bluuebunny/crossref_metadata_2025 huggingface dataset:
Internal Friction Angle of Cohesionless Binary Mixture Sand–Granular Rubber Using Experimental Study and Machine Learning
Authors: Daghistani Firas , Baghbani Abolfazl , Abuel Naga Hossam , Faradonbeh Roohollah Shirani
Published: June 2023

This study aimed to examine the shear strength characteristics of sand–granular rubber mixtures in direct shear tests. Two different sizes of rubber and one of sand were used in the experiment, with the sand being mixed with various percentages of rubber (0%, 10%, 20%, 30%, and 50%). The mixtures were prepared at three different densities (loose, slightly dense, and dense), and shear stress was tested at four normal stresses (30, 55, 105, and 200 kPa). The results of 80 direct shear tests were used to calculate the peak and residual internal friction angles of the mixtures, and it was found that the normal stress had a significant effect on the internal friction angle, with an increase in normal stress leading to a decrease in the internal friction angle. These results indicated that the Mohr–Coulomb theory, which applies to rigid particles only, is not applicable in sand–rubber mixtures, where stiff particles (sand) and soft particles (rubber) are mixed. The shear strength of the mixtures was also influenced by multiple factors, including particle morphology (size ratio, shape, and gradation), mixture density, and normal stress. For the first time in the literature, genetic programming, classification and regression random forests, and multiple linear regression were used to predict the peak and residual internal friction angles. The genetic programming resulted in the creation of two new equations based on mixture unit weight, normal stress, and rubber content. Both artificial intelligence models were found to be capable of accurately predicting the peak and residual internal friction angles of sand–rubber mixtures.
Violence and Post-National Costa Rican Identity in Limón Reggae
Authors: Stachura Anne Marie
Published: June 2023

Anacristina Rossi’s novels have received critical attention relating to their presentation of pan-Caribbean identity and other challenges to the mythical national identity of the tico. Building on scholarship by Manizal and Kearns, I argue that Limón Reggae presents a representation of the post-national community and that the violent conditions that mark the protagonist’s life not only debunk the national myth of a peaceful Costa Rica, but also comment on the impossibility of belonging in the post-national community. The pain that the protagonist experiences as a result of her interpersonal relationships reflects the difficulty of forming a community after the bounds of the nation have become less defined by globalization, even to individuals who come from groups not traditionally included in the definition of a Costa Rican citizen, such as the protagonist. With the breakdown of categories of affiliation across lines of geography, race, language, and class, the protagonist is able to move easily between places and groups, but her encounters with ‘others’ are complicated by the post-national condition.
Imagine All the People: A Guided Internet-Based Imagery Training to Increase Assertiveness among University Students—Study Protocol for a Randomized Controlled Trial
Authors: Di Consiglio Micaela , Burrai Jessica , Mari Emanuela , Giannini Anna Maria , Couyoumdjian Alessandro
Published: June 2023

The importance of communication skills for well-being and self-realization is widely accepted. Despite that, research on assertiveness and assertiveness training has declined significantly in recent decades. Consequently, traditional training does not consider the most recent novel technologies used to spread psychological interventions. This study proposes the development of ComunicaBene: a guided Internet-based imagery intervention to promote assertiveness. Moreover, it describes the study protocol for a randomized control trial to investigate the intervention’s efficacy and acceptability. Participants will be randomly assigned to an experimental (ComunicaBene) or waitlist control condition. ComunicaBene consists of different online training modules corresponding to three phases: psychoeducation, imaginative exposure, and in vivo-exposure. Each module provides participants with theoretical and practical content about needs, emotions, communication style, and assertiveness. Moreover, during the program, every student is supervised by a Tutor. Participants in the control condition will be included in a waiting list. Primary and secondary outcomes will include changes in assertiveness, well-being, emotional awareness, worry, and rumination. Outcomes will be assessed at pre- and post-intervention, and via a 6-month follow-up. We expect that the results will support the efficacy of ComunicaBene as an innovative, scalable, affordable, and acceptable intervention to spread assertive training through the Internet and among a broad population.
Little but Intense: Using a HIIT-Based Strategy to Improve Mood and Cognitive Functioning in College Students
Authors: Martínez-Díaz Inmaculada Concepción , Carrasco Páez Luis
Published: June 2023

Looking for useful and motivational strategies for promoting healthy habits and improving cognitive functioning in young populations, the aim of the present study was to determine if a single bout of high-intensity interval exercise could stimulate mood and working memory in college students. A total of 25 male subjects (mean ± SD, age: 21.7 ± 2.1 years; height: 1.77 ± 0.06 m; weight: 72.6 ± 8.4 kg; body mass index: 23.1 ± 1.4 kg/m2; VO2peak: 47.1 ± 9.3 mL/kg/min) participated voluntarily in this study. Participants underwent a high-intensity interval exercise consisting of 10 × 1 min of cycling at VO2peak power output. The Profile of Mood States (POMS) questionnaire and Digit Span Test (DST) were administered at three assessment time points: (a) pre-intervention assessment, (b) post-intervention assessment, and (d) 30 min post-intervention. The mood states decreased significantly after exercise; however, a significant increase in mood was found after 30 min of recovery. A significant post-exercise increase in DST performance was observed; moreover, DST scores obtained 30 min after exercise remained higher than those assessed pre-exercise. In conclusion, a single bout of HIIT induces acute positive changes in mood states in male college students and seems to be a powerful stimulus for cognitive functioning.
The Facial Characteristics of Individuals with Posterior Crossbite: A Cross-Sectional Study
Authors: Kienkas Karlina , Jakobsone Gundega , Salms Girts
Published: June 2023

Facial morphology is known to be influenced by genetic and environmental factors. Scientific evidence regarding facial parameters in patients with posterior crossbite is lacking. This study aimed to investigate the association between posterior crossbite and facial parameters. This cross-sectional study included 34 adolescents with and 34 adolescents without posterior crossbite in the age range from 13 to 15 years. Facial surface scans were acquired with a 3dMD imaging system, and landmark-based analysis was performed. Data were analyzed using the Mann-Whitney U test and Spearman’s correlations. Individuals in the control group had lower face heights (females: p = 0.003, r = 0.45; males: p = 0.005, r = 0.57). The control group females presented with smaller intercanthal width (p = 0.04; r = 0.31) and anatomical nose width (p = 0.004; r = 0.43) compared with the crossbite group females. The males in the control group had wider nostrils. In the control group, significant correlations among different facial parameters were more common, including the correlations between eye width and other transversal face measurements. On the contrary, the facial width was correlated with nasal protrusion (r = 0.657; p < 0.01) and the morphological width of the nose (r = 0.505; p < 0.05) in the crossbite group alone. In both groups, the philtrum width was linked with the anatomical and morphological widths of the nose. Conclusions: Patients with posterior crossbites have increased face height and different patterns of facial proportions compared with individuals without crossbites.
Shifting the Forensic Anthropological Paradigm to Incorporate the Transgender and Gender Diverse Community
Authors: Adams Donovan M. , Blatt Samantha H. , Flaherty Taylor M. , Haug Jaxson D. , Isa Mariyam I. , Michael Amy R. , Smith Ashley C.
Published: June 2023

Forensic anthropology and, more broadly, the forensic sciences have only recently begun to acknowledge the importance of lived gender identity in the resolution of forensic cases, the epidemic of anti-transgender violence, and the need to seek practical solutions. The current literature suggests that forensic anthropologists are becoming aware of these issues and are working toward efforts to improve identification of transgender and gender diverse (TGD) persons. The scope of the problem, however, is not limited to methodology and instead can be traced to systemic anti-trans stigma ingrained within our cultural institutions. As such, we call on forensic anthropologists to counteract cisgenderism and transphobia and promote gender equity and inclusion in their practice. In this paper, we identify three areas in which forensic anthropologists may be positioned to intervene on cisgenderist practices and systems: in casework, research, and education. This paper aims to provide strategies for forensic anthropologists to improve resolution of TGD cases, produce more nuanced, gender-informed research, and promote gender equity and inclusion in the field.
Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine
Authors: Lee Dongun , Hong Jeong Hee
Published: June 2023

Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.
Molecular Mechanism in the Development of Pulmonary Fibrosis in Patients with Sarcoidosis
Authors: Cocconcelli Elisabetta , Bernardinello Nicol , Castelli Gioele , Petrarulo Simone , Bellani Serena , Saetta Marina , Spagnolo Paolo , Balestro Elisabetta
Published: June 2023

Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of granulomas in various organs, especially lung and mediastinal hilar lymph nodes. The clinical course and manifestations are unpredictable: spontaneous remission can occur in approximately two thirds of patients; up to 20% of patients have chronic course of the lung disease (called advanced pulmonary sarcoidosis, APS) resulting in progressive loss of lung function, sometimes life-threatening that can lead to respiratory failure and death. The immunopathology mechanism leading from granuloma formation to the fibrosis in APS still remains elusive. Recent studies have provided new insights into the genetic factors and immune components involved in the clinical manifestation of the disease. In this review we aim to summarize the clinical-prognostic characteristics and molecular pathways which are believed to be associated with the development of APS.
Yeast Heterologous Expression Systems for the Study of Plant Membrane Proteins
Authors: Popova Larissa G. , Khramov Dmitrii E. , Nedelyaeva Olga I. , Volkov Vadim S.
Published: June 2023

Researchers are often interested in proteins that are present in cells in small ratios compared to the total amount of proteins. These proteins include transcription factors, hormones and specific membrane proteins. However, sufficient amounts of well-purified protein preparations are required for functional and structural studies of these proteins, including the creation of artificial proteoliposomes and the growth of protein 2D and 3D crystals. This aim can be achieved by the expression of the target protein in a heterologous system. This review describes the applications of yeast heterologous expression systems in studies of plant membrane proteins. An initial brief description introduces the widely used heterologous expression systems of the baker’s yeast Saccharomyces cerevisiae and the methylotrophic yeast Pichia pastoris. S. cerevisiae is further considered a convenient model system for functional studies of heterologously expressed proteins, while P. pastoris has the advantage of using these yeast cells as factories for producing large quantities of proteins of interest. The application of both expression systems is described for functional and structural studies of membrane proteins from plants, namely, K+- and Na+-transporters, various ATPases and anion transporters, and other transport proteins.
Effects of miR-33 Deficiency on Metabolic and Cardiovascular Diseases: Implications for Therapeutic Intervention
Authors: Ortega Rebeca , Liu Bo , Persaud Shanta J.
Published: June 2023

MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally inhibit gene expression. These small molecules are involved in several biological conditions such as inflammation, cell growth and proliferation, and regulation of energy metabolism. In the context of metabolic and cardiovascular diseases, miR-33 is of particular interest as it has been implicated in the regulation of lipid and glucose metabolism. This miRNA is located in introns harboured in the genes encoding sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, which are key transcription factors involved in lipid biosynthesis and cholesterol efflux. This review outlines the role of miR-33 in a range of metabolic and cardiovascular pathologies, such as dyslipidaemia, nonalcoholic fatty liver disease (NAFLD), obesity, diabetes, atherosclerosis, and abdominal aortic aneurysm (AAA), and it provides discussion about the effectiveness of miR-33 deficiency as a possible therapeutic strategy to prevent the development of these diseases.
The Critical Assessment of Oxidative Stress Parameters as Potential Biomarkers of Carbon Monoxide Poisoning
Authors: Hydzik Piotr , Francik Renata , Francik Sławomir , Gomółka Ewa , Eker Ebru Derici , Krośniak Mirosław , Noga Maciej , Jurowski Kamil
Published: June 2023

In conventional clinical toxicology practice, the blood level of carboxyhemoglobin is a biomarker of carbon monoxide (CO) poisoning but does not correspond to the complete clinical picture and the severity of the poisoning. Taking into account articles suggesting the relationship between oxidative stress parameters and CO poisoning, it seems reasonable to consider this topic more broadly, including experimental biochemical data (oxidative stress parameters) and patients poisoned with CO. This article aimed to critically assess oxidative-stress-related parameters as potential biomarkers to evaluate the severity of CO poisoning and their possible role in the decision to treat. The critically set parameters were antioxidative, including catalase, 2,2-diphenyl-1-picryl-hydrazyl, glutathione, thiol and carbonyl groups. Our preliminary studies involved patients (n = 82) admitted to the Toxicology Clinical Department of the University Hospital of Jagiellonian University Medical College (Kraków, Poland) during 2015–2020. The poisoning was diagnosed based on medical history, clinical symptoms, and carboxyhemoglobin blood level. Blood samples for carboxyhemoglobin and antioxidative parameters were collected immediately after admission to the emergency department. To evaluate the severity of the poisoning, the Pach scale was applied. The final analysis included a significant decrease in catalase activity and a reduction in glutathione level in all poisoned patients based on the severity of the Pach scale: I°–III° compared to the control group. It follows from the experimental data that the poisoned patients had a significant increase in level due to thiol groups and the 2,2-diphenyl-1-picryl-hydrazyl radical, with no significant differences according to the severity of poisoning. The catalase-to-glutathione and thiol-to-glutathione ratios showed the most important differences between the poisoned patients and the control group, with a significant increase in the poisoned group. The ratios did not differentiate the severity of the poisoning. The carbonyl level was highest in the control group compared to the poisoned group but was not statistically significant. Our critical assessment shows that using oxidative-stress-related parameters to evaluate the severity of CO poisoning, the outcome, and treatment options is challenging.
Characterization of Two Na+(K+, Li+)/H+ Antiporters from Natronorubrum daqingense
Authors: Wang Qi , Qiao Mengwei , Song Jinzhu
Published: June 2023

The Na+/H+ antiporter NhaC family protein is a kind of Na+/H+ exchanger from the ion transporter (IT) superfamily, which has mainly been identified in the halophilic bacteria of Bacillus. However, little is known about the Na+/H+ antiporter NhaC family of proteins in the extremely halophilic archaea. In this study, two Na+/H+ antiporter genes, nhaC1 and nhaC2, were screened from the genome of Natronorubrum daqingense based on the gene library and complementation of salt-sensitive Escherichia coli KNabc. A clone vector pUC18 containing nhaC1 or nhaC2 could make KNabc tolerate 0.6 M/0.7 M NaCl or 30 mM/40 mM LiCl and a pH of up to 8.5/9.5, respectively. Functional analysis shows that the Na+(K+, Li+)/H+ antiport activities of NhaC1 and NhaC2 are both pH-dependent in the range of pH 7.0–10.0, and the optimal pH is 9.5. Phylogenetic analysis shows that both NhaC1 and NhaC2 belong to the Na+/H+ antiporter NhaC family of proteins and are significantly distant from the identified NhaC proteins from Bacillus. In summary, we have identified two Na+(K+, Li+)/H+ antiporters from N. daqingense.
The Impact of Hypromellose on Pharmaceutical Properties of Alginate Microparticles as Novel Drug Carriers for Posaconazole
Authors: Kruk Katarzyna , Szekalska Marta , Basa Anna , Winnicka Katarzyna
Published: June 2023

Fungal infections are a group of diseases which are challenging to treat because of drug-resistant fungi species, drug toxicity, and often severe patient conditions. Hence, research into new treatments, including new therapeutic substances and novel drug delivery systems, is being performed. Mucoadhesive dosage forms are beneficial to improving drug bioavailability by prolonging the residence time at the site of application. Sodium alginate is a natural polymer with favorable mucoadhesive and gelling properties, although its precipitation in acidic pH significantly disrupts the process of drug release in gastric conditions. Hypromellose is a hydrophilic, semi-synthetic cellulose derivative with mucoadhesive properties, which is widely used as a control release agent in pharmaceutical technology. The aim of this study was to evaluate the impact of hypromellose on alginate microparticles with posaconazole, designed to modify drug release and to improve their mucoadhesive properties for both oral or vaginal application.
Identification of lncRNAs Deregulated in Epithelial Ovarian Cancer Based on a Gene Expression Profiling Meta-Analysis
Authors: Salamini-Montemurri Martín , Lamas-Maceiras Mónica , Lorenzo-Catoira Lidia , Vizoso-Vázquez Ángel , Barreiro-Alonso Aida , Rodríguez-Belmonte Esther , Quindós-Varela María , Cerdán M. Esperanza
Published: June 2023

Epithelial ovarian cancer (EOC) is one of the deadliest gynecological cancers worldwide, mainly because of its initially asymptomatic nature and consequently late diagnosis. Long non-coding RNAs (lncRNA) are non-coding transcripts of more than 200 nucleotides, whose deregulation is involved in pathologies such as EOC, and are therefore envisaged as future biomarkers. We present a meta-analysis of available gene expression profiling (microarray and RNA sequencing) studies from EOC patients to identify lncRNA genes with diagnostic and prognostic value. In this meta-analysis, we include 46 independent cohorts, along with available expression profiling data from EOC cell lines. Differential expression analyses were conducted to identify those lncRNAs that are deregulated in (i) EOC versus healthy ovary tissue, (ii) unfavorable versus more favorable prognosis, (iii) metastatic versus primary tumors, (iv) chemoresistant versus chemosensitive EOC, and (v) correlation to specific histological subtypes of EOC. From the results of this meta-analysis, we established a panel of lncRNAs that are highly correlated with EOC. The panel includes several lncRNAs that are already known and even functionally characterized in EOC, but also lncRNAs that have not been previously correlated with this cancer, and which are discussed in relation to their putative role in EOC and their potential use as clinically relevant tools.
Antibodies Capable of Enhancing SARS-CoV-2 Infection Can Circulate in Patients with Severe COVID-19
Authors: Matveev Andrey , Pyankov Oleg , Khlusevich Yana , Tyazhelkova Olga , Emelyanova Lyudmila , Timofeeva Anna , Shipovalov Andrey , Chechushkov Anton , Zaitseva Natalia , Kudrov Gleb , Yusubalieva Gaukhar , Yussubaliyeva Saule , Zhukova Oxana , Baklaushev Vladimir , Sedykh Sergey , Lifshits Galina , Tikunov Artem , Tikunova Nina
Published: June 2023

Antibody-dependent enhancement (ADE) has been shown previously for SARS-CoV-1, MERS-CoV, and SARS-CoV-2 infection in vitro. In this study, the first monoclonal antibody (mAb) that causes ADE in a SARS-CoV-2 in vivo model was identified. mAb RS2 against the SARS-CoV-2 S-protein was developed using hybridoma technology. mAb RS2 demonstrated sub-nanomolar affinity and ability to neutralize SARS-CoV-2 infection in vitro with IC50 360 ng/mL. In an animal model of SARS-CoV-2 infection, the dose-dependent protective efficacy of mAb RS2 was revealed. However, in post-exposure prophylaxis, the administration of mAb RS2 led to an increase in the viral load in the respiratory tract of animals. Three groups of blood plasma were examined for antibodies competing with mAb RS2: (1) plasmas from vaccinated donors without COVID-19; (2) plasmas from volunteers with mild symptoms of COVID-19; (3) plasmas from patients with severe COVID-19. It was demonstrated that antibodies competing with mAb RS2 were significantly more often recorded in sera from volunteers with severe COVID-19. The results demonstrated for the first time that in animals, SARS-CoV-2 can induce antibody/antibodies that can elicit ADE. Moreover, in the sera of patients with severe COVID-19, there are antibodies competing for the binding of an epitope that is recognized by the ADE-eliciting mAb.
A Novel Strategy for Screening Tumor-Specific Variable Domain of Heavy-Chain Antibodies
Authors: Rafique Abdur , Hichiwa Genki , Jatnika Muhammad Feisal , Ito Yuji
Published: June 2023

The properties of the variable domain of heavy-chain (VHH) antibodies are particularly relevant in cancer therapy. To isolate tumor cell-specific VHH antibodies, VHH phage libraries were constructed from multiple tumor cells. After enriching the libraries against particular tumor cell lines, a next-generation sequencer was used to screen the pooled phages of each library for potential antibody candidates. Based on high amplification folds, 50 sequences from each library were used to construct phylogenetic trees. Several clusters with identical CDR3 were observed. Groups X, Y, and Z were assigned as common sequences among the different trees. These identical groups over the trees were considered to be cross-reactive antibodies. To obtain monoclonal antibodies, we assembled 200 sequences (top 50 sequences from each library) and rebuilt a combined molecular phylogenetic tree. Groups were categorized as A–G. For each group, we constructed a phagemid and determined its binding specificity with tumor cells. The phage-binding results were consistent with the phylogenetic tree-generated groups, which indicated particular tumor-specific clusters; identical groups showed cross-reactivity. The strategy used in the current study is effective for screening and isolating monoclonal antibodies. Specific antibodies can be identified, even when the target markers of cancer cells are unknown.
A Comparative Study of Skin Changes in Different Species of Mice in Chronic Photoaging Models
Authors: Lin Meifen , Liu Xiaoran , Wang Xueer , Chen Yinyan , Zhang Yijia , Xu Jinfu , Bu Lingwei , Zhang Yarui , Liang Fengting , Zhang Xinyue , Huang Bingli , Zhang Min , Zhang Lin
Published: June 2023

This study aimed to design a novel mouse model of chronic photoaging. We used three different species of mice (C57BL/6J, ICR, and KM) to create a chronic photoaging model of the skin. The irradiation time was gradually increased for 40 consecutive days. The skins of the mice were removed on day 41 and subjected to staining to observe them for morphological changes. Immunohistochemistry was used to detect tumor necrosis factor-α (TNF-α) and p53 expression; superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as well. Compared with C57BL/J mice, which showed hyperpigmentation, the irradiated skin of ICR and KM mice showed more obvious skin thickening and photoaging changes of the collagen and elastic fibers. KM mice had higher levels of inflammation, oxidative stress, and senescent cells. Compared with the 5-month-old KM mice, the photoaging changes of the 9-month-old KM mice were more pronounced, the SOD values were lower, and the MDA values were higher. In summary, KM mice have higher levels of abnormal elastic fibers, inflammation, cellular senescence, and oxidative stress than ICR mice, and are more suitable for studies related to chronic skin photoaging. C57BL/6J mice were found to be suitable for studies related to skin pigmentation due to photoaging.
Oxytocin Modulates Osteogenic Commitment in Human Adipose-Derived Stem Cells
Authors: Petrocelli Giovannamaria , Abruzzo Provvidenza , Pampanella Luca , Tassinari Riccardo , Marini Serena , Zamagni Elena , Ventura Carlo , Facchin Federica , Canaider Silvia
Published: June 2023

Human adipose-derived stem cells (hASCs) are commonly harvested in minimally invasive contexts with few ethical concerns, and exhibit self-renewal, multi-lineage differentiation, and trophic signaling that make them attractive candidates for cell therapy approaches. The identification of natural molecules that can modulate their biological properties is a challenge for many researchers. Oxytocin (OXT) is a neurohypophyseal hormone that plays a pivotal role in the regulation of mammalian behavior, and is involved in health and well-being processes. Here, we investigated the role of OXT on hASC proliferation, migratory ability, senescence, and autophagy after a treatment of 72 h; OXT did not affect hASC proliferation and migratory ability. Moreover, we observed an increase in SA-β-galactosidase activity, probably related to the promotion of the autophagic process. In addition, the effects of OXT were evaluated on the hASC differentiation ability; OXT promoted osteogenic differentiation in a dose-dependent manner, as demonstrated by Alizarin red staining and gene/protein expression analysis, while it did not affect or reduce adipogenic differentiation. We also observed an increase in the expression of autophagy marker genes at the beginning of the osteogenic process in OXT-treated hASCs, leading us to hypothesize that OXT could promote osteogenesis in hASCs by modulating the autophagic process.
The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment
Authors: Isola Jorma , Mäki Markku , Hils Martin , Pasternack Ralf , Viiri Keijo , Dotsenko Valeriia , Montonen Toni , Zimmermann Timo , Mohrbacher Ralf , Greinwald Roland , Schuppan Detlef
Published: June 2023

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crosslinking of gliadin peptides. Our aim was to study the accumulation of ZED1227 after oral administration of the drug. We studied duodenal biopsies derived from a phase 2a clinical drug trial using an antibody that detects ZED1227 when bound to the catalytic center of TG2. Human epithelial organoids were studied in vitro for the effect of ZED1227 on the activity of TG2 using the 5-biotin-pentylamine assay. The ZED1227-TG2 complex was found mainly in the villous enterocytes in post-treatment biopsies. The signal of ZED1227-TG2 was strongest in the luminal epithelial brush border, while the intensity of the signal in the lamina propria was only ~20% of that in the villous enterocytes. No signal specific to ZED1227 could be detected in pretreatment biopsies or in biopsies from patients randomized to the placebo treatment arm. ZED1227-TG2 staining co-localized with total TG2 and native and deamidated gliadin peptides on the enterocyte luminal surface. Inhibition of TG2 activity by ZED1227 was demonstrated in epithelial organoids. Our findings suggest that active TG2 is present at the luminal side of the villous epithelium and that inhibition of TG2 activity by ZED1227 occurs already there before gliadin peptides enter the lamina propria.
PROTEIN PHOSPHATASE 2C08, a Negative Regulator of Abscisic Acid Signaling, Promotes Internode Elongation in Rice
Authors: Song Jaeeun , Ga Eunji , Park Sangkyu , Lee Hyo , Yoon In Sun , Lee Saet Buyl , Lee Jong-Yeol , Kim Beom-Gi
Published: June 2023

Clade A protein phosphatase 2Cs (PP2CAs) negatively regulate abscisic acid (ABA) signaling. Here, we investigated the functions of OsPP2CAs and their crosstalk with ABA and gibberellic acid (GA) signaling pathways in rice (Oryza sativa). Among the nine OsPP2CAs, OsPP2C08 had the highest amino acid sequence similarity with OsPP2C51, which positively regulates GA signaling in rice seed germination. However, OsPP2C08 was expressed in different tissues (internodes, sheaths, and flowers) compared to OsPP2C51, which was specifically expressed in seeds, and showed much stronger induction under abiotic stress than OsPP2C51. Transgenic rice lines overexpressing OsPP2C08 (OsPP2C08-OX) had a typical ABA-insensitive phenotype in a post-germination assay, indicating that OsPP2C08, as with other OsPP2CAs, negatively regulates ABA signaling. Furthermore, OsPP2C08-OX lines had longer stems than wild-type (WT) plants due to longer internodes, especially between the second and third nodes. Internode cells were also longer in OsPP2C08-OX lines than in the WT. As GA positively regulates plant growth, these results suggest that OsPP2C08 might positively regulate GA biosynthesis. Indeed, the expression levels of GA biosynthetic genes including gibberellin 20-oxidase (OsGA20ox4) and Ent-kaurenoic acid oxidase (OsKAO) were increased in OsPP2C08-OX lines, and we observed that GIBBERELLIN 2-OXIDASE 4 (OsGA2ox4), encoding an oxidase that catalyzes the 2-beta-hydroxylation of several biologically active GAs, was repressed in the OsPP2C08-OX lines based on a transcriptome deep sequencing and RT-qPCR analysis. Furthermore, we compared the accumulation of SLENDER RICE 1 (SLR1), a DELLA protein involved in GA signaling, in OsPP2C08-OX and WT plants, and observed lower levels of SLR1 in the OsPP2C08-OX lines than in the WT. Taken together, our results reveal that OsPP2C08 negatively regulates ABA signaling and positively regulates GA signaling in rice. Our study provides valuable insight into the molecular mechanisms underlying the crosstalk between GA and ABA signaling in rice.
Lung Surfactant Protein B Peptide Mimics Interact with the Human ACE2 Receptor
Authors: Waring Alan J. , Jung Grace C.-L. , Sharma Shantanu K. , Walther Frans J.
Published: June 2023

Lung surfactant is a complex mixture of phospholipids and surfactant proteins that is produced in alveolar type 2 cells. It prevents lung collapse by reducing surface tension and is involved in innate immunity. Exogenous animal-derived and, more recently, synthetic lung surfactant has shown clinical efficacy in surfactant-deficient premature infants and in critically ill patients with acute respiratory distress syndrome (ARDS), such as those with severe COVID-19 disease. COVID-19 pneumonia is initiated by the binding of the viral receptor-binding domain (RBD) of SARS-CoV-2 to the cellular receptor angiotensin-converting enzyme 2 (ACE2). Inflammation and tissue damage then lead to loss and dysfunction of surface activity that can be relieved by treatment with an exogenous lung surfactant. Surfactant protein B (SP-B) is pivotal for surfactant activity and has anti-inflammatory effects. Here, we study the binding of two synthetic SP-B peptide mimics, Super Mini-B (SMB) and B-YL, to a recombinant human ACE2 receptor protein construct using molecular docking and surface plasmon resonance (SPR) to evaluate their potential as antiviral drugs. The SPR measurements confirmed that both the SMB and B-YL peptides bind to the rhACE2 receptor with affinities like that of the viral RBD–ACE2 complex. These findings suggest that synthetic lung surfactant peptide mimics can act as competitive inhibitors of the binding of viral RBD to the ACE2 receptor.
Focus on Prevention: Peripheral Arterial Disease and the Central Role of the Cardiologist
Authors: Fioretti Vincenzo , Gerardi Donato , Giugliano Giuseppe , Di Fazio Aldo , Stabile Eugenio
Published: June 2023

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerotic disease. PAD patients have a poor prognosis with an increased risk of cardiovascular (CV) events, including myocardial infarction (MI), stroke, limb ischemia and CV death; therefore, it is important to detect and treat PAD early. PAD and coronary artery disease (CAD) share a common pathogenesis and risk factors for development; therefore, cardiologists are in a unique position to screen, diagnosis and treat PAD. Moreover, PAD and CAD also share some treatment goals, including an aggressive modification of risk factors to reduce the risk of CV events. However, PAD remains an underdiagnosed and undertreated disease with medico-legal implications. As the role of cardiologists is expanding, the purpose of this review was to awaken the clinicians to the significance of PAD.
Risk Stratification in Pulmonary Arterial Hypertension, Update and Perspectives
Authors: Vraka Argyro , Diamanti Eleni , Kularatne Mithum , Yerly Patrick , Lador Frédéric , Aubert John-David , Lechartier Benoit
Published: June 2023

Risk stratification in pulmonary arterial hypertension (PAH) is crucial in assessing patient prognosis. It serves a prominent role in everyday patient care and can be determined using several validated risk assessment scores worldwide. The recently published 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines underline the importance of risk stratification not only at baseline but also during follow-up. Achieving a low-risk status has now become the therapeutic goal, emphasising the importance of personalised therapy. The application of these guidelines is also important in determining the timing for lung transplantation referral. In this review, we summarise the most relevant prognostic factors of PAH as well as the parameters used in PAH risk scores and their evolution in the guidelines over the last decade. Finally, we describe the central role that risk stratification plays in the current guidelines not only in European countries but also in Asian countries.
High Prevalence of Non-Responders Based on Quadriceps Force after Pulmonary Rehabilitation in COPD
Authors: Desachy Marion , Alexandre François , Varray Alain , Molinier Virginie , Four Elodie , Charbonnel Laurène , Héraud Nelly
Published: June 2023

Pulmonary rehabilitation (PR) in patients with COPD improves quality of life, dyspnea, and exercise tolerance. However, 30 to 50% of patients are “non-responders” (NRs) according to considered variables. Surprisingly, peripheral muscle force is never taken into account to attest the efficacy of PR, despite its major importance. Thus, we aimed to estimate the prevalence of force in NRs, their characteristics, and predictors of non-response. In total, 62 COPD patients were included in this retrospective study (May 2019 to December 2020). They underwent inpatient PR, and their quadriceps isometric maximal force (QMVC) was assessed. The PR program followed international guidelines. Patients with a QMVC increase <7.5 N·m were classified as an NR. COPD patients showed a mean improvement in QMVC after PR (10.08 ± 12.97 N·m; p < 0.001). However, 50% of patients were NRs. NRs had lower pre-PR values for body mass, height, body mass index, PaO2, and QMVC. Non-response can be predicted by low QMVC, high PaCO2, and gender (when male). This model has a sensitivity of 74% and specificity of 81%. The study highlights the considerable number of NRs and potential risk factors for non-response. To systematize the effects, it may be interesting to implement blood gas correction and/or optimize the programs to enhance peripheral and central effects.
Total Knee Arthroplasty in Haemophilia: Long-Term Results and Survival Rate of a Modern Knee Implant with an Oxidized Zirconium Femoral Component
Authors: Carulli Christian , Innocenti Matteo , Tambasco Rinaldo , Perrone Alessandro , Civinini Roberto
Published: June 2023

(1) Background: Total Knee Arthroplasty (TKA) in patient with haemophilia (PWH) has usually been performed with the use of cobalt-chrome femoral and titanium tibial components, coupled with standard polyethylene (PE) inserts. The aim of this retrospective study was to evaluate the long-term outcomes and survival rates of TKA in a series of consecutive PWH affected by severe knee arthropathy at a single institution. (2) Methods: We followed 65 patients undergoing 91 TKA, implanted using the same implant, characterized by an oxidized zirconium femoral component, coupled with a titanium tibial component, and a highly crosslinked PE. At 1, 6, and 12 months; then every year for 5 years; and finally, every other 3 years, all patients were scored for pain (VAS), function (HJHS; KSS), ROM, and radiographic changes. Kaplan–Meier survivorship curves were used to calculate the implant survival rates. (3) Results: The mean follow-up was 12.3 years (4.2–20.6). All clinical and functional scores improved significantly from preoperatively to the latest follow-up (VAS: from 6.9 to 1.3; HJHS: from 13.4 to 1.9; KSS: from 19.4 to 79; ROM: from 42.4° to 83.6°). The overall survivorship of the implants was 97.5% at the latest follow-up. (4) Conclusions: The present series showed a high survival rate of specific implants potentially linked to the choice of an oxidized zirconium coupled with a highly crosslinked PE. We promote the use of modern implants in these patients in order to ensure long-lasting positive outcomes.
Machine-Learning-Based Tool to Predict Target Prostate Biopsy Outcomes: An Internal Validation Study
Authors: Checcucci Enrico , Rosati Samanta , De Cillis Sabrina , Giordano Noemi , Volpi Gabriele , Granato Stefano , Zamengo Davide , Verri Paolo , Amparore Daniele , De Luca Stefano , Manfredi Matteo , Fiori Cristian , Di Dio Michele , Balestra Gabriella , Porpiglia Francesco
Published: June 2023

The aim of this study is to present a personalized predictive model (PPM) with a machine learning (ML) system that is able to identify and classify patients with suspected prostate cancer (PCa) following mpMRI. We extracted all the patients who underwent fusion biopsy (FB) from March 2014 to December 2019, while patients from August 2020 to April 2021 were included as a validation set. The proposed system was based on the following four ML methods: a fuzzy inference system (FIS), the support vector machine (SVM), k-nearest neighbors (KNN), and self-organizing maps (SOMs). Then, a system based on fuzzy logic (FL) + SVM was compared with logistic regression (LR) and standard diagnostic tools. A total of 1448 patients were included in the training set, while 181 patients were included in the validation set. The area under the curve (AUC) of the proposed FIS + SVM model was comparable with the LR model but outperformed the other diagnostic tools. The FIS + SVM model demonstrated the best performance, in terms of negative predictive value (NPV), on the training set (78.5%); moreover, it outperformed the LR in terms of specificity (92.1% vs. 83%). Considering the validation set, our model outperformed the other methods in terms of NPV (60.7%), sensitivity (90.8%), and accuracy (69.1%). In conclusion, we successfully developed and validated a PPM tool using the FIS + SVM model to calculate the probability of PCa prior to a prostate FB, avoiding useless ones in 15% of the cases.
Risk Scoring Systems for Preterm Birth and Their Performance: A Systematic Review
Authors: Ferreira Amaro , Bernardes João , Gonçalves Hernâni
Published: June 2023

Introduction: Nowadays, the risk stratification of preterm birth (PTB) and its prediction remain a challenge. Many risk factors associated with PTB have been identified, and risk scoring systems (RSSs) have been developed to face this challenge. The objectives of this systematic review were to identify RSSs for PTB, the variables they consist of, and their performance. Materials and methods: Two databases were searched, and two authors independently performed the screening and eligibility phases. Records studying an RSS, based on specified variables, with an evaluation of the predictive value for PTB, were considered eligible. Reference lists of eligible studies and review articles were also searched. Data from the included studies were extracted. Results: A total of 56 studies were included in this review. The most frequently incorporated variables in the RSS included in this review were maternal age, weight, history of smoking, history of previous PTB, and cervical length. The performance measures varied widely among the studies, with sensitivity ranging between 4.2% and 92.0% and area under the curve (AUC) between 0.59 and 0.95. Conclusions: Despite the recent technological and scientifical evolution with a better understanding of variables related to PTB and the definition of new ultrasonographic parameters and biomarkers associated with PTB, the RSS’s ability to predict PTB remains poor in most situations, thus compromising the integration of a single RSS in clinical practice. The development of new RSSs, the identification of new variables associated with PTB, and the elaboration of a large reference dataset might be a step forward to tackle the problem of PTB.
Guideline-Adherent Hypertension in Children and Adolescents: A Multi-Institutional Database Analysis from Taiwan
Authors: Chien Shao-Ju , Li Lung-Chih , Kuo Hsiao-Ching , Tain You-Lin , Hsu Chien-Ning
Published: June 2023

Background/Aims: Childhood-onset hypertension is associated with cardiovascular morbidity and adult mortality. This study aimed to assess guideline-adherent hypertension among Taiwanese youth and the agreement on hypertension between the 2017 American Academy of Pediatrics guidelines and the 2004 Fourth Report. Methods: In this cross-sectional study, we collected outpatient blood pressure (OBP) measurements obtained during routine care visits from a large healthcare delivery system between 2009 and 2018 to evaluate the rate of guideline-adherent hypertension and assess patient-related factors of pediatric hypertension. Results: In total, 12,469 children and adolescents who underwent three separate ≥3 OBP measurements over 33,369 person-years with a total of 95,608 BP measurements in an outpatient setting were analyzed. According to the 2017 American Academy of Pediatrics (AAP) guidelines, the rate of pediatric hypertension in the study setting, which included participants aged 1 to 17 years, ranged from 0.78 to 5.95 per 1000 persons. Although there was perfect agreement between the thresholds of the two guidelines for defining hypertension in the age groups of 1–7, 8–12, and 13–17 years (all κ statistic ≥ 0.85), the use of the AAP threshold classified more adolescents as having hypertension. Children and adolescents with hypertension often had complex chronic diseases and required substantial healthcare services in outpatient, emergency, and inpatient settings. Conclusions: The present study provides evidence of guideline-adherent pediatric hypertension and highlights the importance of regularly monitoring blood pressure to identify and manage hypertension in children and adolescents. Further research is required to determine the impact of new thresholds on the detection of target organ damage at a pediatric age.
CFD Analysis of Biofouling Effect on Submarine Resistance and Wake
Authors: Utama I Ketut Aria Pria , Farhan Fertisio , Nasirudin Ahmad , Ariesta Rizky Chandra , Renilson Martin Robert
Published: June 2023

It is well known that biofouling increases a ship’s resistance and nominal wake. For submarines, any change to the circumferential variation of the nominal wake in the propeller plane will affect the variation of the flow over the propeller blade, and hence the fluctuating forces, and noise, generated by the propeller. The ANSYS FLUENT commercial Reynolds-Averaged Navier Stokes Computational Fluid Dynamics solver was used to investigate the influence of both the longitudinal and vertical distribution of biofouling on the resistance and wake, including the circumferential variation of the nominal wake, on a submarine, using the well-known Suboff standard submarine. For the present work, the k-ε turbulence model was selected, as this is commonly used in this field and is generally considered acceptable. To handle different boundary layer thicknesses in the flow fields, the whole y+ formulation was employed, enabling automatic switching between low and high Reynolds boundary wall models. The numerical solver used for the simulations is based on the finite volume method, which discretizes the RANS equations. In this approach, a segregated model was utilized in the solver, and the convection terms were discretized using the second-order upwind scheme to enhance solution accuracy. The criteria for the near wall are between 30 and 100, and the value of y+ for the present case is 84. It is shown that fouling over only the forward third of the submarine results in a greater increase in resistance than fouling over only the aft third. Fouling over only the lower half of the submarine results in greater resistance than fouling over only the forward third, but less than fouling over the whole of the hull. Fouling over only the forward third of the hull has less influence on the circumferential variation of the wake than fouling over the aft third only of the hull. The results show the importance of keeping the forward area of the hull clean when considering resistance only, whereas keeping the aft area of the hull clean is important when considering the uniformity of the nominal wake into the propeller.