bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis–van Creveld Syndrome
Authors: Negrete-Torres Nancy , Chima-Galán María del Carmen , Sierra-López Ernesto Antonio , Sánchez-Ramos Janet , Álvarez-González Isela , Reyes-Reali Julia , Mendoza-Ramos María Isabel , Garrido-Guerrero Efraín , Amato Dante , Méndez-Catalá Claudia Fabiola , Pozo-Molina Glustein , Méndez-Cruz Adolfo René
Published: April 2023

Background: Ellis–van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients. Methods: Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made. Results: One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis–van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons. Conclusion: The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis–van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.
Effect of Mobile Health Interventions on Lifestyle and Anthropometric Characteristics of Uncontrolled Hypertensive Participants: Secondary Analyses of a Randomized Controlled Trial
Authors: David Caroline Nespolo , Iochpe Cirano , Harzheim Erno , Sesin Guilhermo Prates , Gonçalves Marcelo Rodrigues , Moreira Leila Beltrami , Fuchs Flavio Danni , Fuchs Sandra Costa
Published: April 2023

Our objective was to evaluate the effect of a mobile health (mHealth) intervention on lifestyle adherence and anthropometric characteristics among individuals with uncontrolled hypertension. We performed a randomized controlled trial (ClinicalTrials.gov NCT03005470) where all participants received lifestyle counseling at baseline and were randomly allocated to receive (1) an automatic oscillometric device to measure and register blood pressure (BP) via a mobile application, (2) personalized text messages to stimulate lifestyle changes, (3) both mHealth interventions, or (4) usual clinical treatment (UCT) without technology (control). The outcomes were achieved for at least four of five lifestyle goals (weight loss, not smoking, physical activity, moderate or stopping alcohol consumption, and improving diet quality) and improved anthropometric characteristics at six months. mHealth groups were pooled for the analysis. Among 231 randomized participants (187 in the mHealth group and 45 in the control group), the mean age was 55.4 ± 9.5 years, and 51.9% were men. At six months, achieving at least four of five lifestyle goals was 2.51 times more likely (95% CI: 1.26; 5.00, p = 0.009) to be achieved among participants receiving mHealth interventions. The between-group difference reached clinically relevant, but marginally significant, reduction in body fat (−4.05 kg 95% CI: −8.14; 0.03, p = 0.052), segmental trunk fat (−1.69 kg 95% CI: −3.50; 0.12, p = 0.067), and WC (−4.36 cm 95% CI: −8.81; 0.082, p = 0.054), favoring the intervention group. In conclusion, a six-month lifestyle intervention supported by application-based BP monitoring and text messages significantly improves adherence to lifestyle goals and is likely to reduce some anthropometric characteristics in comparison with the control without technology support.
Effectiveness of Respiratory Rehabilitation in COVID-19’s Post-Acute Phase: A Systematic Review
Authors: Tamburlani Matteo , Cuscito Rossana , Servadio Annamaria , Galeoto Giovanni
Published: April 2023

Background: The COVID-19 pandemic, caused by the new grave and acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), generated an unprecedented danger to public health. This condition may impact survivors’ quality of life and includes extensive pulmonary and respiratory outcomes. Respiratory rehabilitation is known for its effects in improving dyspnea, alleviating anxiety and depression, reducing complications, preventing and ameliorating dysfunctions, reducing morbidity, preserving functions and improving subjects’ quality of life. For this reason, respiratory rehabilitation may be recommended for this category of patients. Objective: Our objective was to evaluate the effectiveness and benefits produced by the adoption of pulmonary rehabilitation (PR) programs in COVID-19’s post-acute phase. Material and Methods: A search of relevant publications was conducted using the following electronic databases: PubMed, Scopus, PEDro, and Cochrane Library. A single reviser selected pertinent articles that studied the effects of pulmonary rehabilitation during COVID-19’s post-acute phase in improving the respiratory function, physical performance, autonomy and quality of life (QoL). Results: After an initial selection, 18 studies were included in this systematic review, of which 14 concern respiratory rehabilitation delivered in conventional form and 4 concern respiratory rehabilitation provided in telehealth. Conclusions: Pulmonary rehabilitation combining different types of training—breathing, aerobic, fitness and strength—and not bypassing the neuropsychological aspects revealed itself to be capable of improving pulmonary and muscular functions, general health and quality of life in post-acute COVID-19 patients, besides increasing workout capacity and muscle strength, improving fatigue states and reducing anxiety and depression.
Changes in Injury Pattern and Outcomes of Trauma Patients after COVID-19 Pandemic: A Retrospective Cohort Study
Authors: Jang Myungjin , Lee Mina , Lee Giljae , Lee Jungnam , Choi Kangkook , Yu Byungchul
Published: April 2023

The COVID-19 pandemic, starting in 2020, changed the daily activities of people in the world and it might also affect patterns of major trauma. This study aimed to compare the epidemiology and outcomes of trauma patients before and after the COVID-19 outbreak. This was a retrospective study, conducted in a single regional trauma center in Korea, and patients were grouped as pre- and post-COVID-19 and compared in terms of demographics, clinical characteristics, and clinical outcomes. A total of 4585 patients were included in the study and the mean age was 57.60 ± 18.55 and 59.06 ± 18.73 years in the pre- and post-COVID-19 groups, respectively. The rate of elderly patients (age ≥ 65) significantly increased in the post-COVID-19 group. In terms of injury patterns, self-harm was significantly increased after COVID-19 (2.6% vs. 3.5%, p = 0.021). Mortality, hospital length of stay, 24 h, and transfusion volume were not significantly different. Among the major complications, acute kidney injury, surgical wound infection, pneumonia, and sepsis were significantly different between the groups. This study revealed changes in the age of patients, injury patterns and severity, and major complication rates after the COVID-19 outbreak.
Wheeled and Seated Mobility Devices Provision: Quantitative Findings and SWOT Thematic Analysis of a Global Occupational Therapist Survey
Authors: Sarsak Hassan Izzeddin , von Zweck Claudia , Ledgerd Ritchard ,   on behalf of the World Federation of Occupational Therapists
Published: April 2023

Purpose: To better understand the global role of occupational therapists and explore facilitators and barriers impacting user access to high quality, affordable wheeled and seated mobility device (WSMD) provision worldwide. Methods: Mixed-method approach utilizing quantitative findings and qualitative strengths, weaknesses, opportunities, and threats (SWOT) analysis of a global online survey. Results: A total of 696 occupational therapists from 61 countries completed the survey. Almost 49% had 10 or more years of experience with the provision of WSMDs. WSMD provision had positive, significant associations with attainment of certification (0.000), higher service funding (0.000), higher country income (0.001), standardized training (0.003), continuous professional development (0.004), higher experience (0.004), higher user satisfaction (0.032), custom-made device provision (0.038), higher staff capacity (0.040), and more time working with users (0.050); negative, significant associations were identified with high cost of WSMDs (0.006) and pre-made device provision (0.019). SWOT analysis identified high country income, funding, experience, training, certification from global partners, variety of roles and practice settings, and interdisciplinary teamwork as strengths and opportunities for professional growth, while low country income, lack of time/staff capacity/standardization/support services, and poor access to proper devices were indicated as weaknesses and threats. Conclusion: Occupational therapists are skilled healthcare professionals and provide a variety of WSMD services. Efforts to build collaborative partnerships, enhance access to occupational therapists and funding options, improve service and standards for WMSD service delivery, and promote professional development will help to overcome challenges and facilitate WSMD provision globally. Promoting practices based on best available evidence for WSMD provision worldwide should be prioritized.
The Moderating Effects of Social Responsibility Climate and Safety Climate in Keeping Healthcare Workers’ Engagement during COVID-19
Authors: Ding Bin , Miao Tianyi
Published: April 2023

Objective: The outbreak of COVID-19 brings an overload of physical and mental demands to healthcare professionals. Keeping healthcare professionals sustainable, engaged, and performing at their highest levels becomes critical and nonetheless difficult. The objective of this research is to link the literature on organizational climates, corporate social responsibility, safety science, and work engagement, and propose a research framework that investigates the factors influencing healthcare professionals’ engagement during COVID-19. Methodology: We propose that when healthcare workers’ career callings are triggered by COVID-19, it influences their perceptions of the work’s meaningfulness, which ultimately enhances their work engagement. We argue that creating a social responsibility climate and a safety climate inside the hospital facilitates the process of turning healthcare workers’ perceived work meaningfulness into work engagement. We collected data from 112 healthcare professionals, including nurses, doctors, and executive staff, from 16 wards in a public hospital in China to test our hypotheses. Results: Hierarchical linear regression analysis provided empirical support for our research model. We find that healthcare professionals’ career callings during COVID-19 enhanced their perceived work meaningfulness, which results in increased work engagement. Moreover, a social responsibility climate and a safety climate strengthens the link between work meaningfulness and work engagement among participants. Conclusions: Creating a social responsibility climate and a safety climate in the workplace are effective management approaches to realize healthcare workers’ feelings of work meaningfulness and turn them into work engagement.
Traditional Natural Dyeing Materials Used in Greece from the 19th Century Onwards
Authors: Tsatsarou Athanasia , Alexopoulou Athina , Macha Nadia Bizoumi , Karatzani Anna
Published: April 2023

Textiles and clothing were and still are an important source of culture as well as an indicator of a robust economy and social status. Textile household goods and clothing are important heirlooms, providing valuable information about the standard of living, socio-political events, and cultural influences of the regions from which they originate. This paper presents the preliminary results of a research project dealing with the traditional natural dyes used in Greece for the decoration of garments from the 19th century onwards (from the 19th until the mid-20th century). The research aims to identify and record all the different plants and dyeing techniques used in Greece during this period and also to propose a non-destructive methodology for the study of dyed textiles in order to facilitate their preservation. In this paper, the focus is on the presentation of the classification and identification data of the plants used as the dyeing sources, according to recipes collected in various areas in Greece, as well as the description of their botanical characteristics. The research was based on the study of more than 2000 manuscripts and many interviews with older people who have used these materials. Thus, more than 140 plants have been documented, together with their recipes. The data produced include the phytological characteristics of the plants, as well as the parts of the plant used, the period collected and the areas they were used, together with images of the plants and various details regarding the recipes used in many places around Greece, along with the related documentation. The study also refers to ethics and traditions related to the dyes, the color, or the dyeing procedures used. Woolen samples were prepared based on the data collected in order to investigate how the differences recorded from place to place are reflected in the final result. Through this research, it was possible to identify and replicate some of the non-common recipes which use the Mediterranean strawflower, Helichrysum stoechas (L.) Moench, red algae, Rytiphloea tinctoria (Clemente) C.Agardh, and the common poppy Papaver rhoeas L as dyestuffs.
A Tale of Two Cities: COVID-19 Vaccine Hesitancy as a Result of Racial, Socioeconomic, Digital, and Partisan Divides
Authors: Li Rui , Erickson Daniel , Belcaid Mareyam , Chinedu Madu Franklin , Akanbi Oluwabukola Olufunke
Published: April 2023

The unprecedented COVID-19 pandemic has drawn great attention to the issue of vaccine hesitancy, as the acceptance of the innovative RNA vaccine is relatively low. Studies have addressed multiple factors, such as socioeconomic, political, and racial backgrounds. These studies, however, rely on survey data from participants as part of the population. This study utilizes the actual data from the U.S. Census Bureau as well as actual 2020 U.S. presidential election results to generate four major category of factors that divide the population: socioeconomic status, race and ethnicity, access to technology, and political identification. This study then selects a region in a traditionally democratic state (Capital Region in New York) and a region in a traditionally republican state (Houston metropolitan area in Texas). Statistical analyses such as correlation and geographically weighted regression reveal that factors such as political identification, education attainment, and non-White Hispanic ethnicity in both regions all impact vaccine acceptance significantly. Other factors, such as poverty and particular minority races, have different influences in each region. These results also highlight the necessity of addressing additional factors to further shed light on vaccine hesitancy and potential solutions according to identified factors.
SAM-GAN: Supervised Learning-Based Aerial Image-to-Map Translation via Generative Adversarial Networks
Authors: Xu Jian , Zhou Xiaowen , Han Chaolin , Dong Bing , Li Hongwei
Published: April 2023

Accurate translation of aerial imagery to maps is a direction of great value and challenge in mapping, a method of generating maps that does not require using vector data as traditional mapping methods do. The tremendous progress made in recent years in image translation based on generative adversarial networks has led to rapid progress in aerial image-to-map translation. Still, the generated results could be better regarding quality, accuracy, and visual impact. This paper proposes a supervised model (SAM-GAN) based on generative adversarial networks (GAN) to improve the performance of aerial image-to-map translation. In the model, we introduce a new generator and multi-scale discriminator. The generator is a conditional GAN model that extracts the content and style space from aerial images and maps and learns to generalize the patterns of aerial image-to-map style transformation. We introduce image style loss and topological consistency loss to improve the model’s pixel-level accuracy and topological performance. Furthermore, using the Maps dataset, a comprehensive qualitative and quantitative comparison is made between the SAM-GAN model and previous methods used for aerial image-to-map translation in combination with excellent evaluation metrics. Experiments showed that SAM-GAN outperformed existing methods in both quantitative and qualitative results.
RNA-Dependent RNA Targeting by CRISPR-Cas Systems: Characterizations and Applications
Authors: Gunitseva Natalia , Evteeva Marta , Borisova Anna , Patrushev Maxim , Subach Fedor
Published: April 2023

Genome editing technologies that are currently available and described have a fundamental impact on the development of molecular biology and medicine, industrial and agricultural biotechnology and other fields. However, genome editing based on detection and manipulation of the targeted RNA is a promising alternative to control the gene expression at the spatiotemporal transcriptomic level without complete elimination. The innovative CRISPR-Cas RNA-targeting systems changed the conception of biosensing systems and also allowed the RNA effectors to be used in various applications; for example, genomic editing, effective virus diagnostic tools, biomarkers, transcription regulations. In this review, we discussed the current state-of-the-art of specific CRISPR-Cas systems known to bind and cleave RNA substrates and summarized potential applications of the versatile RNA-targeting systems.
IRAPs in Combination with Highly Informative ISSRs Confer Effective Potentials for Genetic Diversity and Fidelity Assessment in Rhododendron
Authors: Wen Sulin , Zhao Hong , Zhang Manying , Qiao Guang , Shen Xiaohui
Published: April 2023

The species belonging to the Rhododendron genus are well-known for their colorful corolla. Molecular marker systems have the potential to elucidate genetic diversity as well as to assess genetic fidelity in rhododendrons. In the present study, the reverse transcription domains of long terminal repeat retrotransposons were cloned from rhododendrons and used to develop an inter-retrotransposon amplified polymorphism (IRAP) marker system. Subsequently, 198 polymorphic loci were generated from the IRAP and inter-simple sequence repeat (ISSR) markers, of which 119 were derived from the IRAP markers. It was shown that in rhododendrons, IRAP markers were superior to the ISSRs in some polymorphic parameters, such as the average number of polymorphic loci (14.88 versus 13.17). The combination of the IRAP and ISSR systems was more discriminative for detecting 46 rhododendron accessions than each of the systems on their own. Furthermore, IRAP markers demonstrated more efficiency in genetic fidelity detection of in-vitro-grown R. bailiense Y.P.Ma, C.Q.Zhang and D.F.Chamb, an endangered species recently recorded in Guizhzhou Province, China. The available evidence revealed the distinct properties of IRAP and ISSR markers in the rhododendron-associated applications, and highlighted the availability of highly informative ISSR and IRAP markers in the evaluation of genetic diversity and genetic fidelity of rhododendrons, which may facilitate preservation and genetic breeding of rhododendron plants.
YTHDF1 Promotes Bladder Cancer Cell Proliferation via the METTL3/YTHDF1–RPN2–PI3K/AKT/mTOR Axis
Authors: Zhu Junlong , Tong Hang , Sun Yan , Li Tinghao , Yang Guang , He Weiyang
Published: April 2023

N6-methyladenosine (m6A) is the most common mRNA modification and it plays a critical role in tumor progression, prognoses and therapeutic response. In recent years, more and more studies have shown that m6A modifications play an important role in bladder carcinogenesis and development. However, the regulatory mechanisms of m6A modifications are complex. Whether the m6A reading protein YTHDF1 is involved in the development of bladder cancer remains to be elucidated. The aims of this study were to determine the association between METTL3/YTHDF1 and bladder cancer cell proliferation and cisplatin resistance to explore the downstream target genes of METTL3/YTHDF1 and to explore the therapeutic implications for bladder cancer patients. The results showed that the reduced expression of METTL3/YTHDF1 could lead to decreased bladder cancer cell proliferation and cisplatin sensitivity. Meanwhile, overexpression of the downstream target gene, RPN2, could rescue the effect of reduced METTL3/YTHDF1 expression on bladder cancer cells. In conclusion, this study proposes a novel METTL3/YTHDF1–RPN2–PI3K/AKT/mTOR regulatory axis that affects bladder cancer cell proliferation and cisplatin sensitivity.
Dual-Stimuli-Sensitive Smart Hydrogels Containing Magnetic Nanoparticles as Antitumor Local Drug Delivery Systems—Synthesis and Characterization
Authors: Kasiński Adam , Świerczek Agata , Zielińska-Pisklak Monika , Kowalczyk Sebastian , Plichta Andrzej , Zgadzaj Anna , Oledzka Ewa , Sobczak Marcin
Published: April 2023

The aim of this study was to develop an innovative, dual-stimuli-responsive smart hydrogel local drug delivery system (LDDS), potentially useful as an injectable simultaneous chemotherapy and magnetic hyperthermia (MHT) antitumor treatment device. The hydrogels were based on a biocompatible and biodegradable poly(ε-caprolactone-co-rac-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-rac-lactide) (PCLA-PEG-PCLA, PCLA) triblock copolymer, synthesized via ring-opening polymerization (ROP) in the presence of a zirconium(IV) acetylacetonate (Zr(acac)4) catalyst. The PCLA copolymers were successfully synthesized and characterized using NMR and GPC techniques. Furthermore, the gel-forming and rheological properties of the resulting hydrogels were thoroughly investigated, and the optimal synthesis conditions were determined. The coprecipitation method was applied to create magnetic iron oxide nanoparticles (MIONs) with a low diameter and a narrow size distribution. The magnetic properties of the MIONs were close to superparamagnetic upon TEM, DLS, and VSM analysis. The particle suspension placed in an alternating magnetic field (AMF) of the appropriate parameters showed a rapid increase in temperature to the values desired for hyperthermia. The MIONs/hydrogel matrices were evaluated for paclitaxel (PTX) release in vitro. The release was prolonged and well controlled, displaying close to zero-order kinetics; the drug release mechanism was found to be anomalous. Furthermore, it was found that the simulated hyperthermia conditions had no effect on the release kinetics. As a result, the synthesized smart hydrogels were discovered to be a promising antitumor LDDS, allowing simultaneous chemotherapy and hyperthermia treatment.
Anti-Mitochondrial and Insecticidal Effects of Artemisinin against Drosophila melanogaster
Authors: Zhong Mengjiao , Sun Chen , Zhou Bing
Published: April 2023

Artemisinin (ART) is an endoperoxide molecule derived from the medicinal plant Artemisia annua L. and is clinically used as an antimalarial drug. As a secondary metabolite, the benefit of ART production to the host plant and the possible associated mechanism are not understood. It has previously been reported that Artemisia annua L. extract or ART can inhibit both insect feeding behaviors and growth; however, it is not known whether these effects are independent of each other, i.e., if growth inhibition is a direct outcome of the drug’s antifeeding activity. Using the lab model organism Drosophila melanogaster, we demonstrated that ART repels the feeding of larvae. Nevertheless, feeding inhibition was insufficient to explain its toxicity on fly larval growth. We revealed that ART provoked a strong and instant depolarization when applied to isolated mitochondria from Drosophila while exerting little effect on mitochondria isolated from mice tissues. Thus, ART benefits its host plant through two distinct activities on the insect: a feeding-repelling action and a potent anti-mitochondrial action which may underlie its insect inhibitory activities.
Efficacy of Immunization against a Novel Synthetic 13-Amino Acid Betaglycan-Binding Peptide Sequence of Inhibin α Subunit on Promoting Fertility in Female Rats
Authors: Han Xingfa , Xia Xue , Chen Weihao , Meng Fengyan , Cao Xiaohan , Bu Guixian , Gan Tian , Du Xiaogang , Liang Qiuxia , Zeng Xianyin
Published: April 2023

Inhibins suppress the FSH production in pituitary gonadotrope cells by robustly antagonizing activin signaling by competitively binding to activin type II receptors (ACTR II). The binding of inhibin A to ACTR II requires the presence of its co-receptor, namely, betaglycan. In humans, the critical binding site for betaglycan to inhibin A was identified on the inhibin α subunit. Through conservation analysis, we found that a core 13-amino-acid peptide sequence  within the betaglycan-binding epitope on human inhibin α subunit is highly conserved across species. Based on the tandem sequence of such a conserved 13-amino-acid betaglycan-binding epitope (INHα13AA-T), we developed a novel inhibin vaccine and tested its efficacy in promoting female fertility using the female rat as a model. Compared with placebo-immunized controls, INHα13AA-T immunization induced a marked (p < 0.05) antibody generation, enhanced (p < 0.05) ovarian follicle development, and increased ovulation rate and litter sizes. Mechanistically, INHα13AA-T immunization promoted (p < 0.05) pituitary Fshb transcription and increased (p < 0.05) serum FSH and 17β-estradiol concentrations. In summary, active immunization against INHα13AA-T potently increased FSH levels, ovarian follicle development, ovulation rate and litter sizes, thus causing super-fertility in females. Therefore, immunization against INHα13AA is a promising alternative to the conventional approach of multiple ovulation and super-fertility in mammals.
Transcriptomics Reveal Molecular Differences in Equine Oocytes Vitrified before and after In Vitro Maturation
Authors: Angel-Velez Daniel , Meese Tim , Hedia Mohamed , Fernandez-Montoro Andrea , De Coster Tine , Pascottini Osvaldo Bogado , Van Nieuwerburgh Filip , Govaere Jan , Van Soom Ann , Pavani Krishna , Smits Katrien
Published: April 2023

In the last decade, in vitro embryo production in horses has become an established clinical practice, but blastocyst rates from vitrified equine oocytes remain low. Cryopreservation impairs the oocyte developmental potential, which may be reflected in the messenger RNA (mRNA) profile. Therefore, this study aimed to compare the transcriptome profiles of metaphase II equine oocytes vitrified before and after in vitro maturation. To do so, three groups were analyzed with RNA sequencing: (1) fresh in vitro matured oocytes as a control (FR), (2) oocytes vitrified after in vitro maturation (VMAT), and (3) oocytes vitrified immature, warmed, and in vitro matured (VIM). In comparison with fresh oocytes, VIM resulted in 46 differentially expressed (DE) genes (14 upregulated and 32 downregulated), while VMAT showed 36 DE genes (18 in each category). A comparison of VIM vs. VMAT resulted in 44 DE genes (20 upregulated and 24 downregulated). Pathway analyses highlighted cytoskeleton, spindle formation, and calcium and cation ion transport and homeostasis as the main affected pathways in vitrified oocytes. The vitrification of in vitro matured oocytes presented subtle advantages in terms of the mRNA profile over the vitrification of immature oocytes. Therefore, this study provides a new perspective for understanding the impact of vitrification on equine oocytes and can be the basis for further improvements in the efficiency of equine oocyte vitrification.
Structure-Based Design and Pharmacophore-Based Virtual Screening of Combinatorial Library of Triclosan Analogues Active against Enoyl-Acyl Carrier Protein Reductase of Plasmodium falciparum with Favourable ADME Profiles
Authors: Bieri Cecile , Esmel Akori , Keita Melalie , Owono Luc Calvin Owono , Dali Brice , Megnassan Eugene , Miertus Stanislav , Frecer Vladimir
Published: April 2023

Cost-effective therapy of neglected and tropical diseases such as malaria requires everlasting drug discovery efforts due to the rapidly emerging drug resistance of the plasmodium parasite. We have carried out computational design of new inhibitors of the enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum (PfENR) using computer-aided combinatorial and pharmacophore-based molecular design. The Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) complexation QSAR model was developed for triclosan-based inhibitors (TCL) and a significant correlation was established between the calculated relative Gibbs free energies of complex formation (∆∆Gcom) between PfENR and TCL and the observed inhibitory potencies of the enzyme (IC50exp) for a training set of 20 known TCL analogues. Validation of the predictive power of the MM-PBSA QSAR model was carried out with the generation of 3D QSAR pharmacophore (PH4). We obtained a reasonable correlation between the relative Gibbs free energy of complex formation ∆∆Gcom and IC50exp values, which explained approximately 95% of the PfENR inhibition data: pIC50exp=−0.0544×∆∆Gcom+6.9336,R2=0.95. A similar agreement was established for the PH4 pharmacophore model of the PfENR inhibition (pIC50exp=0.9754×pIC50pre+0.1596, R2=0.98). Analysis of enzyme–inhibitor binding site interactions suggested suitable building blocks to be used in a virtual combinatorial library of 33,480 TCL analogues. Structural information derived from the complexation model and the PH4 pharmacophore guided us through in silico screening of the virtual combinatorial library of TCL analogues to finally identify potential new TCL inhibitors effective at low nanomolar concentrations. Virtual screening of the library by PfENR-PH4 led to a predicted IC50pre value for the best inhibitor candidate as low as 1.9 nM. Finally, the stability of PfENR-TCLx complexes and the flexibility of the active conformation of the inhibitor for selected top-ranking TCL analogues were checked with the help of molecular dynamics. This computational study resulted in a set of proposed new potent inhibitors with predicted antimalarial effects and favourable pharmacokinetic profiles that act on a novel pharmacological target, PfENR.
Spectroscopic and Spectroelectrochemical Studies of Hexapentyloxytriphenylene—A Model Discotic Molecule
Authors: Ślęczkowski Piotr
Published: April 2023

The electrochemical and spectroelectrochemical properties of the discotic mesogen 2,3,6,7,10,11-pentyloxytriphenylene (H5T) were studied with the use of cyclic voltammetry combined with UV-Vis and electron paramagnetic resonance (EPR) spectroscopy in solution. The UV-Vis absorption spectroscopy of H5T in dichloromethane showed its monomeric state in a concentration range up to 10−3 mol dm−3. The reversible process of the electrochemical formation of the radical cation was evidenced within the experimentally accessible potential window. The in situ UV-Vis spectroelectrochemical measurements further enabled identification of the product of the redox process and evaluation of the effect of aggregation in the concentration range of 5 × 10−3 mol dm−3. The results are discussed in the frame of solvent effects on the self-assembly propensity of solute molecules, in a wide range of concentrations. In particular, the crucial role of the solvent polarity is indicated, which contributes to the understanding of solution effects and pre-programming of supramolecular organic materials, in particular anisotropic disc-shaped hexa-substituted triphenylenes.
Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need
Authors: Vanni Silvia , Fausti Valentina , Fonzi Eugenio , Liverani Chiara , Miserocchi Giacomo , Spadazzi Chiara , Cocchi Claudia , Calabrese Chiara , Gurrieri Lorena , Riva Nada , Recine Federica , Casadei Roberto , Pieri Federica , Guerrieri Ania Naila , Serra Massimo , Ibrahim Toni , Mercatali Laura , De Vita Alessandro
Published: April 2023

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50–60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification.
The Ying and Yang of Sphingosine-1-Phosphate Signalling within the Bone
Authors: Frost Kathryn , Naylor Amy J. , McGettrick Helen M.
Published: April 2023

Bone remodelling is a highly active and dynamic process that involves the tight regulation of osteoblasts, osteoclasts, and their progenitors to allow for a balance of bone resorption and formation to be maintained. Ageing and inflammation are risk factors for the dysregulation of bone remodelling. Once the balance between bone formation and resorption is lost, bone mass becomes compromised, resulting in disorders such as osteoporosis and Paget’s disease. Key molecules in the sphingosine-1-phosphate signalling pathway have been identified for their role in regulating bone remodelling, in addition to its more recognised role in inflammatory responses. This review discusses the accumulating evidence for the different, and, in certain circumstances, opposing, roles of S1P in bone homeostasis and disease, including osteoporosis, Paget’s disease, and inflammatory bone loss. Specifically, we describe the current, often conflicting, evidence surrounding S1P function in osteoblasts, osteoclasts, and their precursors in health and disease, concluding that S1P may be an effective biomarker of bone disease and also an attractive therapeutic target for disease.
Biosynthesis and the Transcriptional Regulation of Terpenoids in Tea Plants (Camellia sinensis)
Authors: Wei Junchi , Yang Yun , Peng Ye , Wang Shaoying , Zhang Jing , Liu Xiaobo , Liu Jianjun , Wen Beibei , Li Meifeng
Published: April 2023

Terpenes, especially volatile terpenes, are important components of tea aroma due to their unique scents. They are also widely used in the cosmetic and medical industries. In addition, terpene emission can be induced by herbivory, wounding, light, low temperature, and other stress conditions, leading to plant defense responses and plant–plant interactions. The transcriptional levels of important core genes (including HMGR, DXS, and TPS) involved in terpenoid biosynthesis are up- or downregulated by the MYB, MYC, NAC, ERF, WRKY, and bHLH transcription factors. These regulators can bind to corresponding cis-elements in the promoter regions of the corresponding genes, and some of them interact with other transcription factors to form a complex. Recently, several key terpene synthesis genes and important transcription factors involved in terpene biosynthesis have been isolated and functionally identified from tea plants. In this work, we focus on the research progress on the transcriptional regulation of terpenes in tea plants (Camellia sinensis) and thoroughly detail the biosynthesis of terpene compounds, the terpene biosynthesis-related genes, the transcription factors involved in terpene biosynthesis, and their importance. Furthermore, we review the potential strategies used in studying the specific transcriptional regulation functions of candidate transcription factors that have been discriminated to date.
Human Male Genital Tract Microbiota
Authors: Zuber Arnaud , Peric Adriana , Pluchino Nicola , Baud David , Stojanov Milos
Published: April 2023

The human body is vastly colonised by microorganisms, whose impact on health is increasingly recognised. The human genital tract hosts a diverse microbiota, and an increasing number of studies on the male genital tract microbiota suggest that bacteria have a role in male infertility and pathological conditions, such as prostate cancer. Nevertheless, this research field remains understudied. The study of bacterial colonisation of the male genital tract is highly impacted by the invasive nature of sampling and the low abundance of the microbiota. Therefore, most studies relied on the analysis of semen microbiota to describe the colonisation of the male genital tract (MGT), which was thought to be sterile. The aim of this narrative review is to present the results of studies that used next-generation sequencing (NGS) to profile the bacterial colonisation patterns of different male genital tract anatomical compartments and critically highlight their findings and their weaknesses. Moreover, we identified potential research axes that may be crucial for our understanding of the male genital tract microbiota and its impact on male infertility and pathophysiology.
Genetic Characterization of Non-Lymphogranuloma venereum Chlamydia trachomatis Indicates Distinct Infection Transmission Networks in Spain
Authors: Piñeiro Luis , Villa Laura , Salmerón Paula , Maciá Maria Dolores , Otero Luis , Vall-Mayans Martí , Milagro Ana , Bernal Samuel , Manzanal Ayla , Ansa Iñigo , Cilla Gustavo
Published: April 2023

Chlamydia trachomatis infection is an important public health problem. Our objective was to assess the dynamics of the transmission of this infection, analysing the distribution of circulating ompA genotypes and multilocus sequence types of C. trachomatis in Spain as a function of clinical and epidemiological variables. During 2018 and 2019, we genetically characterized C. trachomatis in tertiary hospitals in six areas in Spain (Asturias, Barcelona, Gipuzkoa, Mallorca, Seville and Zaragoza), with a catchment population of 3.050 million people. Genotypes and sequence types were obtained using polymerase chain reaction techniques that amplify a fragment of the ompA gene, and five highly variable genes (hctB, CT058, CT144, CT172 and pbpB), respectively. Amplicons were sequenced and phylogenetic analysis was conducted. We obtained genotypes in 636/698 cases (91.1%). Overall and by area, genotype E was the most common (35%). Stratifying by sex, genotypes D and G were more common among men, and genotypes F and I among women (p < 0.05). Genotypes D, G and J were more common in men who have sex with men (MSM) than in men who have sex with women (MSW), in whom the most common genotypes were E and F. The diversity index was higher in sequence typing (0.981) than in genotyping (0.791), and the most common sequence types were ST52 and ST108 in MSM, and ST30, ST148, ST276 and ST327 in MSW. Differences in genotype distribution between geographical areas were attributable to differences in population characteristics. The transmission dynamics varied with sexual behaviour: the predominant genotypes and most frequent sequence types found in MSM were different to those detected in MSW and women.
Overview of Prostaglandin E2 (PGE2)-Targeting Radiolabelled Imaging Probes from Preclinical Perspective: Lessons Learned and Road Ahead
Authors: Képes Zita , Dénes Noémi , Kertész István , Hajdu István , Trencsényi György
Published: April 2023

As malignancies still represent one of the major health concerns worldwide, early tumor identification is among the priorities of today’s science. Given the strong association between cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), PGE2 receptors (EPs), and carcinogenesis, target-specific molecules directed towards the components of the COX2/PGE2/EP axis seem to be promising imaging probes in the diagnostics of PGE2pos. neoplasms and in the design of anti-cancer drugs. Featured with outstanding inclusion forming capability, β-cyclodextrins (CDs) including randomly methylated β-CD (RAMEB) were reported to complex with PGE2. Therefore, radiolabelled β-CDs could be valuable vectors in the molecular imaging of PGE2-related tumorigenesis. In vivo preclinical small animal model systems applying positron emission tomography (PET) ensure a well-suited scenario for the assessment of PGE2-affine labelled CD derivatives. Previous translational studies dealt with the evaluation of the tumor-homing capability of Gallium-68 (68Ga) and Bismuth-205/206 (205/206Bi)-appended β-CD compounds conjugated with chelator NODAGA or DOTAGA: [68Ga]Ga-NODAGA-2-hydroxypropyl-β-cyclodextrin/HPBCD, [68Ga]Ga-NODAGA-RAMEB, [68Ga]Ga-DOTAGA-RAMEB, and [205/206Bi]Bi-DOTAGA-RAMEB in experimental tumors with different PGE2 expression. These imaging probes project the establishment of tailor-made PET diagnostics of PGE2pos. malignancies. In the present review, we provide a detailed overview of the in vivo investigations of radiolabelled PGE2-directed CDs, highlighting the importance of the integration of translational discoveries into routine clinical usage.
Synaptic Targets of Glycinergic Neurons in Laminae I–III of the Spinal Dorsal Horn
Authors: Miranda Camila Oliveira , Hegedüs Krisztina , Kis Gréta , Antal Miklós
Published: April 2023

A great deal of evidence supports the inevitable importance of spinal glycinergic inhibition in the development of chronic pain conditions. However, it remains unclear how glycinergic neurons contribute to the formation of spinal neural circuits underlying pain-related information processing. Thus, we intended to explore the synaptic targets of spinal glycinergic neurons in the pain processing region (laminae I–III) of the spinal dorsal horn by combining transgenic technology with immunocytochemistry and in situ hybridization accompanied by light and electron microscopy. First, our results suggest that, in addition to neurons in laminae I–III, glycinergic neurons with cell bodies in lamina IV may contribute substantially to spinal pain processing. On the one hand, we show that glycine transporter 2 immunostained glycinergic axon terminals target almost all types of excitatory and inhibitory interneurons identified by their neuronal markers in laminae I–III. Thus, glycinergic postsynaptic inhibition, including glycinergic inhibition of inhibitory interneurons, must be a common functional mechanism of spinal pain processing. On the other hand, our results demonstrate that glycine transporter 2 containing axon terminals target only specific subsets of axon terminals in laminae I–III, including nonpeptidergic nociceptive C fibers binding IB4 and nonnociceptive myelinated A fibers immunoreactive for type 1 vesicular glutamate transporter, indicating that glycinergic presynaptic inhibition may be important for targeting functionally specific subpopulations of primary afferent inputs.
A Novel Microbial Consortia Catalysis Strategy for the Production of Hydroxytyrosol from Tyrosine
Authors: Gong Pengfei , Tang Jiali , Wang Jiaying , Wang Chengtao , Chen Wei
Published: April 2023

Hydroxytyrosol, a valuable plant-derived phenolic compound, is increasingly produced from microbial fermentation. However, the promiscuity of the key enzyme HpaBC, the two-component flavin-dependent monooxygenase from Escherichia coli, often leads to low yields. To address this limitation, we developed a novel strategy utilizing microbial consortia catalysis for hydroxytyrosol production. We designed a biosynthetic pathway using tyrosine as the substrate and selected enzymes and overexpressing glutamate dehydrogenase GdhA to realize the cofactor cycling by coupling reactions catalyzed by the transaminase and the reductase. Additionally, the biosynthetic pathway was divided into two parts and performed by separate E. coli strains. Furthermore, we optimized the inoculation time, strain ratio, and pH to maximize the hydroxytyrosol yield. Glycerol and ascorbic acid were added to the co-culture, resulting in a 92% increase in hydroxytyrosol yield. Using this approach, the production of 9.2 mM hydroxytyrosol was achieved from 10 mM tyrosine. This study presents a practical approach for the microbial production of hydroxytyrosol that can be promoted to produce other value-added compounds.
Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer
Authors: Munkácsy Gyöngyi , Santarpia Libero , Győrffy Balázs
Published: April 2023

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell–cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.