bluuebunny/crossref_metadata_2025 huggingface dataset:
A Narrative Inquiry into the Practices of Healthcare Workers’ Wellness Program: The SEED Experience in New South Wales, Australia
Authors: Olcoń Katarzyna , Allan Julaine , Fox Mim , Everingham Ruth , Pai Padmini , Keevers Lynne , Mackay Maria , Degeling Chris , Cutmore Sue-Anne , Finlay Summer , Falzon Kristine
Published: October 2022

The 2019–2020 Australian bushfires followed by the COVID-19 pandemic brought the significant mental health implications of working in healthcare to the fore. The importance of appropriate support services to ensure the resilience and recovery of healthcare workers has been highlighted. In response to healthcare staff experiences during the bushfires, the SEED Wellness Program was created in 2020 in the Illawarra Shoalhaven Local Health District in New South Wales, Australia. SEED used a participant-led design to engage healthcare staff in workplace-based restorative activities. Guided by practice theory, this study aimed to identify and describe SEED wellness practices that supported healthcare staff. Thirty-three healthcare workers participated in focus groups or individual interviews between June 2021 and March 2022. The analysis involved inductive thematic individual and collective exploration of SEED practices, including co-analysis with participants. Eight core practices that supported participants’ wellbeing were identified, including responsive and compassionate leading, engaging staff at every stage of the recovery process, creating a sense of connection with others, and collective caring. The study found that workplace wellness initiatives are optimised when they are place-based and grounded in local knowledge, needs, and resources incorporating a collective and supportive team approach. Moreover, to ensure engagement in, and sustainability of these initiatives, both bottom-up and top-down commitment is required.
When Lights Can Breathe: Investigating the Influences of Breathing Lights on Users’ Emotion
Authors: Wang Junfeng , Lu Jingjing , Xu Zhiyu , Wang Xi
Published: October 2022

Light can significantly influence users’ physiological and behavioural performance. However, how light breathing influences users’ mood regulation remains unknown. To fill this gap, this study conducted a 2-by-2 experiment (N = 20) with light breathing as the between-subject factor and light condition as the within-subject factor. Both physiological indicators and subjective indicators are measured to reflect mood regulation. The data were analysed using a generalised linear mixed model. The results showed that breathing lights are effective in regulating users’ moods. More specifically, breathing lights help users lower their electrodermal values and heart rates. Users did not report any significant difference in terms of subjective measures, which suggest that the influence of a breathing light happens unconsciously. Furthermore, this effect is significant for both cold and warm colour temperatures. Designers and engineers can use the research findings to manage user emotion when necessary.
The Effect of Healthy Lifestyle Changes on Work Ability and Mental Health Symptoms: A Randomized Controlled Trial
Authors: Shiri Rahman , Väänänen Ari , Mattila-Holappa Pauliina , Kauppi Krista , Borg Patrik
Published: October 2022

Objective: The effects of lifestyle interventions on the prevention of a decline in work ability and mental health are not well known. The aim of this randomized controlled trial was to examine the effects of healthy lifestyle changes on work ability, sleep, and mental health. Methods: Workers aged 18–65 years, who were free from cardiovascular diseases, diabetes, and malignant diseases, and did not use medication for obesity or lipids were included (N = 319). Based on their cholesterol balance, participants were classified into medium-risk and high-risk groups and were randomized into four arms: group lifestyle coaching (N = 107), individual lifestyle coaching (N = 53), the control group for group coaching (N = 106), and the control group for individual coaching (N = 53). The intervention groups received eight sessions of mostly remote coaching for 8 weeks about healthy diet, physical activity, other lifestyle habits, and sources/management of stress and sleep problems, and the control groups received no intervention. In individual coaching, the coach focused more on individual problem solving and the possibilities for motivation and change. The intention-to-treat principle was applied, and missing data on the outcomes were imputed using multiple imputation. Results: After the completion of the intervention, the risk of depressive symptoms was lower by 53% (95% CI 1–77%) in participants who received individual lifestyle coaching compared with the control group. The intervention had no beneficial effects on anxiety, work ability, sleep duration, or daily stress. In subgroup analyses, group lifestyle coaching had beneficial effects on depressive symptoms and work ability in participants with less tight schedules or less stretching work, whereas individual lifestyle coaching lowered the risk of depressive symptoms in those with fewer overlapping jobs, less tight schedules, or less stretching work. Conclusion: Short but intensive remote lifestyle coaching can reduce depressive symptoms and improve work ability, and time-related resources at work may improve mental health in the context of individual lifestyle intervention. However, further randomized controlled trials are needed to confirm the findings.
Profiling Substrate Specificity of the SUMO Protease Ulp1 by the YESS–PSSC System to Advance the Conserved Mechanism for Substrate Cleavage
Authors: Zhang Faying , Zheng Hui , Xian Yufan , Song Haoyue , Wang Shengchen , Yun Yueli , Yi Li , Zhang Guimin
Published: October 2022

SUMO modification is a vital post-translational regulation process in eukaryotes, in which the SUMO protease is responsible for the maturation of the SUMO precursor and the deconjugation of the SUMO protein from modified proteins by accurately cleaving behind the C-terminal Gly–Gly motif. To promote the understanding of the high specificity of the SUMO protease against the SUMO protein as well as to clarify whether the conserved Gly–Gly motif is strictly required for the processing of the SUMO precursor, we systematically profiled the specificity of the S. cerevisiae SUMO protease (Ulp1) on Smt3 at the P2–P1↓P1’ (Gly–Gly↓Ala) position using the YESS–PSSC system. Our results demonstrated that Ulp1 was able to cleave Gly–Gly↓ motif-mutated substrates, indicating that the diglycine motif is not strictly required for Ulp1 cleavage. A structural-modeling analysis indicated that it is the special tapered active pocket of Ulp1 conferred the selectivity of small residues at the P1–P2 position of Smt3, such as Gly, Ala, Ser and Cys, and only which can smoothly deliver the scissile bond into the active site for cleavage. Meanwhile, the P1’ position Ala of Smt3 was found to play a vital role in maintaining Ulp1’s precise cleavage after the Gly–Gly motif and replacing Ala with Gly in this position could expand Ulp1 inclusivity against the P1 and P2 position residues of Smt3. All in all, our studies advanced the traditional knowledge of the SUMO protein, which may provide potential directions for the drug discovery of abnormal SUMOylation-related diseases.
PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease
Authors: Papotti Bianca , Adorni Maria Pia , Marchi Cinzia , Zimetti Francesca , Ronda Nicoletta , Panighel Giovanni , Lupo Maria Giovanna , Vilella Antonietta , Giuliani Daniela , Ferri Nicola , Bernini Franco
Published: October 2022

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer’s disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD.
Does Intrauterine Injection of hCG Improve IVF Outcome? A Systematic Review and a Meta-Analysis
Authors: Conforti Alessandro , Longobardi Salvatore , Carbone Luigi , Iorio Giuseppe Gabriele , Cariati Federica , Campitiello Maria Rosaria , Strina Ida , Palese Michela , D’Hooghe Thomas , Alviggi Carlo
Published: October 2022

Various interventions have been proposed to improve embryo implantation in IVF. Among these, intrauterine injections of human chorionic gonadotropin seem to have promising results. Consequently, we conducted a review and meta-analysis to assess IVF outcomes by comparing couples who underwent intrauterine hCG injection transfer versus those who underwent embryo transfer with intrauterine injection of placebo, or without any additional intervention. The primary outcome was the clinical pregnancy rate. Secondary outcomes were the implantation rate, miscarriage rate, and live birth rate. A meta-analysis was conducted using the random effects model, while bias within studies was detected using the Cochrane risk of bias tool. Ectopic pregnancies and stillbirths were also assessed. The clinical pregnancy (RR 1.38, 95% CI 1.17–1.62, p < 0.0001) and implantation rate (RR 1.40, 95% CI 1.12–1.75, p = 0.003) were significantly higher in women who underwent hCG injection than in the control group. These significant effects persisted only in women who underwent cleavage-stage embryo transfer. No significant differences between groups were observed in the other secondary outcomes. In conclusion, our systematic review and meta-analysis demonstrate that intrauterine injection of hCG could be a valuable approach in women who undergo cleavage-stage embryo transfer. Given the lack of data about the live birth rate, caution should be exercised in interpreting these data.
Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
Authors: Stahl Stephen M. , De Martin Sara , Mattarei Andrea , Bettini Ezio , Pani Luca , Guidetti Clotilde , Folli Franco , de Somer Marc , Traversa Sergio , Inturrisi Charles E. , Pappagallo Marco , Gentilucci Marco , Alimonti Andrea , Fava Maurizio , Manfredi Paolo L.
Published: October 2022

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.
The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms
Authors: Butnariu Lăcrămioara Ionela , Gorduza Eusebiu Vlad , Florea Laura , Țarcă Elena , Moisă Ștefana Maria , Trandafir Laura Mihaela , Stoleriu Simona , Bădescu Minerva Codruța , Luca Alina-Costina , Popa Setalia , Radu Iulian , Cojocaru Elena
Published: October 2022

Vascular anomalies (VAs) are morphogenesis defects of the vascular system (arteries, capillaries, veins, lymphatic vessels) singularly or in complex combinations, sometimes with a severe impact on the quality of life. The progress made in recent years with the identification of the key molecular pathways (PI3K/AKT/mTOR and RAS/BRAF/MAPK/ERK) and the gene mutations that lead to the appearance of VAs has allowed the deciphering of their complex genetic architecture. Understanding these mechanisms is critical both for the correct definition of the phenotype and classification of VAs, as well as for the initiation of an optimal therapy and the development of new targeted therapies. The purpose of this review is to present in synthesis the current data related to the genetic factors involved in the etiology of VAs, as well as the possible directions for future research. We analyzed the data from the literature related to VAs, using databases (Google Scholar, PubMed, MEDLINE, OMIM, MedGen, Orphanet) and ClinicalTrials.gov. The obtained results revealed that the phenotypic variability of VAs is correlated with genetic heterogeneity. The identification of new genetic factors and the molecular mechanisms in which they intervene, will allow the development of modern therapies that act targeted as a personalized therapy. We emphasize the importance of the geneticist in the diagnosis and treatment of VAs, as part of a multidisciplinary team involved in the management of VAs.
Impact of Exosomes Released by Different Corneal Cell Types on the Wound Healing Properties of Human Corneal Epithelial Cells
Authors: Desjardins Pascale , Berthiaume Rébecca , Couture Camille , Le-Bel Gaëtan , Roy Vincent , Gros-Louis François , Moulin Véronique J. , Proulx Stéphanie , Chemtob Sylvain , Germain Lucie , Guérin Sylvain L.
Published: October 2022

Corneal wound healing involves communication between the different cell types that constitute the three cellular layers of the cornea (epithelium, stroma and endothelium), a process ensured in part by a category of extracellular vesicles called exosomes. In the present study, we isolated exosomes released by primary cultured human corneal epithelial cells (hCECs), corneal fibroblasts (hCFs) and corneal endothelial cells (hCEnCs) and determined whether they have wound healing characteristics of their own and to which point they modify the genetic and proteomic pattern of these cell types. Exosomes released by all three cell types significantly accelerated wound closure of scratch-wounded hCECs in vitro compared to controls (without exosomes). Profiling of activated kinases revealed that exosomes from human corneal cells caused the activation of signal transduction mediators that belong to the HSP27, STAT, β-catenin, GSK-3β and p38 pathways. Most of all, data from gene profiling analyses indicated that exosomes, irrespective of their cellular origin, alter a restricted subset of genes that are completely different between each targeted cell type (hCECs, hCFS, hCEnCs). Analysis of the genes specifically differentially regulated for a given cell-type in the microarray data using the Ingenuity Pathway Analysis (IPA) software revealed that the mean gene expression profile of hCECs cultured in the presence of exosomes would likely promote cell proliferation and migration whereas it would reduce differentiation when compared to control cells. Collectively, our findings represent a conceptual advance in understanding the mechanisms of corneal wound repair that may ultimately open new avenues for the development of novel therapeutic approaches to improve closure of corneal wounds.
Hydrogen Sulfide and Its Donors: Keys to Unlock the Chains of Nonalcoholic Fatty Liver Disease
Authors: Li Xianghui , Jiang Kaixin , Ruan Yantian , Zhao Siyuan , Zhao Yiming , He Yuhua , Wang Zhili , Wei Jiacun , Li Qiming , Yang Changyong , Li Yanzhang , Teng Tieshan
Published: October 2022

Hydrogen sulfide (H2S) has emerged as the third “gasotransmitters” and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced.
Osteoclast-Driven Osteogenesis, Bone Remodeling and Biomaterial Resorption: A New Profile of BMP2-CPC-Induced Alveolar Bone Regeneration
Authors: Shen Hongzhou , Zhuang Yu , Zhang Chenglong , Zhang Changru , Yuan Yuan , Yu Hongbo , Si Jiawen , Shen Guofang
Published: October 2022

This bedside-to-bench study aimed to systematically investigate the value of applying BMP2-loaded calcium phosphate cement (BMP2-CPC) in the restoration of large-scale alveolar bone defects. Compared to deproteinized bovine bone (DBB), BMP2-CPC was shown to be capable of inducing a favorable pattern of bone regeneration and bone remodeling accompanied by active osteoclastogenesis and optimized biomaterial resorption when applied in reconstructive periodontally accelerated osteogenic orthodontics (PAOO) surgery. To verify the regulatory role of osteoclasts in the BMP2-CPC-induced pattern of bone regeneration, in vitro and in vivo studies were designed to elucidate the underlying mechanism. Our results revealed that osteoclasts played a multifaceted role (facilitating osteogenesis, bone remodeling and biomaterial resorption) in the BMP2-CPC-induced bone regeneration. Osteoclasts contributed to the osteogenic differentiation of mesenchymal stem cells (MSCs) by secreting calcium ions, CTHRC1 and PDGF-B. Moreover, the increased osteoclasts promoted the remodeling of new bone and BMP2-CPC resorption, leading to a harmonized replacement of biomaterials with mature bone. In conclusion, the in vitro and in vivo experimental results corresponded with the clinical results and showed the optimized properties of BMP2-CPC in activating osteoclast-driven bone regeneration and remodeling, thus indicating the highly promising prospects of BMP2-CPC as an ideal therapeutic for alveolar bone defects.
Prospects of Testing Diurnal Profiles of Expressions of TSH-R and Circadian Clock Genes in Thyrocytes for Identification of Preoperative Biomarkers for Thyroid Carcinoma
Authors: Putilov Arcady
Published: October 2022

Thyroid Nodules (TN) are frequent but mostly benign, and postoperative rate of benign TN attains the values from 70% to 90%. Therefore, there is an urgent need for identification of reliable preoperative diagnosis markers for patients with indeterminate thyroid cytology. In this study, an earlier unexplored design of research on preoperative biomarkers for thyroid malignancies was proposed. Evaluation of reported results of studies addressing the links of thyroid cancer to the circadian clockwork dysfunctions and abnormal activities of Thyroid-Stimulating Hormone (TSH) and its receptor (TSH-R) suggested diagnostic significance of such links. However, there is still a gap in studies of interrelationships between diurnal profiles of expression of circadian clock genes and TSH-R in indeterminate thyroid tissue exposed to different concentrations of TSH. These interrelationships might be investigated in future in vitro experiments on benign and malignant thyrocytes cultivated under normal and challenged TSH levels. Their design requires simultaneous measurement of diurnal profiles of expression of both circadian clock genes and TSH-R. Experimental results might help to bridge previous studies of preoperative biomarkers for thyroid carcinoma exploring diagnostic value of diurnal profiles of serum TSH levels, expression of TSH-R, and expression of circadian clock genes.
Culturomics to Investigate the Endometrial Microbiome: Proof-of-Concept
Authors: Vanstokstraeten Robin , Mackens Shari , Callewaert Ellen , Blotwijk Susanne , Emmerechts Kristof , Crombé Florence , Soetens Oriane , Wybo Ingrid , Vandoorslaer Kristof , Mostert Laurence , De Geyter Deborah , Muyldermans Astrid , Blockeel Christophe , Piérard Denis , Demuyser Thomas
Published: October 2022

The microbiome of the reproductive tract has been associated with (sub)fertility and it has been suggested that dysbiosis reduces success rates and pregnancy outcomes. The endometrial microbiome is of particular interest given the potential impact on the embryo implantation. To date, all endometrial microbiome studies have applied a metagenomics approach. A sequencing-based technique, however, has its limitations, more specifically in adequately exploring low-biomass settings, such as intra-uterine/endometrial samples. In this proof-of-concept study, we demonstrate the applicability of culturomics, a high-throughput culturing approach, to investigate the endometrial microbiome. Ten subfertile women undergoing diagnostic hysteroscopy and endometrial biopsy, as part of their routine work-up at Brussels IVF, were included after their informed consent. Biopsies were used to culture microbiota for up to 30 days in multiple aerobic and anaerobic conditions. Subsequent WASPLab®-assisted culturomics enabled a standardized methodology. Matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI-TOF MS) or 16S rRNA sequencing was applied to identify all of bacterial and fungal isolates. Eighty-three bacterial and two fungal species were identified. The detected species were in concordance with previously published metagenomics-based endometrial microbiota analyses as 77 (91%) of them belonged to previously described genera. Nevertheless, highlighting the added value of culturomics to identify most isolates at the species level, 53 (62.4%) of the identified species were described in the endometrial microbiota for the first time. This study shows the applicability and added value of WASPLab®-assisted culturomics to investigate the low biomass endometrial microbiome at a species level.
Cell Junction and Vesicle Trafficking-Mediated Melanosome/Melanin Transfer Are Involved in the Dynamic Transformation of Goldfish Carassius auratus Skin Color
Authors: Liu Lili , Wang Xiaowen , Zhang Rong , Li Huijuan , Zhu Hua
Published: October 2022

Goldfish are one of the most popular models for studying the genetic diversity of skin color. Transcriptome sequencing (RNA-seq) and whole genome bisulfate sequencing (WGBS) of skin tissues from the third filial (F3) cyan (CN), black (BK), and white (WH) goldfish were conducted to analyze the molecular mechanism of color transformation in fish. The RNA-seq yielded 56 Gb of clean data and 56,627 transcripts from nine skin samples. The DEGs (differentially expressed genes) were enriched in cell junction cellular components and the tight junction pathway. Ninety-five homologs of the claudin family were predicted and 16 claudins were identified in correlation with skin color transformation. WGBS yielded 1079 Gb of clean data from 15 samples. Both the DEGs and the DMRs (differentially methylated regions) in the BK_CN group were found to be enriched in cytoskeleton reorganization and vesicle trafficking. Masson staining and TEM (transmission electron microscopy) confirmed the varied distribution and processes of melanosome/melanin in skin tissues. Our results suggested that cytoskeleton reorganization, cell junction, and the vesicle trafficking system played key roles in the transfer of the melanosome/melanin, and it was the extracellular translocation rather than the biosynthesis or metabolism of the melanin process that resulted in the color transformation of cyan goldfish. The data will facilitate the understanding of the molecular mechanisms underlying dynamic skin color transformation in goldfish.
Androgen-Responsive Oncogenic lncRNA RP11-1023L17.1 Enhances c-Myc Protein Stability in Prostate Cancer
Authors: Huang Wenhua , Chen Qin , Lu Yali , Kong Zhe , Wan Xuechao , Huang Yan , Qiu Minyan , Li Yao
Published: October 2022

Long noncoding RNAs (lncRNAs) have been found as novel participants in the pathophysiology of prostate cancer (PCa), which is predominantly regulated by androgen and its receptor. The biological function of androgen-responsive lncRNAs remains poorly understood. Here, we identified that lncRNA RP11-1023L17.1, which is highly expressed in PCa. RP11-1023L17.1 expression, can be directly repressed by the androgen receptor in PCa cells. RP11-1023L17.1 depletion inhibited the proliferation, migration, and cell cycle progression, and promoted the apoptosis of PCa cells, indicating that RP11-1023L17.1 acts as an oncogene in PCa cells. Microarray results revealed that RP11-1023L17.1 depletion downregulated the c-Myc transcription signature in PCa cells. RP11-1023L17.1 depletion-induced cellular phenotypes can be overcome by ectopically overexpressed c-Myc. Mechanistically, RP11-1023L17.1 represses FBXO32 mRNA expression, thereby enhancing c-Myc protein stability by blocking FBXO32-mediated c-Myc degradation. Our findings reveal the previously unrecognized roles of RP11-1023L17.1 in c-Myc-dependent PCa tumorigenesis.
Blockade of Platelet CysLT1R Receptor with Zafirlukast Counteracts Platelet Protumoral Action and Prevents Breast Cancer Metastasis to Bone and Lung
Authors: Saier Lou , Ribeiro Johnny , Daunizeau Thomas , Houssin Audrey , Ichim Gabriel , Barette Caroline , Bouazza Lamia , Peyruchaud Olivier
Published: October 2022

Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell–platelet interactions via platelet–CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis.
Biological Activity of Different Forms of Oxidized Parathyroid Hormone
Authors: Hasan Ahmed A. , Hocher Carl-Friedrich , Kleuser Burkhard , Krämer Bernhard K. , Hocher Berthold
Published: October 2022

Preclinical studies have shown that parathyroid hormone (PTH) loses its biological effects through oxidation. PTH can be oxidized at methionines 8 and 18. Three possible variations of oxidized PTH (oxPTH) exist: Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH. A recent study showed that Met18(ox)PTH retained biological activity and was able to upregulate Fgf23 gene expression, whereas Met8(ox)PTH and Met8, Met18(di-ox)PTH showed less or no biological activity. An earlier study likewise showed that the oxidation of Met18 has minor effects on the secondary structure of PTH, whereas the oxidation of Met8 causes substantial structural changes, consistent with another study showing that oxidization just at Met8 blocks the generation of the second messenger cAMP, whereas the effect of the oxidation of Met18 is much less potent in inhibiting cAMP formation. A considerable percentage of circulating PTH in chronic kidney disease (CKD) patients is oxidized. However, we do not know the relative amounts of the different forms of oxPTH with agonistic, partial agonistic, or even antagonistic biological actions in different CKD populations. This might explain different clinical findings in the different CKD populations analyzed so far. The currently available method that was used in these clinical studies just distinguishes between oxPTH and noxPTH without being able to differentiate between different forms of oxPTH. Only methods of PTH measurement that are able to differentiate between PTH forms (noxPTH, Met8(ox)PTH, Met18(ox)PTH, and Met8, Met18(di-ox)PTH) have the potential to improve patient care, because only these methods will definitively separate bioactive from non-bioactive PTH forms. Such methods need to be developed, validated, and used in prospective randomized clinical trials to define the potential value of bioactive PTH forms as a predictor of cardiovascular events, mortality, and bone turnover.
Comparative Analysis of Antibody Titers against the Spike Protein of SARS-CoV-2 Variants in Infected Patient Cohorts and Diverse Vaccination Regimes
Authors: Odainic Alexandru , Spitzer Jasper , Szlapa Jennifer Barbara , Schade Simon , Krämer Tim Jonas , Neuberger Jakob , Bode Christian , Steinhagen Folkert , Schmithausen Ricarda Maria , Wilbring Gero , Sib Esther , Mutters Nico Tom , Rabenschlag Frederik , Kettel Lisa , Woznitza Maike , van Bremen Kathrin , Peers Tina , Medinger Gez , Kudaliyanage Anushka , Kreutzenbeck Maike , Strube Ulrike , Johnson Joseph M. , Mattoon Dawn , Ball Andrew J. , Scory Stefan , McGuire Richard , Putensen Christian , Abdullah Zeinab , Latz Catharina , Schmidt Susanne Viktoria
Published: October 2022

The presence of neutralizing antibodies against SARS-CoV-2 correlates with protection against infection and severe COVID-19 disease courses. Understanding the dynamics of antibody development against the SARS-CoV-2 virus is important for recommendations on vaccination strategies and on control of the COVID-19 pandemic. This study investigates the dynamics and extent of α-Spike-Ab development by different vaccines manufactured by Johnson & Johnson, AstraZeneca, Pfizer-BioNTech and Moderna. On day 1 after vaccination, we observed a temporal low-grade inflammatory response. α-Spike-Ab titers were reduced after six months of vaccination with mRNA vaccines and increased 14 days after booster vaccinations to a maximum that exceeded titers from mild and critical COVID-19 and Long-COVID patients. Within the group of critical COVID-19 patients, we observed a trend for lower α-Spike-Ab titers in the group of patients who survived COVID-19. This trend accompanied higher numbers of pro-B cells, fewer mature B cells and a higher frequency of T follicular helper cells. Finally, we present data demonstrating that past infection with mild COVID-19 does not lead to long-term increased Ab titers and that even the group of previously infected SARS-CoV-2 patients benefit from a vaccination six months after the infection.
Lipofuscin-Mediated Photic Stress Induces a Dark Toxic Effect on ARPE-19 Cells
Authors: Feldman Tatiana , Ostrovskiy Dmitriy , Yakovleva Marina , Dontsov Alexander , Borzenok Sergey , Ostrovsky Mikhail
Published: October 2022

Lipofuscin granules from retinal pigment epithelium (RPE) cells contain bisretinoid fluorophores, which are photosensitizers and are phototoxic to cells. In the presence of oxygen, bisretinoids are oxidized to form various products, containing aldehydes and ketones, which are also potentially cytotoxic. In a prior study, we identified that bisretinoid oxidation and degradation products have both hydrophilic and amphiphilic properties, allowing their diffusion through the lipofuscin granule membrane into the RPE cell cytoplasm, and are thiobarbituric acid (TBA)-active. The purpose of the present study was to determine if these products exhibit a toxic effect to the RPE cell also in the absence of light. The experiments were performed using the lipofuscin-fed ARPE-19 cell culture. The RPE cell viability analysis was performed with the use of flow cytofluorimetry and laser scanning confocal microscopy. The results obtained indicated that the cell viability of the lipofuscin-fed ARPE-19 sample was clearly reduced not immediately after visible light irradiation for 18 h, but after 4 days maintaining in the dark. Consequently, we could conclude that bisretinoid oxidation products have a damaging effect on the RPE cell in the dark and can be considered as an aggravating factor in age-related macular degeneration progression.
The Impacts of Cholesterol, Oxysterols, and Cholesterol Lowering Dietary Compounds on the Immune System
Authors: Yanagisawa Rintaro , He Chaoqi , Asai Akira , Hellwig Michael , Henle Thomas , Toda Masako
Published: October 2022

Cholesterol and its oxidized forms, oxysterols, are ingested from foods and are synthesized de novo. Cholesterol and oxysterols influence molecular and cellular events and subsequent biological responses of immune cells. The amount of dietary cholesterol influence on the levels of LDL cholesterol and blood oxysterols plays a significant role in the induction of pro-inflammatory state in immune cells, leading to inflammatory disorders, including cardiovascular disease. Cholesterol and oxysterols synthesized de novo in immune cells and stroma cells are involved in immune homeostasis, which may also be influenced by an excess intake of dietary cholesterol. Dietary compounds such as β-glucan, plant sterols/stanols, omega-3 lipids, polyphenols, and soy proteins, could lower blood cholesterol levels by interfering with cholesterol absorption and metabolism. Such dietary compounds also have potential to exert immune modulation through diverse mechanisms. This review addresses current knowledge about the impact of dietary-derived and de novo synthesized cholesterol and oxysterols on the immune system. Possible immunomodulatory mechanisms elicited by cholesterol-lowering dietary compounds are also discussed.
How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors
Authors: Alharbi Abdulrahman G. , Tobin Andrew B. , Milligan Graeme
Published: October 2022

FFA1 and FFA4, two G protein-coupled receptors that are activated by long chain fatty acids, play crucial roles in mediating many biological functions in the body. As a result, these fatty acid receptors have gained considerable attention due to their potential to be targeted for the treatment of type-2 diabetes. However, the relative contribution of canonical G protein-mediated signalling versus the effects of agonist-induced phosphorylation and interactions with β-arrestins have yet to be fully defined. Recently, several reports have highlighted the ability of β-arrestins and GRKs to interact with and modulate different functions of both FFA1 and FFA4, suggesting that it is indeed important to consider these interactions when studying the roles of FFA1 and FFA4 in both normal physiology and in different disease settings. Here, we discuss what is currently known and show the importance of understanding fully how β-arrestins and GRKs regulate the function of long chain fatty acid receptors.
Insights on Microbial Communities Inhabiting Non-Volcanic Hot Springs
Authors: Escuder-Rodríguez Juan-José , DeCastro María-Eugenia , Saavedra-Bouza Almudena , Becerra Manuel , González-Siso María-Isabel
Published: October 2022

The northwest of Spain has an abundance of non-volcanic hot springs that, until recently, had only been used for thermalism activities. One of such hot springs, Muiño da Veiga, has now been explored using metagenomics to study the microbial community that inhabits these high-temperature circumneutral continental waters. Sequencing of the metagenome allowed the characterization of its composition, diversity, metabolic connections and potential as a source for thermozymes, as well as its ability to assemble MAGs. A diverse microbial community dominated by Bacteria domain members was revealed, particularly from the early-branching Aquificales group. The most abundant genus was Sulfurihydrogenibium, known for its implication in sulfur cycling and for forming mats that enable novel niches. The variety of primary producers with autotrophic pathways (and specifically the sulfur oxidizing pathway) expands the range of available nutrients, and the increase in biomass forms thicker mats, resulting in more available niches and broader microbial diversity. Nonetheless, certain metabolic pathways were attributed to less abundant members of the microbial community, reinforcing the idea that the rare biosphere plays important roles in the network of interactions present in an ecosystem and acts as genetic reservoirs. In addition, three of the assembled MAGs represent novel microbial diversity found in this hot spring. Moreover, the presence of enzymes and microorganisms with possible biotechnological applications was confirmed, including proteases, lipases and cell-wall degrading enzymes, pointing to the potential for the hot spring as a source for thermozymes.
Dietary Selenomethionine Reduce Mercury Tissue Levels and Modulate Methylmercury Induced Proteomic and Transcriptomic Alterations in Hippocampi of Adolescent BALB/c Mice
Authors: Mellingen Ragnhild Marie , Myrmel Lene Secher , Rasinger Josef Daniel , Lie Kai Kristoffer , Bernhard Annette , Madsen Lise , Nøstbakken Ole Jakob
Published: October 2022

Methylmercury (MeHg) is a well-known environmental contaminant, particularly harmful to the developing brain. The main human dietary exposure to MeHg occurs through seafood consumption. However, seafood also contains several nutrients, including selenium, which has been shown to interact with MeHg and potentially ameliorate its toxicity. The aim of this study was to investigate the combined effects of selenium (as selenomethionine; SeMet) and MeHg on mercury accumulation in tissues and the effects concomitant dietary exposure of these compounds exert on the hippocampal proteome and transcriptome in mice. Adolescent male BALB/c mice were exposed to SeMet and two different doses of MeHg through their diet for 11 weeks. Organs, including the brain, were sampled for mercury analyses. Hippocampi were collected and analyzed using proteomics and transcriptomics followed by multi-omics bioinformatics data analysis. The dietary presence of SeMet reduced the amount of mercury in several organs, including the brain. Proteomic and RNA-seq analyses showed that both protein and RNA expression patterns were inversely regulated in mice receiving SeMet together with MeHg compared to MeHg alone. Several pathways, proteins and RNA transcripts involved in conditions such as immune responses and inflammation, oxidative stress, cell plasticity and Alzheimer’s disease were affected inversely by SeMet and MeHg, indicating that SeMet can ameliorate several toxic effects of MeHg in mice.
Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects
Authors: Smyk Julia M. , Szydłowska Natalia , Szulc Weronika , Majewska Anna
Published: October 2022

Viral evolution refers to the genetic changes that a virus accumulates during its lifetime which can arise from adaptations in response to environmental changes or the immune response of the host. Influenza A virus is one of the most rapidly evolving microorganisms. Its genetic instability may lead to large changes in its biological properties, including changes in virulence, adaptation to new hosts, and even the emergence of infectious diseases with a previously unknown clinical course. Genetic variability makes it difficult to implement effective prophylactic programs, such as vaccinations, and may be responsible for resistance to antiviral drugs. The aim of the review was to describe the consequences of the variability of influenza viruses, mutations, and recombination, which allow viruses to overcome species barriers, causing epidemics and pandemics. Another consequence of influenza virus evolution is the risk of the resistance to antiviral drugs. Thus far, one class of drugs, M2 protein inhibitors, has been excluded from use because of mutations in strains isolated in many regions of the world from humans and animals. Therefore, the effectiveness of anti-influenza drugs should be continuously monitored in reference centers representing particular regions of the world as a part of epidemiological surveillance.
Elucidating the Ability of CGRP to Modulate Microvascular Events in Mouse Skin
Authors: Zarban Ali A. , Chaudhry Hiba , de Sousa Valente João , Argunhan Fulye , Ghanim Hala , Brain Susan D.
Published: October 2022

Oedema formation and polymorphonuclear leukocyte (neutrophil) accumulation are involved in both acute and chronic inflammation. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that is released from stimulated sensory nerves. CGRP is a potent vasodilator neuropeptide, especially when administered to the cutaneous microvasculature, with a long duration of action. Here, we have investigated the ability of vasodilator amounts of CGRP to modulate oedema formation and neutrophil accumulation induced in the cutaneous microvasculature of the mouse. To learn more about the mechanism of action of endogenous CGRP, we have investigated the response to the inflammatory stimulants tumour necrosis factor alpha (TNFα) and carrageenan in three different murine models: a model where sensory nerves were depleted by resiniferatoxin (RTX); a pharmacological method to investigate the effect of a selective CGRP receptor antagonist; and a genetic approach using wildtype (WT) and αCGRP knockout (KO) mice. Our results show that exogenous CGRP potentiates oedema formation induced by substance P (SP) and TNFα. This is further supported by our findings from sensory nerve-depleted mice (in the absence of all neuropeptides), which indicated that sensory nerves are involved in mediating the oedema formation and neutrophil accumulation induced by TNFα, and also carrageenan in cutaneous microvasculature. Furthermore, endogenous CGRP was shown to contribute to this inflammatory response as carrageenan-induced oedema formation is attenuated in WT mice treated with the CGRP receptor antagonist, and in αCGRPKO mice. It is therefore concluded that CGRP can contribute to inflammation by promoting oedema formation in skin, but this response is dependent on the pro-inflammatory stimulus and circumstance.
Volatile Anaesthesia versus Total Intravenous Anaesthesia for Cardiac Surgery—A Narrative Review
Authors: Ștefan Mihai , Predoi Cornelia , Goicea Raluca , Filipescu Daniela
Published: October 2022

Recent research has contested the previously accepted paradigm that volatile anaesthetics improve outcomes in cardiac surgery patients when compared to intravenous anaesthesia. In this review we summarise the mechanisms of myocardial ischaemia/reperfusion injury and cardioprotection in cardiac surgery. In addition, we make a comprehensive analysis of evidence comparing outcomes in patients undergoing cardiac surgery under volatile or intravenous anaesthesia, in terms of mortality and morbidity (cardiac, neurological, renal, pulmonary).
Modeling Grinding Processes—Mesh or Mesh-Free Methods, 2D or 3D Approach?
Authors: Sridhar Praveen , Rodríguez Prieto Juan Manuel , de Payrebrune Kristin M.
Published: October 2022

The objectives of this study are mainly two: (1) to validate whether a single grain scratch process can be modeled in two dimensions under the assumption of plane strain, and (2) to select the best discretization approach to model a single grain scratch process. This paper first focuses on the simulation of the orthogonal cutting process (aluminum alloy A2024 T351) using two mesh-based discretization approaches, the pure Lagrangian method (LAG) and the arbitrary Lagrangian–Eulerian method (ALE), and two particle-based approaches, the particle finite element method (PFEM) and smooth particle hydrodynamics (SPH), for both positive and negative rake angles. Benchmarking of the orthogonal cutting models at a rake angle of γ=20∘ is performed with the results of the process forces (cutting and passive forces) of a turning experiment from the literature. It is shown that all models are able to predict the cutting forces, but not the passive force. The orthogonal cutting model is further extended to simulate the cutting mechanism with negative rake tool geometries typically found in grinding and single grit scratching processes. The effects of the negative rake angles on the discretization approaches are studied. The calculated process forces are also compared to the measurements of the single grit scratch process performed at our laboratory. The 2D orthogonal cutting models significantly overestimate the process forces. One of the reasons why the orthogonal 2D cutting model is inadequate is that it cannot describe the complex mechanisms of material removal such as rubbing, plowing, and cutting. To account for these phenomena in LAG, ALE, and SPH discretization approaches, a 3D scratch model is developed. When comparing the process forces of the 3D model with the experimental measurements, all three discretization approaches show good agreement. However, it can be seen that the ALE model most closely matches the process forces with the experimental results. Finally, the ALE 3D scratch model was subjected to sensitivity analysis by changing the cutting speed, the depth of cut and the tool geometry. The results clearly show that the ALE method not only predicts the process forces and form the trends observed in the scratching experiments, but also predicts the scratch topography satisfactorily. Hence, we conclude that a 3D model is necessary to describe a scratch process and that the ALE method is the best discretization method.
New Species of Nectriaceae (Hypocreales) from China
Authors: Zeng Zhao-Qing , Zhuang Wen-Ying
Published: October 2022

Species of Nectriaceae commonly occur on living and decaying woody substrates, soil, fruitbodies of other fungi, and insects. Some of them are reported as endophytes, opportunistic pathogens of crops and humans, or producers of mycotoxins. To explore the species diversity of the family, specimens from different regions of China were collected and examined. Four novel taxa of Penicillifer, Pseudocosmospora, and Thelonectria were introduced on the basis of morphological characteristics and DNA sequence analyses of combined datasets of the act, ITS, LSU, rpb1, rpb2, tef1, and tub2 regions. Differences between the new species and their close relatives were compared and discussed.
Ocular Fungal Infections
Authors: Ramírez-Soto Max Carlos , Bonifaz Alexandro
Published: October 2022

Fungal infections of the eye continue to be an important cause of ocular morbidity and loss of vision, particularly in the developing world [...]