bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Playground Shade Structures on Ultraviolet Radiation Exposure and Physical Activity among Children at a Childcare Facility
Authors: Corcoran Breann , Bhatti Parveen , Peters Cheryl E , Feldman Fabio , Darvishian Maryam
Published: July 2023

Skin cancer is the most common cancer in Canada, and rates continue to rise. While sunscreen and protective clothing remain critical strategies to reduce skin cancer risk, shade is generally the most effective way to control exposure. There remains a lack of data, particularly in British Columbia (BC), demonstrating the extent to which shade availability reduces ultraviolet radiation (UVR) exposure in a real-world setting and the potential impacts of shade provision on physical activity. We evaluated the impact of shade structures on UVR exposure and physical activity at a Vancouver-area childcare center with an outdoor play area with limited existing shade. 22 children, aged 3–5 years, participated in the study. Three removable shade sails were installed in the outdoor play space, and UVR and physical activity measurements were collected during the spring, summer, and fall months. Ultraviolet B (UVB) radiation data was measured using UVB dosimeters, and physical activity data was measured using accelerometers. Data were collected during each season over a total of four days—two days with shade sails installed and two days with shade sails removed. Overall, with shade installation, UVR exposures and physical activity levels among children were reduced by 50% and 20%, respectively. This study supports the use of shade sails to significantly reduce UVR exposures among preschool-aged children in BC; however, the potential for decreased physical activity from shade sails should be further explored in future research.
Leukemia Mortality among Benzene-Exposed Workers in Brazil (2006–2011)
Authors: Moura-Corrêa Maria
Published: July 2023

Background: In this study, the annual leukemia mortality rate is estimated by occupational groups potentially exposed to benzene in Brazil and compared to non-exposed workers by sex. Methods: Data were extracted from the Mortality Information System and the National Institute of Geography and Statistics from 2006 to 2011. Occupational groups exposed to benzene were defined by using the Finnish Job-Exposure Matrix, FINJEM. Results: We found 21,049 leukemia deaths in 1917 in occupational groups potentially exposed to benzene, corresponding to an annual average mortality rate of 4.5/100,000, higher than the estimate for non-exposed workers: 2.6/100,000, corresponding to a Mortality rate ratio MRR = 1.7. Each benzene-exposed occupational group had increased leukemia mortality, and printers and occupations in graphics presented the highest MRR (2.7), followed by laboratory assistants (MRR = 2.6), laundry workers, chemists, and upholsterers, each of these occupational groups presenting MRR = 2.3. Conclusions: Benzene shows the need for better enforcement of protective norms against this known carcinogen. Our results support the need for better enforcement of protective norms to reduce benzene exposure.
Mouse Models to Examine Differentiated Thyroid Cancer Pathogenesis: Recent Updates
Authors: Choi Hye , Kim Kwangsoon
Published: July 2023

Although the overall prognosis of differentiated thyroid cancer (DTC), the most common endocrine malignancy, is favorable, a subset of patients exhibits aggressive features. Therefore, preclinical models that can be utilized to investigate DTC pathogenesis and novel treatments are necessary. Various mouse models have been developed based on advances in thyroid cancer genetics. This review focuses on recent progress in mouse models that have been developed to elucidate the molecular pathogenesis of DTC.
Serum-Circulating microRNAs in Sporadic Inclusion Body Myositis
Authors: Lucchini Matteo , De Arcangelis Valeria , Santoro Massimo , Morosetti Roberta , Broccolini Aldobrando , Mirabella Massimiliano
Published: July 2023

Background: Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative–autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To evaluate the expression of selected pre-amplified miRNAs in the serum of s-IBM patients compared to those of a sex- and age-matched healthy control group, we enrolled 14 consecutive s-IBM patients and 8 sex- and age-matched healthy controls. By using two different normalization approaches, we found one downregulated and three upregulated miRNAs. hsa-miR-192-5p was significantly downregulated, while hsa-miR-372-3p was found to be upregulated more in the s-IBM patients compared to the level of the controls. The other two miRNAs had a very low expression levels (raw Ct data > 29). hsa-miR-192-5p and hsa-miR-372-3p were found to be significantly dysregulated in the serum of s-IBM patients. These miRNAs are involved in differentiation and regeneration processes, thus possibly reflecting pathological mechanisms in s-IBM muscles and potentially representing disease biomarkers.
rAAV TGF-β and FGF-2 Overexpression via pNaSS-Grafted PCL Films Stimulates the Reparative Activities of Human ACL Fibroblasts
Authors: Amini Mahnaz , Venkatesan Jagadeesh K. , Nguyen Tuan N. , Liu Wei , Leroux Amélie , Madry Henning , Migonney Véronique , Cucchiarini Magali
Published: July 2023

Lesions in the human anterior cruciate ligament (ACL) are frequent, unsolved clinical issues due to the limited self-healing ability of the ACL and lack of treatments supporting full, durable ACL repair. Gene therapy guided through the use of biomaterials may steadily activate the processes of repair in sites of ACL injury. The goal of the present study was to test the hypothesis that functionalized poly(sodium styrene sulfonate)-grafted poly(ε-caprolactone) (pNaSS-grafted PCL) films can effectively deliver recombinant adeno-associated virus (rAAV) vectors as a means of overexpressing two reparative factors (transforming growth factor beta-TGF-β and basic fibroblast growth factor-FGF-2) in primary human ACL fibroblasts. Effective, durable rAAV reporter red fluorescent protein and candidate TGF-β and FGF-2 gene overexpression was achieved in the cells for at least 21 days, especially when pNaSS-grafted PCL films were used versus control conditions, such as ungrafted films and systems lacking vectors or films (between 1.8- and 5.2-fold differences), showing interactive regulation of growth factor production. The expression of TGF-β and FGF-2 from rAAV via PCL films safely enhanced extracellular matrix depositions of type-I/-III collagen, proteoglycans/decorin, and tenascin-C (between 1.4- and 4.5-fold differences) in the cells over time with increased levels of expression of the specific transcription factors Mohawk and scleraxis (between 1.7- and 3.7-fold differences) and without the activation of the inflammatory mediators IL-1β and TNF-α, most particularly with pNaSS-grafted PCL films relative to the controls. This work shows the value of combining rAAV gene therapy with functionalized PCL films to enhance ACL repair.
Treatment-Resistant Depression (TRD): Is the Opioid System Involved?
Authors: Schreiber Shaul , Keidan Lee , Pick Chaim G.
Published: July 2023

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.
SWI/SNF Complex Alterations in Tumors with Rhabdoid Features: Novel Therapeutic Approaches and Opportunities for Adoptive Cell Therapy
Authors: Soto-Castillo Juan José , Llavata-Marti Lucía , Fort-Culillas Roser , Andreu-Cobo Pablo , Moreno Rafael , Codony Carles , García del Muro Xavier , Alemany Ramon , Piulats Josep M. , Martin-Liberal Juan
Published: July 2023

The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.
Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice
Authors: Vallés-Saiz Laura , Ávila Jesús , Hernández Félix
Published: July 2023

The dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription in Drosophila models as well as in human tauopathies. In this context, we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheimer’s disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology.
Effects of Homogeneous and Heterogeneous Crowding on Translational Diffusion of Rigid Bovine Serum Albumin and Disordered Alfa-Casein
Authors: Kusova Aleksandra M. , Rakipov Ilnaz T. , Zuev Yuriy F.
Published: July 2023

Intracellular environment includes proteins, sugars, and nucleic acids interacting in restricted media. In the cytoplasm, the excluded volume effect takes up to 40% of the volume available for occupation by macromolecules. In this work, we tested several approaches modeling crowded solutions for protein diffusion. We experimentally showed how the protein diffusion deviates from conventional Brownian motion in artificial conditions modeling the alteration of medium viscosity and rigid spatial obstacles. The studied tracer proteins were globular bovine serum albumin and intrinsically disordered α-casein. Using the pulsed field gradient NMR, we investigated the translational diffusion of protein probes of different structures in homogeneous (glycerol) and heterogeneous (PEG 300/PEG 6000/PEG 40,000) solutions as a function of crowder concentration. Our results showed fundamentally different effects of homogeneous and heterogeneous crowded environments on protein self-diffusion. In addition, the applied “tracer on lattice” model showed that smaller crowding obstacles (PEG 300 and PEG 6000) create a dense net of restrictions noticeably hindering diffusing protein probes, whereas the large-sized PEG 40,000 creates a “less restricted” environment for the diffusive motion of protein molecules.
MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells
Authors: Pratelli Giovanni , Carlisi Daniela , Di Liberto Diana , Notaro Antonietta , Giuliano Michela , D’Anneo Antonella , Lauricella Marianna , Emanuele Sonia , Calvaruso Giuseppe , De Blasio Anna
Published: July 2023

Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial–Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.
Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles to Treat PCOS
Authors: Park Hang-Soo , Cetin Esra , Siblini Hiba , Seok Jin , Alkelani Hiba , Alkhrait Samar , Liakath Ali Farzana , Mousaei Ghasroldasht Mohammad , Beckman Analea , Al-Hendy Ayman
Published: July 2023

Polycystic ovary syndrome (PCOS) is known as the most common endocrine disorder in women. Previously, we suggested that human mesenchymal stem cells (MSCs) can reverse the PCOS condition by secreting factors. Here, we evaluated the therapeutic capability of MSC-derived extracellular vesicles (EVs), also known as exosomes, in both in vitro and in vivo PCOS models. Exosomes were used to treat androgen-producing H293R cells and injected in a mouse model through intraovarian and intravenous injection into a letrozole (LTZ)-induced PCOS mouse model. We assessed the effects of the exosomes on androgen-producing cells or the PCOS mouse model by analyzing steroidogenic gene expression (quantitative real-time polymerase chain reaction (qRT–PCR)), body weight change, serum hormone levels, and fertility by pup delivery. Our data show the therapeutic effect of MSC-derived EVs for reversing PCOS conditions, including fertility issues. Interestingly, intravenous injection was more effective for serum glucose regulation, and an intraovarian injection was more effective for ovary restoration. Our study suggests that MSC-derived exosomes can be promising biopharmaceutics for treating PCOS conditions as a novel therapeutic option. Despite the fact that we need more validation in human patients, we may evaluate this novel treatment option for PCOS with the following clinical trials.
Interplay between the RNA Chaperone Hfq, Small RNAs and Transcriptional Regulator OmpR Modulates Iron Homeostasis in the Enteropathogen Yersinia enterocolitica
Authors: Jaworska Karolina , Konarska Julia , Gomza Patrycja , Rożen Paula , Nieckarz Marta , Krawczyk-Balska Agata , Brzostek Katarzyna , Raczkowska Adrianna
Published: July 2023

Iron is both essential for and potentially toxic to bacteria, so the precise maintenance of iron homeostasis is necessary for their survival. Our previous study indicated that in the human enteropathogen Yersinia enterocolitica, the regulator OmpR directly controls the transcription of the fur, fecA and fepA genes, encoding the ferric uptake repressor and two transporters of ferric siderophores, respectively. This study was undertaken to determine the significance of the RNA chaperone Hfq and the small RNAs OmrA and RyhB1 in the post-transcriptional control of the expression of these OmpR targets. We show that Hfq silences fur, fecA and fepA expression post-transcriptionally and negatively affects the production of FLAG-tagged Fur, FecA and FepA proteins. In addition, we found that the fur gene is under the negative control of the sRNA RyhB1, while fecA and fepA are negatively regulated by the sRNA OmrA. Finally, our data revealed that the role of OmrA results from a complex interplay of transcriptional and post-transcriptional effects in the feedback circuit between the regulator OmpR and the sRNA OmrA. Thus, the expression of fur, fecA and fepA is subject to complex transcriptional and post-transcriptional regulation in order to maintain iron homeostasis in Y. enterocolitica.
Disorder of Biological Quality and Autophagy Process in Bovine Oocytes Exposed to Heat Stress and the Effectiveness of In Vitro Fertilization
Authors: Wrzecińska Marcjanna , Kowalczyk Alicja , Kordan Władysław , Cwynar Przemysław , Czerniawska-Piątkowska Ewa
Published: July 2023

The main problem in dairy herds is reproductive disorders, which are influenced by many factors, including temperature. Heat stress reduces the quality of oocytes and their maturation through the influence of, e.g., mitochondrial function. Mitochondria are crucial during oocyte maturation as well as the process of fertilization and embryonic development. Disturbances related to high temperature will be increasingly observed due to global warming. In present studies, we have proven that exposure to high temperatures during the cleaving of embryos statistically significantly (at the level of p < 0.01) reduces the percentage of oocytes that cleaved and developed into blastocysts eight days after insemination. The study showed the highest percentage of embryos that underwent division in the control group (38.3 °C). The value was 88.10 ± 6.20%, while the lowest was obtained in the study group at 41.0 °C (52.32 ± 8.40%). It was also shown that high temperature has a statistically significant (p < 0.01) effect on the percentage of embryos that developed from the one-cell stage to blastocysts. The study showed that exposure to a temperature of 41.0 °C significantly reduced the percentage of embryos that split relative to the control group (38.3 °C; 88.10 ± 6.20%). Moreover, it was noted that the highest tested temperature limits the development of oocytes to the blastocyst stage by 5.00 ± 9.12% compared to controls (33.33 ± 7.10%) and cleaved embryos to blastocysts by 3.52 ± 6.80%; the control was 39.47 ± 5.40%. There was also a highly significant (p < 0.0001) effect of temperature on cytoplasmic ROS levels after 6 and 12 h IVM. The highest level of mitochondrial ROS was found in the group of oocytes after 6 h IVM at 41.0 °C and the lowest was found in the control group. In turn, at 41.0 °C after 12 h of IVM, the mitochondrial ROS level had a 2.00 fluorescent ratio, and the lowest in the group was 38.3 °C (1.08). Moreover, with increasing temperature, a decrease in the expression level of both LC3 and SIRT1 protein markers was observed. It was proved that the autophagy process was impaired as a result of high temperature. Understanding of the cellular and molecular responses of oocytes to elevated temperatures will be helpful in the development of heat resistance strategies in dairy cattle.
Feruloyl Esterase (LaFae) from Lactobacillus acidophilus: Structural Insights and Functional Characterization for Application in Ferulic Acid Production
Authors: Jeon Sangeun , Hwang Jisub , Do Hackwon , Le Ly Thi Huong Luu , Lee Chang Woo , Yoo Wanki , Lee Min Ju , Shin Seung Chul , Kim Kyeong Kyu , Kim Han-Woo , Lee Jun Hyuck
Published: July 2023

Ferulic acid and related hydroxycinnamic acids, used as antioxidants and preservatives in the food, cosmetic, pharmaceutical and biotechnology industries, are among the most abundant phenolic compounds present in plant biomass. Identification of novel compounds that can produce ferulic acid and hydroxycinnamic acids, that are safe and can be mass-produced, is critical for the sustainability of these industries. In this study, we aimed to obtain and characterize a feruloyl esterase (LaFae) from Lactobacillus acidophilus. Our results demonstrated that LaFae reacts with ethyl ferulate and can be used to effectively produce ferulic acid from wheat bran, rice bran and corn stalks. In addition, xylanase supplementation was found to enhance LaFae enzymatic hydrolysis, thereby augmenting ferulic acid production. To further investigate the active site configuration of LaFae, crystal structures of unliganded and ethyl ferulate-bound LaFae were determined at 2.3 and 2.19 Å resolutions, respectively. Structural analysis shows that a Phe34 residue, located at the active site entrance, acts as a gatekeeper residue and controls substrate binding. Mutating this Phe34 to Ala produced an approximately 1.6-fold increase in LaFae activity against p-nitrophenyl butyrate. Our results highlight the considerable application potential of LaFae to produce ferulic acid from plant biomass and agricultural by-products.
Aprotinin—Drug against Respiratory Diseases
Authors: Ivachtchenko Alexandre V. , Ivashchenko Andrey A. , Shkil Dmitrii O. , Ivashchenko Ilya A.
Published: July 2023

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical “magic shotgun”. Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015–2020, after re-analysis of these clinical trials’ data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.
Experimental Models of Traumatic Injuries: Do They Capture the Coagulopathy and Underlying Endotheliopathy Induced by Human Trauma?
Authors: Barrett Liam , Curry Nicola , Abu-Hanna Jeries
Published: July 2023

Trauma-induced coagulopathy (TIC) is a major cause of morbidity and mortality in patients with traumatic injury. It describes the spectrum of coagulation abnormalities that occur because of the trauma itself and the body’s response to the trauma. These coagulation abnormalities range from hypocoagulability and hyperfibrinolysis, resulting in potentially fatal bleeding, in the early stages of trauma to hypercoagulability, leading to widespread clot formation, in the later stages. Pathological changes in the vascular endothelium and its regulation of haemostasis, a phenomenon known as the endotheliopathy of trauma (EoT), are thought to underlie TIC. Our understanding of EoT and its contribution to TIC remains in its infancy largely due to the scarcity of experimental research. This review discusses the mechanisms employed by the vascular endothelium to regulate haemostasis and their dysregulation following traumatic injury before providing an overview of the available experimental in vitro and in vivo models of trauma and their applicability for the study of the EoT and its contribution to TIC.
Opposite Auxin Dynamics Determine the Gametophytic and Embryogenic Fates of the Microspore
Authors: Pérez-Pérez Yolanda , Solís María Teresa , Albacete Alfonso , Testillano Pilar S.
Published: July 2023

The microspore can follow two different developmental pathways. In vivo microspores follow the gametophytic program to produce pollen grains. In vitro, isolated microspores can be reprogrammed by stress treatments and follow the embryogenic program, producing doubled-haploid embryos. In the present study, we analyzed the dynamics and role of endogenous auxin in microspore development during these two different scenarios, in Brassica napus. We analyzed auxin concentration, cellular accumulation, the expression of the TAA1 auxin biosynthesis gene, and the PIN1-like efflux carrier gene, as well as the effects of inhibiting auxin biosynthesis by kynurenine on microspore embryogenesis. During the gametophytic pathway, auxin levels and TAA1 and PIN1-like expression were high at early stages, in tetrads and tapetum, while they progressively decreased during gametogenesis in both pollen and tapetum cells. In contrast, in microspore embryogenesis, TAA1 and PIN1-like genes were upregulated, and auxin concentration increased from the first embryogenic divisions. Kynurenine treatment decreased both embryogenesis induction and embryo production, indicating that auxin biosynthesis is required for microspore embryogenesis initiation and progression. The findings indicate that auxin exhibits two opposite profiles during these two microspore developmental pathways, which determine the different cell fates of the microspore.
Deep Characterization of a Greek Patient with Desmin-Related Myofibrillar Myopathy and Cardiomyopathy
Authors: Papadopoulos Constantinos , Malfatti Edoardo , Métay Corinne , Keren Boris , Lejeune Elodie , Buratti Julien , Xirou Sophia , Chrysanthou-Piterou Margarita , Papadimas George K.
Published: July 2023

Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene (DES) result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the DES gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic.
Current Trends in MOF (Metal-Organic Framework) and Metal X-ides
Authors: Wen Xinxin , Lin Lili , Li Siwei
Published: July 2023

Metal–organic frameworks (MOFs) are a class of porous two- or three-dimensional infinite structure materials consisting of metal ions or clusters and organic linkers, which are connected via coordination bonds [...]
Dissecting the Therapeutic Mechanisms of Sphingosine-1-Phosphate Receptor Agonism during Ischaemia and Reperfusion
Authors: Wilkins Georgina C. , Gilmour Jenny , Giannoudaki Eirini , Kirby John A. , Sheerin Neil S. , Ali Simi
Published: July 2023

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PR) regulate many cellular processes, including lymphocyte migration and endothelial barrier function. As neutrophils are major mediators of inflammation, their transendothelial migration may be the target of therapeutic approaches to inflammatory conditions such as ischaemia–reperfusion injury (IRI). The aim of this project was to assess whether these therapeutic effects are mediated by S1P acting on neutrophils directly or indirectly through the endothelial cells. First, our murine model of peritoneum cell recruitment demonstrated the ability of S1P to reduce CXCL8-mediated neutrophil recruitment. Mechanistic in vitro studies revealed that S1P signals in neutrophils mainly through the S1PR1 and 4 receptors and induces phosphorylation of ERK1/2; however, this had no effect on neutrophil transmigration and adhesion. S1P treatment of endothelial cells significantly reduced TNF-α-induced neutrophil adhesion under flow (p < 0.01) and transendothelial migration towards CXCL8 during in vitro chemotaxis assays (p < 0.05). S1PR1 agonist CYM5442 treatment of endothelial cells also reduced neutrophil transmigration (p < 0.01) and endothelial permeability (p < 0.005), as shown using in vitro permeability assays. S1PR3 agonist had no effects on chemotaxis or permeability. In an in vivo mouse model of renal IRI, S1PR agonism with CYM5442 reduced endothelial permeability as shown by reduced Evan’s Blue dye extravasation. Western blot was used to assess phosphorylation at different sites on vascular endothelial (VE)–cadherin and showed that CYM5442 reduced VEGF-mediated phosphorylation. Taken together, the results of this study suggest that reductions in neutrophil infiltration during IRI in response to S1P are mediated primarily by S1PR1 signalling on endothelial cells, possibly by altering phosphorylation of VE–cadherin. The results also demonstrate the therapeutic potential of S1PR1 agonist during IRI.
Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat
Authors: Winzenried Eric T. , Everett Anna C. , Saito Erin R. , Miller Roxanne M. , Johnson Taylor , Neal Eliza , Boyce Zachary , Smith Calvin , Jensen Chloe , Kimball Spencer , Brantley Adam , Melendez Gabriel , Moffat Devin , Davis Erin , Aponik Lyndsey , Crofts Tyler , Dabney Bryson , Edwards Jeffrey G.
Published: July 2023

Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory—e.g., the amygdala and hippocampus—are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing β-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects.
Telling Your Right Hand from Your Left: The Effects of DNA Supercoil Handedness on the Actions of Type II Topoisomerases
Authors: Jian Jeffrey Y. , Osheroff Neil
Published: July 2023

Type II topoisomerases are essential enzymes that modulate the topological state of DNA supercoiling in all living organisms. These enzymes alter DNA topology by performing double-stranded passage reactions on over- or underwound DNA substrates. This strand passage reaction generates a transient covalent enzyme–cleaved DNA structure known as the cleavage complex. Al-though the cleavage complex is a requisite catalytic intermediate, it is also intrinsically dangerous to genomic stability in biological systems. The potential threat of type II topoisomerase function can also vary based on the nature of the supercoiled DNA substrate. During essential processes such as DNA replication and transcription, cleavage complex formation can be inherently more dangerous on overwound versus underwound DNA substrates. As such, it is important to understand the profound effects that DNA topology can have on the cellular functions of type II topoisomerases. This review will provide a broad assessment of how human and bacterial type II topoisomerases recognize and act on their substrates of various topological states.
Rifaximin Use, Adherence and Persistence in Patients with Hepatic Encephalopathy: A Real-World Study in the South of Italy
Authors: Pandico Fulvio , Citarella Anna , Cammarota Simona , Bernardi Francesca Futura , Claar Ernesto , Coppola Carmine , Cozzolino Marianna , De Rosa Federica , Di Gennaro Massimo , Fogliasecca Marianna , Giordana Roberta , Pacella Daniela , Russo Alessandro , Salerno Vito , Scafa Luca , Trama Ugo
Published: July 2023

Real-world data on the therapeutic management of hepatic encephalopathy (HE) patients are limited. The aim of this study was to evaluate the HE medications prescribed in an Italian cohort of HE patients post-discharge and to assess the real-world rifaximin adherence and persistence over 1 year. An observation retrospective study was conducted using data retrieved from outpatient pharmaceutical databases and hospital discharge records of the Campania region. For all subjects hospitalized for HE during 2019 (cohort 1), the HE medications prescribed within 60 days after discharge were evaluated. Adherence (proportion of days covered, PDC) and persistence were estimated for rifaximin 550 mg incident users over 1 year (cohort 2). Patients with PDC ≥80% were considered adherents. Persistence was defined as the period of time from the first rifaximin prescription to the date of discontinuation. Discontinuation was assessed using the permissible gap method. In cohort 1, 544 patients were identified; 58.5% received rifaximin while 15.6% only received non-absorbable disaccharides and 25.9% did not receive any HE medications. In cohort 2, 650 users were selected; only 54.5% were adherents and 35% were persistent users at 1 year. This real-world study highlights that quality improvement in therapeutic management is needed to potentially improve the outcomes of HE patients.
Personality Traits and Fatigue in Multiple Sclerosis: A Narrative Review
Authors: Ciancio Alessia , Moretti Maria Claudia , Natale Antimo , Rodolico Alessandro , Signorelli Maria Salvina , Petralia Antonino , Altamura Mario , Bellomo Antonello , Zanghì Aurora , D’Amico Emanuele , Avolio Carlo , Concerto Carmen
Published: July 2023

(1) Background: Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease. Fatigue is a prevalent and debilitating symptom that significantly impacts the quality of life of these patients. A relationship between personality traits and fatigue in MS has been hypothesized but not clearly defined. (2) Methods: A literature search was carried out from databases up to April 2023 for studies correlating personality traits and fatigue in patients suffering from MS. (3) Results: A total of ten articles was included; most of the studies depict a neuroticism–fatigue correlation; however, they were not consistent in terms of the fatigue, personality, and covariate assessments. (4) Conclusions: The clinical and methodological heterogeneity of the included studies prevented us from drawing any firm conclusion on the link between personality traits and fatigue in MS. Several models of personality and different fatigue assessments have been found. Despite this, a common pathway shows that the neuroticism trait or similar personality patterns has a role in fatigue diagnosis. This may be a useful target to improve the quality of life and enhance the modification of the disease treatment results. Further homogeneous and longitudinal studies are needed.
Flow Dynamic Pattern in Liver and Renal Transplantation under Exercise Prescription Program
Authors: Corsi Marco , Falconi Edoardo , Palazzo Roberto , Bini Vittorio , Mascherini Gabriele , Mancini Sabrina , Maglione Marco , Stefani Laura
Published: July 2023

Background: Cardiovascular diseases in the context of renal and liver transplants remain the leading cause of morbidity and mortality. Physical exercise at a moderate intensity is allowed to contrast the risk profile. Echocardiographic evaluation is essential to stratifying potential cardiotoxicity by the standard and, more recently, the deformation and dynamic study of the intracardiac vortex. This study aims to investigate the vortex echo parameters of solid-organ-transplanted subjects who are physically active compared to a control group of healthy subjects. Methods: A group of 33 transplanted subjects (16 kidneys and 17 livers) was studied via a transthoracic echocardiography exam, comprehending the myocardial deformation parameters of global longitudinal strain (GLS), twisting of the left ventricle (LV) chamber, and HyperDoppler image acquisition. Results: The subjects enrolled in this study were 50 in total: there were 33 transplanted and 17 healthy subjects. The transplanted subjects presented higher values of interventricular septum in diastole (IVSd p = 0.001), posterior wall diastolic (PWd p = 0.05), and left ventricle mass index (LVMI p = 0.029); ejection fraction (EF) was found to be higher in athletes (p < 0.001). Transplanted subjects presented mild diastolic dysfunction, emerging only from septal E values (p = 0.001). The 4DStrain (p = 0.018) and GLS2c (p = 0.017) were significantly better in the athletes. All of the geometrical and energetical vortex data were in the normal range and no significant differences were found. An interesting positive correlation was evident for the diastolic parameter, particularly the E/A ratio (p = 0.023) and E’ septal value (p = 0.049), along with the vorticity fluctuation. This behavior was present for all subjects, particularly those that were transplanted (p = 0.005). Conclusions: In the vortex investigation, especially in cases of normal EF, the positive correlation of some diastolic parameters with the flow dynamic patterns corroborates this hypothesis. The HyperDoppler analysis could be helpful to detecting potential damage earlier in the diastolic time before a systolic deficiency.
Effects of Fremanezumab on Psychiatric Comorbidities in Difficult-to-Treat Patients with Chronic Migraine: Post Hoc Analysis of a Prospective, Multicenter, Real-World Greek Registry
Authors: Vikelis Michail , Dermitzakis Emmanouil V. , Xiromerisiou Georgia , Rallis Dimitrios , Soldatos Panagiotis , Litsardopoulos Pantelis , Rikos Dimitrios , Argyriou Andreas A.
Published: July 2023

Objective: this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or depression. Methods: We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients’ changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed. Results: Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with (n = 38/65; 58.5%) and without (n = 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable (p = 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean −8.9 (standard error: 6.8); p < 0.001) and without PCs (−9.8 (7.5); p < 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab. Conclusions: fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression.
Group-Based Trajectory Modelling of Changes in Mobility over Six Years in Type 2 Diabetes: The Fremantle Diabetes Study Phase II
Authors: Bruce David G. , Davis Wendy A. , Davis Timothy M. E.
Published: July 2023

To investigate temporal changes in mobility in community-based people with type 2 diabetes, Fremantle Diabetes Study Phase II (FDS2) data were analysed. The baseline assessment included the Timed Up and Go (TUG) test, which was repeated biennially for up to six years. Group-based trajectory modelling (GBTM) identified TUG trajectory groups in participants with ≥2 tests. Independent associates of group membership were assessed using multinomial regression. Of 1551 potential FDS2 participants, 1116 (72.0%; age 64.9 ± 11.0 years, 45.6% female) were included in the modelling. The best-fitting GBTM model identified two groups with linear, minimally changing trajectories (76.2% and 19.4% of participants; baseline TUG times 8 ± 2 and 12 ± 3 s, respectively), and a third (4.5%; baseline TUG 17 ± 5 s) with a TUG that increased over time then fell at Year 6, reflecting participant attrition. Both slower groups were older, more likely to be female, obese, and had greater diabetes-associated complications and comorbidities. Almost one-quarter of the FDS2 cohort had clinically relevant mobility impairment that persisted or worsened over six years, was multifactorial in origin, and was associated with excess late withdrawals and deaths. The TUG may have important clinical utility in assessing mobility and its consequences in adults with type 2 diabetes.
Bone Regeneration: Overview and Future Trends
Authors: De Angelis Nicola , Bagnasco Francesco , Amaroli Andrea
Published: July 2023

It has been calculated that 8 [...]
Numerical Modeling of Nearshore Wave Transformation and Breaking Processes in the Yellow River Delta with FUNWAVE-TVD Wave Model
Authors: Nguyen Quan Trong , Mao Miaohua , Xia Meng
Published: July 2023

The presence of wave coherence, which contributes to the inhomogeneity of wave characteristics and significantly affects wave processes over nearshore regions of the Yellow River Delta (YRD), was simulated and analyzed in this study. A phase-resolving Boussinesq-type wave model, FUNWAVE-TVD, was used to simulate waves with desirable coherency effects. Bathymetry and topography data were obtained from the Chinese nautical chart and E.U. Copernicus Marine Service Information. After the model configuration, spatial distributions of the root mean square and significant wave heights, and the maximum cross-shore current velocity and vorticity over the domain with respect to different degrees of wave coherence and energy spectrum discretization were investigated. The results indicate that the complexity of the spatial distribution and magnitude of longshore variations in wave statistics are proportional to the degree of coherence. Waves with higher coherency exhibit more complex variabilities and stronger fluctuations along the longshore direction. The influence of morphological changes on wave height in the YRD was discernible by comparing the results with and without coherency effects. The cross-shore current velocity decreased as the waves moved toward the surf zone, while the vorticity accelerated, indicating a higher shear wave magnitude. The simulated wave dissipates more than 60% (80%) of its energy when it reaches water depths of less than 5 m (2 m) and completely dissipates when it breaks at the shore.
A Machine-Learning-Based Method for Ship Propulsion Power Prediction in Ice
Authors: Zhou Li , Sun Qianyang , Ding Shifeng , Han Sen , Wang Aimin
Published: July 2023

In recent years, safety issues respecting polar ship navigation in the presence of ice have become a research hotspot. The accurate prediction of propulsion power plays an important role in ensuring safe ship navigation and evaluating ship navigation ability, and deep learning has been widely applied in the field of shipping, of which the artificial neural network (ANN) is a common method. This study combines the scientific problems of ice resistance and propulsion power for polar ship design, focusing on the design of an ANN model for predicting the propulsion power of polar ships. Reference is made to the traditional propulsion power requirements of various classification societies, as well as ship model test and full-scale test data, to select appropriate input features and a training dataset. Three prediction methods are considered: building a radial basis function–particle swarm optimization algorithm (RBF-PSO) model to directly predict the propulsion power; based on the full-scale test and model test data, calculating the propulsion power using the Finnish–Swedish Ice Class Rules (FSICR) formula; using an ice resistance artificial neural network model (ANN-IR) to predict the ice resistance and calculate the propulsion power using the FSICR formula. Prediction errors are determined, and a sensitivity analysis is carried out with respect to the relevant parameters of propulsion power based on the above methods. This study shows that the RBF-PSO model based on nine feature inputs has a reasonable generalization effect. Compared with the data of the ship model test and full-scale test, the average error is about 14%, which shows that the method has high accuracy and can be used as a propulsion power prediction tool.