bluuebunny/crossref_metadata_2025 huggingface dataset:
PDE4 Gene Family Variants Are Associated with Response to Apremilast Treatment in Psoriasis
Authors: Liadaki Kalliopi , Zafiriou Efterpi , Giannoulis Themistoklis , Alexouda Sofia , Chaidaki Kleoniki , Gidarokosta Polyxeni , Roussaki-Schulze Angeliki-Viktoria , Tsiogkas Sotirios G. , Daponte Athina , Mamuris Zissis , Bogdanos Dimitrios P. , Moschonas Nicholas K. , Sarafidou Theologia
Published: March 2024

Moderate-to-severe psoriasis (Ps) treatment includes systemic drugs and biological agents. Apremilast, a small molecule primarily metabolized by cytochrome CYP3A4, modulates the immune system by specifically inhibiting phosphodiesterase type 4 (PDE4) isoforms and is currently used for the treatment of Ps and psoriatic arthritis (PsA). Clinical trials and real-world data showed variable efficacy in response among Ps patients underlying the need for personalized therapy. This study implements a candidate-gene and a network-based approach to identify genetic markers associated with apremilast response in forty-nine Greek Ps patients. Our data revealed an association of sixty-four SNPs within or near PDE4 and CYP3A4 genes, four SNPs in ncRNAs ANRIL, LINC00941 and miR4706, which influence the abundance or function of PDE4s, and thirty-three SNPs within fourteen genes whose protein products either interact directly with PDE4 proteins or constitute components of the cAMP signaling pathway which is modulated by PDE4s. Notably, fifty-six of the aforementioned SNPs constitute eQTLs for the respective genes in relevant to psoriasis tissues/cells implying that these variants could be causal. Our analysis provides a number of novel genetic variants that, upon validation in larger cohorts, could be utilized as predictive markers regarding the response of Ps patients to apremilast treatment.
Enhancing Variant Prioritization in VarFish through On-Premise Computational Facial Analysis
Authors: Bhasin Meghna Ahuja , Knaus Alexej , Incardona Pietro , Schmid Alexander , Holtgrewe Manuel , Elbracht Miriam , Krawitz Peter M. , Hsieh Tzung-Chien
Published: March 2024

Genomic variant prioritization is crucial for identifying disease-associated genetic variations. Integrating facial and clinical feature analyses into this process enhances performance. This study demonstrates the integration of facial analysis (GestaltMatcher) and Human Phenotype Ontology analysis (CADA) within VarFish, an open-source variant analysis framework. Challenges related to non-open-source components were addressed by providing an open-source version of GestaltMatcher, facilitating on-premise facial analysis to address data privacy concerns. Performance evaluation on 163 patients recruited from a German multi-center study of rare diseases showed PEDIA’s superior accuracy in variant prioritization compared to individual scores. This study highlights the importance of further benchmarking and future integration of advanced facial analysis approaches aligned with ACMG guidelines to enhance variant classification.
Karyotype Diversification and Chromosome Rearrangements in Squamate Reptiles
Authors: Mezzasalma Marcello , Macirella Rachele , Odierna Gaetano , Brunelli Elvira
Published: March 2024

Karyotype diversification represents an important, yet poorly understood, driver of evolution. Squamate reptiles are characterized by a high taxonomic diversity which is reflected at the karyotype level in terms of general structure, chromosome number and morphology, and insurgence of differentiated simple or multiple-sex-chromosome systems with either male or female heterogamety. The potential of squamate reptiles as unique model organisms in evolutionary cytogenetics has been recognised in recent years in several studies, which have provided novel insights into the chromosome evolutionary dynamics of different taxonomic groups. Here, we review and summarize the resulting complex, but promising, general picture from a systematic perspective, mapping some of the main squamate karyological characteristics onto their phylogenetic relationships. We highlight how all the major categories of balanced chromosome rearrangements contributed to the karyotype evolution in different taxonomic groups. We show that distinct karyotype evolutionary trends may occur, and coexist, with different frequencies in different clades. Finally, in light of the known squamate chromosome diversity and recent research advances, we discuss traditional and novel hypotheses on karyotype evolution and propose a scenario of circular karyotype evolution.
Selected Geoheritage Resources of “Atlantic Geopark” Project (Central Portugal)
Authors: Custódio Salomé C. , Henriques Maria Helena , Rosado-González Emmaline M. , Vaz Nuno M. , Sá Artur A.
Published: March 2024

The “Atlantic Geopark” Project corresponds to the first stage of a broad project addressing a future application to the Global Geopark Network of a territory located in Portugal: “The Atlantic Geopark: 600 million of geological history”. It covers six central littoral and rural municipalities (Cantanhede, Figueira da Foz, Mealhada, Mira, Montemor-o-Velho, and Penacova), which display special and singular geodiversity, and it includes geological heritage with international relevance representing the opening and closing of the Rheic Ocean, the formation and breakup of Pangea, and the opening of the North Atlantic Ocean. Besides the geological heritage, here presented through the description and characterization of six geological sites (one per municipality) which served as anchors for the development of the project currently underway, the territory also provides other geoheritage resources related to uses of the local geological features. These resources hold significance in bolstering an application to the Global Geopark Network soon. They encompass partially artificial elements such as road excavations, agricultural soils, and quarries, as well as entirely artificial elements such as interpretation centers and museums. These elements serve as tangible representations of the various ways in which the Earth and local communities interact.
A Critical Review on In Vitro and Ex Vivo Models of the Intestinal Epithelium of Humans and Monogastric Animals
Authors: Costa Célia Maria , de Carvalho Nelson Mota , de Oliveira Diana Luazi , Madureira Ana Raquel
Published: March 2024

Recently, the bioactive potential of several functional ingredients and biomolecules has been evaluated regarding human and animal nutrition. The digestive process from food intake to absorption and metabolism are important events that induce changes in ingredients, which affect their bioactivity. Consequently, there is a need to assess the bioavailability and bioaccessibility of these compounds. The methodology for the simulation of the human gastrointestinal tract has been standardized (INFOGEST protocol), while a gastrointestinal protocol for other animals (e.g., ruminants or broilers) has yet to be established. However, INFOGEST allows us only to predict bioaccessibility, leaving a gap regarding a methodology able to assess bioavailability by mimicking intestinal permeability and absorption. Several approaches—including in vitro, ex vivo, in situ and in vivo methods—can be found in the literature, aiming to tackle transepithelial routes, but leading to different results concerning the bioefficiency of the compounds studied. Therefore, this review aims to assess the current state-of-the-art regarding monogastric intestinal dynamics, absorption, and permeability events. Moreover, it compiled methodologies for simulating intestinal absorption in several biological systems, while reasoning their advantages, disadvantages, applications in ingredient development and the existing gaps.
Multidirectional Heritage-Led Knowledge Exchange: Learning from Practice in 19 Rural Territories
Authors: Åberg Hanna Elisabet , Pavlova Irina , Santangelo Angela , Amirzada Zahra , Heirman Katrien , Tondelli Simona
Published: March 2024

Rural areas are regaining attention as key resource holders. This includes the attractiveness of intact and traditional cultural elements and heritage which helps to create new opportunities. However, renewal is needed for rural areas to be competitive beyond tourism. Knowledge exchange and transfer is seen as an enabling tool for regeneration and heritage valorization, although it has mostly been applied in an urban context. The aim of this paper is to explore the role of capacity building and knowledge exchange at different levels in promoting rural regeneration through heritage-led initiatives. The article describes a multi-directional knowledge transfer and exchange in 19 rural areas. The applied knowledge exchange methodology was designed to be a dynamic and vibrant exchange of capacity building and mutual learning. This exchange of knowledge enabled the local communities involved to explore new ideas and viable solutions for the regeneration of rural areas through the valorization of cultural and natural heritage. The research findings show that structuring a knowledge transfer and capacity building process that also involves key local stakeholders and the rural communities is an important milestone in the regeneration process. In addition, it can be a unique opportunity to start and build new professional long-term relationships.
Surveillance of Infections and Antibiotic Use in 21 Nursing Home Wards during the COVID-19 Pandemic: A Systematic Assessment
Authors: Sandbekken Ida Hellum , Hermansen Åsmund , Grov Ellen Karine , Utne Inger , Løyland Borghild
Published: March 2024

Residents in nursing homes are fragile and at high risk of serious illness or death from healthcare-associated infections. The COVID-19 pandemic posed a significant risk of suffering and mortality for residents of nursing homes. Surveillance of infections is essential for infection prevention and is missing in many countries. The aim of this study is to explore infection rates and antibiotic use in nursing homes during the COVID-19 pandemic. Data collection was conducted from February to September 2021. Each week, healthcare workers at 21 nursing home wards answered a questionnaire on infections, antibiotic use, deaths, and hospital admissions related to infections. A total of 495 infections were reported, and 97.6% were treated with antibiotics. The total infection rate was 5.37 per 1000 bed days, and there were reported 53 hospital admissions and 11 deaths related to or caused by infections. The infection rate and high use of antibiotics found in this study indicated that it is difficult to treat infections in residents in nursing homes and make it difficult to achieve the global goal of reducing infections and antibiotic resistance rates. This emphasizes the need for stricter infection control programs to reduce antibiotic use and patient suffering.
The Screening of microRNAs in Chronic Myeloid Leukemia: A Clinical Evaluation
Authors: Wosniaki Denise Kusma , Marin Anelis Maria , Oliveira Rafaela Noga , Koerich Gabriela Marino , Munhoz Eduardo Cilião , Farias João Samuel de Holanda , Beltrame Miriam Perlingeiro , Zanette Dalila Luciola , Aoki Mateus Nóbrega
Published: March 2024

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.
Roles of DNA Methylation in Color Alternation of Eastern Honey Bees (Apis cerana) Induced by the Royal Jelly of Western Honey Bees (Apis mellifera)
Authors: Abdelmawla Amal , Li Xin , Shi Wenkai , Zheng Yunlin , Zeng Zhijiang , He Xujiang
Published: March 2024

Honey bees have a very interesting phenomenon where the larval diets of two different honey bee species are exchanged, resulting in altered phenotypes, namely, a honey bee nutritional crossbreed. This is a classical epigenetic process, but its underlying mechanisms remain unclear. This study aims to investigate the contribution of DNA methylation to the phenotypic alternation of a Apis mellifera–Apis cerana nutritional crossbreed. We used a full nutritional crossbreed technique to rear A. cerana queens by feeding their larvae with A. mellifera royal-jelly-based diets in an incubator. Subsequently, we compared genome-wide methylation sequencing, body color, GC ratio, and the DMRs between the nutritional crossbreed, A. cerana queens (NQs), and control, A. cerana queens (CQs). Our results showed that the NQ’s body color shifted to yellow compared to the black control queens. Genome methylation sequencing revealed that NQs had a much higher ratio of mCG than that of CQs. A total of 1020 DMGs were identified, of which 20 DMGs were enriched into key pathways for melanin synthesis, including tryptophan, tyrosine, dopamine, and phenylalanine KEGG pathways. Three key differentially methylated genes [OGDH, ALDH(NAD+) and ALDH7] showed a clear, altered DNA methylation in multiple CpG islands in NQs compared to CQs. Consequently, these findings revealed that DNA methylation participates in A. cerana–A. mellifera nutritional crossbreeding as an important epigenetic modification. This study serves as a model of cross-kingdom epigenetic mechanisms in insect body color induced by environmental factors.
Gastric Cancer in the Era of Epigenetics
Authors: Christodoulidis Grigorios , Koumarelas Konstantinos-Eleftherios , Kouliou Marina-Nektaria , Thodou Eleni , Samara Maria
Published: March 2024

Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein–Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor’s metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
Infectious and Commensal Bacteria in Rheumatoid Arthritis—Role in the Outset and Progression of the Disease
Authors: Korzeniowska Aleksandra , Bryl Ewa
Published: March 2024

Rheumatoid arthritis (RA) is a chronic, autoimmune disease with a complex outset. Besides the genetic susceptibility in its pathogenesis, various environmental factors also participate. Of these, in recent years, there have been increasing reports of the involvement of bacteria in the disease’s outset and development, especially gut microbiota and oral pathogens. Most recent reports about bacteria participation in RA pathogenesis focus on Prevotella copri and Porphyromonas gingivalis. There are also reports about the involvement of respiratory and urinary tract pathogens. The exact mechanisms leading to RA development used by bacteria are not well known; however, some mechanisms by which bacteria can interact with the immune system are known and can potentially lead to RA development. The aim of this study is to provide a comprehensive review of the potential bacteria participating in RA development and the mechanism involved in that process.
Xanthohumol—A Miracle Molecule with Biological Activities: A Review of Biodegradable Polymeric Carriers and Naturally Derived Compounds for Its Delivery
Authors: Oledzka Ewa
Published: March 2024

Xanthohumol (Xn), a prenylated chalcone found in Hop (Humulus lupulus L.), has been shown to have potent anti-aging, diabetes, inflammation, microbial infection, and cancer properties. Unfortunately, this molecule has undesirable characteristics such as inadequate intake, low aqueous solubility, and a short half-life. To address these drawbacks, researchers have made numerous attempts to improve its absorption, solubility, and bioavailability. Polymeric drug delivery systems (PDDSs) have experienced significant development over the last two decades. Polymeric drug delivery is defined as a formulation or device that allows the introduction of a therapeutic substance into the body. Biodegradable and bioreducible polymers are the ideal choice for a variety of new DDSs. Xn formulations based on biodegradable polymers and naturally derived compounds could solve some of the major drawbacks of Xn-based drug delivery. In this regard, the primary concern of this study is on presenting innovative formulations for Xn delivery, such as nanoparticles (NPs), nanomicelles, nanoliposomes, solid lipid nanoparticles (SLNs), and others, as well as the received in vitro and in vivo data. Furthermore, this work describes the chemistry and broad biological activity of Xn, which is particularly useful in modern drug technology as well as the cosmetics industry. It is also important to point out that the safety of using Xn, and its biotransformation, pharmacokinetics, and clinical applications, have been thoroughly explained in this review.
Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management
Authors: Traeger-Synodinos Joanne , Vrettou Christina , Sofocleous Christalena , Zurlo Matteo , Finotti Alessia , Gambari Roberto
Published: March 2024

In this short review, we presented and discussed studies on the expression of globin genes in β-thalassemia, focusing on the impact of α-globin gene expression and α-globin modifiers on the phenotype and clinical severity of β-thalassemia. We first discussed the impact of the excess of free α-globin on the phenotype of β-thalassemia. We then reviewed studies focusing on the expression of α-globin-stabilizing protein (AHSP), as a potential strategy of counteracting the effects of the excess of free α-globin on erythroid cells. Alternative processes controlling α-globin excess were also considered, including the activation of autophagy by β-thalassemia erythroid cells. Altogether, the studies reviewed herein are expected to have a potential impact on the management of patients with β-thalassemia and other hemoglobinopathies for which reduction in α-globin excess is clinically beneficial.
Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review
Authors: Lin En-Shyh , Huang Cheng-Yang
Published: March 2024

5-Fluorouracil (5-FU) stands as one of the most widely prescribed chemotherapeutics. Despite over 60 years of study, a systematic synopsis of how 5-FU binds to proteins has been lacking. Investigating the specific binding patterns of 5-FU to proteins is essential for identifying additional interacting proteins and comprehending their medical implications. In this review, an analysis of the 5-FU binding environment was conducted based on available complex structures. From the earliest complex structure in 2001 to the present, two groups of residues emerged upon 5-FU binding, classified as P- and R-type residues. These high-frequency interactive residues with 5-FU include positively charged residues Arg and Lys (P type) and ring residues Phe, Tyr, Trp, and His (R type). Due to their high occurrence, 5-FU binding modes were simplistically classified into three types, based on interactive residues (within <4 Å) with 5-FU: Type 1 (P-R type), Type 2 (P type), and Type 3 (R type). In summary, among 14 selected complex structures, 8 conform to Type 1, 2 conform to Type 2, and 4 conform to Type 3. Residues with high interaction frequencies involving the N1, N3, O4, and F5 atoms of 5-FU were also examined. Collectively, these interaction analyses offer a structural perspective on the specific binding patterns of 5-FU within protein pockets and contribute to the construction of a structural interactome delineating the associations of the anticancer drug 5-FU.
FvMYB108, a MYB Gene from Fragaria vesca, Positively Regulates Cold and Salt Tolerance of Arabidopsis
Authors: Song Penghui , Yang Ruihua , Jiao Kuibao , Guo Baitao , Zhang Lei , Li Yuze , Zhang Kun , Zhou Shuang , Wu Xinjuan , Li Xingguo
Published: March 2024

MYB (myoblast) protein comes in large quantities and a wide variety of types and plays a role in most eukaryotes in the form of transcription factors (TFs). One of its important functions is to regulate plant responses to various stresses. However, the role of MYB TFs in regulating stress tolerance in strawberries is not yet well understood. Therefore, in order to investigate the response of MYB family members to abiotic stress in strawberries, a new MYB TF gene was cloned from Fragaria vesca (a diploid strawberry) and named FvMYB108 based on its structural characteristics and evolutionary relationships. After a bioinformatics analysis, it was determined that the gene belongs to the R2R3-MYB subfamily, and its conserved domain, phylogenetic relationships, predicted protein structure and physicochemical properties, subcellular localization, etc. were analyzed. After qPCR analysis of the expression level of FvMYB108 in organs, such as the roots, stems, and leaves of strawberries, it was found that this gene is more easily expressed in young leaves and roots. After multiple stress treatments, it was found that the target gene in young leaves and roots is more sensitive to low temperatures and salt stimulation. After these two stress treatments, various physiological and biochemical indicators related to stress in transgenic Arabidopsis showed corresponding changes, indicating that FvMYB108 may be involved in regulating the plant’s ability to cope with cold and high-salt stress. Further research has found that the overexpression of this gene can upregulate the expression of AtCBF1, AtCOR47, AtERD10, and AtDREB1A related to low-temperature stress, as well as AtCCA1, AtRD29a, AtP5CS1, and AtSnRK2.4 related to salt stress, enhancing the ability of overexpressed plants to cope with stress.
Perineuronal Nets in the CNS: Architects of Memory and Potential Therapeutic Target in Neuropsychiatric Disorders
Authors: Li Xue , Wu Xianwen , Lu Tangsheng , Kuang Chenyan , Si Yue , Zheng Wei , Li Zhonghao , Xue Yanxue
Published: March 2024

The extracellular matrix (ECM) within the brain possesses a distinctive composition and functionality, influencing a spectrum of physiological and pathological states. Among its constituents, perineuronal nets (PNNs) are unique ECM structures that wrap around the cell body of many neurons and extend along their dendrites within the central nervous system (CNS). PNNs are pivotal regulators of plasticity in CNS, both during development and adulthood stages. Characterized by their condensed glycosaminoglycan-rich structures and heterogeneous molecular composition, PNNs not only offer neuroprotection but also participate in signal transduction, orchestrating neuronal activity and plasticity. Interfering with the PNNs in adult animals induces the reactivation of critical period plasticity, permitting modifications in neuronal connections and promoting the recovery of neuroplasticity following spinal cord damage. Interestingly, in the adult brain, PNN expression is dynamic, potentially modulating plasticity-associated states. Given their multifaceted roles, PNNs have emerged as regulators in the domains of learning, memory, addiction behaviors, and other neuropsychiatric disorders. In this review, we aimed to address how PNNs contribute to the memory processes in physiological and pathological conditions.
Snail Transcriptionally Represses Brachyury to Promote the Mesenchymal-Epithelial Transition in Ascidian Notochord Cells
Authors: Wu Bingtong , Ouyang Xiuke , Yang Xiuxia , Dong Bo
Published: March 2024

Mesenchymal-epithelial transition (MET) is a widely spread and evolutionarily conserved process across species during development. In Ciona embryogenesis, the notochord cells undergo the transition from the non-polarized mesenchymal state into the polarized endothelial-like state to initiate the lumen formation between adjacent cells. Based on previously screened MET-related transcription factors by ATAC-seq and Smart-Seq of notochord cells, Ciona robusta Snail (Ci-Snail) was selected for its high-level expression during this period. Our current knockout results demonstrated that Ci-Snail was required for notochord cell MET. Importantly, overexpression of the transcription factor Brachyury in notochord cells resulted in a similar phenotype with failure of lumen formation and MET. More interestingly, expression of Ci-Snail in the notochord cells at the late tailbud stage could partially rescue the MET defect caused by Brachyury-overexpression. These results indicated an inverse relationship between Ci-Snail and Brachyury during notochord cell MET, which was verified by RT-qPCR analysis. Moreover, the overexpression of Ci-Snail could significantly inhibit the transcription of Brachyury, and the CUT&Tag-qPCR analysis demonstrated that Ci-Snail is directly bound to the upstream region of Brachyury. In summary, we revealed that Ci-Snail promoted the notochord cell MET and was essential for lumen formation via transcriptionally repressing Brachyury.
In Vitro Modelling of Osteogenesis Imperfecta with Patient-Derived Induced Mesenchymal Stem Cells
Authors: Claeys Lauria , Zhytnik Lidiia , Ventura Laura , Wisse Lisanne E. , Eekhoff Elisabeth M. W. , Pals Gerard , Bravenboer Nathalie , Heine Vivi M. , Micha Dimitra
Published: March 2024

(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2, NANOG, and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR, TFAP2A, and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73, CD105, and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells.
Correction: Cserző et al. The First Quarter Century of the Dense Alignment Surface Transmembrane Prediction Method. Int. J. Mol. Sci. 2023, 24, 14016
Authors: Cserző Miklós , Eisenhaber Birgit , Eisenhaber Frank , Magyar Csaba , Simon István
Published: March 2024

There was an error in the original publication [...]
Nocardia cyriacigeorgica Elicits Gut Disturbances in a Leaky Gut Model of Colitis, but Not the Harmful Cascade Leading to Gut-First Parkinson’s Disease
Authors: Magalhães João Duarte , Candeias Emanuel , Melo-Marques Inês , Abreu António E. , Pereira-Santos Ana Raquel , Esteves Ana Raquel , Cardoso Sandra Morais , Empadinhas Nuno
Published: March 2024

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with an unknown cause. Recent research has highlighted the importance of the gut in neuronal and immune maturation through the exchange of nutrients and cellular signals. This has led to the “gut-first PD” hypothesis, which aims to explain many of the sporadic cases and their prodromal intestinal symptoms, such as constipation and intestinal α-synuclein (aSyn) aggregation. The link between mitochondrial dysfunction and aSyn deposition is central to PD pathophysiology, since they can also trigger pro-inflammatory signals associated with aSyn deposition, potentially contributing to the onset of PD. As mitochondria are derived from ancestral alpha-proteobacteria, other bacteria may specifically target this organelle. We sought to use Nocardia cyriacigeorgica, a bacterium previously associated with parkinsonism, and dextran sulfate sodium (DSS) as pro-inflammatory modulators to gain further insight into the onset of PD. This study indicates that aSyn aggregation plus mitochondrial dysfunction without intestinal barrier leakage are not sufficient to trigger gut-first PD.
The Role of Health Institutions in Training Healthcare Personnel for the Digital Transition: The International Training Program of the Order of Physicians and Dentists of Rome
Authors: Gatto Maria Chiara , Frisicale Emanuela Maria , Palopoli Pietro , Sapienza Martina , Caroppo Emanuele , Patrizi Cristina , Migliano Giovanni , Damiani Gianfranco
Published: March 2024

Digital health, encompassing the use of digital technologies in healthcare, and telemedicine, facilitating healthcare delivery across long distances, have witnessed widespread applications across various healthcare domains. The COVID-19 pandemic accelerated the adoption of digital solutions in healthcare, overcoming barriers to access and fostering transitions to new care models. However, healthcare professionals often lack digital health competencies, necessitating targeted training initiatives. This study presents a project initiated by the Order of Physicians and Dentists of Rome, promoting a comprehensive training program in digital health for healthcare professionals. This investigation aims to describe the project, report demographic characteristics of participants, and analyze survey results on participants’ perceptions of the training program. The Erasmus+ project, titled ‘Training of Physician Trainers in Telemedicine, eHealth, and Digital Medicine,’ facilitated the digital transition of the healthcare sector through international training. The project involved structured courses, job-shadowing, and support activities in Malta and Madrid. A survey, developed using the Delphi methodology, assessed participants’ views on telemedicine. Thirty participants, selected based on merit, engaged in the project. Survey responses highlighted a strong impact on participants’ understanding of digital health concepts and increased confidence in utilizing digital tools. Notably, 85% acknowledged significant skill acquisition in healthcare digitalization. The project addressed a critical training gap among healthcare professionals, emphasizing the need for ongoing education in digital health. Despite existing recommendations, formal digital health education remains limited. The study underscores the importance of educational efforts to foster a digitalized healthcare model.
The Impact of Antimicrobial Resistance in Cystic Fibrosis
Authors: Vitiello Antonio , Blasi Francesco , Sabbatucci Michela , Zovi Andrea , Miele Francesco , Ponzo Annarita , Langella Roberto , Boccellino Mariarosaria
Published: March 2024

The phenomenon of antimicrobial resistance (AMR) is a critical global health challenge, with prospects indicating its potential to become the leading cause of death worldwide in the coming years. Individuals with pre-existing conditions, such as neoplastic disease undergoing chemotherapy, those on immunosuppressive therapy, and individuals with rare diseases like cystic fibrosis (CF), face heightened challenges due to AMR. CF is a rare disease caused by a deficiency in the synthesis of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel protein, resulting in multi-organ clinical symptoms, particularly in the respiratory system. PwCF experience recurrent pulmonary exacerbations triggered by bacterial or viral infections, making them particularly vulnerable to the impact of AMR. This review delves into the complex relationship between AMR and climate dynamics, focusing on the unique challenges faced by individuals with CF. It discusses the methods employed to measure AMR, its global impact on antibiotic resistance, and the specific microbial communities present in the CF airway. The review also explores the intricacies of antimicrobial resistance within the context of cystic fibrosis, emphasizing the urgent need for research in this field.
Resistance Exercise Program Is Feasible and Effective in Improving Functional Strength in Post-COVID Survivors
Authors: Kaczmarczyk Katarzyna , Matharu Yogi , Bobowik Patrycja , Gajewski Jan , Maciejewska-Skrendo Agnieszka , Kulig Kornelia
Published: March 2024

Background: Evidence suggests that COVID-19 infection can cause lasting health consequences. Multidisciplinary rehabilitation services have been recommended to reduce the sequalae. However, the effectiveness of physical exercise interventions remains insufficiently documented. The aim of this study was to develop and implement a specific and well-tolerated protocol-based intervention to reduce muscle weakness in older adults impacted by COVID-19. Methods: Forty-six older adults were randomized into intervention and control groups. Isometric and isokinetic strength assessments were conducted for selected muscle groups using a JBA Staniak® torquemeter and Biodex System 3 dynamometer. Functional abilities were evaluated with the Time Up and Go test and Chair Stand Tests. Results: Men in the intervention group demonstrated a significant improvement in static conditions for knee flexors (KFs), trunk extensors (TEs) and trunk flexors (TFs) and in dynamic conditions for knee extensors (KEs). Women in the intervention group showed a significant improvement in static conditions for EFs, KFs, TEs and TFs and in dynamic conditions for a KE and a KF. The interaction GROUP × TESTING SESSION was significant for the Chair Test (s) and Chair Test (n). Conclusions: Our results demonstrate the effectiveness of a well-tolerated, protocol-based approach that can be used to diminish long-lasting functional deficits in post-COVID survivors.
Effect of a Gluten-Free Diet on Whole Gut Transit Time in Celiac Disease (CD) and Non-Celiac Gluten Sensitivity (NCGS) Patients: A Study Using the Wireless Motility Capsule (WMC)
Authors: Cobos-Quevedo Orestes , Hernández Gildardo Alfonso , Rivera-Gutiérrez Xaira Jimena , Grube-Pagola Peter , Remes-Troche José María
Published: March 2024

Background: This study explores the impact of a gluten-free diet (GFD) on regional gastrointestinal (GI) transit times in individuals with celiac disease (CD) and non-celiac gluten sensitivity (NCGS). While a GFD is established for managing CD and wheat allergy, its effects on NCGS remain controversial due to inconclusive evidence. Methods: Utilizing a wireless motility and pH capsule (WMC) to assess regional (measurements of gastric, small bowel, and colonic transit times) and whole gut transit, newly diagnosed CD (n = 12) and NCGS (n = 12) patients underwent evaluations at baseline and 4 weeks after having a GFD. Results: At baseline conditions, individuals diagnosed with CD exhibited prolonged colonic and intestinal transit times when compared to those with NCGS (p < 0.05). Following a 4-week GFD, CD patients experienced significant reductions in both intestinal and colonic transit times, along with enhanced small intestine contractility. NCGS individuals showed improvements in intestinal transit time and contractility with a GFD, although the colon exhibited no discernible effect. The GFD did not significantly impact intragastric, intestinal, or colonic pH. Conclusions: This study, employing WMC for the first time, provides novel insights into the positive effects of a GFD on intestinal and colonic transit, as well as contractility, in CD patients, and to a lesser extent, in those with NCGS.
Prevention of Cerebrospinal Fluid Leakage in the Anterior Transpetrosal Approach
Authors: Shibao Shunsuke , Yoshida Kazunari , Sasao Ryota , Nishimoto Masaaki
Published: March 2024

Background: The anterior transpetrosal approach (ATPA) is effective for reaching petroclival lesions, and it allows for complications such as impaired venous return and neuropathy to be resolved. However, there is still room for improvement regarding cerebrospinal fluid (CSF) leakage. Here, we aim to focus on describing specific preoperative, intraoperative, and postoperative countermeasures for preventing CSF leakage when using the ATPA. Methods: Eleven patients treated using the ATPA, who were treated at our hospital from June 2019 to February 2023, were included in this descriptive study. Preoperatively, we performed a 3D simulation of the opened air cells. Then, we classified patterns of dural closure into three types based on intradural manipulation and whether it involved opened air cells or not. Intraoperatively, we performed a dural closure that included the use of more-watertight sutures (DuraGen®) and an endoscope. Furthermore, temporal bone air cell volume measurements were performed to confirm the correlation between the volume and factors related to CSF leakage. Results: No postoperative CSF leakage was observed in any patient. The temporal bone air cell volumes significantly corelated with the air cells of the petrous apex, the high-risk tract in the petrous apex, and postoperative fluid collection in mastoid air cells. Conclusions: We have described countermeasures for preventing CSF leakage when using the ATPA. Preoperative simulations and the use of multiple-layered dural reconstructions with endoscopes could be considered more reliable methods for preventing CSF leakage when using the ATPA.
A Survey to Quantify the Number and Structure of Extracorporeal Membrane Oxygenation Retrieval Programs in the United States
Authors: Mihu Mircea R. , Swant Laura V. , Schoaps Robert S. , Johnson Caroline , El Banayosy Aly
Published: March 2024

(1) Background: Extracorporeal membrane oxygenation (ECMO) represents a potentially lifesaving support for respiratory and/or circulatory failure but its availability is limited to larger medical centers. A well-organized regional ECMO center with remote cannulation and retrieval ability can offer this intervention to patients treated at hospitals without ECMO. Information regarding the number and structure of ECMO retrieval programs in the United States is limited and there are no data regarding the size and structure of existing programs and which physician specialists perform cannulations and provide management. (2) Methods: We created a survey of 12 questions that was sent out to all adult US ECMO programs registered in the ELSO database. The data for the study were collected through an online survey instrument that was developed in Survey Monkey (Monkey Headquarters, Portland, OR). (3) Results: Approximately half of the centers that received the survey responded: 136 out of 274 (49.6%). Sixty-three centers (46%) have an ECMO retrieval program; 58 of these offer both veno-arterial (V-A) and veno-venous (V-V) ECMO, while 5 programs offer V-V ECMO rescue only. Thirty-three (52%) centers perform less than 10 ECMO retrievals per year, and only five (8%) hospitals can perform more than 50 ECMO rescues per year. Cardiothoracic surgeons perform the majority of the ECMO cannulations during retrievals in 30 programs (48%), followed by intensivists in eight (13%) programs and cardiologists in three (5%) centers. (4) Conclusions: Many ECMO centers offer ECMO retrievals; however, only a minority of the programs perform a large number of rescues per year. These cannulations are primarily performed by cardiothoracic surgeons.
Effects of Probiotic Supplementation during Chronic Rhinosinusitis on the Microbiome
Authors: Standyło Arkadiusz , Obuchowska Aleksandra , Horaczyńska-Wojtaś Anna , Mielnik-Niedzielska Grażyna
Published: March 2024

Probiotics are live microorganisms that induce health benefits to the host. The consumption of probiotics can result in both prophylactic and therapeutic effects. Chronic rhinosinusitis (CRS) is an inflammatory condition that has a significant health and economic impact worldwide. Despite its great burden on the health-care system and patients’ quality of life, the variety of therapy options for CRS is currently limited. Inflammation, mucociliary dysfunction and changes in the microbial environment are thought to be the main factors causing the disease. Probiotics are a relatively new intervention, with a focus on the probiotic qualities and adaptive elements required for a bacterial strain to have a positive impact on CRS. The aim of this review was to review studies evaluating the potential beneficial effects of probiotics in the treatment of chronic rhinosinusitis. Future prospects and difficulties for probiotics in CRS are also highlighted.
Early HbA1c Levels as a Predictor of Adverse Obstetric Outcomes: A Systematic Review and Meta-Analysis
Authors: Mañé Laura , Navarro Humberto , Pedro-Botet Juan , Chillarón Juan José , Ballesta Silvia , Payà Antonio , Amador Verónica , Flores-Le Roux Juana Antonia , Benaiges David
Published: March 2024

Background: The objective was to assess the association between early HbA1c levels and pregnancy complications and whether this relationship is affected when HbA1c thresholds are greater than or less than 39 mmol/mol (5.7%). Methods: Electronic searches of the MEDLINE and EMBASE databases up to October 2022 were conducted. We included retrospective and prospective observational studies. The inclusion criteria were as follows: HbA1c measurements taken at <20 weeks’ gestation, singleton pregnancy, and no pre-existing diabetes mellitus. Results: We assessed the certainty of the evidence with the GRADE system. We determined the proportion of patients in each group who met the criteria for obstetrical outcomes and pooled data into two subgroups according to the HbA1c threshold: <39 mmol/mol or >39 mmol/mol (5.7%). Sixteen studies with a total of 43,627 women were included. An association between elevated early HbA1c levels and pre-eclampsia, large for gestational age (LGA), macrosomia, and preterm delivery (RR 2.02, 95% CI 1.53–2.66; RR 1.38, 95% CI 1.15–1.66; RR 1.40, 95% CI 1.07–1.83; and RR 1.67, 95% CI 1.39–2.0, respectively) was shown, with a moderate–high grade of certainty. According to the subgroup analysis of all studies, LGA, pre-eclampsia, and labour induction were associated with elevated HbA1c levels only in studies using an HbA1c threshold >39 mmol/mol (5.7%). The association between HbA1c levels and premature birth was statistically significant in studies using both higher and lower HbA1c thresholds. Conclusions: Women with high early HbA1c levels below the range of diabetes presented an increased risk of pregnancy complications such as macrosomia, LGA, and pre-eclampsia. An early HbA1c threshold of >39 mmol/mol (5.7%) showed the strongest association with pregnancy complications.
Evaluation of the Fusion Rate and Safety of Escherichia coli-Derived rhBMP-2 in Transforaminal Lumbar Interbody Fusion for Patients with Degenerative Lumbar Disease: A Prospective, Multicenter, Single-Arm Trial
Authors: Kwon Ji-Won , Cho Jae Hwan , Lee Jong Beom , Kim Jae Hong
Published: March 2024

Background: Few studies have documented the viability of E. coli-derived recombinant human bone morphogenetic protein-2 (rhBMP-2) in transforaminal lumbar interbody fusion (TLIF). This study aimed to assess the safety and fusion rate of rhBMP-2 in TLIF. Methods: The study was conducted as a prospective, multicenter, single-arm trial, and 30 patients needing one- or two-level TLIF were enrolled. Fusion rate was assessed using the 12-month interbody fusion rate on CT. Postoperative problems, including seroma, radiculitis, and ectopic bone formation, which have been documented as risks associated with rhBMP-2 in prior studies, were recorded. Results: The study demonstrated fusion outcomes in all instances at 52 and 104 weeks post-surgery. Significant improvements were observed in clinical outcomes, with ODI, SF-36, and VAS scores, all achieving statistical significance (p < 0.0001). No perioperative adverse events requiring reoperation were reported, and there were no incidences of seroma, radiculitis, cage migration, grafted bone extrusion, postoperative neurologic deficit, or deep wound infection. Conclusions: The study demonstrates the high safety and efficacy in inducing bone fusion of E. coli-derived rhBMP-2 in TLIF, with a notable absence of adverse postoperative complications. Trial registration: This study protocol was registered at Korea Clinical Research Information Service (number identifier: KCT0004738) on July 2020.