bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Diameters as Predictive Factors of Recanalization Surgery Outcomes in Internal Carotid Artery Occlusion
Authors: Yan Chengrui , Wang Jiaru , Guo Ruohan , Jin Weitao , Zhao Yang , Wang Rong
Published: September 2021

Background: Revascularization surgery sometimes can achieve recanalization in patients with internal carotid artery occlusion (ICAO). High-resolution vessel wall magnetic resonance imaging (HRVWI) is a feasible technique to give detailed characteristics of the vessel wall, which may help to identify patients that carry higher success rates and more suitable for revascularization surgery.

Objective: To examine the association between HRVWI characteristics of ICAO and the success rate of revascularization surgery in ICAO patients.

Methods: We conducted a retrospective analysis of 31 ICAO recanalization patients enrolled from October 2017 to May 2019. The clinical data of patients and lesions were collected and analyzed.

Results: A total of 31 ICAO patients were enrolled in this study. No significant differences were found between recanalization success and recanalization failure groups with regard to occlusion length, distal end of the occluded segment, and the treatment applied. The ipsilateral-to-contralateral diameter ratios (I/C ratios) of C1 or C2 and the diameter of C7 were positively related to recanalization success. A two-factor predictive model was constructed, and the I/C ratio of C2 < 0.86 and the diameter of C7 < 1.75mm were separately assigned 1 point. The ICAO patients who scored 0, 1, or 2 points had a risk of 5.6% (1/18), 55.6% (5/9), or 100% (4/4) to fail in the recanalization.

Conclusions: The I/C ratios of C1 or C2 and the diameter of C7 are predictive factors of a revascularization surgery success in ICAO patients. A risk stratification model involving C2 and C7 was constructed for future clinical applications.
Application of High-Resolution Flat Detector Computed Tomography in Stent Implantation for Intracranial Atherosclerotic Stenosis
Authors: Li Tengfei , Wang Yuting , Ma Ji , Levitt Michael , Mossa-Basha Mahmud , Shi Chengcheng , Ran Yuncai , Ren Jianzhuang , Han Xinwei , Zhu Chengcheng
Published: September 2021

Objective

To evaluate the utility of high-resolution flat-detector computed tomography (HR-FDCT) compared with conventional flat-detector computed tomography (FDCT) for stent placement in symptomatic intracranial atherosclerotic stenosis (ICAS).

Methods

We retrospectively reviewed the clinical data of 116 patients with symptomatic ICAS who underwent stent implantation. Images were acquired using conventional FDCT [voxel size = 0.43 mm (isotropic)] and HR-FDCT [voxel size = 0.15 mm (isotropic)]. Immediately after stent deployment, dual-volume three-dimensional (3D) fusion images were obtained from 3D digital subtraction angiography (DSA) and HR-FDCT. The image quality for stent visualization was graded from 0 to 2 (0: not able to assess; 1: limited, but able to assess; 2: clear visualization), and the stent-expansion status (“full,” “under-expanded” or “poor apposition”) was recorded.

Results

A total of 116 patients with symptomatic ICAS were treated successfully using 116 stents (58 NeuroformTM EZ, 42 EnterpriseTM, and 16 ApolloTM). The mean pre-stent stenosis was 80.5 ± 6.4%, which improved to 20.8 ± 6.9% after stenting. Compared with FDCT, HR-FDCT improved visualization of the fine structures of the stent to improve the image quality that significantly (mean score: 1.63 ± 0.60 vs. 0.41 ± 0.59, P < 0.001). In 19 patients, stent under-expansion (n = 11) or poor apposition (n = 8) was identified by HR-FDCT but not by conventional FDCT. After balloon dilatation, stent malapposition was shown to have improved on HR-FDCT. None of the 19 patients with stent malapposition experienced short-term complications during hospitalization or had in-stent stenosis at 6-month follow-up.

Conclusion

High-resolution flat-detector computed tomography (HR-FDCT) improves visualization of the fine structures of intracranial stents deployed for symptomatic ICAS compared with that visualized using conventional FDCT. High-resolution flat-detector computed tomography improves assessment of stent deployment and could reduce the risk of complications.
PRG5 Knockout Precipitates Late-Onset Hypersusceptibility to Pilocarpine-Induced Juvenile Seizures by Exacerbating Hippocampal Zinc Signaling-Mediated Mitochondrial Damage
Authors: Wang Dandan , Jin Mei-fang , Li Lili , Liu Yueying , Sun Yuxiao , Ni Hong
Published: September 2021

Introduction

Epileptogenesis is understood as the plastic process that produces a persistent reorganization of the brain’s neural network after a precipitating injury (recurrent neonatal seizures, for instance) with a latent period, finally leading to neuronal hyperexcitability. Plasticity-related genes (PRGs), also known as lipid phosphate phosphatase-related proteins (PLPPRs), are regulators of mitochondrial membrane integrity and energy metabolism. This study was undertaken to determine whether PRG5 gene knockout contributes to the delayed hypersensitivity induced by developmental seizures and the aberrant sprouting of hippocampal mossy fibers, and to determine whether it is achieved through the mitochondrial pathway. Here, we developed a “twist” seizure model by coupling pilocarpine-induced juvenile seizures with later exposure to penicillin to test the long-term effects of PRG5 knockout on seizure latency through comparison with wild-type (WT) mice. Hippocampal mossy fiber sprouting (MFS) was detected by Timm staining. In order to clarify the mechanism of the adverse reactions triggered by PRG5 knockout, hippocampal HT22 neuronal cultures were exposed to glutamate, with or without PRG5 interference. Mitochondrial function, oxidative stress indicators and zinc ion content were detected.

Results

PRG5 gene knockout significantly reduced the seizure latency, and aggravated the lowered seizure threshold induced by developmental seizures. Besides, knockout of the PRG5 gene reduced the MFS scores to a certain extent. Furthermore, PRG5 gene silencing significantly increases the zinc ion content in hippocampal neurons, impairs neuronal activity and mitochondrial function, and exacerbates glutamate-induced oxidative stress damage.

Conclusion

In summary, PRG5 KO is associated with significantly greater hypersusceptibility to juvenile seizures in PRG5(–/–) mice compared with WT mice. These effects may be related to the hippocampal zinc signaling. The effects do not appear to be related to changes in MFS because KO mice with juvenile seizures had the shortest seizure latencies but exhibited less MFS than WT mice with juvenile seizures.
Supplementation of Kiwifruit Polyphenol Extract Attenuates High Fat Diet Induced Intestinal Barrier Damage and Inflammation via Reshaping Gut Microbiome
Authors: Yuan Minlan , Chen Xiao , Su Tianxia , Zhou Yan , Sun Xiaohong
Published: September 2021

Background: Impaired intestinal integrity and barrier function is associated with various diseases, including inflammatory bowel disease and metabolic syndrome. In recent years, plant-derived polyphenols have attracted much attention on regulating intestinal barrier function. Kiwifruit was recorded as a traditional Chinese medicine which can treat gastrointestinal diseases, but the mechanism was still unclear. In this study we investigated the effects of kiwifruit polyphenol extracts (KPE) on high fat diet induced intestinal permeability and its possible mechanism.

Results: Dietary supplementation of KPE with 50 or 100 mg/kg bw could inhibit the increase of intestinal permeability caused by HFD and promote the expression of tight junction protein (Claudin-1, Occludin and ZO-1). From microbial diversity and RT-PCR, KPE administration reshaping gut microbiome, the relative abundance of Lactobacillus and Bifidobacterium were increased, and the relative abundance of Clostridium and Desulfovibrionaceae were decreased. The changes in microbe may influence intestinal inflammatory status. Then the expression of TLRs and cytokines were detected. KPE supplementation showed anti-inflammatory effect, the expression of IL-10 was increased and the expression of TLR-2, TLR-4, TNF-α and IL-1β were decreased. Correlation analysis indicated that the expression of tight junction protein was negative correlation with TLR-2, TLR-4, TNF-α and IL-1β expression, but positively correlated with Bacteroidete, Bifidobacterium and IL-10 expression; the expression of Bacteroidete, Lactobacillusand and Bifidobacterium were negative correlation with TLR4, TNF-α, and IL-1β expression.

Conclusion: KPE treatment relieve the intestinal damage caused by HFD, which was related to the regulation of Bacteroidete, Lactobacillusand, and Bifidobacterium expression and inhibit intestinal inflammation. KPE could be a functional component for preventing gut damage and its related disease.
Brief Research Report: Estimation of the Protein Digestibility-Corrected Amino Acid Score of Defatted Walnuts
Authors: Lackey Kimberly A. , Fleming Stephen A.
Published: September 2021

Introduction: Walnuts are considered a good source of essential fatty acids, which is unique among tree nuts. Walnuts are also composed of about 10–15% protein, but the quality of this protein has not been evaluated. Pistachios and almonds have been evaluated for their protein content using a protein digestibility-corrected amino acid score (PDCAAS), but it is unclear how the quality of protein in walnuts relates to that in other commonly consumed tree nuts. The objective of this study was to substantiate the protein quality of walnuts by determining their PDCAAS.

Methods: A small, 10-day dietary intervention trial was conducted using male Sprague-Dawley rats (n = 8, 4 per group) with two diets: a nitrogen-free diet and a diet containing protein exclusively from defatted walnuts. Feed intake and fecal output of nitrogen were measured to estimate the true protein digestibility, and the amino acid compositions of walnuts compared to child and adult populations were used to calculate amino acid scores (AAS) and PDCAAS.

Results: The true protein digestibility score of raw walnuts was calculated to be 86.22%. Raw walnuts contained 15.6 g protein/g walnut with AAS of 0.45 and 0.63 for children aged 6 months to 3 years and 3–10 years, respectively. For each population, a PDCAAS of 39 and 46% was calculated, respectively, using a protein conversion constant of 5.30. Using a protein constant of 6.25, a PDCAAS of 39% (6 months - 3 years) or 46% (3-10 years) was calculated.

Conclusions: This is the first known assessment of the PDCAAS of walnuts. Like almonds, they appear to have a low-to-moderate score, indicating they are not a quality source of protein.
Effects of Dietary Supplementation of Bovine Lactoferricin on Rumen Microbiota, Lactation, and Health in Dairy Goats
Authors: Shao Yuexin , Zhang Xian , Zhang Huawen , Tian Bowen , Weng Yunan , Huang Jiangtao , Lu Christopher D. , Shi Huaiping
Published: September 2021

This study aimed to investigate the biological effects of supplementation of bovine lactoferricin (BLFc) at the rate of 100 mg/kg/day (LF-1) or 200 mg/kg/day (LF-2) in lactating dairy goats. Dietary BLFc supplementation increased the concentration of lactoferrin (LF) in the milk and serum (p < 0.05) without affecting the feed intake. In the LF-1 group, serum Fe, total antioxidant (T-AOC), and immunoglobulin A (IgA) were increased (p < 0.05), while malondialdehyde (MDA) was decreased (p < 0.05). In the LF-2 group, ruminal fluid pH value was decreased (p < 0.05), and the composition of ruminal microflora on day 42 was more diversified. Firmicutes phylum in the LF-2 group was the most abundant phyla. In contrast, Bacteroidetes phylum in the control group and the LF-1 group were the most abundant. Lower milk somatic cell count and higher IgA were observed in the LF-1 group and the LF-2 group than those in the control group (p < 0.05). These results suggested beneficial effects of supplementation of 100 mg/kg/day BLFc on reducing the oxidative stress and altering diversity of ruminal microflora.
The Impact of Maternal High-Fat Diet on Bone Microarchitecture in Offspring
Authors: Buckels Emma J. , Bolam Scott M. , Tay Mei Lin , Matthews Brya G.
Published: September 2021

The incidence of obesity in women of reproductive age has significantly increased over the past 100 years. There is a well-established connection between maternal obesity during pregnancy and an increased risk of developing non-communicable cardiometabolic diseases in her offspring. This mini-review focuses on evidence examining the effect of maternal high-fat diet (HFD) on skeletal development and bone health in later life in offspring. The majority of rodent studies indicate that maternal HFD generally negatively affects both embryonic bone development and bone volume in adult animals. Details surrounding the mechanisms of action that drive changes in the skeleton in offspring remain unclear, although numerous studies suggest that some effects are sex-specific. Human studies in this area are limited but also suggest that HFD during pregnancy may impair bone formation and increase fracture risk during childhood. Given the consequences of low bone mass and deranged bone microarchitecture for offspring, advances in our understanding of the developmental origins of bone health is critical in the battle against osteoporosis.
Biomarkers and Future Perspectives for Hepatocellular Carcinoma Immunotherapy
Authors: He Yuqing , Lu Mengyao , Che Jing , Chu Qian , Zhang Peng , Chen Yuan
Published: September 2021

Hepatocellular cancer is the sixth most frequently diagnosed malignant disease worldwide, and was responsible for tens of millions of deaths in 2020; however, treatment options for patients with advanced hepatocellular carcinoma remain limited. Immunotherapy has undergone rapid development over recent years, especially in the field of immune checkpoint inhibitors (ICIs). These drugs aim to activate and enhance antitumor immunity and represent a new prospect for the treatment of patients with advanced cancer. Nevertheless, only a small proportion of liver cancer patients currently benefit from ICI-based treatment, highlighting the need to better understand how ICIs and tumors interact, as well as identify predictive biomarkers for immunotherapeutic responses. In this review, we highlight clinical trials and basic research in hepatocellular carcinoma, with a particular focus on predictive biomarkers for the therapeutic efficacy of ICIs. Predictive biomarkers for immune-related adverse events are also discussed.
The Ratio of Preoperative Serum Biomarkers Predicts Prognosis in Patients With Oral Squamous Cell Carcinoma
Authors: Ding Meng , Song Yuxian , Jing Junyan , Tian Mei , Ding Liang , Li Qiang , Zhou Chongchong , Dong Heng , Ni Yanhong , Mou Yongbin
Published: September 2021

Background

Dynamic changes in circulating immune-inflammatory cells have been regarded as simple and convenient prognostic biomarkers in various cancers. However, studies on the prognostic values of their ratios in oral squamous cell carcinoma (OSCC) remain limited.

Materials and Methods

A total of 493 OSCC patients were included in the present study. Here, we investigated the prognostic values of the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-white blood cell ratio (NWR), and lymphocyte-to-white blood cell ratio (LWR) in OSCC. The correlations of the NLR, LMR, NWR, and LWR with clinicopathological characteristics were statistically analyzed using the Chi-square test, Kaplan-Meier curves, and univariate and multivariate Cox regression models.

Result

Kaplan-Meier analyses revealed that OSCC patients with a high LMR and low NWR had prolonged overall survival (OS, P<0.001) and disease-free survival (DFS, P<0.001 and P=0.003, respectively), but there were no significant differences in metastasis-free survival (MFS, P=0.053 and P=0.052, respectively). In contrary, a high NLR and low LWR were associated with poor OS (P<0.001 and P=0.0016, respectively), DFS (P=0.0014 and 0.0012, respectively) and MFS (P=0.021 and 0.008, respectively). Additionally, Cox multivariate analyses showed that the LMR was an independent prognostic factor for both OS (P=0.007) and DFS (P=0.017), while the LWR was an independent prognostic factor for MFS (P=0.009).

Conclusion

Preoperative NLR, LMR, NWR, and LWR in the peripheral blood are significant prognostic factors for OSCC and might be helpful in predicting OSCC progression.
Adverse Events as a Potential Clinical Marker of Antitumor Efficacy in Ovarian Cancer Patients Treated With Poly ADP-Ribose Polymerase Inhibitor
Authors: Ni Jing , Cheng Xianzhong , Zhou Rui , Zhao Qian , Xu Xia , Guo Wenwen , Gu Hongyuan , Chen Chen , Chen Xiaoxiang
Published: September 2021

Background

PARP inhibitor (PARPi) is an important progress in ovarian cancer treatment. The available evidence suggests that BRCA mutation and homologous recombination deficiency (HRD) are effective biological markers for PARPi. Here we investigated the relationship between adverse events (AEs) and efficacy of PARPi in ovarian cancer patients.

Methods

Seventy-eight patients with ovarian cancer patients underwent Olaparib and Niraparib from July 2018 to July 2020 were analyzed. AEs were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Chi-square test or fisher exact tests was performed to observe the association between categorical variables. Logistic regression analysis was conducted to investigate the independent variables for disease control response (DCR). Progression-free survival (PFS) was compared between AEs variables by log-rank test.

Results

Patients with AEs in the first one week had a higher DCR compared with those after one week (86.11% versus 60.98%, p=0.013). Patients with serious AEs (SAEs) had a significantly higher DCR (81.40% versus 60.60%, p=0.045). There were associations between anemia and DCR in both occurrence (79.63% versus 56.52%, p=0.037) and grade (100% versus 73.17%, p=0.048). The median PFS of patients with hematological toxicity was longer than that of patients with no-hematological toxicity (30 versus 20 weeks, p=0.047). Patients with hematological toxicity within four weeks had prolonged median PFS than those with hematological toxicity after four weeks (40 versus 22 weeks, p=0.003).

Conclusions

The early presence of AEs and SAEs in hematological toxicity of PARPi were related to the antitumor efficacy, which might be a valid and easily measurable clinical marker in ovarian cancer patients.
A Case of Adult Pancreatoblastoma With Novel APC Mutation and Genetic Heterogeneity
Authors: Suemitsu Yamato , Ono Yusuke , Mizukami Yusuke , Ye Juanjuan , Yamakawa Keiko , Takamoto Takeshi , Nakano-Narusawa Yuko , Mukai Yuri , Takamatsu Manabu , Nakazawa Atsuko , Mino-Kenudson Mari , Kumasaka Toshio , Matsuda Yoko
Published: September 2021

Background

Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas that mainly occurs in children and involves abnormalities in the WNT/β-catenin pathway, such as CTNNB1 mutation. However, the molecular abnormalities in adult pancreatoblastoma are not well known.

Case Presentation

An elderly man, who underwent elective distal pancreatectomy and splenectomy, was referred to our hospital with a mass in the tail of the pancreas. Histologically, the lesion revealed proliferation of clear, basophilic, and cartilaginous tumor cells with lymphatic metastasis. Each of the morphologically distinct tumor components showed different immunohistochemical patterns, indicating heterogeneous differentiation, including epithelial (both acinar and ductal), mesenchymal, and neuroendocrine differentiation. All tumor components showed nuclear expression of β-catenin and cyclin D1. Per next-generation sequencing (NGS), the clear and basophilic tumor cells shared mutations in APC, GRM8, LAMP1, and AKA9. Among the mutations, APC, c.1816_1817insA showed the highest frequency in both cell types, indicating that APC mutation was a driver mutation of the tumor. A diagnosis of PB was rendered.

In conclusion, the clear and basophilic cells of the tumor were supposedly derived from the same clone and subsequently acquired additional mutations. This is the first report of clonal evolution in pancreatoblastoma.
Self-Medication Among Pregnant Women: Prevalence and Associated Factors
Authors: Pereira Gabriela , Surita Fernanda Garanhani , Ferracini Amanda Canato , Madeira Cinthia de Souza , Oliveira Letícia Silva , Mazzola Priscila Gava
Published: September 2021

Objectives: The pregnancy period, with its peculiarities and specific symptoms that may or may not be physiological, can lead to medication use through prescription or even self-medication. This study aimed to assess self-medication practices among pregnant women, the most used medications, symptoms reported, and factors associated with this practice.

Methods: This was a cross-sectional study conducted with pregnant women with an antenatal care (ANC) appointment in a tertiary teaching hospital referral in women’s health. From April 2019 to February 2020, 297 pregnant women were interviewed. Self-medication was considered as the use of any medicine (including medicinal plants (MPs), herbal products, and vitamins) without a medical or dental prescription. The period considered to assess self-medication practice was the last 60 days prior to the study interview.

Results: Among the 297 women interviewed, 107 (36.0%) had practiced self-medication in the previous 60 days. Acetaminophen was the most used medication, and headache was the most frequent symptom reported by self-medicated pregnant women. Pregnant women with high-school (73 (68.2%) (OR = 2.52; 95% CI 1.17–5.43; p = 0.018)) or university-level (23 (21.5%) (OR = 2.82; 95% CI 1.15–6.94; p = 0.024)) education had a higher risk of practicing self-medication when compared to women with lower education. Women in the first gestational trimester (35 (32.7%) (OR = 3.61; 95% CI 1.64–7.96; p = 0.002)) and with two or more pregnancies (87 (81.2%) (OR = 1.96; 95% CI 1.07–3.60; p = 0.029)) were more likely to practice self-medication than pregnant women in the second or third gestational trimester and in the first pregnancy, respectively.

Conclusion: Self-medication was practiced by a considerable proportion of our sample, with the majority being OTC drugs. The factors associated with self-medication can help to improve prevention strategies regarding self-medication during pregnancy.
Network Pharmacology-Based Analysis on the Potential Biological Mechanisms of Sinisan Against Non-Alcoholic Fatty Liver Disease
Authors: Wei Xiaoyi , Hou Weixin , Liang Jiajun , Fang Peng , Dou Bo , Wang Zisong , Sai Jiayang , Xu Tian , Ma Chongyang , Zhang Qiuyun , Cheng Fafeng , Wang Xueqian , Wang Qingguo
Published: September 2021

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in China. Sinisan (SNS) is a traditional Chinese medicine formula that has been widely used in treating chronic liver diseases, including NAFLD. However, its underlying biological mechanisms are still unclear. In this study, we employed a network pharmacology approach consisting of overlapped terms- (genes or pathway terms-) based analysis, protein-protein interaction (PPI) network-based analysis, and PPI clusters identification. Unlike the previous network pharmacology study, we used the shortest path length-based network proximity algorithm to evaluate the efficacy of SNS against NAFLD. And we also used random walk with restart (RWR) algorithm and Community Cluster (Glay) algorithm to identify important targets and clusters. The screening results showed that the mean shortest path length between genes of SNS and NAFLD was significantly smaller than degree-matched random ones. Six PPI clusters were identified and ten hub targets were obtained, including STAT3, CTNNB1, MAPK1, MAPK3, AGT, NQO1, TOP2A, FDFT1, ALDH4A1, and KCNH2. The experimental study indicated that SNS reduced hyperlipidemia, liver steatosis, and inflammation. Most importantly, JAK2/STAT3 signal was inhibited by SNS treatment and was recognized as the most important signal considering the network pharmacology part. This study provides a systems perspective to study the relationship between Chinese medicines and diseases and helps to discover potential mechanisms by which SNS ameliorates NAFLD.
ET-CORM Mediated Vasorelaxation of Small Mesenteric Arteries: Involvement of Kv7 Potassium Channels
Authors: Zhang Danfeng , Krause Bernhard M. , Schmalz Hans-Günther , Wohlfart Paulus , Yard Benito A. , Schubert Rudolf
Published: September 2021

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K+-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein. To this end, 3 different types of ET-CORMs that either contain acetate (rac-1 and rac-4) or pivalate (rac-8) as ester functionality, were tested ex vivo on methoxamine pre-contracted small rat mesenteric arteries in a myograph setting. Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs (rac-1 and rac-4), while treatment with the pivalate containing ET-CORM (rac-8) resulted in no vasodilation. Pre-treatment of mesenteric arteries with the sGC inhibitor ODQ abolished rac-4 mediated vasodilation, similar as for the known sGC activator SNP. Likewise, rac-4 mediated vasodilation did not occur in KCL pretreated mesenteric arteries. Although mesenteric arteries abundantly expressed a variety of K+-channels only Kv7 channels were found to be of functional relevance for rac-4 mediated vasodilation. In conclusion the current results identified Kv7 channels as the main channel by which rac-4 mediates vasodilation. In keeping with the central role of Kv7 in the control of vascular tone and peripheral resistance these promising ex-vivo data warrant further in vivo studies, particularly in models of primary hypertension or cardiac diseases, to assess the potential use of ET-CORMs in these diseases.
A Synthetic Hydrogel, VitroGel® ORGANOID-3, Improves Immune Cell-Epithelial Interactions in a Tissue Chip Co-Culture Model of Human Gastric Organoids and Dendritic Cells
Authors: Cherne Michelle D. , Sidar Barkan , Sebrell T. Andrew , Sanchez Humberto S. , Heaton Kody , Kassama Francis J. , Roe Mandi M. , Gentry Andrew B. , Chang Connie B. , Walk Seth T. , Jutila Mark , Wilking James N. , Bimczok Diane
Published: September 2021

Immunosurveillance of the gastrointestinal epithelium by mononuclear phagocytes (MNPs) is essential for maintaining gut health. However, studying the complex interplay between the human gastrointestinal epithelium and MNPs such as dendritic cells (DCs) is difficult, since traditional cell culture systems lack complexity, and animal models may not adequately represent human tissues. Microphysiological systems, or tissue chips, are an attractive alternative for these investigations, because they model functional features of specific tissues or organs using microscale culture platforms that recreate physiological tissue microenvironments. However, successful integration of multiple of tissue types on a tissue chip platform to reproduce physiological cell-cell interactions remains a challenge. We previously developed a tissue chip system, the gut organoid flow chip (GOFlowChip), for long term culture of 3-D pluripotent stem cell-derived human intestinal organoids. Here, we optimized the GOFlowChip platform to build a complex microphysiological immune-cell-epithelial cell co-culture model in order to study DC-epithelial interactions in human stomach. We first tested different tubing materials and chip configurations to optimize DC loading onto the GOFlowChip and demonstrated that DC culture on the GOFlowChip for up to 20 h did not impact DC activation status or viability. However, Transwell chemotaxis assays and live confocal imaging revealed that Matrigel, the extracellular matrix (ECM) material commonly used for organoid culture, prevented DC migration towards the organoids and the establishment of direct MNP-epithelial contacts. Therefore, we next evaluated DC chemotaxis through alternative ECM materials including Matrigel-collagen mixtures and synthetic hydrogels. A polysaccharide-based synthetic hydrogel, VitroGel®-ORGANOID-3 (V-ORG-3), enabled significantly increased DC chemotaxis through the matrix, supported organoid survival and growth, and did not significantly alter DC activation or viability. On the GOFlowChip, DCs that were flowed into the chip migrated rapidly through the V-ORG matrix and reached organoids embedded deep within the chip, with increased interactions between DCs and gastric organoids. The successful integration of DCs and V-ORG-3 embedded gastric organoids into the GOFlowChip platform now permits real-time imaging of MNP-epithelial interactions and other investigations of the complex interplay between gastrointestinal MNPs and epithelial cells in their response to pathogens, candidate drugs and mucosal vaccines.
Natural Compounds With Antimicrobial and Antiviral Effect and Nanocarriers Used for Their Transportation
Authors: Stan Diana , Enciu Ana-Maria , Mateescu Andreea Lorena , Ion Andreea Cristina , Brezeanu Ariana Cristina , Stan Dana , Tanase Cristiana
Published: September 2021

Due to the increasing prevalence of life-threatening bacterial, fungal and viral infections and the ability of these human pathogens to develop resistance to current treatment strategies, there is a great need to find and develop new compunds to combat them. These molecules must have low toxicity, specific activity and high bioavailability. The most suitable compounds for this task are usually derived from natural sources (animal, plant or even microbial). In this review article, the latest and most promising natural compounds used to combat bacteria, filamentous fungi and viruses are presented and evaluated. These include plant extracts, essential oils, small antimicrobial peptides of animal origin, bacteriocins and various groups of plant compounds (triterpenoids; alkaloids; phenols; flavonoids) with antimicrobial and antiviral activity. Data are presented on the inhibitory activity of each natural antimicrobial substance and on the putative mechanism of action against bacterial and fungal strains. The results show that among the bioactive compounds studied, triterpenoids have significant inhibitory activity against coronaviruses, but flavonoids have also been shown to inhibit SARS-COV-2. The last chapter is devoted to nanocarriers used to improve stability, bioavailability, cellular uptake/internalization, pharmacokinetic profile and reduce toxicity of natural compunds. There are a number of nanocarriers such as liposomes, drug delivery microemulsion systems, nanocapsules, solid lipid nanoparticles, polymeric micelles, dendrimers, etc. However, some of the recent studies have focused on the incorporation of natural substances with antimicrobial/antiviral activity into polymeric nanoparticles, niosomes and silver nanoparticles (which have been shown to have intrinsic antimicrobial activity). The natural antimicrobials isolated from animals and microorganisms have been shown to have good inhibitory effect on a range of pathogens, however the plants remain the most prolific source. Even if the majority of the studies for the biological activity evaluation are in silico or in vitro, their internalization in the optimum nanocarriers represents the future of “green therapeutics” as shown by some of the recent work in the field.
Safety, Pharmacokinetics, and Pharmacodynamics of a Single Bolus of the γ-aminobutyric Acid (GABA) Receptor Potentiator HSK3486 in Healthy Chinese Elderly and Non-elderly
Authors: Li Xiaojiao , Yang Deming , Li Qianqian , Wang Hong , Wang Meng , Yan Pangke , Wu Nan , Li Fangqiong , Ma Shiping , Ding Yanhua , Liu Jingrui , Wang Hushan
Published: September 2021

Background: The present clinical trial investigated the potential influences of dosage and age on the pharmacokinetic properties and safety profile of HSK3486, and whether any adjustment in dosing regimen is necessary in elderly patients.

Methods: Twenty-four elderly participants (65–73 years) were apportioned to three equal cohorts to receive a single IV bolus of 0.2, 0.3, and 0.4 mg/kg HSK3486, respectively. An additional control group comprised eight non-elderly participants (21–44 years), who each received a single IV bolus dose of 0.4 mg/kg. Safety was assessed throughout the study, and the clinical effects were assessed based on modified observer’s assessment of alertness/sedation and bispectral index (BIS) monitor. Pharmacokinetic parameters were calculated.

Results: The rates of drug-related adverse reactions among the elderly groups were a little higher than that of the non-elderly, and were slightly higher in the elderly receiving 0.4 mg/kg compared with the elderly given lower doses. The pharmacokinetic characteristics of 0.4 mg/kg HSK3486 in the elderly and non-elderly were comparable. The time to recovery was similar in elderly 0.3 mg/kg, elderly 0.4 mg/kg and non-elderly 0.4 mg/kg groups. In the elderly 0.2 mg/kg group, the time to loss of consciousness was a little longer, and the time to recovery was shorter, relative to the other three groups.

Conclusions: Administration of 0.3 mg/kg to the elderly and 0.4 mg/kg to the non-elderly were similarly efficacious. A dose of HSK3486 of 0.3 mg/kg may be chosen for clinical use in elderly patients.
Association Between Burst-Suppression Latency and Burst-Suppression Ratio Under Isoflurane or Adjuvant Drugs With Isoflurane Anesthesia in Mice
Authors: Wang Di , Guo Qingchen , Liu Di , Kong Xiang-Xi , Xu Zheng , Zhou Yu , Su Yan , Dai Feng , Ding Hai-Lei , Cao Jun-Li
Published: September 2021

The same doses of anesthesia may yield varying depths of anesthesia in different patients. Clinical studies have revealed a possible causal relationship between deep anesthesia and negative short- and long-term patient outcomes. However, a reliable index and method of the clinical monitoring of deep anesthesia and detecting latency remain lacking. As burst-suppression is a characteristic phenomenon of deep anesthesia, the present study investigated the relationship between burst-suppression latency (BSL) and the subsequent burst-suppression ratio (BSR) to find an improved detection for the onset of intraoperative deep anesthesia. The mice were divided young, adult and old group treated with 1.0% or 1.5% isoflurane anesthesia alone for 2 h. In addition, the adult mice were pretreated with intraperitoneal injection of ketamine, dexmedetomidine, midazolam or propofol before they were anesthetized by 1.0% isoflurane for 2 h. Continuous frontal, parietal and occipital electroencephalogram (EEG) were acquired during anesthesia. The time from the onset of anesthesia to the first occurrence of burst-suppression was defined as BSL, while BSR was calculated as percentage of burst-suppression time that was spent in suppression periods. Under 1.0% isoflurane anesthesia, we found a negative correlation between BSL and BSR for EEG recordings obtained from the parietal lobes of young mice, from the parietal and occipital lobes of adult mice, and the occipital lobes of old mice. Under 1.5% isoflurane anesthesia, only the BSL calculated from EEG data obtained from the occipital lobe was negatively correlated with BSR in all mice. Furthermore, in adult mice receiving 1.0% isoflurane anesthesia, the co-administration of ketamine and midazolam, but not dexmedetomidine and propofol, significantly decreased BSL and increased BSR. Together, these data suggest that BSL can detect burst-suppression and predict the subsequent BSR under isoflurane anesthesia used alone or in combination with anesthetics or adjuvant drugs. Furthermore, the consistent negative correlation between BSL and BSR calculated from occipital EEG recordings recommends it as the optimal position for monitoring burst-suppression.
Trend, Seasonal, and Irregular Variations in Regional Actual Evapotranspiration Over China: A Multi-Dataset Analysis
Authors: Su Tao , Feng Taichen , Huang Bicheng , Han Zixuan , Qian Zhonghua , Feng Guolin , Hou Wei
Published: September 2021

Actual evapotranspiration (AE) is a crucial processes in terrestrial ecosystems. Global warming is expected to increase AE; however, various AE estimation methods or models give inconsistent trends. This study analyzed AE variability in China during 1982–2015 based on the Budyko framework (AE_Budyko), a complementary-relationship-based product (AE_CR), and the weighted average of six reanalyses (AE_WAR). Because the response of AE to driving factors and the performances of AE datasets are both scale-dependent, China has been categorized into six distinct climatic areas. From a regional perspective, the X-12-ARIMA method was used to decompose monthly AE into the trend, seasonal, and irregular components. We examined the main characteristics of these components and the relationships of climate factors with AE. The results indicate that the trend component of AE increased from the mid-1990s to the early 2000s and more recently in the hyper-arid and arid areas. Increasing AE was observed from 1982 to the early 1990s in the semi-arid and dry sub-humid areas. AE increased significantly and had substantial interannual variability for the entire period in the sub-humid and humid areas. Increased precipitation and water supply from terrestrial water storage contributed significantly to increasing AE in the drylands. The simultaneous occurrence of increasing precipitation and wet-day frequency caused increasing AE in the dry sub-humid area. Increased AE could be explained by the increased energy supply and precipitation in the sub-humid and humid areas. Precipitation had the strongest influence on the irregular component of AE in drylands. AE and potential evapotranspiration had a strong positive correlation in the sub-humid and humid areas. Regarding data availability, a discrepancy existed in the trend component of AE_CR because soil moisture was not explicitly considered, whereas the irregular component of AE_Budyko contained distinct variations in humid and sub-humid areas.
Simulated Variation Characteristics of Oceanic CO2 Uptake, Surface Temperature, and Acidification in Zhejiang Province, China
Authors: Wang Kuo , Zhang Han , Fan Gao-Feng , Li Zheng-Quan , Yu Zhen-Yan , Liu Pei-Pei
Published: September 2021

Since preindustrial times, atmospheric CO2 content increased continuously, leading to global warming through the greenhouse effect. Oceanic carbon sequestration mitigates global warming; on the other hand, oceanic CO2 uptake would reduce seawater pH, which is termed ocean acidification. We perform Earth system model simulations to assess oceanic CO2 uptake, surface temperature, and acidification for Zhejiang offshore, one of the most vulnerable areas to marine disasters. In the last 40 years, atmospheric CO2 concentration increased by 71 ppm, and sea surface temperature (SST) in Zhejiang offshore increased at a rate of 0.16°C/10a. Cumulative oceanic CO2 uptake in Zhejiang offshore is 0.3 Pg C, resulting in an increase of 20% in sea surface hydrogen ion concentration, and the acidification rate becomes faster in the last decade. During 2020–2040, under four RCP scenarios, SST in Zhejiang offshore increases by 0.3–0.5°C, whereas cumulative ocean carbon sequestration is 0.150–0.165 Pg C. Relative to RCP2.6, the decrease of surface pH in Zhejiang offshore is doubled under RCP8.5. Furthermore, simulated results show that the relationship between CO2 scenario and oceanic carbon cycle is nonlinear, which hints that deeper reduction of anthropogenic CO2 emission may be needed if we aim to mitigate ocean acidification in Zhejiang offshore under a higher CO2 concentration scenario. Our study quantifies the variation characteristics of oceanic climate and carbon cycle fields in Zhejiang offshore, and provides new insight into the responses of oceanic carbon cycle and the climate system to oceanic carbon sequestration.
Polarization-Sensitive Second Harmonic Generation Microscopy for Investigations of Diseased Collagenous Tissues
Authors: Cisek Richard , Joseph Ariana , Harvey MacAulay , Tokarz Danielle
Published: September 2021

The advancement of non-invasive quantitative optical diagnosis techniques such as polarization-sensitive second harmonic generation microscopy (PSHG) for diseases such as cancer presents opportunities for improving disease understanding and survival rates. Here, novel and developing techniques in PSHG microscopy applied for the differentiation of cancerous or diseased tissues are presented, including circular dichroism, modulation of laser linear polarization, detection of outgoing linear laser polarization, and double-Stokes Mueller. Typically, initial cancer diagnosis is performed by visual inspection of stained biopsy or surgical resection tissue sections under bright-field microscopy, however, early diagnosis is challenging due to variability in morphological interpretation of the tissues, and because cancer initiation regions can be small and easy to miss. Therefore, pathologists could benefit in identifying cancer on biopsy or surgical resection sections by using unbiased quantitative automated technologies with high spatial resolution and improved disease specificity that can check the entire slide pixel-by-pixel. Second harmonic generation microscopy offers the opportunity to measure ultrastructural alterations in collagenous scaffolds of organ tissues virtually background free on submicron-sized tissue regions. The approach is particularly interesting for cancer diagnosis applications, because during cancer initiation and progression, the collagen in the affected tissue extracellular matrix is often deregulated and becomes disorganized. This mini-review contains a thorough summary of PSHG techniques that have interrogated diseased tissues, and discusses their technical variations and successes in disease discrimination.
Altitude, Exercise, and Skeletal Muscle Angio-Adaptive Responses to Hypoxia: A Complex Story
Authors: Lemieux Pierre , Birot Olivier
Published: September 2021

Hypoxia, defined as a reduced oxygen availability, can be observed in many tissues in response to various physiological and pathological conditions. As a hallmark of the altitude environment, ambient hypoxia results from a drop in the oxygen pressure in the atmosphere with elevation. A hypoxic stress can also occur at the cellular level when the oxygen supply through the local microcirculation cannot match the cells’ metabolic needs. This has been suggested in contracting skeletal myofibers during physical exercise. Regardless of its origin, ambient or exercise-induced, muscle hypoxia triggers complex angio-adaptive responses in the skeletal muscle tissue. These can result in the expression of a plethora of angio-adaptive molecules, ultimately leading to the growth, stabilization, or regression of muscle capillaries. This remarkable plasticity of the capillary network is referred to as angio-adaptation. It can alter the capillary-to-myofiber interface, which represent an important determinant of skeletal muscle function. These angio-adaptive molecules can also be released in the circulation as myokines to act on distant tissues. This review addresses the respective and combined potency of ambient hypoxia and exercise to generate a cellular hypoxic stress in skeletal muscle. The major skeletal muscle angio-adaptive responses to hypoxia so far described in this context will be discussed, including existing controversies in the field. Finally, this review will highlight the molecular complexity of the skeletal muscle angio-adaptive response to hypoxia and identify current gaps of knowledges in this field of exercise and environmental physiology.
Uncovering Trait Associations Resulting in Maximal Seed Yield in Winter and Spring Oilseed Rape
Authors: Siles Laura , Hassall Kirsty L. , Sanchis Gritsch Cristina , Eastmond Peter J. , Kurup Smita
Published: September 2021

Seed yield is a complex trait for many crop species including oilseed rape (OSR) (Brassica napus), the second most important oilseed crop worldwide. Studies have focused on the contribution of distinct factors in seed yield such as environmental cues, agronomical practices, growth conditions, or specific phenotypic traits at the whole plant level, such as number of pods in a plant. However, how female reproductive traits contribute to whole plant level traits, and hence to seed yield, has been largely ignored. Here, we describe the combined contribution of 33 phenotypic traits within a B. napus diversity set population and their trade-offs at the whole plant and organ level, along with their interaction with plant level traits. Our results revealed that both Winter OSR (WOSR) and Spring OSR (SOSR); the two more economically important OSR groups in terms of oil production; share a common dominant reproductive strategy for seed yield. In this strategy, the main inflorescence is the principal source of seed yield, producing a good number of ovules, a large number of long pods with a concomitantly high number of seeds per pod. Moreover, we observed that WOSR opted for additional reproductive strategies than SOSR, presenting more plasticity to maximise seed yield. Overall, we conclude that OSR adopts a key strategy to ensure maximal seed yield and propose an ideal ideotype highlighting crucial phenotypic traits that could be potential targets for breeding.
Governance Choices of Genome Editing Patents
Authors: Scheinerman Naomi , Sherkow Jacob S.
Published: September 2021

There are a variety of governance mechanisms concerning the ownership and use of patents. These include government licenses, compulsory licenses, march-in rights for inventions created with federal funding, government use rights, enforcement restrictions, subject-matter restrictions, and a host of private governance regimes. Each has been discussed in various contexts by scholars and policymakers and some, in some degree, have been employed in different cases at different times. But scholars have yet to explore how each of these choices are subject to—or removed from—democratic control. Assessing the range of democratic implications of these patent governance choices is important in understanding the social and political implications of controversial or wide-ranging technologies because their use has a significant potential to affect the polity. This paper seeks to unpack these concerns for genome editing, such as CRISPR, specifically. Patents covering genome editing make an interesting case because, to date, it appears that the polity is concerned less with certain kinds of access, and more with distribution and limits on the technology’s particular uses, such as human enhancement and certain agricultural and environmental applications. Here, we explore what it means for patents to be democratic or non-democratically governed and, in so doing, identify that patents covering many of the most controversial applications—that is, ones most likely to gain public attention—are effectively controlled by either non- or anti-democratic institutions, namely, private restrictions on licensing. This may be effective—for now—but lawmakers should be wary that such restrictions could rapidly reverse themselves. Meanwhile, other choices, like compulsory licenses, more broadly touch on democratic deliberation but, as currently structured, are aimed poorly for particular applications. Insofar as the public wants, or perhaps deserves, a say in the distribution and limits of these applications, illuminating the ways in which these governance choices intersect—or fail to intersect—with democratic institutions is critical. We offer some concluding thoughts about the nature of patents and their relationship with democratic governance as distributed claims to authority, and suggest areas for scholars and policymakers to pay close attention to as the genome editing patent landscape develops.