bluuebunny/crossref_metadata_2025 huggingface dataset:
Coupling and Coordination Relationship between the Tourism Economy and Ecosystem Service Value in Southern Jiangsu, China
Authors: Wang Bin , Hu Chunguang , Li Jianxiong
Published: December 2022

The relationship between the tourism economy and the ecosystem service value (ESV) is crucial for sustainable regional development. This study takes southern Jiangsu as a research object. Firstly, the development level of the tourism economy and ecosystem service value in southern Jiangsu from 2000 to 2020 are evaluated with the entropy method, ecosystem service value is estimated and the dynamic degree of land use is computed. Secondly, the coupling coordination degree model is used to explore the coupling coordination degree between the two systems. Finally, the interaction mechanism between the tourism economy and ecosystem service function is elaborated. The result shows that: (1) There are disparities in the levels of a comprehensive tourism economy in different cities, and the overall development level of the tourism economy in southern Jiangsu shows a cyclical fluctuation pattern. (2) Spatial variation of ecosystem service value exists in different cities in southern Jiangsu, with an overall trend of increasing in the beginning followed by a decline. (3) The coupling coordination degree between the tourism economic system and ecosystem service functions in southern Jiangsu demonstrates an inverted U-shaped development pattern from 2000 to 2020, evolving from mild disorder to intermediate coordination and then back to mild disorder, and the development of two subsystems is unstable and imbalanced. Within the region, Nanjing, Suzhou and Zhenjiang have experienced a rise in coupling coordination degree followed by a decline. This study also reveals the coupling mechanism between ecological service functions and the tourism economic system, and provides suggestions for ecological preservation and sustainable development of tourism industry in southern Jiangsu. This research can be a reference for tourism and regional development in southern Jiangsu and the whole Yangtze Delta region.
Association of Serum Uric Acid with Diabetes in Premenopausal and Postmenopausal Women—A Prospective Cohort Study in Shanghai, China
Authors: Wu Qian , Guan Ying , Xu Chunze , Wang Na , Liu Xing , Jiang Feng , Zhao Qi , Sun Zhongxing , Zhao Genming , Jiang Yonggen
Published: December 2022

There have been few prospective studies on the association between serum uric acid (SUA) and the risk of diabetes in women, and there have been few large-scale Chinese studies based on menopause to investigate the association. Therefore, the present study aimed to investigate the above relationship in Chinese female adults without diabetes. Methods: Data from 5743 premenopausal women and 11,287 postmenopausal women aged 20–74 years were obtained from the Shanghai Suburban Adult Cohort and Biobank (SSACB) study conducted in China. Cox regression models were applied to evaluate the association between SUA levels and the risk of diabetes. Restricted cubic spline analysis and stratified analysis on the basis of menopausal status were performed to explore the dose–response association between SUA levels and diabetes. Results: Among 17,030 participants, incidence rates of diabetes were 3.44/1000 person-years in premenopausal and 8.90/1000 person-years in postmenopausal women. The SUA levels in postmenopausal women were higher than that in premenopausal women (p < 0.0001). In Cox regression analysis, after adjusting for confounding factors, for each 10 µmol/L increase in SUA levels, the adjusted HR of diabetes was 1.01 (95% CI: 0.97–1.04) in postmenopausal women, and 1.03 (95% CI: 1.01–1.04) in premenopausal women. Compared with the lowest quartile of SUA levels, the HR (95% CI) of diabetes in the highest quartile was 0.99 (0.55–1.79) in premenopausal women and 1.39 (1.07–1.81) in postmenopausal women. Compared with those without hyperuricemia, the HR (95% CI) for diabetes was 1.89 (0.67–5.31) in premenopausal women with hyperuricemia, and 1.55 (1.19–2.02) in postmenopausal women. Moreover, restricted cubic splines models showed that there was a linear relationship between SUA levels and diabetes risk in premenopausal (p for nonlinear = 0.99) and postmenopausal women (p for nonlinear = 0.95). Furthermore, the restricted cubic spline graph showed that the risk of diabetes in postmenopausal women increased with an increase in SUA levels (p = 0.002). Conclusions: In a cohort of Chinese adult women, SUA levels are associated with diabetes risk in postmenopausal women, but this association was not observed in premenopausal women.
How Do Primary Care Organizations Rate Their Level of Organizational Health Literacy? Results of a Swiss Pilot-Study
Authors: Beese Anna-Sophia , Nicca Dunja , Jaks Rebecca , Stuermer Natascha , De Gani Saskia Maria
Published: December 2022

Primary care organizations offer a suitable setting to promote organizational health literacy (OHL) since they are a crucial interface for patients and clients. However, a clear picture on the OHL situation in primary care is lacking. The aim of this study was to assess OHL in Swiss primary care organizations by evaluating (i) how they rate their level of OHL and which improvement measures they accordingly plan (organizational level), (ii) what knowledge and attitudes among health professionals in primary care regarding OHL exist (individual level) and (iii) how teams working in general practitioners’ practices and a home care service organization differ regarding OHL (organizational and individual level). The research design included an online survey (N = 74, health professionals) on the individual level and a checklist and intervention documentation (N = 10, primary care teams) on the organizational level. The study reveals a crucial demand regarding organizationally embedded OHL practices in the participating primary care teams, despite a rather comprehensive understanding of the concept. The greatest need for action was identified in strengthening health literacy of staff members, which underlines the necessity to develop interventions to systematically strengthen the health literacy of health professionals.
eDNA, Amyloid Fibers and Membrane Vesicles Identified in Pseudomonas fluorescens SBW25 Biofilms
Authors: Moshynets Olena V. , Pokholenko Ianina , Iungin Olga , Potters Geert , Spiers Andrew J.
Published: December 2022

Pseudomonas fluorescens SBW25 is a model soil- and plant-associated bacterium capable of forming a variety of air–liquid interface biofilms in experimental microcosms and on plant surfaces. Previous investigations have shown that cellulose is the primary structural matrix component in the robust and well-attached Wrinkly Spreader biofilm, as well as in the fragile Viscous Mass biofilm. Here, we demonstrate that both biofilms include extracellular DNA (eDNA) which can be visualized using confocal laser scanning microscopy (CLSM), quantified by absorbance measurements, and degraded by DNase I treatment. This eDNA plays an important role in cell attachment and biofilm development. However, exogenous high-molecular-weight DNA appears to decrease the strength and attachment levels of mature Wrinkly Spreader biofilms, whereas low-molecular-weight DNA appears to have little effect. Further investigation with CLSM using an amyloid-specific fluorophore suggests that the Wrinkly Spreader biofilm might also include Fap fibers, which might be involved in attachment and contribute to biofilm strength. The robust nature of the Wrinkly Spreader biofilm also allowed us, using MALDI-TOF mass spectrometry, to identify matrix-associated proteins unable to diffuse out of the structure, as well as membrane vesicles which had a different protein profile compared to the matrix-associated proteins. CLSM and DNase I treatment suggest that some vesicles were also associated with eDNA. These findings add to our understanding of the matrix components in this model pseudomonad, and, as found in other biofilms, biofilm-specific products and material from lysed cells contribute to these structures through a range of complex interactions.
The Significance of COVID-19 Diseases in Lipid Metabolism Pregnancy Women and Newborns
Authors: Jovandaric Miljana Z. , Dokic Milan , Babovic Ivana R. , Milicevic Srboljub , Dotlic Jelena , Milosevic Branislav , Culjic Miljan , Andric Luka , Dimic Nemanja , Mitrovic Olga , Beleslin Aleksandra , Nikolic Jovana , Jestrovic Zorica , Babic Sandra
Published: December 2022

Coronavirus disease (COVID-19) is an infectious disease caused by SARS-CoV-2. Elderly people, people with immunodeficiency, autoimmune and malignant diseases, as well as people with chronic diseases have a higher risk of developing more severe forms of the disease. Pregnant women and children can becomesick, although more often they are only the carriers of the virus. Recent studies have indicated that infants can also be infected by SARS-CoV-2 and develop a severe form of the disease with a fatal outcome. Acute Respiratory Distress Syndrome (ARDS) ina pregnant woman can affect the supply of oxygen to the fetus and initiate the mechanism of metabolic disorders of the fetus and newborn caused by asphyxia. The initial metabolic response of the newborn to the lack of oxygen in the tissues is the activation of anaerobic glycolysis in the tissues and an increase in the concentration of lactate and ketones. Lipid peroxidation, especially in nerve cells, is catalyzed by iron released from hemoglobin, transferrin and ferritin, whose release is induced by tissue acidosis and free oxygen radicals. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through various pathways, resulting in a decrease in the antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in the cells, ultimately leading to oxidative cell stress, and finally, death. Conclusion: damage to the mitochondria as a result of lipid peroxidation caused by the COVID-19 disease can cause the death of a newborn and pregnant women as well as short time and long-time sequelae.
Human β-Defensin 3 Inhibits Porphyromonas Gingivalis Lipopolysaccharide-Induced Oxidative and Inflammatory Responses of Microglia by Suppression of Cathepsins B and L
Authors: Inoue Erika , Minatozaki Shiyo , Katsuta Yui , Nonaka Saori , Nakanishi Hiroshi
Published: December 2022

Recently, the effects of antibacterial peptides are suggested to have therapeutic potential in Alzheimer’s disease. Furthermore, systemic treatment of Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) induced Alzheimer’s disease-like neuropathological changes in middle-aged mice. Then, we examined whether human β-defensins (hBDs), antimicrobial peptides produced by the oral mucosa and salivary glands, can suppress Pg LPS-induced oxidative and inflammatory responses by microglia. hBD3 (1 μM) significantly suppressed Pg LPS-induced production of nitric oxide and interleukin-6 (IL-6) by MG6 cells, a mouse microglial cell line. hBD3 (1 μM) also significantly inhibited Pg LPS-induced expression of IL-6 by HMC3 cells, a human microglial cell line. In contrast, neither hBD1, hBD2 nor hBD4 failed to inhibit their productions. Furthermore, hBD3 suppressed Pg LPS-induced p65 nuclear translocation through the IκBα degradation. Pg LPS-induced expression of IL-6 was significantly suppressed by E64d, a cysteine protease inhibitor, and CA-074Me, a known specific inhibitor for cathepsin B, but not by pepstatin A, an aspartic protease inhibitor. Interestingly, hBD3 significantly inhibited enzymatic activities of recombinant human cathepsins B and L, lysosomal cysteine proteases, and their intracellular activities in MG6 cells. Therefore, hBD3 suppressed oxidative and inflammatory responses of microglia through the inhibition of cathepsins B and L, which enzymatic activities are necessary for the NF-κB activation.
Biological Age Predictors: The Status Quo and Future Trends
Authors: Erema Veronika V. , Yakovchik Anna Y. , Kashtanova Daria A. , Bochkaeva Zanda V. , Ivanov Mikhail V. , Sosin Dmitry V. , Matkava Lorena R. , Yudin Vladimir S. , Makarov Valentin V. , Keskinov Anton A. , Kraevoy Sergey A. , Yudin Sergey M.
Published: December 2022

There is no single universal biomarker yet to estimate overall health status and longevity prospects. Moreover, a consensual approach to the very concept of aging and the means of its assessment are yet to be developed. Markers of aging could facilitate effective health control, more accurate life expectancy estimates, and improved health and quality of life. Clinicians routinely use several indicators that could be biomarkers of aging. Duly validated in a large cohort, models based on a combination of these markers could provide a highly accurate assessment of biological age and the pace of aging. Biological aging is a complex characteristic of chronological age (usually), health-to-age concordance, and medically estimated life expectancy. This study is a review of the most promising techniques that could soon be used in routine clinical practice. Two main selection criteria were applied: a sufficient sample size and reliability based on validation. The selected biological age calculators were grouped according to the type of biomarker used: (1) standard clinical and laboratory markers; (2) molecular markers; and (3) epigenetic markers. The most accurate were the calculators, which factored in a variety of biomarkers. Despite their demonstrated effectiveness, most of them require further improvement and cannot yet be considered for use in standard clinical practice. To illustrate their clinical application, we reviewed their use during the COVID-19 pandemic.
Dihydromyricetin Inhibited Migration and Invasion by Reducing S100A4 Expression through ERK1/2/β-Catenin Pathway in Human Cervical Cancer Cell Lines
Authors: Hsin Min-Chieh , Hsiao Yi-Hsuan , Chen Pei-Ni , Lin Chiao-Wen , Wang Po-Hui , Yang Shun-Fa , Lee Chung-Yuan
Published: December 2022

Cervical cancer has a poor prognosis and is the fourth most common cancer among women. Dihydromyricetin (DHM), a flavonoid compound, exhibits several pharmacological activities, including anticancer effects; however, the effects of DHM on cervical cancer have received insufficient research attention. This study examined the antitumor activity and underlying mechanisms of DHM on human cervical cancer. Our results indicated that DHM inhibits migration and invasion in HeLa and SiHa cell lines. Mechanistically, RNA sequencing analysis revealed that DHM suppressed S100A4 mRNA expression in HeLa cells. Moreover, DHM inhibited the protein expressions of β-catenin and GSK3β through the regulated extracellular-signal-regulated kinase (ERK)1/2 signaling pathway. By using the ERK1/2 activator, T-BHQ, reverted β-catenin and S100A4 protein expression and cell migration, which were reduced in response to DHM. In conclusion, our study indicated that DHM inhibited cell migration by reducing the S100A4 expression through the ERK1/2/β-catenin pathway in human cervical cancer cell lines.
Tomato Sterol 22-desaturase Gene CYP710A11: Its Roles in Meloidogyne incognita Infection and Plant Stigmasterol Alteration
Authors: Cabianca Alessandro , Ruthes Andrea Caroline , Pawlowski Katharina , Dahlin Paul
Published: December 2022

Sterols are isoprenoid-derived lipids that play essential structural and functional roles in eukaryotic cells. Plants produce a complex mixture of sterols, and changes in plant sterol profiles have been linked to plant–pathogen interactions. β-Sitosterol and stigmasterol, in particular, have been associated with plant defense. As nematodes have lost the ability to synthesize sterols de novo, they require sterols from the host. Tomato (Solanum lycopersicum) plants infected by the plant parasitic nematode Meloidogyne incognita show a reduced level of stigmasterol and a repression of the gene CYP710A11, encoding the sterol C-22 desaturase that is responsible for the conversion of β-sitosterol to stigmasterol. In this study, we investigated the role of the tomato sterol C-22 desaturase gene CYP710A11 in the response to infection by M. incognita. We explored the plant–nematode interaction over time by analyzing the plant sterol composition and CYP710A11 gene regulation in S. lycopersicum after M. incognita infection. The temporal gene expression analysis showed that 3 days after inoculation with M. incognita, the CYP710A11 expression was significantly suppressed in the tomato roots, while a significant decrease in the stigmasterol content was observed after 14 days. A cyp710a11 knockout mutant tomato line lacking stigmasterol was analyzed to better understand the role of CYP710A11 in nematode development. M. incognita grown in the mutant line showed reduced egg mass counts, presumably due to the impaired growth of the mutant. However, the nematodes developed as well as they did in the wild-type line. Thus, while the suppression of CYP710A11 expression during nematode development may be a defense response of the plant against the nematode, the lack of stigmasterol did not seem to affect the nematode. This study contributes to the understanding of the role of stigmasterol in the interaction between M. incognita and tomato plants and shows that the sterol C-22 desaturase is not essential for the success of M. incognita.
Ex Vivo Evaluation of Ethosomes and Transethosomes Applied on Human Skin: A Comparative Study
Authors: Esposito Elisabetta , Calderan Laura , Galvan Andrea , Cappellozza Enrica , Drechsler Markus , Mariani Paolo , Pepe Alessia , Sguizzato Maddalena , Vigato Enrico , Dalla Pozza Edoardo , Malatesta Manuela
Published: December 2022

In this study, the transdermal fate of vesicular nanosystems was investigated. Particularly, ethosomes based on phosphatidylcholine 0.9% w/w and transethosomes based on phosphatidylcholine 0.9 or 2.7% w/w plus polysorbate 80 0.3% w/w as an edge activator were prepared and characterized. The vesicle mean size, morphology and deformability were influenced by both phosphatidylcholine and polysorbate 80. Indeed, the mean diameters of ethosome were around 200 nm, while transethosome’s mean diameters were 146 or 350 nm in the case of phosphatidylcholine 0.9 or 2.7%, w/w, respectively. The highest deformability was achieved by transethosomes based on phosphatidylcholine 0.9%, w/w. The three types of vesicular nanosystems were applied on explanted human skin maintained in a bioreactor. Transmission electron microscopy demonstrated that all vesicles were able to enter the skin, keeping their structural integrity. Notably, the vesicle penetration capability was influenced by their physical-chemical features. Indeed, ethosomes reached keratinocytes and even the dermis, phosphatidylcholine 0.9% transethosomes were found in keratinocytes and phosphatidylcholine 2.7% transethosomes were found only in corneocytes of the outer layer. These findings open interesting perspectives for a differentiated application of these vesicles for transdermal drug delivery as a function of the cutaneous pathology to be addressed.
Selectively Halogenated Flavonolignans—Preparation and Antibacterial Activity
Authors: Hurtová Martina , Káňová Kristýna , Dobiasová Simona , Holasová Kateřina , Čáková Denisa , Hoang Lan , Biedermann David , Kuzma Marek , Cvačka Josef , Křen Vladimír , Viktorová Jitka , Valentová Kateřina
Published: December 2022

A library of previously unknown halogenated derivatives of flavonolignans (silybins A and B, 2,3-dehydrosilybin, silychristin A, and 2,3-dehydrosilychristin A) was prepared. The effect of halogenation on the biological activity of flavonolignans was investigated. Halogenated derivatives had a significant effect on bacteria. All prepared derivatives inhibited the AI-2 type of bacterial communication (quorum sensing) at concentrations below 10 µM. All prepared compounds also inhibited the adhesion of bacteria (Staphyloccocus aureus and Pseudomonas aeruginosa) to the surface, preventing biofilm formation. These two effects indicate that the halogenated derivatives are promising antibacterial agents. Moreover, these derivatives acted synergistically with antibiotics and reduced the viability of antibiotic-resistant S. aureus. Some flavonolignans were able to reverse the resistant phenotype to a sensitive one, implying that they modulate antibiotic resistance.
A Pleomorphic Puzzle: Heterogeneous Pulmonary Vascular Occlusions in Patients with COVID-19
Authors: Singh Jeeshan , Herrmann Irmgard , Mahajan Aparna , Schauer Christine , Shan Xiaomei , Hartmann Arndt , Rieker Ralf J. , Evert Katja , Falkeis Christina , Naschberger Elisabeth , von Stillfried Saskia , Boor Peter , Muñoz Luis E. , Schett Georg , Herrmann Martin , Knopf Jasmin
Published: December 2022

Vascular occlusions in patients with coronavirus diseases 2019 (COVID-19) have been frequently reported in severe outcomes mainly due to a dysregulation of neutrophils mediating neutrophil extracellular trap (NET) formation. Lung specimens from patients with COVID-19 have previously shown a dynamic morphology, categorized into three types of pleomorphic occurrence based on histological findings in this study. These vascular occlusions in lung specimens were also detected using native endogenous fluorescence or NEF in a label-free method. The three types of vascular occlusions exhibit morphology of DNA rich neutrophil elastase (NE) poor (type I), NE rich DNA poor (type II), and DNA and NE rich (type III) cohort of eleven patients with six males and five females. Age and gender have been presented in this study as influencing variables linking the occurrence of several occlusions with pleomorphic contents within a patient specimen and amongst them. This study reports the categorization of pleomorphic occlusions in patients with COVID-19 and the detection of these occlusions in a label-free method utilizing NEF.
Post-Translational Modification of ZEB Family Members in Cancer Progression
Authors: Park Mi Kyung , Lee Ho , Lee Chang Hoon
Published: December 2022

Post-translational modification (PTM), the essential regulatory mechanisms of proteins, play essential roles in physiological and pathological processes. In addition, PTM functions in tumour development and progression. Zinc finger E-box binding homeobox (ZEB) family homeodomain transcription factors, such as ZEB1 and ZEB2, play a pivotal role in tumour progression and metastasis by induction epithelial-mesenchymal transition (EMT), with activation of stem cell traits, immune evasion and epigenetic reprogramming. However, the relationship between ZEB family members’ post-translational modification (PTM) and tumourigenesis remains largely unknown. Therefore, we focussed on the PTM of ZEBs and potential therapeutic approaches in cancer progression. This review provides an overview of the diverse functions of ZEBs in cancer and the mechanisms and therapeutic implications that target ZEB family members’ PTMs.
Key Amino Acids for Transferase Activity of GDSL Lipases
Authors: Yamashiro Takanori , Shiraishi Akira , Nakayama Koji , Satake Honoo
Published: December 2022

The Gly-Asp-Ser-Leu (GDSL) motif of esterase/lipase family proteins (GELPs) generally exhibit esterase activity, whereas transferase activity is markedly preferred in several GELPs, including the Tanacetum cinerariifolium GDSL lipase TciGLIP, which is responsible for the biosynthesis of the natural insecticide, pyrethrin I. This transferase activity is due to the substrate affinity regulated by the protein structure and these features are expected to be conserved in transferase activity-exhibiting GELPs (tr-GELPs). In this study, we identified two amino acid residues, [N/R]208 and D484, in GELP sequence alignments as candidate key residues for the transferase activity of tr-GELPs by two-entropy analysis. Molecular phylogenetic analysis demonstrated that each tr-GELP is located in the clusters for non-tr-GELPs, and most GELPs conserve at least one of the two residues. These results suggest that the two conserved residues are required for the acquisition of transferase activity in the GELP family. Furthermore, substrate docking analyses using ColabFold-generated structure models of both natives and each of the two amino acids-mutated TciGLIPs also revealed numerous docking models for the proper access of substrates to the active site, indicating crucial roles of these residues of TciGLIP in its transferase activity. This is the first report on essential residues in tr-GELPs for the transferase activity.
Transcriptomic Analysis Revealed Antimicrobial Mechanisms of Lactobacillus rhamnosus SCB0119 against Escherichia coli and Staphylococcus aureus
Authors: Peng Huan , Zhou Gang , Yang Xi-Miao , Chen Guo-Jun , Chen Hai-Bin , Liao Zhen-Lin , Zhong Qing-Ping , Wang Li , Fang Xiang , Wang Jie
Published: December 2022

Lactic acid bacteria were reported as a promising alternative to antibiotics against pathogens. Among them, Lactobacillus rhamnosus could be used as probiotics and inhibit several pathogens, but its antibacterial mechanisms are still less known. Here, L. rhamnosus SCB0119 isolated from fermented pickles could inhibit bacterial growth or even cause cell death in Escherichia coli ATCC25922 and Staphylococcus aureus ATCC6538, which was mainly attributed to the cell-free culture supernatant (CFS). Moreover, CFS induced the accumulation of reactive oxygen species and destroyed the structure of the cell wall and membrane, including the deformation in cell shape and cell wall, the impairment of the integrity of the cell wall and inner membrane, and the increases in outer membrane permeability, the membrane potential, and pH gradient in E. coli and S. aureus. Furthermore, the transcriptomic analysis demonstrated that CFS altered the transcripts of several genes involved in fatty acid degradation, ion transport, and the biosynthesis of amino acids in E. coli, and fatty acid degradation, protein synthesis, DNA replication, and ATP hydrolysis in S. aureus, which are important for bacterial survival and growth. In conclusion, L. rhamnosus SCB0119 and its CFS could be used as a biocontrol agent against E. coli and S. aureus.
Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression
Authors: Zhou Julie Xia , Agborbesong Ewud , Li Linda Xiaoyan , Li Xiaogang
Published: December 2022

TP53 is the most common mutated gene in human cancer. Mutant p53 protein loses its tumor-suppressor properties and gains oncogenic activity. Mutant p53 is a therapeutic target in a broad range of cancer types. However, how mutant p53 is epigenetically regulated during tumor progression remains elusive. In this study, we found that the upregulation of mutant p53 is mediated by bromodomain protein BRD4 in triple-negative breast cancer (TNBC) cells. Inhibition of BRD4 with its inhibitor JQ1 or knockdown of BRD4 suppressed the transcription of mutant p53, which led to the re-expression of p21, the inhibition of S-phase entry, and colony formation in TNBC cells. BRD4 also positively regulated the transcription of wild-type p53, whereas JQ1 treatment and knockdown of BRD4 decreased the expression of p21 in MCF-7 cells. Knockdown of BRD4 resulted in attenuation of TNBC tumor growth in vivo. Taken together, our results uncover a novel regulatory mechanism of mutant p53 via BRD4, and suggest that the bromodomain inhibitor suppresses tumorigenesis through targeting mutant p53 in TNBC.
Red Cell Microparticles Suppress Hematoma Growth Following Intracerebral Hemorrhage in Chronic Nicotine-Exposed Rats
Authors: Rehni Ashish K. , Cho Sunjoo , Zhang Zhexuan , Khushal Priyanka , Raval Ami P. , Koch Sebastian , Perez-Pinzon Miguel A. , Zhao Weizhao , Jy Wenche , Dave Kunjan R.
Published: December 2022

Spontaneous intracerebral hemorrhage (sICH) is a disabling stroke sub-type, and tobacco use is a prominent risk factor for sICH. We showed that chronic nicotine exposure enhances bleeding post-sICH. Reduction of hematoma growth is a promising effective therapy for sICH in smoking subjects. Red-blood-cell-derived microparticles (RMPs) are hemostatic agents that limit hematoma expansion following sICH in naïve rats. Considering the importance of testing the efficacy of experimental drugs in animal models with a risk factor for a disease, we tested RMP efficacy and the therapeutic time window in limiting hematoma growth post-sICH in rats exposed to nicotine. Young rats were chronically treated with nicotine using osmotic pumps. sICH was induced in rats using an injection of collagenase in the right striatum. Vehicle/RMPs were administered intravenously. Hematoma volume and neurological impairment were quantified ≈24 h after sICH. Hematoma volumes in male and female nicotine-exposed rats that were treated with RMPs at 2 h post-sICH were significantly lower by 26 and 31% when compared to their respective control groups. RMP therapy was able to limit hematoma volume when administered up to 4.5 h post-sICH in animals of both sexes. Therefore, RMPs may limit hematoma growth in sICH patients exposed to tobacco use.
Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation
Authors: Picón-Pagès Pol , Fanlo-Ucar Hugo , Herrera-Fernández Víctor , Ausellé-Bosch Sira , Galera-López Lorena , Gutiérrez Daniela A. , Ozaita Andrés , Álvarez Alejandra R. , Oliva Baldomero , Muñoz Francisco J.
Published: December 2022

Alzheimer’s disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aβ) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aβ oligomers (oAβ) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAβ on CaMKIIα. We found that oAβ produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAβ.
Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy
Authors: Hillenaar Tamara , Beekman Jeffrey , van der Sluijs Peter , Braakman Ineke
Published: December 2022

Mutations in CFTR cause misfolding and decreased or absent ion-channel function, resulting in the disease Cystic Fibrosis. Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question ‘What characterizes the exceptions: the mutants that functionally respond either not or extremely well’. A functional response is the product of the number of CFTR molecules on the cell surface, open probability, and conductivity of the CFTR chloride channel. By combining biosynthetic radiolabeling with protease-susceptibility assays, we have followed CF-causing mutants during the early and late stages of folding in the presence and absence of modulators. Most CFTR mutants showed typical biochemical responses for each modulator, such as a TMD1 conformational change or an increase in (cell-surface) stability, regardless of a functional response. These modulators thus should still be considered for hypo-responder genotypes. Understanding both biochemical and functional phenotypes of outlier mutations will boost our insights into CFTR folding and misfolding, and lead to improved therapeutic strategies.
URVA and Local Mode Analysis of an Iridium Pincer Complex Efficiently Catalyzing the Hydrogenation of Carbon Dioxide
Authors: Freindorf Marek , Kraka Elfi
Published: December 2022

The catalytic effects of iridium pincer complexes for the hydrogenation of carbon dioxide were investigated with the Unified Reaction Valley Approach (URVA), exploring the reaction mechanism along the reaction path traced out by the reacting species on the potential energy surface. Further details were obtained with the Local Mode Analysis performed at all stationary points, complemented by the Natural Bond Orbital and Bader’s Quantum Atoms in Molecules analyses. Each of the five reaction paths forming the catalytic cycle were calculated at the DFT level complemented with DLPNO-CCSD(T) single point calculations at the stationary points. For comparison, the non-catalytic reaction was also investigated. URVA curvature profiles identified all important chemical events taking place in the non-catalyzed reaction and in the five reactions forming the catalytic cycle, and their contribution to the activation energy was disclosed. The non-catalytic reaction has a large unfavorable activation energy of 76.3 kcal/mol, predominately caused by HH bond cleave in the H2 reactant. As shown by our study, the main function of the iridium pincer catalyst is to split up the one–step non-catalytic reaction into an energy efficient multistep cycle, where HH bond cleavage is replaced by the cleavage of a weaker IrH bond with a small contribution to the activation energy. The dissociation of the final product from the catalyst requires the cleavage of an IrO bond, which is also weak, and contributes only to a minor extent to the activation energy. This, in summary, leads to the substantial lowering of the overall activation barrier by about 50 kcal/mol for the catalyzed reaction. We hope that this study inspires the community to add URVA to their repertoire for the investigation of catalysis reactions.
Back to the Middle Ages: Entomological and Botanical Elements Reveal New Aspects of the Burial of Saint Davino of Armenia
Authors: Loni Augusto , Vanin Stefano , Fornaciari Antonio , Tomei Paolo Emilio , Giuffra Valentina , Benelli Giovanni
Published: December 2022

The natural mummy of Saint Davino Armeno (11th century) is preserved in the church of Saint Michele in Foro in the city of Lucca (Tuscany, Central Italy). The body of Davino is one of the oldest Italian mummies of a Saint, and his paleopathological study was performed in 2018. In the present research, we investigated the arthropod fragments and botanical remains collected from the body, coffin, and fabrics of Saint Davino. Entomological analyses outlined the presence of 192 arthropod fragments. Among these, Diptera, Muscidae (Hydrotaea capensis and Muscina sp.), and Phoridae (Conicera sp.) puparia were the most abundant. Regarding Coleoptera, Ptinidae (Anobium punctatum) were the most frequent, followed by Cleridae (Necrobia sp.), Trogidae (Trox scaber), Curculionidae (Sitophilus granarius), and Histeridae (Gnathoncus). Cocoons of Tineidae and Pyralidae moths were found, along with a propodeum joined to the petiole and a mesopleuron of an Ichneumoninae parasitoid. Numerous metamera of Julida and three scorpion fragments were also found. Botanical samples indicated the presence of a quite broad botanical community, including gramineous species, olives, evergreen oaks, and grapevine. Overall, entomological data allow us to argue that Saint Davino was first buried into the soil, probably in a wooden coffin, thus supporting the historical-hagiographic tradition according to which he was buried sub divo in the cemetery of Saint Michele. The preservation of the body as a natural mummy may have been facilitated by burial in a coffin that prevented direct contact of the corpse with the earth. Botanical remains offer confirmation of a late medieval urban environment rich in horticultural areas and trees, giving us a landscape that is very different from the current Tuscan city.
American Sign Language Alphabet Recognition Using Inertial Motion Capture System with Deep Learning
Authors: Gu Yutong , Sherrine Sherrine , Wei Weiyi , Li Xinya , Yuan Jianan , Todoh Masahiro
Published: December 2022

Sign language is designed as a natural communication method for the deaf community to convey messages and connect with society. In American sign language, twenty-six special sign gestures from the alphabet are used for the fingerspelling of proper words. The purpose of this research is to classify the hand gestures in the alphabet and recognize a sequence of gestures in the fingerspelling using an inertial hand motion capture system. In this work, time and time-frequency domain features and angle-based features are extracted from the raw data for classification with convolutional neural network-based classifiers. In fingerspelling recognition, we explore two kinds of models: connectionist temporal classification and encoder-decoder structured sequence recognition model. The study reveals that the classification model achieves an average accuracy of 74.8% for dynamic ASL gestures considering user independence. Moreover, the proposed two sequence recognition models achieve 55.1%, 93.4% accuracy in word-level evaluation, and 86.5%, 97.9% in the letter-level evaluation of fingerspelling. The proposed method has the potential to recognize more hand gestures of sign language with highly reliable inertial data from the device.
Interventricular Septum Thickness for the Prediction of Coronary Heart Disease and Myocardial Infarction in Hypertension Population: A Prospective Study
Authors: Yang Yiqing , Li Zhao , Guo Xiaofan , Zhou Ying , Chang Ye , Yang Hongmei , Yu Shasha , Ouyang Nanxiang , Chen Shuang , Sun Guozhe , Hua Yu , Sun Yingxian
Published: December 2022

The aim of the present study was to evaluate the prognostic value of interventricular septum thickness (IVSd) on the incidence of cardiovascular diseases. Based on the general population in Northeast China, 10,349 participants were successfully followed up for echocardiography over a median follow-up time of 4.66 years, among which 4801 were hypertensive. Coronary heart disease (CHD) and myocardial infarction (MI) incidence were followed up. Cox proportional hazards models were used to estimate the association of the baseline IVSd with adverse outcomes. IVS hypertrophy increased incident rates of CHD and MI compared with normal IVSd in the overall population and in the female sex-stratification group. In males, IVS hypertrophy had parallel increase rates of CHD (all p < 0.05). Kaplan–Meier analysis showed that IVS hypertrophy could predict CHD and MI incidence and CHD-free and MI-free survival. Multivariable Cox analysis revealed that IVS hypertrophy was correlated with CHD incidence (HR = 1.155, 95% CI = 1.155–2.861, p = 0.01) and MI incidence (HR = 2.410, 95% CI = 1.303–4.458, p = 0.005). In women, IVS hypertrophy was independently associated with CHD and MI incidence (all p < 0.05). Our prospective cohort study illustrated that IVS hypertrophy detected by echocardiography has a prognostic significance for CHD and MI. Therefore, the early detection of IVSd should be conducted to avoid adverse outcomes in further clinical practice.
The Triglyceride-Glucose Index Is Associated with Longitudinal Cognitive Decline in a Middle-Aged to Elderly Population: A Cohort Study
Authors: Li Siqi , Deng Xuan , Zhang Yumei
Published: December 2022

Background: To examine the effect of the triglyceride-glucose (TyG) index on longitudinal cognitive decline in a healthy middle-aged-to-elderly population. Methods: We conducted a population-based longitudinal study. A total of 1774 participants without cognitive impairment were enrolled in the 4-year follow-up. They were divided into four groups according to the quartile of the TyG index. Multivariable-adjusted Cox proportional hazard models were performed to examine the association between the TyG index and cognitive decline. Discrimination tests were used to evaluate the incremental predictive value of the TyG index beyond conventional risk factors. Results: During the follow-up, compared with those in the bottom quartile group, participants in the top TyG quartile group presented a 51% increase in the risk of cognitive decline (OR 1.51 (95% CI: 1.06–2.14)). As shown by discrimination tests, adding the TyG index into the conventional model resulted in a slight improvement in predicting the risk of cognitive decline (NRI 16.00% (p = 0.004)). Conclusion: This study demonstrated that increasing values of the TyG index were positively associated with the risk of cognitive decline. Monitoring the TyG index may help in the early identification of individuals at high risk of cognitive deterioration.
The Plasma DIA-Based Quantitative Proteomics Reveals the Pathogenic Pathways and New Biomarkers in Cervical Cancer and High Grade Squamous Intraepithelial Lesion
Authors: Han Sai , Zhang Junhua , Sun Yu , Liu Lu , Guo Lingyu , Zhao Chunru , Zhang Jiaxin , Qian Qiuhong , Cui Baoxia , Zhang Youzhong
Published: December 2022

Objective: The process of normal cervix changing into high grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer is long and the mechanisms are still not completely clear. This study aimed to reveal the protein profiles related to HSIL and cervical cancer and find the diagnostic and prognostic molecular changes. Methods: Data-independent acquisition (DIA) analysis was performed to identify 20 healthy female volunteers, 20 HSIL and 20 cervical patients in a cohort to screen differentially expressed proteins (DEPs) for the HSIL and cervical cancer. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional annotation of DEPs; the protein–protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) were performed for detection of key molecular modules and hub proteins. They were validated using the Enzyme-Linked Immunosorbent Assay (ELISA). Results: A total of 243 DEPs were identified in the study groups. GO and KEGG analysis showed that DEPs were mainly enriched in the complement and coagulation pathway, cholesterol metabolism pathway, the IL-17 signaling pathway as well as the viral protein interaction with cytokine and cytokine receptor pathway. Subsequently, the WGCNA analysis showed that the green module was highly correlated with the cervical cancer stage. Additionally, six interesting core DEPs were verified by ELISA, APOF and ORM1, showing nearly the same expression pattern with DIA. The area under the curve (AUC) of 0.978 was obtained by using ORM1 combined with APOF to predict CK and HSIL+CC, and in the diagnosis of HSIL and CC, the AUC can reach to 0.982. The high expression of ORM1 is related to lymph node metastasis and the clinical stage of cervical cancer patients as well as the poor prognosis. Conclusion: DIA-ELSIA combined analysis screened and validated two previously unexplored but potentially useful biomarkers for early diagnosis of HSIL and cervical cancer, as well as possible new pathogenic pathways and therapeutic targets.
A Comparison among Nonvitamin K Antagonist Oral Anticoagulants in Asian Patients with Venous Thromboembolism: A Multi-Institutional Study
Authors: Tsai Ming-Lung , Lee Cheng-Hung , Hsieh Ming-Jer , Chen Shao-Wei , Chang Shang-Hung , Tseng Chi-Nan , Chu Pao-Hsien , Hsieh I-Chang , Ko Po-Chuan , Huang Yu-Tung , Chen Dong-Yi
Published: December 2022

The comparison of clinical effectiveness and safety across different nonvitamin K antagonist direct oral anticoagulants (DOACs) in Asian patients with venous thromboembolism (VTE) remains unclear. Therefore, we assessed the real-world benefits of different DOACs in these patients. A cohort of 1480 patients with VTE were identified from the Chang Gung Research Database between 1 January 2012, and 31 December 2019. The composite outcomes of recurrent VTE and major bleeding were evaluated for four DOACs. The composite outcomes of recurrent VTE and major bleeding occurred in 9.06%, 9.80%, 8.61%, and 10.86% of the apixaban, dabigatran, edoxaban, and rivaroxaban groups, respectively, within 12 months of treatment initiation. The risk of the composite outcomes was similar in the rivaroxaban group and the apixaban, dabigatran, and edoxaban groups, with a subdistribution hazard ratio (SHR) of 0.80 (95% CI, 0.49–1.29), 0.81 (95% CI, 0.34–1.95), and 0.76 (95% CI, 0.42–1.39), respectively. No significant differences in the rates of recurrent VTE or major bleeding were observed between the rivaroxaban and other DOAC groups at the 12-month follow-up. According to real-world practice in Asian patients with VTE, the DOAC type was not associated with the differences in the risk of recurrent VTE or major bleeding within 12 months of treatment initiation.
Differences in Pulmonary Function Improvement after Once-Daily LABA/LAMA Fixed-Dose Combinations in Patients with COPD
Authors: Huang Wei-Chun , Chen Chih-Yu , Liao Wei-Chih , Wu Biing-Ru , Chen Wei-Chun , Tu Chih-Yen , Chen Chia-Hung , Cheng Wen-Chien
Published: December 2022

This real-world study evaluated the efficacy of once-daily long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for improving lung function in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD who were treated with once-daily LABA/LAMA FDCs for 12 months were included. We evaluated their lung function improvement after 12 months of treatment with different LABA/LAMA FDCs. A total of 198 patients with COPD who were treated with once-daily LABA/LAMA FDCs were analyzed. A total of 114 patients were treated with umeclidinium/vilanterol (UMEC/VIL); 34 patients were treated with indacaterol/glycopyrronium (IND/GLY); and 50 patients were treated with tiotropium/olodaterol (TIO/OLO). The forced expiratory volume in 1 s (FEV1) was significantly increased in the patients treated with all three once-daily FDCs (55.2% to 60.9%, p = 0.012 for UMEC/VIL, 58.2% to 63.6%, p = 0.023 for IND/GLY, and 54.1% to 57.7%, p = 0.009 for TIO/OLO). The treatment of COPD patients with TIO/OLO resulted in a significant improvement in both forced vital capacity (FVC%) (71.7% to 77.9%, p = 0.009) and residual volume (RV%) (180.1% to 152.5%, p < 0.01) compared with those treated with UMEC/VIL (FVC%: 75.1% to 81.5%, p < 0.001; RV%:173.8% to 165.2%, p = 0.231) or IND/GLY (FVC%: 73.9% to 79.3%, p = 0.08; RV%:176.8% to 168.3%, p = 0.589). Patients treated with UMEC/VIL or TIO/OLO showed significant improvement in FVC. In addition, those receiving TIO/OLO also showed significant improvement in RV reduction.
Measuring the Quality of Life in Patients with Chronic Venous Disease before and Short Term after Surgical Treatment—A Comparison between Different Open Surgical Procedures
Authors: Matei Sergiu-Ciprian , Dumitru Cristina Ștefania , Radu Daniela
Published: December 2022

Chronic venous disease (CVD) is a common pathology that significantly affects the quality of life (QoL) of patients. Methods: QoL was assessed in 317 patients diagnosed with CVD who underwent surgeries, including cryostripping (n = 113), high ligation and stripping (HL&S, n = 96), and phlebectomies (n = 108). CVD symptoms and QoL were assessed before surgery and 2 weeks after surgery using the following questionnaires: CIVIQ-20, VAS, Eq-5D, PHQ-9 and GAD-9. Results. The results reveal a significant correlation (p < 0.05) between CEAP score and QoL questionnaires performed preoperatively and postoperatively in all three surgical technique groups, with a statistical improvement postoperatively. Phlebectomy had the best postoperative QoL score (r = 0.495) compared to the other two types of procedures. Conclusions: Analyzing patients’ subjective perception following conventional surgery for CVD treatment, an improved QoL is observed both in functional and psychosocial aspects, even early postoperatively. Classical surgical procedures remain an effective and feasible option in CVD treatment.