bluuebunny/crossref_metadata_2025 huggingface dataset:
A Modified Mediterranean Diet Improves Fasting and Postprandial Glucoregulation in Adults with Overweight and Obesity: A Pilot Study
Authors: Gioxari Aristea , Grammatikopoulou Maria G. , Katsarou Christina , Panagiotakos Demosthenes B. , Toutouza Marina , Kavouras Stavros A. , Sidossis Labros S. , Maraki Maria I.
Published: November 2022

The ideal lifestyle intervention to battle both obesity and diabetes is currently unknown. The aim of this pilot uncontrolled intervention trial was to assess the effect of a modified Mediterranean diet (MedDiet) on weight loss and glucoregulation among overweight/obese adults. Eleven men and women with overweight/obesity, aged 37 ± 12 years, participated in a free-living intervention until 10% weight loss was achieved. Participants followed an individualized MedDiet high in monounsaturated fat and protein with decreased carbohydrate and saturated fat contents. Physical activity and dietary intake were monitored with pedometers and food records, respectively. Upon weight loss achievement, anthropometric measurements, blood metabolic profiles and individual responses to oral glucose and mixed-meal tests were evaluated pre- and post-intervention. The results showed significant ameliorations in body fat, waist circumference and leptin levels (p < 0.01), with concomitant increases in adiponectin–leptin ratios (p < 0.001). Glucoregulation was significantly improved according to glucose and insulin responses, homeostatic model assessment of insulin resistance indices and postprandial insulin sensitivity indices (p < 0.05). In conclusion, the modified Mediterranean diet may induce significant improvements in body composition, adipocytokine profile and glucose metabolism in overweight/obese individuals. Notably, ameliorated glycemia and increased insulin sensitivity may be retained even at postprandial level, irrespective of the meal consumed.
Disaster Evacuation for Home-Based Patients with Special Healthcare Needs: A Cross-Sectional Study
Authors: Matsumoto Yukari , Nakai Hisao , Koga Yumi , Hasegawa Tamayo , Miyagi Yumiko
Published: November 2022

Recent super-typhoons and torrential rains triggered by global warming have had disproportionately large effects on medically vulnerable people in Japan. This study aimed to identify factors associated with intention to evacuate to the nearest public shelter among family caregivers of pediatric patients receiving home medical care. The study included family caregivers of these patients from the Department of Pediatrics, Fukuoka University Hospital, Japan, including family caregivers of young adults with special healthcare needs. An original questionnaire was prepared drawing on previous studies and used for an interview survey. Overall, 57 individuals provided valid data and were included in the analysis. Factors associated with evacuation intention were non-use of a home ventilator (odds ratio [OR] 3.99, 95% confidence interval [CI]: 1.13–14.03) and not having made arrangements to use a non-public shelter (OR 7.29 95% CI: 1.62–32.88). This means that those who use mechanical ventilation or have secured alternative places to go if they need to evacuate their homes may not use the nearest public shelter in a disaster. We recommend that policy makers consider the use of mechanical ventilation and the availability of non-public shelters as predictors of evacuation behavior when considering disaster preparedness for these patients.
Multi-Scenario Simulation to Predict Ecological Risk Posed by Urban Sprawl with Spontaneous Growth: A Case Study of Quanzhou
Authors: Liao Jiangfu , Tang Lina , Shao Guofan
Published: November 2022

The rapid expansion of different types of urban land continues to erode natural and semi-natural ecological space and causes irreversible ecological damage to rapidly industrialized and urbanized areas. This work considers Quanzhou, a typical industrial and trade city in southeastern China as the research area and uses a Markov chain integrated into the patch-generating land use simulation (PLUS) model to simulate the urban expansion of Quanzhou from 2005 to 2018. The PLUS model uses the random forest algorithm to determine the contribution of driving factors and simulate the organic and spontaneous growth process based on the seed generation mechanism of multi-class random patches. Next, leveraging the importance of ecosystem services and ecological sensitivity as indicators of evaluation endpoints, we explore the temporal and spatial evolution of ecological risks from 2018 to 2031 under the scenarios of business as usual (BAU), industrial priority, and urban transformation scenarios. The evaluation endpoints cover water conservation service, soil conservation service, biodiversity maintenance service, soil erosion sensitivity, riverside sensitivity, and soil fertility. The ecological risk studied in this work involves the way in which different types of construction land expansion can possibly affect the ecosystem. The ecological risk index is divided into five levels. The results show that during the calibration simulation period from 2005 to 2018 the overall accuracy and Kappa coefficient reached 91.77% and 0.878, respectively. When the percent-of-seeds (PoS) parameter of random patch seeds equals 0.0001, the figure of merit of the simulated urban construction land improves by 3.9% compared with the logistic-based cellular automata model (Logistic-CA) considering organic growth. When PoS = 0.02, the figure of merit of the simulated industrial and mining land is 6.5% higher than that of the Logistic-CA model. The spatial reconstruction of multiple types of construction land under different urban development goals shows significant spatial differentiation on the district and county scale. In the industrial-priority scenario, the area of industrial and mining land is increased by 20% compared with the BAU scenario, but the high-level risk area is 42.5% larger than in the BAU scenario. Comparing the spatial distribution of risks under the BAU scenario, the urban transition scenario is mainly manifested as the expansion of medium-level risk areas around Quanzhou Bay and the southern region. In the future, the study area should appropriately reduce the agglomeration scale of urban development and increase the policy efforts to guide the development of industrial land to the southeast.
Identification of the Major Effector StSROs in Potato: A Potential StWRKY-SRO6 Regulatory Pathway Enhances Plant Tolerance to Cadmium Stress
Authors: He Yeqing , He Guandi , Lou Fei , Zhou Zheng , Liu Yao , Zhang Yule , He Tengbing
Published: November 2022

SIMILAR TO RCD-ONE (SRO) family members and transcription factors (TFs) often improve plant antioxidant capacity through interaction and co-regulation and participate in plant resistance to drought and high-salt stress. However, whether SROs are involved in the response to heavy metal stress, especially SRO genes with a specific response and tolerance characteristics to cadmium (Cd) stress, remains unclear. We first identified six SRO genes in the potato genome by PARP and RST domains. Special and conserved StSROs were found, and the spatio temporal tissue-specific expression patterns and co-expression network diagrams of StSROs under the stress of 5 heavy metals were constructed. Second, we identified StSRO6 as a major effector gene (StSRO6-MEG) and StSRO5 as a secondary effector gene (StSRO5-SEG) through a comprehensive analysis. Interestingly, they may hold true for various physiological or stress responses in plants. In addition, using systematic genomics and comparative omics techniques, the key gene StSRO6 that affects the difference in Cd accumulation was discovered, cloned in the low-Cd accumulation “Yunshu 505”, and transformed into the yeast mutant ycf1 for overexpression. The results proved that StSRO6 could confer Cd tolerance. Finally, through transient expression and in vitro culture tests, we hypothesized that StSROs 5/6 are regulated by the transcription factor StWRKY6 and mediates the reactive oxygen species (ROS) system to confer Cd tolerance. These findings offer a new perspective for understanding the mechanisms underlying Cd tolerance in plants, and simultaneously provide clues for the development of biological agents for preventing and controlling Cd migration and transformation.
TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region
Authors: Pakmanesh Hamid , Anvari Omid , Forey Nathalie , Weiderpass Elisabete , Malekpourafshar Reza , Iranpour Maryam , Shahesmaeili Armita , Ahmadi Nahid , Bazrafshan Azam , Zendehdel Kazem , Kannengiesser Caroline , Ba Ibrahima , McKay James , Zvereva Maria , Hosen Md Ismail , Sheikh Mahdi , Calvez-Kelm Florence Le
Published: November 2022

Bladder cancer (BC) is the 10th most common cancer in the world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity to be integrated into clinical practice. Telomerase Reverse Transcriptase (TERT) gene mutations have been identified as the most common BC mutations that could potentially be used as non-invasive urinary biomarkers to detect BC. This study aims to evaluate the validity of these tests to detect BC in the Kerman province of Iran, where BC is the most common cancer in men. Urine samples of 31 patients with primary (n = 11) or recurrent (n = 20) bladder tumor and 50 controls were prospectively collected. Total urinary DNA was screened for the TERT promoter mutations (uTERTpm) by Droplet Digital PCR (ddPCR) assays. The performance characteristics of uTERTpm and the influence by disease stage and grade were compared to urine cytology results. The uTERTpm was 100% sensitive and 88% specific to detect primary BC, while it was 50% sensitive and 88% specific in detecting recurrent BC. The overall sensitivity and specificity of uTERTpm to detect bladder cancer were 67.7% and 88.0%, respectively, which were consistent across different tumor stages and grades. The most frequent uTERTpm mutations among BC cases were C228T (18/31), C250T (4/31), and C158A (1/31) with mutant allelic frequency (MAF) ranging from 0.2% to 63.3%. Urine cytology demonstrated a similar sensitivity (67.7%), but lower specificity (62.0%) than uTERTpm in detecting BC. Combined uTERTpm and urine cytology increased the sensitivity to 83.8%, but decreased the specificity to 52.0%. Our study demonstrated promising diagnostic accuracy for the uTERTpm as a non-invasive urinary biomarker to detect, in particular, primary BC in this population.
Paracrine and Autocrine Effects of VEGF Are Enhanced in Human eMSC Spheroids
Authors: Kozhukharova Irina , Minkevich Natalia , Alekseenko Larisa , Domnina Alisa , Lyublinskaya Olga
Published: November 2022

The mechanisms underlying the therapeutic potential of MSCs are the focus of intense research. We studied human MSCs isolated from desquamated endometrium (eMSCs), which, as previously shown, have high regenerative potential in various disease models. The aim was to evaluate the role of secreted VEGF in stimulating angiogenesis and maintaining eMSC viability and migration, which is important for improving the therapeutic properties of MSCs. We compared three eMSC cultures differing in the level of VEGF secretion: 3D spheroids, monolayer eMSCs, and monolayer eMSCs with VEGF knockdown. Spheroid eMSCs produced higher amounts of VEGF and had the strongest paracrine effect on HUVEC. eMSCs with VEGF knockdown did not stimulate angiogenesis. Monolayered eMSCs expressed VEGFR1, while spheroid eMSCs expressed both VEGFR1 and VEGFR2 receptors. The knockdown of VEGF caused a significant decrease in the viability and migration of eMSCs. eMSCs from 3D spheroids enhanced proliferation and migration in response to exogenous VEGF, in contrast to monolayered eMSCs. Our results suggest that the VEGF–VEGFR1 loop appears to be autocrine-involved in maintaining the viability of eMSCs, and VEGFR2 expression enhances their response to exogenous VEGF, so the angiogenic potential of eMSC can be up- or downregulated by intrinsic VEGF signals.
Structural and Dynamic Features of Liver Mitochondria and Mitophagy in Rats with Hyperthyroidism
Authors: Venediktova Natalya , Solomadin Ilya , Starinets Vlada , Mironova Galina
Published: November 2022

This work investigated the effect of thyroxine on the biogenesis and quality control system of rat liver mitochondria. Chronic administration of thyroxine to experimental animals induced hyperthyroidism, which was confirmed by a severalfold increase in serum-free triiodothyronine and thyroxine concentrations. The uptake of oxygen was found to increase with a decrease in ADP phosphorylation efficiency and respiratory state ratio. Electron microscopy showed 36% of liver mitochondria to be swollen and approximately 18% to have a lysed matrix with a reduced number of cristae. Frequently encountered multilamellar bodies associated with defective mitochondria were located either at the edge of or inside the organelle. The number, area and perimeter of hyperthyroid rat mitochondria increased. Administration of thyroxine increased mitochondrial biogenesis and the quantity of mitochondrial DNA in liver tissue. Mitochondrial dynamics and mitophagy changed significantly. The data obtained indicate that excess thyroid hormones cause a disturbance of the mitochondrial quality control system and ultimately to the incorporation of potentially toxic material in the mitochondrial pool.
Effects of Alhagi Honey Polysaccharides as Feed Supplement on Intestine Function and Microbiome, Immune Function, and Growth Performance in Chicken
Authors: Cai Gaofeng , Mao Ningning , Gu Pengfei , Zhu Tianyu , He Jin , Peng Song , Yang Yang , Liu Zhenguang , Hu Yuanliang , Wang Deyun
Published: November 2022

Hy-Line Brown chickens’ health is closely related to poultry productivity and it is mainly maintained by the immune system, healthy intestinal function, and microflora of chicken. Polysaccharides are biological macromolecules with a variety of activities that can be used as a potential prebiotic to improve poultry health. In this experiment, the function of Alhagi honey polysaccharides (AH) as an immunomodulator on the chicken was investigated. All chicken (120) were randomly distributed to four groups (five replicas/group, six hens/replica). A total of 0.5 mL water was taken orally by the chicken in control group. AH (0.5 mL) in different concentrations (three dosages, 0.3 g/kg, 0.6 g/k, and 1.2 g/kg) were used for the AH-0.3 g/kg, AH-0.6 g/k, and AH-1.2 g/kg group, respectively. The results showed that the growth performance of the chickens and the index of immune organs (the weight of immune organs/the body weight) were enhanced significantly after being AH-treated (p < 0.05). The content of sIgA and cytokines was upregulated remarkably in the intestine after being AH-treated (p < 0.05). The AH treatment significantly enhanced the intestinal epithelial barrier (p < 0.05). Moreover, the percentage of CD4+ and CD8+ T cells in the ileum, spleen, and serum were obviously upscaled (p < 0.05). In addition, the AH treatment significantly enhanced the production of short chain fatty acids (SCFAs) and improved the structure of gut microbiota (p < 0.05). In conclusion, we found that AH-1.2g/kg was the best dosage to improve the chicken’s health, and these data demonstrated that AH could be used as a potential tool to enhance growth performance through improving intestine function, immunity, and gut microbiome in chicken.
Scalable Generation of Nanovesicles from Human-Induced Pluripotent Stem Cells for Cardiac Repair
Authors: Lozano Jonathan , Rai Alin , Lees Jarmon G. , Fang Haoyun , Claridge Bethany , Lim Shiang Y. , Greening David W.
Published: November 2022

Extracellular vesicles (EVs) from stem cells have shown significant therapeutic potential to repair injured cardiac tissues and regulate pathological fibrosis. However, scalable generation of stem cells and derived EVs for clinical utility remains a huge technical challenge. Here, we report a rapid size-based extrusion strategy to generate EV-like membranous nanovesicles (NVs) from easily sourced human iPSCs in large quantities (yield 900× natural EVs). NVs isolated using density-gradient separation (buoyant density 1.13 g/mL) are spherical in shape and morphologically intact and readily internalised by human cardiomyocytes, primary cardiac fibroblasts, and endothelial cells. NVs captured the dynamic proteome of parental cells and include pluripotency markers (LIN28A, OCT4) and regulators of cardiac repair processes, including tissue repair (GJA1, HSP20/27/70, HMGB1), wound healing (FLNA, MYH9, ACTC1, ILK), stress response/translation initiation (eIF2S1/S2/S3/B4), hypoxia response (HMOX2, HSP90, GNB1), and extracellular matrix organization (ITGA6, MFGE8, ITGB1). Functionally, NVs significantly promoted tubule formation of endothelial cells (angiogenesis) (p < 0.05) and survival of cardiomyocytes exposed to low oxygen conditions (hypoxia) (p < 0.0001), as well as attenuated TGF-β mediated activation of cardiac fibroblasts (p < 0.0001). Quantitative proteome profiling of target cell proteome following NV treatments revealed upregulation of angiogenic proteins (MFGE8, MYH10, VDAC2) in endothelial cells and pro-survival proteins (CNN2, THBS1, IGF2R) in cardiomyocytes. In contrast, NVs attenuated TGF-β-driven extracellular matrix remodelling capacity in cardiac fibroblasts (ACTN1, COL1A1/2/4A2/12A1, ITGA1/11, THBS1). This study presents a scalable approach to generating functional NVs for cardiac repair.
Integrating Single-Cell Transcriptome and Network Analysis to Characterize the Therapeutic Response of Chronic Myeloid Leukemia
Authors: Ma Jialu , Pettit Nathan , Talburt John , Wang Shanzhi , Weissman Sherman M. , Yang Mary Qu
Published: November 2022

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by a unique BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) were developed to target the BCR-ABL oncoprotein, inhibiting its abnormal kinase activity. TKI treatments have significantly improved CML patient outcomes. However, the patients can develop drug resistance and relapse after therapy discontinues largely due to intratumor heterogeneity. It is critical to understand the differences in therapeutic responses among subpopulations of cells. Single-cell RNA sequencing measures the transcriptome of individual cells, allowing us to differentiate and analyze individual cell populations. Here, we integrated a single-cell RNA sequencing profile of CML stem cells and network analysis to decipher the mechanisms of distinct TKI responses. Compared to normal hematopoietic stem cells, a set of genes that were concordantly differentially expressed in various types of stem cells of CML patients was revealed. Further transcription regulatory network analysis found that most of these genes were directly controlled by one or more transcript factors and the genes have more regulators in the cells of the patients who responded to the treatment. The molecular markers including a known drug-resistance gene and novel gene signatures for treatment response were also identified. Moreover, we combined protein–protein interaction network construction with a cancer drug database and uncovered the drugs that target the marker genes directly or indirectly via the protein interactions. The gene signatures and their interacted proteins identified by this work can be used for treatment response prediction and lead to new strategies for drug resistance monitoring and prevention. Our single-cell-based findings offered novel insights into the mechanisms underlying the therapeutic response of CML.
Coordinative Combination of Nitroamine and Gem-Dinitromethyl with Fused Ring for Enhanced Oxygen Balances and Detonation Properties
Authors: Zhang Xun , Wang Yaxi , Zhao Xinyuan , He Chunlin , Pang Siping
Published: November 2022

Oxygen balance and heat of formation are closely related to the nitrogen and oxygen content in a molecule and have a significant effect on the detonation performance of energetic materials. Here a new family of 1,2,4-triazolo [4,3-b][1,2,4,5]-tetrazine containing gem-dinitromethyl and nitroamine with high nitrogen-oxygen content was synthesized and characterized. Moreover, the structure of the guanidine salt (3) and TATOT salt (4) were confirmed by single-crystal X-ray diffraction. The nitrogen and oxygen content of ammonium salt 2 reached 82.5%, with a high density (1.805 g cm−3) and high detonation properties (D = 8900 m s−1; P = 32.4 GPa), which were similar to those of RDX.
Targeting the Complement–Sphingolipid System in COVID-19 and Gaucher Diseases: Evidence for a New Treatment Strategy
Authors: Trivedi Vyoma Snehal , Magnusen Albert Frank , Rani Reena , Marsili Luca , Slavotinek Anne Michele , Prows Daniel Ray , Hopkin Robert James , McKay Mary Ashley , Pandey Manoj Kumar
Published: November 2022

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced disease (COVID-19) and Gaucher disease (GD) exhibit upregulation of complement 5a (C5a) and its C5aR1 receptor, and excess synthesis of glycosphingolipids that lead to increased infiltration and activation of innate and adaptive immune cells, resulting in massive generation of pro-inflammatory cytokines, chemokines and growth factors. This C5a–C5aR1–glycosphingolipid pathway- induced pro-inflammatory environment causes the tissue damage in COVID-19 and GD. Strikingly, pharmaceutically targeting the C5a–C5aR1 axis or the glycosphingolipid synthesis pathway led to a reduction in glycosphingolipid synthesis and innate and adaptive immune inflammation, and protection from the tissue destruction in both COVID-19 and GD. These results reveal a common involvement of the complement and glycosphingolipid systems driving immune inflammation and tissue damage in COVID-19 and GD, respectively. It is therefore expected that combined targeting of the complement and sphingolipid pathways could ameliorate the tissue destruction, organ failure, and death in patients at high-risk of developing severe cases of COVID-19.
Saliva and Plasma Neutralizing Activity Induced by the Administration of a Third bnt162b2 Vaccine Dose
Authors: Garziano Micaela , Utyro Olga , Strizzi Sergio , Vanetti Claudia , Saulle Irma , Conforti Chiara , Cicilano Federica , Ardizzone Francesco , Cappelletti Gioia , Clerici Mario , Limanaqi Fiona , Biasin Mara
Published: November 2022

The BNT162b2 vaccine induces neutralizing activity (NA) in serum, but no data are available on whether a third-dose activates specific-immunity within the oral mucosa, representing the primary route of viral-entry. To carefully address this issue, we investigated if such immunity is boosted by SARS-CoV-2-infection; how long it is maintained over-time; and if it protects against the SARS-CoV-2 lineage B.1 (EU) and the emerging Delta and Omicron variants. NA was measured in plasma and saliva samples from: uninfected SARS-CoV-2-Vaccinated (SV), subjects infected prior to vaccination (SIV), and subjects who were infected after the second (SIV2) or the third (SIV3) vaccine dose. Samples were collected immediately before (T0), 15 days (T1), and 90 days (T2) post third-dose administration (SV and SIV), or 15 days post-infection (SIV2 and SIV3). In all the enrolled groups, NA in plasma and saliva: (i) was higher against EU compared to the other variants at all time-points (SV: T0 and T1, EU vs. both Delta and Omicron p < 0.001; T2 p < 0.01) (SIV: T0, EU vs. Delta p < 0.05; EU vs. Omi p < 0.01; T1 and T2 EU vs. Delta p < 0.01; EU vs. Omi p < 0.001); (ii) was boosted by the administration of the third dose; iii) declined over-time, albeit being detectable in almost all subjects at T2. The monitoring of NA over time will be important in clarifying if different NA levels may influence either acquisition or course of infection to properly plan the timing of a fourth vaccine dose administration.
Development of a Multi-Criteria Decision-Making Approach for Evaluating the Comprehensive Application of Herbaceous Peony at Low Latitudes
Authors: Wang Xiaobin , Zhang Runlong , Zhang Kaijing , Shao Lingmei , Xu Tong , Shi Xiaohua , Li Danqing , Zhang Jiaping , Xia Yiping
Published: November 2022

The growing region of herbaceous peony (Paeonia lactiflora) has been severely constrained due to the intensification of global warming and extreme weather events, especially at low latitudes. Assessing and selecting stress-tolerant and high-quality peony germplasm is essential for maintaining the normal growth and application of peonies under adverse conditions. This study proposed a modified multi-criteria decision-making (MCDM) model for assessing peonies adapted to low-latitude climates based on our previous study. This model is low-cost, timesaving and suitable for screening the adapted peony germplasm under hot and humid climates. The evaluation was conducted through the analytic hierarchy process (AHP), three major criteria, including adaptability-related, ornamental feature-related and growth habits-related criteria, and eighteen sub-criteria were proposed and constructed in this study. The model was validated on fifteen herbaceous peonies cultivars from different latitudes. The results showed that ‘Meiju’, ‘Hang Baishao’, ‘Hongpan Tuojin’ and ‘Bo Baishao’ were assessed as Level I, which have strong growth adaptability and high ornamental values, and were recommended for promotion and application at low latitudes. The reliability and stability of the MCDM model were further confirmed by measuring the chlorophyll fluorescence of the selected adaptive cultivars ‘Meiju’ and ‘Hang Baishao’ and one maladaptive cultivar ‘Zhuguang’. This study could provide a reference for the introduction, breeding and application of perennials under everchanging unfavorable climatic conditions.
The Role of Type VI Collagen in Alveolar Bone
Authors: Komori Taishi , Pham Hai , Jani Priyam , Perry Sienna , Wang Yan , Kilts Tina M. , Li Li , Young Marian F.
Published: November 2022

Many studies have been conducted to elucidate the role of Type VI collagen in muscle and tendon, however, its role in oral tissues remains unclear. In this study, an α2(VI) deficient mouse (Col6α2-KO) model was used to examine the role of Type VI collagen in oral tissues. Tissue volume and mineral density were measured in oral tissues by µCT. Proteome analysis was performed using protein extracted from alveolar bone. In addition, alveolar bone was evaluated with a periodontitis induced model. µCT analysis showed the Col6α2-KO mice had less volume of alveolar bone, dentin and dental pulp, while the width of periodontal ligament (PDL) was greater than WT. The mineral density in alveolar bone and dentin were elevated in Col6α2-KO mice compared with WT. Our proteome analysis showed significant changes in proteins related to ECM organization and elevation of proteins associated with biomineralization in the Col6α2-KO mice. In induced periodontitis, Col6α2-KO mice had greater alveolar bone loss compared with WT. In conclusion, Type VI collagen has a role in controlling biomineralization in alveolar bone and that changes in the ECM of alveolar bone could be associated with greater bone loss due to periodontitis.
Diastereoselective Synthesis of Novel Spiro-Phosphacoumarins and Evaluation of Their Anti-Cancer Activity
Authors: Sennikova Valeriia V. , Zalaltdinova Alena V. , Sadykova Yulia M. , Khamatgalimov Ayrat R. , Gazizov Almir S. , Voloshina Alexandra D. , Lyubina Anna P. , Amerhanova Syumbelya K. , Voronina Julia K. , Chugunova Elena A. , Appazov Nurbol O. , Burilov Alexander R. , Pudovik Michail A.
Published: November 2022

Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular [3 + 2] cycloaddition reaction. The presented approach is complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.
Antiandrogenic Effects of a Polyphenol in Carex kobomugi through Inhibition of Androgen Synthetic Pathway and Downregulation of Androgen Receptor in Prostate Cancer Cell Lines
Authors: Kudo Yudai , Endo Satoshi , Tanio Masatoshi , Saka Tomofumi , Himura Rin , Abe Naohito , Takeda Mitsumi , Yamaguchi Eiji , Yoshino Yuta , Arai Yuki , Kashiwagi Hirohito , Oyama Masayoshi , Itoh Akichika , Shiota Masaki , Fujimoto Naohiro , Ikari Akira
Published: November 2022

Prostate cancer (PC) represents the most common cancer disease in men. Since high levels of androgens increase the risk of PC, androgen deprivation therapy is the primary treatment; however this leads to castration-resistant PC (CRPC) with a poor prognosis. The progression to CRPC involves ectopic androgen production in the adrenal glands and abnormal activation of androgen signaling due to mutations and/or amplification of the androgen receptor (AR) as well as activation of androgen-independent proliferative pathways. Recent studies have shown that adrenal-derived 11-oxygenated androgens (11-ketotestosterone and 11-ketodihydrotestosterone) with potencies equivalent to those of traditional androgens (testosterone and dihydrotestosterone) are biomarkers of CRPC. Additionally, dehydrogenase/reductase SDR family member 11 (DHRS11) has been reported to be a 17β-hydroxysteroid dehydrogenase that catalyzes the production of the 11-oxygenated and traditional androgens. This study was conducted to evaluate the pathophysiological roles of DHRS11 in PC using three LNCaP, C4-2 and 22Rv1 cell lines. DHRS11 silencing and inhibition resulted in suppression of the androgen-induced expression of AR downstream genes and decreases in the expression of nuclear AR and the proliferation marker Ki67, suggesting that DHRS11 is involved in androgen-dependent PC cell proliferation. We found that 5,7-dihydroxy-8-methyl-2-[2-(4-hydroxyphenyl)ethenyl]-4H-1-benzopyran-4-one (Kobochromone A, KC-A), an ingredient in the flowers of Carex kobomugi, is a novel potent DHRS11 inhibitor (IC50 = 0.35 μM). Additionally, KC-A itself decreased the AR expression in PC cells. Therefore, KC-A suppresses the androgen signaling in PC cells through both DHRS11 inhibition and AR downregulation. Furthermore, KC-A enhanced the anticancer activity of abiraterone, a CRPC drug, suggesting that it may be a potential candidate for the development of drugs for the prevention and treatment of CRPC.
Giardia lamblia G6PD::6PGL Fused Protein Inhibitors Decrease Trophozoite Viability: A New Alternative against Giardiasis
Authors: Morales-Luna Laura , Hernández-Ochoa Beatriz , Martínez-Rosas Víctor , Navarrete-Vázquez Gabriel , Ortega-Cuellar Daniel , Rufino-González Yadira , González-Valdez Abigail , Arreguin-Espinosa Roberto , Franco-Vásquez Adrián Marcelo , Pérez de la Cruz Verónica , Enríquez-Flores Sergio , Martínez-Conde Carlos , Canseco-Ávila Luis Miguel , Gómez-Chávez Fernando , Gómez-Manzo Saúl
Published: November 2022

Treatments to combat giardiasis have been reported to have several drawbacks, partly due to the drug resistance and toxicity of current antiparasitic agents. These constraints have prompted many researchers to investigate new drugs that act against protozoan parasites. Enzyme inhibition is an important means of regulating pathogen metabolism and has recently been identified as a significant alternative target in the search for new treatments. Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase (G6PD::6PGL) is a bifunctional enzyme involved in the pentose phosphate pathway (PPP) in Giardia lamblia (G. lamblia). The G. lamblia enzyme is unusual since, unlike the human enzyme, it is a fused enzyme. Here, we show, through inhibition assays, that an in-house chemical library of 120 compounds and four target compounds, named CNZ-7, CNZ-8, CMC-1, and FLP-2, are potent inhibitors of the G. lamblia G6PD::6PGL fused enzyme. With a constant (k2) of 2.3, 3.2, and 2.8 M−1 s−1, respectively, they provoke alterations in the secondary and tertiary protein structure and global stability. As a novel approach, target compounds show antigiardial activity, with IC50 values of 8.7, 15.2, 15.3, and 24.1 µM in trophozoites from G. lamblia. Moreover, these compounds show selectivity against G. lamblia, since, through counter-screening in Caco-2 and HT29 human cells, they were found to have low toxicity. This finding positions these compounds as a potential and attractive starting point for new antigiardial drugs.
Galectin-1 and Galectin-3 in B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Fei Fei , Zhang Mingfeng , Tarighat Somayeh S. , Joo Eun Ji , Yang Lu , Heisterkamp Nora
Published: November 2022

Acute lymphoblastic leukemias arising from the malignant transformation of B-cell precursors (BCP-ALLs) are protected against chemotherapy by both intrinsic factors as well as by interactions with bone marrow stromal cells. Galectin-1 and Galectin-3 are lectins with overlapping specificity for binding polyLacNAc glycans. Both are expressed by bone marrow stromal cells and by hematopoietic cells but show different patterns of expression, with Galectin-3 dynamically regulated by extrinsic factors such as chemotherapy. In a comparison of Galectin-1 x Galectin-3 double null mutant to wild-type murine BCP-ALL cells, we found reduced migration, inhibition of proliferation, and increased sensitivity to drug treatment in the double knockout cells. Plant-derived carbohydrates GM-CT-01 and GR-MD-02 were used to inhibit extracellular Galectin-1/-3 binding to BCP-ALL cells in co-culture with stromal cells. Treatment with these compounds attenuated migration of the BCP-ALL cells to stromal cells and sensitized human BCP-ALL cells to vincristine and the targeted tyrosine kinase inhibitor nilotinib. Because N-glycan sialylation catalyzed by the enzyme ST6Gal1 can regulate Galectin cell-surface binding, we also compared the ability of BCP-ALL wild-type and ST6Gal1 knockdown cells to resist vincristine treatment when they were co-cultured with Galectin-1 or Galectin-3 knockout stromal cells. Consistent with previous results, stromal Galectin-3 was important for maintaining BCP-ALL fitness during chemotherapy exposure. In contrast, stromal Galectin-1 did not significantly contribute to drug resistance, and there was no clear effect of ST6Gal1-catalysed N-glycan sialylation. Taken together, our results indicate a complicated joint contribution of Galectin-1 and Galectin-3 to BCP-ALL survival, with different roles for endogenous and stromal produced Galectins. These data indicate it will be important to efficiently block both extracellular and intracellular Galectin-1 and Galectin-3 with the goal of reducing BCP-ALL persistence in the protective bone marrow niche during chemotherapy.
Chemical Element Profiling in the Sera and Brain of Bipolar Disorders Patients and Healthy Controls
Authors: Sampath Vishnu Priya , Singh Shiv Vardan , Pelov Ilana , Tirosh Ofir , Erel Yigal , Lichtstein David
Published: November 2022

Bipolar Disorder (BD) is a severe recurrent affective mood disorder characterized by a wide range of lifelong mood swings, varying between depressive and manic states. BD affects more than 1% of the world’s population irrespective of nationality, ethnic origin, or socioeconomic status and is one of the main causes of disability among young people, leading to cognitive and functional impairment and raised mortality, particularly death by suicide. Trace elements play a vital role in many biochemical and physiological processes. Compelling evidence shows that element toxicity might play a crucial role in the onset and progression of neurodegenerative disorders, but their involvement in mood disorders has been scarcely studied. In the present investigation, we determined the concentration of 26 elements in the serum of BD patients before and after treatment and in postmortem brain samples from BD patients and compared them with matched controls. The only element that was reduced significantly in the serum following treatment was vanadium (V). Furthermore, the concentration of Al, B, Cu, K, Mg and V were significantly lower in the pre-frontal cortex of BD patients compared with those of the controls. A comparison of Spearman’s rank correlation coefficients between the elements in the serum and brain of BD patients and control groups pointed to boron and aluminum as being involved in the disease. These results suggest that there is a disturbance in the elements’ homeostasis and the inter-elements’ relationship in the brain of BD patients and advocate a thorough examination of the possible involvement of chemical elements in different stages of the disease.
Lectin-Based Study Reveals the Presence of Disease-Relevant Glycoepitopes in Bladder Cancer Cells and Ectosomes
Authors: Surman Magdalena , Wilczak Magdalena , Przybyło Małgorzata
Published: November 2022

Bladder cancer is a malignancy that remains a therapeutic challenge and requires the identification of new biomarkers and mechanisms of progression. Several studies showed that extracellular vesicles promote angiogenesis, migration and metastasis, and inhibit apoptosis in bladder cancer. This effect may depend on their glycosylation status. Thus, the aim of this study was to compare glycosylation profiles of T-24 urothelial bladder cancer cells, HCV-29 normal ureter epithelial cells, and ectosomes released by both cell lines using lectin blotting and flow cytometry. Ectosomes displayed distinct total and surface glycosylation profiles with abundance of β-1,6-branched glycans and sialilated structures. Then, it was investigated whether the glycosylation status of the T-24 and HCV-29 cells is responsible for the effect exerted by ectosomes on the proliferation and migration of recipient cells. Stronger proproliferative and promigratory activity of T-24-derived ectosomes was observed in comparison to ectosomes from HCV-29 cells. When ectosomes were isolated from DMJ-treated cells, the aforementioned effects were diminished, suggesting that glycans carried by ectosomes were involved in modulation of recipient cell function. HCV-29- and T-24-derived ectosomes also increased the viability and motility of endothelial HUVEC cells and Hs27 fibroblasts. This supports the hypothesis that ectosomes can modulate the function of various cells present in the tumor microenvironment.
Evaluation of Reference Genes for Real-Time Quantitative PCR Analysis in Tissues from Bumble Bees (Bombus Terrestris) of Different Lines
Authors: Sankar Kathannan , Yoon Hyung Joo , Lee Young Bo , Lee Kyeong Yong
Published: November 2022

Bumble bees are important alternative pollinators and model insects due to their highly developed sociality and colony management. In order to better understand their molecular mechanisms, studies focusing on the genetic and molecular aspects of their development and behavior are needed. Although quantitative real-time polymerase chain reaction (qRT-PCR) can be used to quantify the relative expression of target genes, internal reference genes (which are stably expressed across different lines and tissues) must first be identified to ensure the accurate normalization of target genes. In order to contribute to molecular studies on bumble bees, we used Bombus terrestris to determine the expression stability of eight reference genes (β-actin (ACT), Arginine Kinase (AK), Phospholipase A2 (PLA2), Elongation factor 1 alpha (EF-1), Ribosomal proteins (S5, S18, S28) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) in five different lines and several tissues (ovary, thorax, fat body, and head) using RT-qPCR procedures and four analysis programs (RefFinder, NormFinder, BestKeeper, and geNorm). In general, the S28, S5, and S18 ribosomal protein genes and the PLA2 and EF-1 genes showed the highest stability and were therefore identified as suitable reference genes for the bumble bee species and their defined lines and tissues. Our results also emphasized the need to evaluate the stability of candidate reference genes for any differently designed lines and tissue conditions in bumble bee species.
Unusual Effect of α-olefins as Chain Transfer Agents in Ethylene Polymerization over the Catalyst with Nonsymmetrical Bis(imino)pyridine Complex of Fe(II) and Modified Methylalumoxane (MMAO) Cocatalyst
Authors: Semikolenova Nina V. , Matsko Mikhail A. , Zakharov Vladimir A. , Sun Wen-Hua
Published: November 2022

Ethylene polymerization with bis(imino)pyridlyiron precatalysts generally produces linear polyethylene (PE) even with the presence of α-olefins because α-olefins are not incorporated into polymeric products. Interestingly, α-olefins, such as hexene-1 or butene-1, have been found to act as effective chain transfer agents in the ethylene polymerization promoted by nonsymmetrical bis(imino)pyridyliron complexes with modified methylalumoxane (MMAO), resulting in higher catalytic activities with higher amounts of polymers with lower molecular weights, and, more importantly, narrower molecular weight distributions of the resultant polyethylenes (PE). This phenomenon confirms the assistance of α-olefins in the chain-termination reaction of iron-initiated polymerization and regeneration of the active species for further polymerization. Besides higher activities of the catalytic system, the formation of linear PE with trans-vinylene terminal groups and lower molecular weights are explained. The observation will provide a new pathway for enhancing catalytic activity and improving the quality of polyethylenes obtained by regulation of molecular weights and molecular weight distribution.
Emerging Roles of Type-I Interferons in Neuroinflammation, Neurological Diseases, and Long-Haul COVID
Authors: Tan Ping-Heng , Ji Jasmine , Hsing Chung-Hsi , Tan Radika , Ji Ru-Rong
Published: November 2022

Interferons (IFNs) are pleiotropic cytokines originally identified for their antiviral activity. IFN-α and IFN-β are both type I IFNs that have been used to treat neurological diseases such as multiple sclerosis. Microglia, astrocytes, as well as neurons in the central and peripheral nervous systems, including spinal cord neurons and dorsal root ganglion neurons, express type I IFN receptors (IFNARs). Type I IFNs play an active role in regulating cognition, aging, depression, and neurodegenerative diseases. Notably, by suppressing neuronal activity and synaptic transmission, IFN-α and IFN-β produced potent analgesia. In this article, we discuss the role of type I IFNs in cognition, neurodegenerative diseases, and pain with a focus on neuroinflammation and neuro-glial interactions and their effects on cognition, neurodegenerative diseases, and pain. The role of type I IFNs in long-haul COVID-associated neurological disorders is also discussed. Insights into type I IFN signaling in neurons and non-neuronal cells will improve our treatments of neurological disorders in various disease conditions.
Nuclear Factor of Activated T Cells-5 Regulates Notochord Lumenogenesis in Chordate Larval Development
Authors: He Muchun , Wei Jiankai , Li Yuting , Dong Bo
Published: November 2022

Osmoregulation is essential for organisms to adapt to the exterior environment and plays an important role in embryonic organogenesis. Tubular organ formation usually involves a hyperosmotic lumen environment. The mechanisms of how the cells respond and regulate lumen formation remain largely unknown. Here, we reported that the nuclear factor of activated T cells-5 (NFAT5), the only transcription factor in the NFAT family involved in the cellular responses to hypertonic stress, regulated notochord lumen formation in chordate Ciona. Ciona NFAT5 (Ci-NFAT5) was expressed in notochord, and its expression level increased during notochord lumen formation and expansion. Knockout and expression of the dominant negative of NFAT5 in Ciona embryos resulted in the failure of notochord lumen expansion. We further demonstrated that the Ci-NFAT5 transferred from the cytoplasm into nuclei in HeLa cells under the hyperosmotic medium, indicating Ci-NFAT5 can respond the hypertonicity. To reveal the underly mechanisms, we predicted potential downstream genes of Ci-NFAT5 and further validated Ci-NFAT5-interacted genes by the luciferase assay. The results showed that Ci-NFAT5 promoted SLC26A6 expression. Furthermore, expression of a transport inactivity mutant of SLC26A6 (L421P) in notochord led to the failure of lumen expansion, phenocopying that of Ci-NFAT5 knockout. These results suggest that Ci-NFAT5 regulates notochord lumen expansion via the SLC26A6 axis. Taken together, our results reveal that the chordate NFAT5 responds to hypertonic stress and regulates lumen osmotic pressure via an ion channel pathway on luminal organ formation.
Turner Syndrome Mosaicism 45,X/46,XY with Genital Ambiguity and Duchenne Muscular Dystrophy: Translational Approach of a Rare Italian Case
Authors: Lamanna Bruno , Vinciguerra Marina , Dellino Miriam , Cascella Gabriele , Cazzato Gerardo , Macorano Enrica , Malvasi Antonio , Scacco Salvatore , Cicinelli Ettore , Loizzi Vera , Vimercati Antonella , Cormio Gennaro , Paduano Francesco , Cascardi Eliano , Tatullo Marco
Published: November 2022

Turner syndrome (gonadal dysgenesis with short stature and sterility) is characterized by chromosomal karyotype 45,X in 50% of cases or by mosaicism (45,X/46,XX and 45,X/46,XY) in 30–40% or X structural defects (deletions, long arm isochromosome, ring chromosome). When mosaic Turner syndrome (TS) occurs with a Y chromosome, there may be ambiguous genitalia. Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disease with an X-Linked recessive pattern of inheritance that predominantly affects males, while females are usually asymptomatic. DMD has also been observed in groups of females affected by TS, not homozygous for the mutation. Here, we report a case of an Indian neonate born with ambiguous genitalia diagnosed prenatally by ultrasound who had a karyotype of 45,X/46,XY and who also had Duchenne muscular dystrophy caused by a de novo mutation in the DMD gene. Physical examination was normal without the typical dysmorphic features of TS with the exception of the genitourinary system showing ambiguous genitalia. Gender was assigned as female. At the age of three years, she had increasing difficulty walking, running, jumping and climbing stairs, proximal upper and lower extremity muscle weakness and a positive Gowers’ sign. In addition, the serum creatine kinase (CK) value was over 30X the upper limit of normal. This study shows that DMD can occur in females with TS having 45,X/46,XY mosaicism and that this coexistence should be considered in women affected by TS who start to develop potential typical symptoms such as motor or developmental delay.