been treated with the p64MW-HPC between March 2020 and March 2021. Clinical data, aneurysm characteristics, and follow-up results, including procedural and post-procedural complications, were recorded. The hemodynamic effect was assessed using the O'Kelly–Marotta Scale (OKM).

Results: Thirty-two patients (22 female, mean age 57.1 years) with 33 aneurysms (27 anterior circulation and six posterior circulation) were successfully treated with the p64MW-HPC. In 30/32 patients (93.75%), aneurysmal perfusion was significantly reduced immediately post implantation. Follow-up imaging was available for 23 aneurysms. Delayed aneurysm perfusion (OKM A3: 8.7%), reduction in aneurysm size (OKM B1-3: 26.1%), or sufficient separation from the parent vessel (OKM C1-3 and D1: 65.2%) was demonstrated at the last available follow-up after a mean of 5.9 months. In two cases, device thrombosis after early discontinuation of DAPT occurred. One delayed rupture caused a caroticocavernous fistula. The complications were treated sufficiently and all patients recovered without permanent significant morbidity.

Conclusion: Treatment with the p64MW-HPC is safe and feasible and achieves good early aneurysm occlusion rates in the proximal intracranial circulation, which are comparable to those of well-established FDS. Sudden interruption of DAPT in the early post-interventional phase can cause in-stent thrombosis despite the HPC surface modification. Deliverability via the 0.021” microcatheter facilitates treatment in challenging vascular anatomies.
Brain Activation Induced by Myopic and Hyperopic Defocus From Spectacles
Authors: Kang Meng-Tian , Wang Bo , Ran An-Ran , Gan Jiahe , Du Jialing , Yusufu Mayinuer , Liang Xintong , Li Shi-Ming , Wang Ningli
Published: September 2021

Purpose: To assess neural changes in perceptual effects induced by myopic defocus and hyperopic defocus stimuli in ametropic and emmetropic subjects using functional magnetic resonance imaging (fMRI).

Methods: This study included 41 subjects with a mean age of 26.0 ± 2.9 years. The mean spherical equivalence refraction was −0.54 ± 0.51D in the emmetropic group and −3.57 ± 2.27D in the ametropic group. The subjects were instructed to view through full refractive correction, with values of +2.00D to induce myopic defocus state and −2.00D to induce hyperopic defocus state. This was carried over in three random sessions. Arterial spin labeling (ASL) perfusion was measured using fMRI to obtain quantified regional cerebral blood flow (rCBF). Behavioral tests including distant visual acuity (VA) and contrast sensitivity (CS), were measured every 5 min for 30 min.

Results: Myopic defocus induced significantly greater rCBF increase in four cerebral regions compared with full correction: right precentral gyrus, right superior temporal gyrus, left inferior parietal lobule, and left middle temporal gyrus (P < 0.001). The differences were less significant in low myopes than emmetropes. In the hyperopic defocus session, the increased responses of rCBF were only observed in the right and left precentral gyrus. Myopic defocused VA and CS improved significantly within 5 min and reached a plateau shortly after.

Conclusion: This study revealed that myopic defocus stimuli can significantly increase blood perfusion in visual attention-related cerebral regions, which suggests a potential direction for future investigation on the relationship between retinal defocus and its neural consequences.
Multimodal MR Images-Based Diagnosis of Early Adolescent Attention-Deficit/Hyperactivity Disorder Using Multiple Kernel Learning
Authors: Zhou Xiaocheng , Lin Qingmin , Gui Yuanyuan , Wang Zixin , Liu Manhua , Lu Hui
Published: September 2021

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common brain diseases among children. The current criteria of ADHD diagnosis mainly depend on behavior analysis, which is subjective and inconsistent, especially for children. The development of neuroimaging technologies, such as magnetic resonance imaging (MRI), drives the discovery of brain abnormalities in structure and function by analyzing multimodal neuroimages for computer-aided diagnosis of brain diseases. This paper proposes a multimodal machine learning framework that combines the Boruta based feature selection and Multiple Kernel Learning (MKL) to integrate the multimodal features of structural and functional MRIs and Diffusion Tensor Images (DTI) for the diagnosis of early adolescent ADHD. The rich and complementary information of the macrostructural features, microstructural properties, and functional connectivities are integrated at the kernel level, followed by a support vector machine classifier for discriminating ADHD from healthy children. Our experiments were conducted on the comorbidity-free ADHD subjects and covariable-matched healthy children aged 9–10 chosen from the Adolescent Brain and Cognitive Development (ABCD) study. This paper is the first work to combine structural and functional MRIs with DTI for early adolescents of the ABCD study. The results indicate that the kernel-level fusion of multimodal features achieves 0.698 of AUC (area under the receiver operating characteristic curves) and 64.3% of classification accuracy for ADHD diagnosis, showing a significant improvement over the early feature fusion and unimodal features. The abnormal functional connectivity predictors, involving default mode network, attention network, auditory network, and sensorimotor mouth network, thalamus, and cerebellum, as well as the anatomical regions in basal ganglia, are found to encode the most discriminative information, which collaborates with macrostructure and diffusion alterations to boost the performances of disorder diagnosis.
Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases
Authors: Fernandes Luiza , Cardim-Pires Thyago R. , Foguel Debora , Palhano Fernando L.
Published: September 2021

The accumulation of protein aggregates in human tissues is a hallmark of more than 40 diseases called amyloidoses. In seven of these disorders, the aggregation is associated with neurodegenerative processes in the central nervous system such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aggregation occurs when certain soluble proteins lose their physiological function and become toxic amyloid species. The amyloid assembly consists of protein filament interactions, which can form fibrillar structures rich in β-sheets. Despite the frequent incidence of these diseases among the elderly, the available treatments are limited and at best palliative, and new therapeutic approaches are needed. Among the many natural compounds that have been evaluated for their ability to prevent or delay the amyloidogenic process is epigallocatechin-3-gallate (EGCG), an abundant and potent polyphenolic molecule present in green tea that has extensive biological activity. There is evidence for EGCG’s ability to inhibit the aggregation of α-synuclein, amyloid-β, and huntingtin proteins, respectively associated with PD, AD, and HD. It prevents fibrillogenesis (in vitro and in vivo), reduces amyloid cytotoxicity, and remodels fibrils to form non-toxic amorphous species that lack seed propagation. Although it is an antioxidant, EGCG in an oxidized state can promote fibrils’ remodeling through formation of Schiff bases and crosslinking the fibrils. Moreover, microparticles to drug delivery were synthesized from oxidized EGCG and loaded with a second anti-amyloidogenic molecule, obtaining a synergistic therapeutic effect. Here, we describe several pre-clinical and clinical studies involving EGCG and neurodegenerative diseases and their related mechanisms.
Protective Effects of Ellagic Acid Against Alcoholic Liver Disease in Mice
Authors: Zhao Liang , Mehmood Arshad , Soliman Mohamed Mohamed , Iftikhar Asra , Iftikhar Maryam , Aboelenin Salama Mostafa , Wang Chengtao
Published: September 2021

Ellagic acid, a natural polyphenolic compound commonly present in vegetables, fruits, nuts, and other edible plants, exerts many pharmacological activities. The present project was designed to explore the hepatoprotective effect of ellagic acid against alcohol-induced liver disease (ALD) and the correlation among alcohol, oxidative stress, inflammation, and gut microbiota. Fifty percent (v/v) alcohol (10 mL/kg bw daily) was orally administrated for 4 weeks in mice along with ellagic acid (50 and 100 mg/kg bw). Alcohol administration significantly (p < 0.05) increased the activities of alanine aminotransferase and serum aspartate aminotransferase, levels of triglyceride, low density lipoprotein, free fatty acid, and total cholesterol, and decreased contents of the high-density lipoprotein in model group compared with the control group, which were further improved by ellagic acid (50 or 100 mg/kg bw). Furthermore, daily supplementation of ellagic acid alleviated hepatic antioxidant activities (glutathione peroxidase, catalase, malondialdehyde, superoxide dismutase, and glutathione), proinflammatory cytokines levels (IL-6, IL-1β, and TNF-α), genes expressions (Tlr4, Myd88, Cd14, Cox2, Nos2, and Nfκb1), and histopathological features in alcohol-induced liver injured mice. Additionally, results also revealed that ellagic acid supplementation improved alcohol-induced gut microbiota dysbiosis. In conclusion, ellagic acid mitigated oxidative stress, inflammatory response, steatosis, and gut microbiota dysbiosis in ALD mice. Our results suggested that ellagic acid could be applied as an ideal dietary therapy against ALD.
Fecal Microbiota and Gut Microbe-Derived Extracellular Vesicles in Colorectal Cancer
Authors: Park Jihye , Kim Nam-Eun , Yoon Hyuk , Shin Cheol Min , Kim Nayoung , Lee Dong Ho , Park Jae Yong , Choi Chang Hwan , Kim Jae Gyu , Kim Yoon-Keun , Shin Tae-Seop , Yang Jinho , Park Young Soo
Published: September 2021

The human microbiota comprises trillions of microbes, and the relationship between cancer and microbiota is very complex. The impact of fecal microbiota alterations on colorectal cancer (CRC) pathogenesis is emerging. This study analyzed changes in the microbial composition in CRC subjects with both fecal microbiota and gut microbe-derived extracellular vesicles (EVs). From August 2017 to August 2018, 70 CRC patients and 158 control subjects were enrolled in the study. Metagenomic profiling of fecal microbiota and gut microbe-derived EVs in stool was performed using 16S ribosomal DNA sequencing. Relative abundance, evenness, and diversity in both the gut microbiota and gut microbe-derived EVs were analyzed. Additionally, microbial composition changes according to the stage and location of CRC were analyzed. Microbial composition was significantly changed in CRC subjects compared to control subjects, with evenness and diversity significantly lower in the fecal microbiota of CRC subjects. Gut microbe-derived EVs of stool demonstrated significant differences in the microbial composition, evenness, and diversity in CRC subjects compared to the control subjects. Additionally, microbial composition, evenness, and diversity significantly changed in late CRC subjects compared to early CRC subjects with both fecal microbiota and gut microbe-derived EVs. Alistipes-derived EVs could be novel biomarkers for diagnosing CRC and predicting CRC stages. Ruminococcus 2-derived EVs significantly decreased in distal CRC subjects than in proximal CRC subjects. Gut microbe-derived EVs in CRC had a distinct microbial composition compared to the controls. Profiling of microbe-derived EVs may offer a novel biomarker for detecting and predicting CRC prognosis.
Identification of the Effects of Chondroitin Sulfate on Inhibiting CDKs in Colorectal Cancer Based on Bioinformatic Analysis and Experimental Validation
Authors: Zhou Yingyu , Li Xuyang , Morita Yuki , Hachimura Satoshi , Miyakawa Takuya , Takahashi Sachiko , Tanokura Masaru
Published: September 2021

With a high occurrence rate and high mortality, the treatment of colorectal cancer (CRC) is increasingly attracting the attention of scholars. Hub genes that determine the phenotypes of CRC become essential for targeted therapy. In the present study, the importance of cyclin-dependent kinases (CDKs) on the occurrence of CRC was identified by data mining of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The results showed that the gene expression levels of CDK1, CDK4, and CDK6 were obviously changed in different stages of CRC. Among the CDKs, CDK4 was suggested as an independent risk factor for CRC based on Cox analysis. Furthermore, chondroitin sulfate (CS), a kind of dietary supplement to treat osteoarthritis, was predicted to treat CRC based on its chemical structure and GEO datasets. Cell assay experiments with the human CRC cell line HCT-116 also verified this prediction. CS inhibited the gene and protein expression levels of CDKs and increased the ratios of apoptotic or dead HCT-116 cells by regulating mitogen-activated protein (MAP) kinase pathways. Our data highlight the essential roles of CDKs in CRC carcinogenesis and the effects of CS on treating CRC, both of which will contribute to the future CRC treatment.
Construction and Validation of Novel Prediction Tools Based on Large Population-Based Database to Predict the Prognosis of Urachal Cancer After Surgery
Authors: Yu Xiaowen , Ma Chong , Wang Maoyu , Ying Yidie , Zhang Zhensheng , Ai Xing , Wang Linhui , Zeng Shuxiong , Xu Chuanliang
Published: September 2021

Background

Urachal cancer is a rare neoplasm in the urological system. To our knowledge, no published study has explored to establish a model for predicting the prognosis of urachal cancer. The present study aims to develop and validate nomograms for predicting the prognosis of urachal cancer based on clinicopathological parameters.

Methods

Based on the data from the Surveillance, Epidemiology, and End Results database, 445 patients diagnosed with urachal cancer between 1975 and 2018 were identified as training and internal validation cohort; 84 patients diagnosed as urachal cancer from 2001 to 2020 in two medical centers were collected as external validation cohort. Nomograms were developed using a multivariate Cox proportional hazards regression analysis in the training cohort, and their performance was evaluated in terms of its discriminative ability, calibration, and clinical usefulness by statistical analysis.

Results

Three nomograms based on tumor–node–metastasis (TNM), Sheldon and Mayo staging system were developed for predicting cancer-specific survival (CSS) of urachal cancer; these nomograms all showed similar calibration and discrimination ability. Further internal (c-index 0.78) and external (c-index 0.81) validation suggested that Sheldon model had superior discrimination and calibration ability in predicting CSS than the other two models. Moreover, we found that the Sheldon model was able to successfully classify patients into different risk of mortality both in internal and external validation cohorts. Decision curve analysis proved that the nomogram was clinically useful and applicable.

Conclusions

The nomogram model with Sheldon staging system was recommended for predicting the prognosis of urachal cancer. The proposed nomograms have promising clinical applicability to help clinicians on individualized patient counseling, decision-making, and clinical trial designing.
The Role of Cellular Prion Protein in Cancer Biology: A Potential Therapeutic Target
Authors: Ding Manqiu , Chen Yongqiang , Lang Yue , Cui Li
Published: September 2021

Prion protein has two isoforms including cellular prion protein (PrPC) and scrapie prion protein (PrPSc). PrPSc is the pathological aggregated form of prion protein and it plays an important role in neurodegenerative diseases. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein that can attach to a membrane. Its expression begins at embryogenesis and reaches the highest level in adulthood. PrPC is expressed in the neurons of the nervous system as well as other peripheral organs. Studies in recent years have disclosed the involvement of PrPC in various aspects of cancer biology. In this review, we provide an overview of the current understanding of the roles of PrPC in proliferation, cell survival, invasion/metastasis, and stem cells of cancer cells, as well as its role as a potential therapeutic target.
Therapeutic Effects of Berberine Hydrochloride on Stress-Induced Diarrhea-Predominant Irritable Bowel Syndrome Rats by Inhibiting Neurotransmission in Colonic Smooth Muscle
Authors: Lu Yulin , Huang Jingjing , Zhang Yao , Huang Zitong , Yan Weiming , Zhou Tianran , Wang Zhesheng , Liao Lu , Cao Hongying , Tan Bo
Published: September 2021

The etiology of diarrhea-predominant irritable bowel syndrome (IBS-D) is complicated and closely related to neurotransmission in the gastrointestinal (GI) tract. Developing new strategies for treating this disease is a major challenge for IBS-D research. Berberine hydrochloride (BBH), the derivative of berberine, is a herbal constituent used to treat IBS. Previous studies have shown that BBH has potential anti-inflammatory, antibacterial, analgesic, and antidiarrheal effects and a wide range of biological activities, especially in regulating the release of some neurotransmitters. A modified IBS-D rat model induced by chronic restraint stress was used in all experiments to study the effects of BBH on the GI tract. This study measured the abdominal withdrawal reflex (AWR) response to graded colorectal distention (CRD; 20, 40, 60, and 80 mmHg) and observed the fecal areas of stress-induced IBS-D model. Experiments were conducted using organ bath techniques, which were performed in vitro using strips of colonic longitudinal smooth muscle. Inhibitory and excitatory neurotransmitter agents were added to each organ bath to observe contractile responses on the strips and the treatment effect exerted by BBH. The IBS-D rat model was successfully induced by chronic restraint stress, which resulted in an increased defecation frequency and visceral hypersensitivity similar to that of humans. BBH could reduce 4-h fecal areas and AWR response to CRD in IBS-D. The stress-induced IBS-D model showed upregulated colonic mRNA expression levels of 5-hydroxytryptamine-3A receptor and downregulated expression levels of neuronal nitric oxide synthase. Meanwhile, BBH could reverse this outcome. The responses of substances that regulate the contraction induced by related neurotransmission in the longitudinal smooth muscle of IBS-D colon (including the agonist of acetylcholine, carbachol; NOS inhibitor, L-NAME; and P2Y1 receptor antagonist, MRS2500) can be inhibited by BBH. In summary, BBH promotes defecation frequency and visceral hypersensitivity in IBS-D and exerts inhibitory effects on contractile responses in colonic longitudinal smooth muscle. Thus, BBH may represent a new therapeutic approach for treating IBS-D.
Prickly Pear Betalain-Rich Extracts as New Promising Strategy for Intestinal Inflammation: Plant Complex vs. Main Isolated Bioactive Compounds
Authors: Smeriglio A. , De Francesco C. , Denaro M. , Trombetta D.
Published: September 2021

Recently, many studies have highlighted the health effects of betalains beyond their use as food dyes. The present study investigated betalain-rich extracts with different colors and their main bioactive compounds in order to provide first evidence as a new promising strategy for intestinal inflammation management. Prickly pear betalain–rich extracts, obtained by a QuEChERS method, have been characterized by LC-DAD-ESI-MS/MS analysis. The potential role of betanin, indicaxanthin, and prickly pear extracts in counteracting the antioxidant and anti-inflammatory events was evaluated by severalin vitrocell-free and cell-based assays. Indicaxanthin and betanin represent the most abundant compounds (≥22.27 ± 4.50 and 1.16 ± 0.17 g/100 g dry extract, respectively). Prickly pear extracts showed the strongest antioxidant and anti-inflammatory activities with respect to the pure betalains both onin vitrocell-free and cell-based assays, demonstrating the occurrence of synergistic activity, without any cytotoxicity or alteration of the barrier systems. The release of reactive oxygen species (ROS) and key inflammatory markers (IL-6, IL-8, and NO) was strongly inhibited by both betalains and even more by prickly pear extracts, which showed a similar and sometimes better profile than the reference compounds trolox and dexamethasone in counteracting the IL-1β–induced intestinal inflammation.
Sex Metabolic Differences and Effects on Blood Coagulation Among Rats Exposed to Sodium Dehydroacetate
Authors: Chen Xin , Hao Fuxing , Zhang Meng , Xiao Jinzha , Zhao Weiya , Zhao Zeting , Zhang Yumei
Published: September 2021

Sodium dehydroacetate (Na-DHA), a fungicide used in food, feed, cosmetics, and medicine, has been found to cause coagulation aberration accompanied by the inhibition of vitamin K epoxide reductase (VKOR) in the liver in rats. VKOR complex 1 (VKORC1) and VKORC1 like-1 (VKORC1L1) are two homologous VKOR proteins. Little information is available on the effect of Na-DHA on VKORC1L1 in the liver or VKORC1/VKORC1L1 in extrahepatic tissue and sex differences in Na-DHA metabolism. In the present study, after administration of 200 mg/kg Na-DHA by gavage, significant inhibition of VKORC1 or VKORC1L1 expression in tissues, as well as prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), were observed. The PT/APTT in the Na-DHA-exposed males were 1.27- to 1.48-fold/1.17- to 1.37-fold, while the corresponding values in the Na-DHA-exposed females were 1.36- to 2.02-fold/1.20- to 1.70-fold. Serum or tissue Na-DHA concentrations were significantly higher in females than in males. The pharmacokinetic parameters (t1/2, Cmax, AUC0∼24 h, and MRT0∼24 h) of Na-DHA in female rats were significantly higher than those in male rats. Furthermore, cytochrome P450 (CYP) activity was investigated using the cocktail probe method. The results revealed that Na-DHA exhibited an inductive effect on CYP1A2, 2D1/2, and 3A1/2 activities by changing the main pharmacokinetic parameters of probe drugs in male rats. However, no significant change in CYP2E1 activity was found. There were sex differences in the metabolism and coagulation in rats exposed to Na-DHA. The lower metabolism and higher blood Na-DHA concentration in females may be the reasons for higher coagulation sensitivity in female rats.
Telmisartan Potentiates Insulin Secretion via Ion Channels, Independent of the AT1 Receptor and PPARγ
Authors: Liu Tao , Cui Lijuan , Xue Huan , Yang Xiaohua , Liu Mengmeng , Zhi Linping , Yang Huanhuan , Liu Zhihong , Zhang Min , Guo Qing , He Peifeng , Liu Yunfeng , Zhang Yi
Published: September 2021

Angiotensin II type 1 (AT1) receptor blockers (ARBs), as antihypertensive drugs, have drawn attention for their benefits to individuals with diabetes and prediabetes. However, the direct effects of ARBs on insulin secretion remain unclear. In this study, we aimed to investigate the insulinotropic effect of ARBs and the underlying electrophysiological mechanism. We found that only telmisartan among the three ARBs (telmisartan, valsartan, and irbesartan) exhibited an insulin secretagogue role in rat islets. Independent of AT1 receptor and peroxisome proliferator-activated receptor γ (PPARγ), telmisartan exerted effects on ion channels including voltage-dependent potassium (Kv) channels and L-type voltage-gated calcium channels (VGCCs) to promote extracellular Ca2+ influx, thereby potentiating insulin secretion in a glucose-dependent manner. Furthermore, we identified that telmisartan directly inhibited Kv2.1 channel on a Chinese hamster ovary cell line with Kv2.1 channel overexpression. Acute exposure of db/db mice to a telmisartan dose equivalent to therapeutic doses in humans resulted in lower blood glucose and increased plasma insulin concentration in OGTT. We further observed the telmisartan-induced insulinotropic and electrophysiological effects on pathological pancreatic islets or β-cells isolated from db/db mice. Collectively, our results establish an important insulinotropic function of telmisartan distinct from other ARBs in the treatment of diabetes.
Immune Cell Landscape of Patients With Diabetic Macular Edema by Single-Cell RNA Analysis
Authors: Ma Pengjuan , Zhang Ping , Chen Shuxia , Shi Wen , Ye Jinguo , Chen Shida , Ju Rong , Liu Bingqian , Zheng Yingfeng , Liu Yizhi
Published: September 2021

Purpose: We performed single-cell RNA sequencing (scRNA-seq), an unbiased and high-throughput single cell technology, to determine phenotype and function of peripheral immune cells in patients with diabetic macular edema (DME).

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from DME patients and healthy controls (HC). The single-cell samples were loaded on the Chromium platform (10x Genomics) for sequencing. R package Seurat v3 was used for data normalizing, clustering, dimensionality reduction, differential expression analysis, and visualization.

Results: We constructed a single-cell RNA atlas comprising 57,650 PBMCs (24,919 HC, 32,731 DME). We divided all immune cells into five major immune cell lineages, including monocytes (MC), T cells (TC), NK cells (NK), B cells (BC), and dendritic cells (DC). Our differential expression gene (DEG) analysis showed that MC was enriched of genes participating in the cytokine pathway and inflammation activation. We further subdivided MC into five subsets: resting CD14++ MC, proinflammatory CD14++ MC, intermediate MC, resting CD16++ MC and pro-inflammatory CD16++ MC. Remarkably, we revealed that the proinflammatory CD14++ monocytes predominated in promoting inflammation, mainly by increasingly production of inflammatory cytokines (TNF, IL1B, and NFKBIA) and chemokines (CCL3, CCL3L1, CCL4L2, CXCL2, and CXCL8). Gene Ontology (GO) and pathway analysis of the DEGs demonstrated that the proinflammatory CD14++ monocytes, especially in DME patients, upregulated inflammatory pathways including tumor necrosis factor-mediated signaling pathway, I-kappaB kinase/NF-kappaB signaling, and toll-like receptor signaling pathway.

Conclusion: In this study, we construct the first immune landscape of DME patients with T2D and confirmed innate immune dysregulation in peripheral blood based on an unbiased scRNA-seq approach. And these results demonstrate potential target cell population for anti-inflammation treatments.
Transition From Targeted Breeding to Mainstreaming of Biofortification Traits in Crop Improvement Programs
Authors: Virk Parminder S. , Andersson Meike S. , Arcos Jairo , Govindaraj Mahalingam , Pfeiffer Wolfgang H.
Published: September 2021

Biofortification breeding for three important micronutrients for human health, namely, iron (Fe), zinc (Zn), and provitamin A (PVA), has gained momentum in recent years. HarvestPlus, along with its global consortium partners, enhances Fe, Zn, and PVA in staple crops. The strategic and applied research by HarvestPlus is driven by product-based impact pathway that integrates crop breeding, nutrition research, impact assessment, advocacy, and communication to implement country-specific crop delivery plans. Targeted breeding has resulted in 393 biofortified crop varieties by the end of 2020, which have been released or are in testing in 63 countries, potentially benefitting more than 48 million people. Nevertheless, to reach more than a billion people by 2030, future breeding lines that are being distributed by Consultative Group on International Agricultural Research (CGIAR) centers and submitted by National Agricultural Research System (NARS) to varietal release committees should be biofortified. It is envisaged that the mainstreaming of biofortification traits will be driven by high-throughput micronutrient phenotyping, genomic selection coupled with speed breeding for accelerating genetic gains. It is noteworthy that targeted breeding gradually leads to mainstreaming, as the latter capitalizes on the progress made in the former. Efficacy studies have revealed the nutritional significance of Fe, Zn, and PVA biofortified varieties over non-biofortified ones. Mainstreaming will ensure the integration of biofortified traits into competitive varieties and hybrids developed by private and public sectors. The mainstreaming strategy has just been initiated in select CGIAR centers, namely, International Maize and Wheat Improvement Center (CIMMYT), International Rice Research Institute (IRRI), International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), International Institute of Tropical Agriculture (IITA), and International Center for Tropical Agriculture (CIAT). This review will present the key successes of targeted breeding and its relevance to the mainstreaming approaches to achieve scaling of biofortification to billions sustainably.
Identification and Characterization of Secondary Wall-Associated NAC Genes and Their Involvement in Hormonal Responses in Tobacco (Nicotiana tabacum)
Authors: Xu Na , Meng Lin , Song Lin , Li Xiaoxu , Du Shasha , Hu Fengqin , Lv Yuanda , Song Wenjing
Published: September 2021

Secondary wall-associated NAC (SWN) genes are a subgroup of NAC (NAM, ATAF, and CUC) transcription factors (TF) that play a key role in regulating secondary cell wall biosynthesis in plants. However, this gene family has not been systematically characterized, and their potential roles in response to hormones are unknown in Nicotiana tabacum. In this study, a total of 40 SWN genes, of which 12 from Nicotiana tomentosiformis, 13 from Nicotiana sylvestris, and 15 from Nicotiana tabacum, were successfully identified. The 15 SWNs from Nicotiana tabacum were further classified into three groups, namely, vascular-related NAC domain genes (NtVNDs), NAC secondary wall thickening promoting factor genes (NtNSTs), and secondary wall-associated NAC domain genes (NtSNDs). The protein characteristic, gene structure, and chromosomal location of 15 NtSWNs (also named Nt1 to Nt15) were also analyzed. The NtVND and NtNST group genes had five conserved subdomains in their N-terminal regions and a motif (LP[Q/x] L[E/x] S[P/A]) in their diverged C- terminal regions. Some hormones, dark and low-temperature related cis-acting elements, were significantly enriched in the promoters of NtSWN genes. A comprehensive expression profile analysis revealed that Nt4 and Nt12 might play a role in vein development. Others might be important for stem development. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that in the NtNST group, genes such as Nt7, Nt8, and Nt13 were more sensitive than the genes in NtVND and NtSND groups under abiotic stress conditions. A transactivation assay further suggested that Nt7, Nt8, and Nt13 showed a significant transactivation activity. Overall, SWN genes were finally identified and characterized in diploid and tetraploid tobacco, revealing new insights into their evolution, variation, and homology relationships. Transcriptome, cis-acting element, qRT-PCR, and transactivation assay analysis indicated the roles in hormonal and stress responses, which provided further resources in molecular mechanism and genetic improvement.
Identification of the Tyrosine- and Phenylalanine-Derived Soluble Metabolomes of Sorghum
Authors: Simpson Jeffrey P. , Olson Jacob , Dilkes Brian , Chapple Clint
Published: September 2021

The synthesis of small organic molecules, known as specialized or secondary metabolites, is one mechanism by which plants resist and tolerate biotic and abiotic stress. Many specialized metabolites are derived from the aromatic amino acids phenylalanine (Phe) and tyrosine (Tyr). In addition, the improved characterization of compounds derived from these amino acids could inform strategies for developing crops with greater resilience and improved traits for the biorefinery. Sorghum and other grasses possess phenylalanine ammonia-lyase (PAL) enzymes that generate cinnamic acid from Phe and bifunctional phenylalanine/tyrosine ammonia-lyase (PTAL) enzymes that generate cinnamic acid and p-coumaric acid from Phe and Tyr, respectively. Cinnamic acid can, in turn, be converted into p-coumaric acid by cinnamate 4-hydroxylase. Thus, Phe and Tyr are both precursors of common downstream products. Not all derivatives of Phe and Tyr are shared, however, and each can act as a precursor for unique metabolites. In this study, 13C isotopic-labeled precursors and the recently developed Precursor of Origin Determination in Untargeted Metabolomics (PODIUM) mass spectrometry (MS) analytical pipeline were used to identify over 600 MS features derived from Phe and Tyr in sorghum. These features comprised 20% of the MS signal collected by reverse-phase chromatography and detected through negative-ionization. Ninety percent of the labeled mass features were derived from both Phe and Tyr, although the proportional contribution of each precursor varied. In addition, the relative incorporation of Phe and Tyr varied between metabolites and tissues, suggesting the existence of multiple pools of p-coumaric acid that are fed by the two amino acids. Furthermore, Phe incorporation was greater for many known hydroxycinnamate esters and flavonoid glycosides. In contrast, mass features derived exclusively from Tyr were the most abundant in every tissue. The Phe- and Tyr-derived metabolite library was also utilized to retrospectively annotate soluble MS features in two brown midrib mutants (bmr6 and bmr12) identifying several MS features that change significantly in each mutant.
Challenges and Approaches to Crop Improvement Through C3-to-C4 Engineering
Authors: Cui Hongchang
Published: September 2021

With a rapidly growing world population and dwindling natural resources, we are now facing the enormous challenge of increasing crop yields while simultaneously improving the efficiency of resource utilization. Introduction of C4 photosynthesis into C3 crops is widely accepted as a key strategy to meet this challenge because C4 plants are more efficient than C3 plants in photosynthesis and resource usage, particularly in hot climates, where the potential for productivity is high. Lending support to the feasibility of this C3-to-C4 engineering, evidence indicates that C4 photosynthesis has evolved from C3 photosynthesis in multiple lineages. Nevertheless, C3-to-C4 engineering is not an easy task, as several features essential to C4 photosynthesis must be introduced into C3 plants. One such feature is the spatial separation of the two phases of photosynthesis (CO2 fixation and carbohydrate synthesis) into the mesophyll and bundle sheath cells, respectively. Another feature is the Kranz anatomy, characterized by a close association between the mesophyll and bundle sheath (BS) cells (1:1 ratio). These anatomical features, along with a C4-specific carbon fixation enzyme (PEPC), form a CO2-concentration mechanism that ensures a high photosynthetic efficiency. Much effort has been taken in the past to introduce the C4 mechanism into C3 plants, but none of these attempts has met with success, which is in my opinion due to a lack of system-level understanding and manipulation of the C3 and C4 pathways. As a prerequisite for the C3-to-C4 engineering, I propose that not only the mechanisms that control the Kranz anatomy and cell-type-specific expression in C3 and C4 plants must be elucidated, but also a good understanding of the gene regulatory network underlying C3 and C4 photosynthesis must be achieved. In this review, I first describe the past and current efforts to increase photosynthetic efficiency in C3 plants and their limitations; I then discuss a systems approach to tackling down this challenge, some practical issues, and recent technical innovations that would help us to solve these problems.
Application of an Online Combination Exercise Intervention to Improve Physical and Mental Health in Obese Children: A Single Arm Longitudinal Study
Authors: Ding Meng , Yi Xiangren , Yan Peisai , McDonough Daniel J. , Gao Zan , Dong Xiaosheng
Published: September 2021

Introduction: Childhood obesity has become a global public health concern in the past decade. The purpose of this study was to explore the effectiveness of an online combination exercise intervention in improving the physical and mental health of obese children.

Methods: This study adopted a one-group pre-test and post-test research design. A total of 28 obese children from 6 elementary schools in Heze City, Shandong Province, China, were recruited. All participants received an 8-week online combination exercise intervention and were tested at a three-month follow-up. Participants were tested and surveyed regarding their demographic, feasibility, and obesity indicators using mental health and quality of life questionnaires. The data were statistically analyzed using a one-way analysis of variance with repeated measures.

Results: A total of 26 obese children (Meanage = 10.15 years) completed the study. The retention rate was 92.9% for the entire trial (two obese children withdrew due to their inability to exercise) and no adverse events were reported. In addition, the obese children completed 25/32 (78.1%) of the online courses. After 8 weeks of the intervention, the changes in the body fat percentage of the obese children [mean difference (MD) = –3.126, p < 0.001, Cohen’s d = –1.777], thinking dimension score (MD = 1.654, p < 0.001, Cohen’s d = 0.603), total quality of life score (MD = 6.385, p < 0.05, Cohen’s d = 0.610), and work attitude dimension score (MD = 1.346, p < 0.001, Cohen’s d = 0.744) showed significant differences compared to the baseline. However, no significant differences were identified between the post-intervention and three-month follow-up measurements (p > 0.05), and we assumed that the intervention effect was maintained three months after the intervention.

Conclusion: An online combination exercise intervention is a safe and feasible option to improve the mental health and quality of life of obese children and may have long-term health benefits.
Biopsychosocial Predictors of Quality of Life in Paediatric Patients With Sickle Cell Disease
Authors: Hood Anna M. , Kölbel Melanie , Stotesbury Hanne , Kawadler Jamie , Slee April , Inusa Baba , Pelidis Maria , Howard Jo , Chakravorty Subarna , Height Sue , Awogbade Moji , Kirkham Fenella J. , Liossi Christina
Published: September 2021

Sickle cell disease (SCD) refers to a group of inherited blood disorders with considerable morbidity that causes severe pain, reduces life expectancy, and requires significant self-management. Acute painful episodes are the hallmark of SCD, but persistent daily pain is also highly prevalent in this population. Characterising the impact and experience of SCD-related morbidity (i.e., sleep disruption, frequent emergency department visits, cognitive dysfunction) on health-related quality of life (HRQOL) requires multiple assessment methods to best capture the underlying mechanisms. To gain a greater understanding of the effect of common symptom categories on HRQOL and to determine potential pain coping targets, the present study investigated whether demographic, socioeconomic, sleepiness, pain burden, frequency of emergency department (ED) visits, and cognition predicted HRQOL in a paediatric sample of patients with SCD. Our study was a secondary analysis of baseline assessment data of children with SCD aged 8–15 years (n = 30) in the Prevention of Morbidity in Sickle Cell Anaemia Phase 2b (POMSb2) randomised controlled clinical trial of auto-adjusting continuous positive airways pressure. Patients completed cognitive testing (IQ, Processing Speed Index, Delis-Kaplan Executive Function Scale (DKEFS) Tower, Conner's Continuous Performance Test), sleepiness (Epworth Sleepiness Scale), and HRQOL (PedsQL Sickle Cell Module) at baseline. Patients reported pain burden (Sickle Cell Pain Burden Inventory-Youth) each month over 8 visits. Caregivers provided demographic information and reported their child's executive function (Behavioural Rating Inventory of Executive Function) at baseline. Data from our analysis demonstrated that demographic factors (i.e., age, gender, level of neighbourhood deprivation) and treatment variables (i.e., hydroxyurea use) did not independently predict HRQOL, and laboratory values (i.e., haemoglobin, haematocrit, mean oxygen saturation) were not significantly correlated with HRQOL (ps > 0.05). However, sleepiness, pain burden, ED visits, and executive dysfunction independently predicted HRQOL (R2 = 0.66) with large effects (η2 = 0.16 to 0.32). These findings identify specific, measurable symptom categories that may serve as targets to improve HRQOL that are responsive to change. This knowledge will be useful for multimodal interventions for paediatric patients with SCD that include sleep management, pain coping strategies, and executive function training.