bluuebunny/crossref_metadata_2025 huggingface dataset:
The Revisions of the First Autobiography of AT Still, the Founder of Osteopathy, as a Step towards Integration in the American Healthcare System: A Comparative and Historiographic Review
Authors: Tuscano Silvia Clara , Haxton Jason , Ciardo Antonio , Ciullo Luigi , Zegarra-Parodi Rafael
Published: January 2024

Introduction: Osteopathy was originally introduced in rural America in 1874 as a comprehensive therapeutic approach aimed at promoting health. This approach was distinct and often conflicting with conventional/allopathic therapeutic methods available at that time to fight disease. We argue that, in struggling to achieve recognition within the American healthcare system and within the educational academic field that was about to be structured, the American osteopathic profession tried to protect itself from the charges of sectarism by starting to embrace principles of the biomedical paradigm. Methods: A comparative and historiographic review of the second version of the autobiography of AT Still (1908), the founder of osteopathy, against the first (1897) was chosen as an example of the adaptation of the American osteopathic profession to its evolving academic environment. Results: Although there were only a few substantial variations, we argue that they aimed to dampen the non-biological components of osteopathy, namely, its philosophical, spiritual, religious, emotional, and Native American roots, in an effort to gain respect and recognition within the emerging gold standard of the Western medical system. The shift towards a distinct, fully integrated profession within regulated Western healthcare systems was perceived by many professionals as a threat to AT Still’s original ideas, and the trend started when he was alive. Conclusion: Our findings suggest that a crucial conversation regarding the future of the professional identity must take place within the osteopathic community.
Management and Outcomes of Traumatic Liver Injury: A Retrospective Analysis from a Tertiary Care Center Experience
Authors: Alanezi Tariq , Altoijry Abdulmajeed , Alanazi Aued , Aljofan Ziyad , Altuwaijri Talal , Iqbal Kaisor , AlSheikh Sultan , Molla Nouran , Altuwaijri Mansour , Aloraini Abdullah , Altuwaijri Fawaz , Aldossary Mohammed Yousef
Published: January 2024

Background: although liver injuries are one of the most critical complications of abdominal trauma, choosing when to operate on these injuries is challenging for surgeons worldwide. Methods: We conducted a retrospective analysis of liver injury cases at our institution from 2016 to 2022 to describe the operative and nonoperative management (NOM) outcomes in patients with traumatic liver injuries. Baseline patient characteristics, liver injury details, treatments, and outcomes were analyzed. Results: Data from 45 patients (male, 77.8%) were analyzed. The mean age was 29.3 years. Blunt trauma was the most common injury mechanism (86.7%), whereas penetrating injuries were 8.9% of cases. Conservative management was associated with 18.9% of complications. The overall complication rate was 26.7%; delirium and sepsis were the most common (13.3%), followed by acute renal failure (4.4%), pneumonia, biliary leaks, and meningitis/seizures. Conclusions: Notwithstanding its limitations, this retrospective analysis demonstrated that NOM can serve as a safe and effective strategy for hemodynamically stable patients with liver trauma, irrespective of the patient’s injury grade. Nevertheless, careful patient selection and monitoring are crucial. Further investigations are necessary to thoroughly evaluate the management of traumatic liver injuries, particularly in the context of multiorgan injuries.
Minority Stress, Self-Awareness, and Coping Strategies during the COVID-19 Pandemic among Italian Transgender Young Adults
Authors: Della Casa Veronica , Gubello Alessio , Malmquist Anna , Mezzalira Selene , Bonato Marina , Simonelli Alessandra , Gatta Michela , Miscioscia Marina
Published: January 2024

Background: The security measures implemented in response to the COVID-19 emergency have caused complex consequences. The aim of the present study is to examine the repercussions of the pandemic on individuals belonging to gender identity minority groups, who have experienced heightened levels of stress in comparison to the general population. Methods: Online interviews with 12 transgender participants who resided in Italy during the pandemic were conducted and subsequently analyzed following the thematic analysis methodology. Results: The majority of the participants reported an increase in stress levels primarily attributed to the lack of acceptance and support within their familial environments, obstacles encountered in accessing specialized healthcare services, and a lack of support from the broader LGBTQ+ community. Despite these challenges, several participants developed effective coping strategies and a subset of them also benefited from multiple resilience factors, including familial support and assistance from mental health professionals. Conclusions: The outcomes of the present study indicate that the COVID-19 pandemic, while fostering certain protective factors within this population, has also given rise to new and critical mental health concerns. These findings hold significant implications for professionals working with transgender populations, highlighting the necessity of addressing these emerging mental health issues.
The Association between Relationship Satisfaction Concordance and Breast Cancer Survivors’ Physical and Psychosocial Well-Being
Authors: Vachon Eric A. , Krueger Ellen , Haggstrom David A. , Champion Victoria L.
Published: January 2024

The purpose of this article is to examine the association of relationship satisfaction concordance between breast cancer survivors (BCSs) and their partners with matched controls on physical and psychosocial outcomes. Dyads of BCSs, age-matched controls, and partners were recruited as part of a larger, cross-sectional QOL survey study. Relationship concordance was measured by the ENRICH marital satisfaction score, with each dyad’s score equaling the absolute value of the difference in satisfaction between survivor/control and their partner (lower score = greater concordance). Dependent variables for survivors/controls were social constraint, physical function, depression, fatigue, attention function, and sleep disturbance. Relationship satisfaction and concordance were used as the primary independent variables, while controlling for dyad category, race, education, income, and age within multiple linear regression models. The sample consisted of 387 dyads (220 BCSs, 167 controls). Relationship satisfaction concordance ranged from 0 to 53.4 (mean = 10.2). The BCS dyads had significantly worse concordance (11.1) than the controls (9.1) (p = 0.050). Within the multiple regression models, lower concordance was significantly associated with increased social constraint (p = 0.029), increased depression (p = 0.038), and increased fatigue (p = 0.006). Poor relationship satisfaction and concordance were significantly associated with poor physical and psychosocial outcomes. The maintenance of relationships should remain a focus through difficulties of cancer and into survivorship for survivors, partners, and providers.
Does Osteopathic Heart-Focused Palpation Modify Heart Rate Variability in Stressed Participants with Musculoskeletal Pain? A Randomised Controlled Pilot Study
Authors: Liem Torsten , Bohlen Lucas , Jung Anna-Moyra , Hitsch Samira , Schmidt Tobias
Published: January 2024

Heart rate variability (HRV) describes fluctuations in time intervals between heartbeats and reflects autonomic activity. HRV is reduced in stressed patients with musculoskeletal pain and improved after osteopathic manipulative treatment and mind–body interventions. Heart-focused palpation (HFP) combines manual and mind–body approaches to facilitate relaxation. This randomised controlled pilot study investigated the feasibility and sample size for a future randomised controlled trial and the effect of a single treatment with HFP or sham HFP (SHAM) on short-term HRV. A total of Thirty-three adults (47.7 ± 13.5 years old) with stress and musculoskeletal pain completed the trial with acceptable rates of recruitment (8.25 subjects per site/month), retention (100%), adherence (100%), and adverse events (0%). HFP (n = 18), but not SHAM (n = 15), significantly increased the root mean square of successive RR interval differences (p = 0.036), standard deviation of the NN intervals (p = 0.009), and ratio of the low-frequency to high-frequency power band (p = 0.026). HFP and SHAM significantly decreased the heart rate (p < 0.001, p = 0.009) but not the stress index and ratio of the Poincaré plot standard deviation along and perpendicular to the line of identity (p > 0.05). A power analysis calculated 72 participants. Taken together, the study was feasible and HFP improved HRV in stressed subjects with musculoskeletal pain, suggesting a parasympathetic effect.
Mobile Apps for COVID-19: A Systematic Review of Reviews
Authors: Holl Felix , Schobel Johannes , Swoboda Walter J.
Published: January 2024

Background: One measure national governments took to react to the acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic was mobile applications (apps). This study aims to provide a high-level overview of published reviews of mobile apps used in association with coronavirus disease 19 (COVID-19), examine factors that contributed to the success of these apps, and provide data for further research into this topic. Methods: We conducted a systematic review of reviews (also referred to as an umbrella review) and searched two databases, Medline and Embase, for peer-reviewed reviews of COVID-19 mobile apps that were written in English and published between January 1st 2020 and April 25th 2022. Results: Out of the initial 17,611 studies, 24 studies were eligible for the analysis. Publication dates ranged from May 2020 to January 2022. In total, 54% (n = 13) of the studies were published in 2021, and 33% (n = 8) were published in 2020. Most reviews included in our review of reviews analyzed apps from the USA, the UK, and India. Apps from most of the African and Middle and South American countries were not analyzed in the reviews included in our study. Categorization resulted in four clusters (app overview, privacy and security, MARS rating, and miscellaneous). Conclusions: Our study provides a high-level overview of 24 reviews of apps for COVID-19, identifies factors that contributed to the success of these apps, and identifies a gap in the current literature. The study provides data for further analyses and further research.
Self-Esteem and Occupational Factors as Predictors of the Incidence of Anxiety and Depression among Healthcare Workers during the COVID-19 Pandemic in Latvia
Authors: Valaine Laura , Grēve Māra , Zolovs Maksims , Ancāne Gunta , Utināns Artūrs , Briģis Ģirts
Published: January 2024

The prevalence of depression and anxiety among healthcare workers (HCWs) during the COVID-19 pandemic is high. The aim of the study is to identify the importance of self-esteem and occupational factors in association with the incidence of depression and anxiety among HCWs through a longitudinal cohort study during the COVID-19 pandemic in Latvia. Participants received seven questionnaires during the COVID-19 pandemic on demographic parameters, work-related information, and contact with COVID-19 patients, and three standardized questionnaires that evaluated symptoms of anxiety (GAD-7), depression (PHQ-9), and self-esteem (Rosenberg’s self-esteem scale). The Generalized Linear Mixed Model (GLMM) was used to identify factors associated with the incidence of depression and anxiety among HCWs. A total of 322 participants were included in the data analysis for depression and 352 for anxiety. HCWs with low self-esteem were 83% more likely to experience depression and 76% more likely to experience anxiety. Working at a general practitioner practice is associated with twice the risk of developing depression and anxiety. A 31% increase in the odds of depression is observed among HCWs with direct contact with COVID-19 patients. The organizational and government levels must look for opportunities to facilitate the mental health of HCWs to ensure better-quality healthcare.
Long-Term Impact of Childhood Adversity on the Gut Microbiome of Nursing Students
Authors: Kazemian Negin , Zhou Tony , Chalasani Naveen , Narayan Apurva , Cedeño Laurent Jose Guillermo , Olvera Alvarez Hector A. , Pakpour Sepideh
Published: January 2024

Adverse childhood experiences (ACEs) encompass negative, stressful, and potentially traumatic events during childhood, impacting physical and mental health outcomes in adulthood. Limited studies suggest ACEs can have short-term effects on children’s gut microbiomes and adult cognitive performance under stress. Nevertheless, the long-term effects of ACEs experienced during adulthood remain unexplored. Thus, this study aimed to assess the long-term effects of ACEs on the gut microbiota of adult nursing students. We employed a multidimensional approach, combining 16S rRNA sequencing, bioinformatics tools, and machine learning to predict functional capabilities. High-ACE individuals had an increased abundance of Butyricimonas spp. and Prevotella spp. and decreased levels of Clostridiales, and Lachnospira spp. Prevotella abundance correlated negatively with L-glutamate and L-glutamine biosynthesis, potentially impacting intestinal tissue integrity. While nursing students with high ACE reported increased depression, evidence for a direct gut microbiota–depression relationship was inconclusive. High-ACE individuals also experienced a higher prevalence of diarrhea. These findings highlight the long-lasting impact of ACEs on the gut microbiota and its functions in adulthood, particularly among nursing students. Further research is warranted to develop targeted interventions and strategies for healthcare professionals, optimizing overall health outcomes.
Genome-Wide Identification and Expression Analysis of GATA Family Genes in Dimocarpus longan Lour
Authors: Zheng Kehui , Lu Jiayue , He Xinyu , Lan Shuoxian , Zhai Tingkai , Cao Shijiang , Lin Yuling
Published: January 2024

GATA transcription factors, which are DNA-binding proteins with type IV zinc finger binding domains, have a role in transcriptional regulation in biological organisms. They have an indispensable role in the growth and development of plants, as well as in improvements in their ability to face various environmental stresses. To date, GATAs have been identified in many gene families, but the GATA gene in longan (Dimocarpus longan Lour) has not been studied in previous explorations. Various aspects of genes in the longan GATA family, including their identification and classification, the distribution of their positions on chromosomes, their exon/intron structures, a synteny analysis, their expression at different temperatures, concentration of PEG, early developmental stages of somatic embryos and their expression levels in different tissues, and concentrations of exogenous hormones, were investigated in this study. This study showed that the 22 DlGATAs could be divided into four subfamilies. There were 10 pairs of homologous GATA genes in the synteny analysis of DlGATA and AtGATA. Four segmental replication motifs and one pair of tandem duplication events were present among the DlGATA family members. The cis-acting elements located in promoter regions were also found to be enriched with light-responsive elements, which contained related hormone-responsive elements. In somatic embryos, DlGATA4 is upregulated for expression at the globular embryo (GE) stage. We also found that DlGATA expression was strongly up-regulated in roots and stems. The study demonstrated the expression of DlGATA under hormone (ABA and IAA) treatments in embryogenic callus of longan. Under ABA treatment, DlGATA4 was up-regulated and the other DlGATA genes did not respond significantly. Moreover, as demonstrated with qRT-PCR, the expression of DlGATA genes showed strong up-regulated expression levels under 100 μmol·L−1 concentration IAA treatment. This experiment further studied these and simulated their possible connections with a drought response mechanism, while correlating them with their expression under PEG treatment. Overall, this experiment explored the GATA genes and dug into their evolution, structure, function, and expression profile, thus providing more information for a more in-depth study of the characteristics of the GATA family of genes.
After the Hurricane: Anti-COVID-19 Drugs Development, Molecular Mechanisms of Action and Future Perspectives
Authors: Khalifa Hazim , Al Ramahi Yousef
Published: January 2024

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new coronavirus in the Coronaviridae family. The COVID-19 pandemic, caused by SARS-CoV-2, has undoubtedly been the largest crisis of the twenty-first century, resulting in over 6.8 million deaths and 686 million confirmed cases, creating a global public health issue. Hundreds of notable articles have been published since the onset of this pandemic to justify the cause of viral spread, viable preventive measures, and future therapeutic approaches. As a result, this review was developed to provide a summary of the current anti-COVID-19 drugs, as well as their timeline, molecular mode of action, and efficacy. It also sheds light on potential future treatment options. Several medications, notably hydroxychloroquine and lopinavir/ritonavir, were initially claimed to be effective in the treatment of SARS-CoV-2 but eventually demonstrated inadequate activity, and the Food and Drug Administration (FDA) withdrew hydroxychloroquine. Clinical trials and investigations, on the other hand, have demonstrated the efficacy of remdesivir, convalescent plasma, and monoclonal antibodies, 6-Thioguanine, hepatitis C protease inhibitors, and molnupiravir. Other therapeutics, including inhaled medicines, flavonoids, and aptamers, could pave the way for the creation of novel anti-COVID-19 therapies. As future pandemics are unavoidable, this article urges immediate action and extensive research efforts to develop potent specialized anti-COVID-19 medications.
Characterisation of Matrix-Bound Nanovesicles (MBVs) Isolated from Decellularised Bovine Pericardium: New Frontiers in Regenerative Medicine
Authors: Di Francesco Dalila , Di Varsavia Carolina , Casarella Simona , Donetti Elena , Manfredi Marcello , Mantovani Diego , Boccafoschi Francesca
Published: January 2024

Matrix-bound nanovesicles (MBVs) are a recently discovered type of extracellular vesicles (EVs), and they are characterised by a strong adhesion to extracellular matrix structural proteins (ECM) and ECM-derived biomaterials. MBVs contain a highly bioactive and tissue-specific cargo that recapitulates the biological activity of the source ECM. The rich content of MBVs has shown to be capable of potent cell signalling and of modulating the immune system, thus the raising interest for their application in regenerative medicine. Given the tissue-specificity and the youthfulness of research on MBVs, until now they have only been isolated from a few ECM sources. Therefore, the objective of this research was to isolate and identify the presence of MBVs in decellularised bovine pericardium ECM and to characterise their protein content, which is expected to play a major role in their biological potential. The results showed that nanovesicles, corresponding to the definition of recently described MBVs, could be isolated from decellularised bovine pericardium ECM. Moreover, these MBVs were composed of numerous proteins and cytokines, thus preserving a highly potential biological effect. Overall, this research shows that bovine pericardium MBVs show a rich and tissue-specific biological potential.
Development of Good Manufacturing Practice-Compatible Isolation and Culture Methods for Human Olfactory Mucosa-Derived Mesenchymal Stromal Cells
Authors: Kelly Christopher J. , Lindsay Susan L. , Smith Rebecca Sherrard , Keh Siew , Cunningham Kyle T. , Thümmler Katja , Maizels Rick M. , Campbell John D. M. , Barnett Susan C.
Published: January 2024

Demyelination in the central nervous system (CNS) resulting from injury or disease can cause loss of nerve function and paralysis. Cell therapies intended to promote remyelination of axons are a promising avenue of treatment, with mesenchymal stromal cells (MSCs) a prominent candidate. We have previously demonstrated that MSCs derived from human olfactory mucosa (hOM-MSCs) promote myelination to a greater extent than bone marrow-derived MSCs (hBM-MSCs). However, hOM-MSCs were developed using methods and materials that were not good manufacturing practice (GMP)-compliant. Before considering these cells for clinical use, it is necessary to develop a method for their isolation and expansion that is readily adaptable to a GMP-compliant environment. We demonstrate here that hOM-MSCs can be derived without enzymatic tissue digestion or cell sorting and without culture antibiotics. They grow readily in GMP-compliant media and express typical MSC surface markers. They robustly produce CXCL12 (a key secretory factor in promoting myelination) and are pro-myelinating in in vitro rodent CNS cultures. GMP-compliant hOM-MSCs are comparable in this respect to those grown in non-GMP conditions. However, when assessed in an in vivo model of demyelinating disease (experimental autoimmune encephalitis, EAE), they do not significantly improve disease scores compared with controls, indicating further pre-clinical evaluation is necessary before their advancement to clinical trials.
The Pivotal Distinction between Antagonists’ and Agonists’ Binding into Dopamine D4 Receptor—MD and FMO/PIEDA Studies
Authors: Śliwa Paweł , Dziurzyńska Magdalena , Kurczab Rafał , Kucwaj-Brysz Katarzyna
Published: January 2024

The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists and antagonists appears to be clinically relevant. The mechanism of binding to the receptor (R) for antagonists and agonists varies. In the present study, we conducted an in-depth computational study, teasing out key similarities and differences in binding modes, complex dynamics, and binding energies for D4R agonists and antagonists. The dynamic network method was applied to investigate the communication paths between the ligand (L) and G-protein binding site (GBS) of human D4R. Finally, the fragment molecular orbitals with pair interaction energy decomposition analysis (FMO/PIEDA) scheme was used to estimate the binding energies of L–R complexes. We found that a strong salt bridge with D3.32 initiates the inhibition of the dopamine D4 receptor. This interaction also occurs in the binding of agonists, but the change in the receptor conformation to the active state starts with interaction with cysteine C3.36. Such a mechanism may arise in the case of agonists unable to form a hydrogen bond with the serine S5.46, considered, so far, to be crucial in the activation of GPCRs. The energy calculations using the FMO/PIEDA method indicate that antagonists show higher residue occupancy of the receptor binding site than agonists, suggesting they could form relatively more stable complexes. Additionally, antagonists were characterized by repulsive interactions with S5.46 distinguishing them from agonists.
Immune-Related Molecules CD3G and FERMT3: Novel Biomarkers Associated with Sepsis
Authors: Li Nanxi , Ren Peng , Wang Jingya , Zhu Xiaohui , Qiao Xuan , Zeng Zhirui , Ye Tong , Wang Shanshan , Meng Zhiyun , Gan Hui , Liu Shuchen , Sun Yunbo , Zhu Xiaoxia , Dou Guifang , Gu Ruolan
Published: January 2024

Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein–protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1β and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study.
First Evidence of Mineralocorticoid Receptor Gene and Protein Expression in Rat and Human Thyroid Tissues and Cell Cultures
Authors: Manso Jacopo , Pedron Maria Chiara , Mondin Alberto , Censi Simona , Pennelli Gianmaria , Galuppini Francesca , Barollo Susi , Bertazza Loris , Radu Claudia Maria , Ghini Francesca , Simioni Paolo , Sabbadin Chiara , Ceccato Filippo , Armanini Decio , Mian Caterina
Published: January 2024

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue.
Cilostazol Stimulates Angiogenesis and Accelerates Fracture Healing in Aged Male and Female Mice by Increasing the Expression of PI3K and RUNX2
Authors: Menger Maximilian M. , Emmerich Maximilian , Scheuer Claudia , Hans Sandra , Ehnert Sabrina , Nüssler Andreas K. , Herath Steven C. , Steinestel Konrad , Menger Michael D. , Histing Tina , Laschke Matthias W.
Published: January 2024

Fracture healing in the aged is associated with a reduced healing capacity, which often results in delayed healing or non-union formation. Many factors may contribute to this deterioration of bone regeneration, including a reduced ‘angiogenic trauma response’. The phosphodiesterase-3 (PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in preclinical studies. Therefore, we herein analyzed in a stable closed femoral fracture model whether this compound also promotes fracture healing in aged mice. Forty-two aged CD-1 mice (age: 16–18 months) were daily treated with 30 mg/kg body weight cilostazol (n = 21) or vehicle (control, n = 21) by oral gavage. At 2 and 5 weeks after fracture, the femora were analyzed by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry, and Western blotting. These analyses revealed a significantly increased bending stiffness at 2 weeks (2.2 ± 0.4 vs. 4.3 ± 0.7 N/mm) and an enhanced bone formation at 5 weeks (4.4 ± 0.7 vs. 9.1 ± 0.7 mm3) in cilostazol-treated mice when compared to controls. This was associated with a higher number of newly formed CD31-positive microvessels (3.3 ± 0.9 vs. 5.5 ± 0.7 microvessels/HPF) as well as an elevated expression of phosphoinositide-3-kinase (PI3K) (3.6 ± 0.8 vs. 17.4 ± 5.5-pixel intensity × 104) and runt-related transcription factor (RUNX)2 (6.4 ± 1.2 vs. 18.2 ± 2.7-pixel intensity × 104) within the callus tissue. These findings indicate that cilostazol accelerates fracture healing in aged mice by stimulating angiogenesis and the expression of PI3K and RUNX2. Hence, cilostazol may represent a promising compound to promote bone regeneration in geriatric patients.
Identification of Hub Genes and Physiological Effects of Overexpressing the Photosynthesis-Related Gene Soly720 in Tomato under High-CO2 Conditions
Authors: Zheng Shaowen , Yang Lingbo , Zheng Hao , Wu Jiayue , Zhou Zijian , Tian Jieyun
Published: January 2024

Changes in the atmospheric CO2 concentration influence plant growth and development by affecting the morphological structure and photosynthetic performance. Despite evidence for the macro-effects of elevated CO2 concentrations on plant morphology and yield in tomato, the gene regulatory network and key genes related to cross-regulation have not been reported. To identify the hub genes and metabolic pathways involved in the response of tomato to CO2 enrichment, weighted gene co-expression network analysis was conducted using gene expression profiles obtained by RNA sequencing. The role of the photosynthesis-related gene Soly720 (Solyc01g007720) in CO2-enriched tomato plants was explored. Tomato plants responded to CO2 enrichment primarily through RNA-related pathways and the metabolism of amino acids, fatty acids, and carbohydrates. The hub genes in co-expression networks were associated with plant growth and development, including cellular components and photosynthesis. Compared to wild-type plants, transgenic plants overexpressing the Soly720 gene exhibited 13.4%, 5.5%, 8.9%, and 4.1% increases in plant height, stem diameter, leaf length, and leaf width, respectively, under high-CO2 conditions. The morphological improvements in transgenic plants were accompanied by enhancement of photosynthetic performance in terms of chlorophyll contents, photosynthetic characteristics, and key enzyme activities. This study elucidates the response network of tomato to CO2 enrichment and demonstrates the regulatory role of Soly720 in photosynthesis under high-CO2 conditions.
Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old
Authors: Curcio Antonio , Scalise Rosa , Indolfi Ciro
Published: January 2024

Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients’ survival rate. Due to empowered diagnostics, it has become increasingly recognized among young individuals as well, in whom it is influenced by a complex interplay of autoimmune, inflammatory, and electrophysiological mechanisms. Deepening our understanding of these mechanisms could contribute to improving AF management and treatment. Inflammation is a complexly regulated process, with interactions among various immune cell types, signaling molecules, and complement components. Addressing circulating antibodies and designing specific autoantibodies are promising therapeutic options. In cardiomyopathies or channelopathies, the first manifestation could be paroxysmal AF; persistent forms tend not to respond to antiarrhythmic drugs in these conditions. Further research, both in vitro and in vivo, on the use of genomic biotechnology could lead to new therapeutic approaches. Additional triggers that can be encountered in AF patients below 60 years of age are systemic hypertension, overweight, diabetes, and alcohol abuse. The aims of this review are to briefly report evidence from basic science and results of clinical studies that might explain the juvenile burden of the most encountered sustained supraventricular tachyarrhythmias in the general population.
Differential microRNA Expression Analysis in Patients with HPV-Infected Ovarian Neoplasms
Authors: Jarych Dariusz , Mikulski Damian , Wilczyński Miłosz , Wilczyński Jacek R. , Kania Katarzyna D. , Haręża Daria , Malinowski Andrzej , Perdas Ewelina , Nowak Mateusz , Paradowska Edyta
Published: January 2024

This study aimed to identify microRNAs (miRNAs) whose expression levels are altered by high-risk human papillomavirus (HR-HPV) infection in women with epithelial ovarian neoplasms. MiRNA expression was quantified by real-time polymerase chain reaction, while HR-HPV DNA was quantified using digital-droplet PCR. Analysis of 11 miRNAs demonstrated significantly lower hsa-miR-25-5p expression in HPV-infected compared to uninfected ovarian tissues (p = 0.0405), while differences in miRNA expression in corresponding serum were statistically insignificant. The expression of hsa-miR-218-5p in ovarian tumors was significantly higher in high-grade serous ovarian carcinoma (HGSOC) cases than in other neoplasms (p = 0.0166). In addition, hsa-miR-218-5p was significantly upregulated, whereas hsa-miR-191-5p was significantly downregulated in tissues with stage III/IV FIGO (p = 0.0009 and p = 0.0305, respectively). Using unsupervised clustering, we identified three unique patient groups with significantly varied frequencies of HPV16/18-positive samples and varied miRNA expression profiles. In multivariate analysis, high expression of hsa-miR-16-5p was an independent prognostic factor for poor overall survival (p = 0.0068). This preliminary analysis showed the changes in miRNA expression in ovarian neoplasms during HPV infection and those collected from HGSOCs or patients with advanced disease. This prospective study can provide new insights into the pathogenesis of ovarian neoplasms and host–virus interactions.
Cadmium Induces Kidney Iron Deficiency and Chronic Kidney Injury by Interfering with the Iron Metabolism in Rats
Authors: Zhang Kanglei , Long Mengfei , Dong Wenxuan , Li Jiahui , Wang Xueru , Liu Wenjing , Huang Qing , Ping Yuyu , Zou Hui , Song Ruilong , Liu Gang , Ran Di , Liu Zongping
Published: January 2024

Cadmium (Cd) is a common environmental pollutant and occupational toxicant that seriously affects various mammalian organs, especially the kidney. Iron ion is an essential trace element in the body, and the disorder of iron metabolism is involved in the development of multiple pathological processes. An iron overload can induce a new type of cell death, defined as ferroptosis. However, whether iron metabolism is abnormal in Cd-induced nephrotoxicity and the role of ferroptosis in Cd-induced nephrotoxicity need to be further elucidated. Sprague Dawley male rats were randomly assigned into three groups: a control group, a 50 mg/L CdCl2-treated group, and a 75 mg/L CdCl2-treated group by drinking water for 1 month and 6 months, respectively. The results showed that Cd could induce renal histopathological abnormalities and dysfunction, disrupt the mitochondria’s ultrastructure, and increase the ROS and MDA content. Next, Cd exposure caused GSH/GPX4 axis blockade, increased FTH1 and COX2 expression, decreased ACSL4 expression, and significantly decreased the iron content in proximal tubular cells or kidney tissues. Further study showed that the expression of iron absorption-related genes SLC11A2, CUBN, LRP2, SLC39A14, and SLC39A8 decreased in proximal tubular cells or kidneys after Cd exposure, while TFRC and iron export-related gene SLC40A1 did not change significantly. Moreover, Cd exposure increased SLC11A2 gene expression and decreased SLC40A1 gene expression in the duodenum. Finally, NAC or Fer-1 partially alleviated Cd-induced proximal tubular cell damage, while DFO and Erastin further aggravated Cd-induced cell damage. In conclusion, our results indicated that Cd could cause iron deficiency and chronic kidney injury by interfering with the iron metabolism rather than typical ferroptosis. Our findings suggest that an abnormal iron metabolism may contribute to Cd-induced nephrotoxicity, providing a novel approach to preventing kidney disease in clinical practice.
CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders
Authors: Pagliaro Luca , Cerretani Elisa , Vento Federica , Montanaro Anna , Moron Dalla Tor Lucas , Simoncini Elisa , Giaimo Mariateresa , Gherli Andrea , Zamponi Raffaella , Tartaglione Isotta , Lorusso Bruno , Scita Matteo , Russo Filomena , Sammarelli Gabriella , Todaro Giannalisa , Silini Enrico Maria , Rigolin Gian Matteo , Quaini Federico , Cuneo Antonio , Roti Giovanni
Published: January 2024

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.
Molecular Biology of Meniscal Healing: A Narrative Review
Authors: Tramś Ewa , Kamiński Rafał
Published: January 2024

This review provides insights at the molecular level into the current and old methods for treating meniscal injuries. Meniscal injuries have been found to have a substantial impact on the progression of osteoarthritis. In line with the “save the meniscus” approach, meniscectomy is considered a last-resort treatment. Nevertheless, it is important to note that mechanical repair alone may not achieve the complete restoration of the meniscus. A deep understanding of the healing pathways could lead to future improvements in meniscal healing. The inclusion of cytokines and chemokines has the potential to facilitate the process of tear repair or impede the inflammatory catabolic cascade. MicroRNA (miRNA) could serve as a potential biomarker for meniscal degeneration, and RNA injections might promote collagen and growth factor production. The critical aspect of the healing process is angiogenesis within the inner zone of the meniscus. The use of collagen scaffolds and the implantation of autologous meniscus fragments have been successfully integrated into clinical settings. These findings are encouraging and underscore the need for well-designed clinical trials to explore the most effective factors that can enhance the process of meniscal repair.
Cholestatic HCV Cryoglobulinemia: A New Clinical and Pathological Entity before and after Direct-Acting Antiviral Therapies—A Case-Control Study
Authors: Ammendola Serena , Romeo Sara , Cattazzo Filippo , Mantovani Anna , Ieluzzi Donatella , Paon Veronica , Montagnana Martina , Pecori Sara , Tomezzoli Anna , Dalbeni Andrea , Sacerdoti David
Published: January 2024

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC− patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35–77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients’ follow-up after antiviral therapies.
Characterization and Potential Action Mode Divergences of Homologous ACO1 Genes during the Organ Development and Ripening Process between Non-Climacteric Grape and Climacteric Peach
Authors: Luo Linjia , Zhao Pengcheng , Su Ziwen , Huang Yuqing , Zhang Yanping , Mu Qian , Xuan Xuxian , Qu Ziyang , Yu Mucheng , Qi Ziyang , Aziz Rana Badar , Gong Peijie , Xie Zhenqiang , Fang Jinggui , Wang Chen
Published: January 2024

Ethylene is one crucial phytohormone modulating plants’ organ development and ripening process, especially in fruits, but its action modes and discrepancies in non-climacteric grape and climacteric peach in these processes remain elusive. This work is focused on the action mode divergences of ethylene during the modulation of the organ development and ripening process in climacteric/non-climacteric plants. We characterized the key enzyme genes in the ethylene synthesis pathway, VvACO1 and PpACO1, and uncovered that their sequence structures are highly conserved, although their promoters exhibit important divergences in the numbers and types of the cis-elements responsive to hormones, implying various responses to hormone signals. Subsequently, we found the two have similar expression modes in vegetative organ development but inverse patterns in reproductive ones, especially in fruits. Then, VvACO1 and PpACO1 were further validated in promoting fruit ripening functions through their transient over-expression/RNAi-expression in tomatoes, of which the former possesses a weaker role than the latter in the fruit ripening process. Our findings illuminated the divergence in the action patterns and function traits of the key VvACO1/PpACO1 genes in the tissue development of climacteric/non-climacteric plants, and they have implications for further gaining insight into the interaction mechanism of ethylene signaling during the modulation of the organ development and ripening process in climacteric/non-climacteric plants.
Mapping and Screening of Candidate Gene Regulating the Biomass Yield of Sorghum (Sorghum bicolor L.)
Authors: Li Mao , Cai Qizhe , Liang Yinpei , Zhao Yaofei , Hao Yaoshan , Qin Yingying , Qiao Xinrui , Han Yuanhuai , Li Hongying
Published: January 2024

Biomass yield is one of the important traits of sorghum, which is greatly affected by leaf morphology. In this study, a lobed-leaf mutant (sblob) was screened and identified, and its F2 inbred segregating line was constructed. Subsequently, MutMap and whole-genome sequencing were employed to identify the candidate gene (sblob1), the locus of which is Sobic.003G010300. Pfam and homologous analysis indicated that sblob1 encodes a Cytochrome P450 protein and plays a crucial role in the plant serotonin/melatonin biosynthesis pathway. Structural and functional changes in the sblob1 protein were elucidated. Hormone measurements revealed that sblob1 regulates both leaf morphology and sorghum biomass through regulation of the melatonin metabolic pathway. These findings provide valuable insights for further research and the enhancement of breeding programs, emphasizing the potential to optimize biomass yield in sorghum cultivation.
Exploring the Cyclic Behaviour of URM Walls with and without Damp-Proof Course (DPC) Membranes through Discrete Element Method
Authors: Pulatsu Bora , Wilson Rhea , Lemos Jose V. , Mojsilović Nebojša
Published: January 2024

Unreinforced masonry (URM) walls are common load-bearing structural elements in most existing buildings, consisting of masonry units (bricks) and mortar joints. They indicate a highly nonlinear and complex behaviour when subjected to combined compression–shear loading influenced by different factors, such as pre-compression load and boundary conditions, among many others, which makes predicting their structural response challenging. To this end, the present study offers a discontinuum-based modelling strategy based on the discrete element method (DEM) to investigate the in-plane cyclic response of URM panels under different vertical pressures with and without a damp-proof course (DPC) membrane. The adopted modelling strategy represents URM walls as a group of discrete rigid block systems interacting along their boundaries through the contact points. A novel contact constitutive model addressing the elasto-softening stress–displacement behaviour of unit–mortar interfaces and the associated stiffness degradation in tension–compression regimes is adopted within the implemented discontinuum-based modelling framework. The proposed modelling strategy is validated by comparing a recent experimental campaign where the essential data regarding geometrical features, material properties and loading histories are obtained. The results show that while the proposed computational modelling strategy can accurately capture the hysteric response of URM walls without a DPC membrane, it may underestimate the load-carrying capacity of URM walls with a DPC membrane.