bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Genetic Characteristics of the Hoxc13 Gene and Association Analysis of Wool Traits
Authors: Sun Hongxian , He Zhaohua , Zhao Fangfang , Hu Jiang , Wang Jiqing , Liu Xiu , Zhao Zhidong , Li Mingna , Luo Yuzhu , Li Shaobin
Published: January 2024

Homobox C13 (Hoxc13) is an important transcription factor in hair follicle cycle development, and its deletion had been found in a variety of animals leading to abnormal hair growth and disruption of the hair follicle system. In this study, we used immunofluorescence, immunohistochemistry, real-time fluorescence quantitative PCR (RT-qPCR), and Kompetitive Allele-Specific PCR (KASP) genotyping to investigate molecular genetic characteristics of the Hoxc13 gene in Gansu alpine fine-wool sheep. The results revealed that Hoxc13 was significantly expressed during both the anagen and catagen phases (p < 0.05). It was found to be highly expressed predominantly in the dermal papillae and the inner and outer root sheaths, showing a distinct spatiotemporal expression pattern. Two single nucleotide polymorphisms (SNPs) in the exon 1 of Hoxc13, both the individual locus genotypes and the combined haplotypes were found to be correlated with wool length (p < 0.05). It was determined the mutations led to changes in mRNA expression, in which higher expression of this gene was related with longer wool length. In summary, this unique spatiotemporal expression pattern of the Hoxc13 gene may regulate the wool length of Gansu alpine fine-wool sheep, which can be used as a molecular genetic marker for wool traits and thus improve the breed.
Highlights on the Effects of Non-Coding RNAs in the Osteonecrosis of the Jaw
Authors: Caserta Santino , Stagno Fabio , Gangemi Sebastiano , Allegra Alessandro
Published: January 2024

Osteonecrosis of the jaw is the progressive loss and destruction of bone affecting the maxilla or mandible in patients treated with antiresorptive and antiangiogenic agents without receiving prior radiation therapy. The pathogenesis involves the inflammatory pathway of receptor activator of nuclear factor NF-kB ligand and the macrophage colony-stimulating factor, essential for osteoclast precursors survival and proliferation and acting through its receptor c-Fms. Evidence has shown the role of non-coding RNAs in the pathogenesis of osteonecrosis of the jaw and this finding might be useful in diagnosis since these small RNAs could be considered as biomarkers of apoptotic activity in bone. Interestingly, it has been proved that miR-29 and miR-31-5p, acting on specific targets such as CALCR and RhoA, promote programmed-cell death and consequently the necrosis of bone tissue. Specific long non-coding RNAs, instead, have been detected both at reduced levels in patients with multiple myeloma and osteonecrosis, and associated with suppression of osteoblast differentiation, with consequences in the progression of mandible lesions. Among non-coding genic material, circular RNAs have the capability to modify the expression of specific mRNAs responsible for the inhibition of bisphosphonates activity on osteoclastogenesis.
Observational Study on a Large Italian Population with Lipedema: Biochemical and Hormonal Profile, Anatomical and Clinical Evaluation, Self-Reported History
Authors: Patton Laura , Ricolfi Lorenzo , Bortolon Micaela , Gabriele Guido , Zolesio Pierluigi , Cione Erika , Cannataro Roberto
Published: January 2024

We analyzed the medical condition of 360 women affected by lipedema of the lower limbs in stages 1, 2, and 3. The data were assessed for the whole population and compared between different clinical stages, distinguishing between obese and non-obese patients. The most frequent clinical signs were pain when pinching the skin, subcutaneous nodules, and patellar fat pads. The most frequently painful site of the lower limbs was the medial lower third of the thigh. The pain score obtained on lower limb points increased progressively with the clinical stage. In all points evaluated, the thickness of the subcutaneous tissue increased with the clinical stage. Analyzing the data on the lower medial third of the leg and considering only patients with type 3 lipedema, the difference between stages was statistically significant after correction for age and BMI. We found higher levels of C-reactive protein at more severe clinical stages, and the difference was significant after correction for age and BMI between the stages. Overall, the prevalence of alterations of glucose metabolism was 34%, with a progressive increase in prevalence with the clinical stage. The most frequent comorbidities were vitamin D insufficiency, chronic venous disease, allergies, dyslipidemia, headache, and depression of mood. Interestingly, in comparison with the general population, we found higher prevalence of chronic autoimmune thyroiditis and polycystic ovary syndrome. Finally, the clinical stage and the involvement of the upper limbs or obesity suggest a worse clinical, anthropometric, and endocrine–metabolic profile.
Bioactive Bismuth Compounds: Is Their Toxicity a Barrier to Therapeutic Use?
Authors: Gonçalves Ângela , Matias Mariana , Salvador Jorge A. R. , Silvestre Samuel
Published: January 2024

Bismuth compounds are considered relatively non-toxic, with their low solubility in aqueous solutions (e.g., biological fluids) being the major contributing factor to this property. Bismuth derivatives are widely used for the treatment of peptic ulcers, functional dyspepsia, and chronic gastritis. Moreover, the properties of bismuth compounds have also been extensively explored in two main fields of action: antimicrobial and anticancer. Despite the clinical interest of bismuth-based drugs, several side effects have also been reported. In fact, excessive acute ingestion of bismuth, or abuse for an extended period of time, can lead to toxicity. However, evidence has demonstrated that the discontinuation of these compounds usually reverses their toxic effects. Notwithstanding, the continuously growing use of bismuth products suggests that it is indeed part of our environment and our daily lives, which urges a more in-depth review and investigation into its possible undesired activities. Therefore, this review aims to update the pharmaco-toxicological properties of bismuth compounds. A special focus will be given to in vitro, in vivo, and clinical studies exploring their toxicity.
Atrazine Desorption Mechanism from an Hydrated Calcium Montmorillonite—A DFT Molecular Dynamics Study
Authors: Desdion Quentin , Bessac Fabienne , Hoyau Sophie
Published: January 2024

Atrazine is one of the most widely used herbicide molecules in the triazine family. Despite its interdiction in the European Union in 2004, atrazine and its main degradation products remain among the most frequently found molecules in freshwater reservoirs in many European Union countries. Our study aims in obtaining insight into the desorption process of atrazine from the main soil absorbent material: clay. Constrained Molecular Dynamics simulations within the Density Functional Theory framework allow us to obtain a free energy desorption profile of atrazine from a Ca2+-montmorillonite surface. The results are interpreted in terms of atrazine inclination to the clay surface and moreover, in terms of hydration states of the cations present in the clay interlayer as well as the hydration state of the atrazine. The desorption mechanism is driven by atrazine alkyl groups and their sizes because of dispersion stabilizing effects. The highest barrier corresponds to the loss of the isopropyl interaction with the surface.
Global Transcriptomic Analysis of Placentas from Women with Gestational SARS-CoV-2 Infection during the Third Trimester of Pregnancy
Authors: Tang Yiqun , Boggavarapu Nageswara Rao , Aronsson Annette , Gemzell-Danielsson Kristina , Lalitkumar Parameswaran Grace
Published: January 2024

The COVID-19 pandemic has had a significant and enduring influence on global health, including maternal and fetal well-being. Evidence suggests that placental dysfunction is a potential consequence of SARS-CoV-2 infection during pregnancy, which may result in adverse outcomes such as preeclampsia and preterm birth. However, the molecular mechanisms underlying this association remain unclear, and it is uncertain whether a mature placenta can protect the fetus from SARS-CoV-2 infection. To address the above gap, we conducted a transcriptome-based study of the placenta in both maternal and fetal compartments. We collected placental samples from 16 women immediately after term delivery, seven of which had SARS-CoV-2 infection confirmed by PCR before parturition. Notably, we did not detect any viral load in either the maternal or fetal compartments of the placenta, regardless of symptomatic status. We separately extracted total RNA from placental tissues from maternal and fetal compartments, constructed cDNA libraries, and sequenced them to assess mRNA. Our analysis revealed 635 differentially expressed genes when a false discovery rate (FDR ≤ 0.05) was applied in the maternal placental tissue, with 518 upregulated and 117 downregulated genes in the SARS-CoV-2-positive women (n = 6) compared with the healthy SARS-CoV-2-negative women (n = 8). In contrast, the fetal compartment did not exhibit any significant changes in gene expression with SARS-CoV-2 infection. We observed a significant downregulation of nine genes belonging to the pregnancy-specific glycoprotein related to the immunoglobulin superfamily in the maternal compartment with active SARS-CoV-2 infection (fold change range from −13.70 to −5.28; FDR ≤ 0.01). Additionally, comparing symptomatic women with healthy women, we identified 1788 DEGs. Furthermore, a signaling pathway enrichment analysis revealed that pathways related to oxidative phosphorylation, insulin secretion, cortisol synthesis, estrogen signaling, oxytocin signaling, antigen processing, and presentation were altered significantly in symptomatic women. Overall, our study sheds light on the molecular mechanisms underlying the reported clinical risks of preeclampsia and preterm delivery in women with SARS-CoV-2 infection. Nonetheless, studies with larger sample sizes are warranted to further deepen our understanding of the molecular mechanisms of the placenta’s anti-viral effects in maternal SARS-CoV-2 infection.
Significantly Improved Cold Preservation of Rat Hind Limb Vascularized Composite Allografts Using the New PrC-210 Free Radical Scavenger
Authors: Fahl William E. , Nkana Zeeda H. , Gitter Maya M. , Zeng Weifeng , Dingle Aaron M.
Published: January 2024

Vascularized composite allotransplantation (VCA) represents a promising reconstructive solution primarily conducted to improve quality of life. However, tissue damage caused by cold-ischemia (CI) storage prior to transplant represents a major factor limiting widespread application. This study investigates the addition of the novel free radical scavenger PrC-210 to UW Organ Preservation Solution (UW Solution) to suppress CI-induced skeletal muscle injury in a rat hind limb amputation model. Lewis rats received systemic perfusion of UW solution +/− PrC-210 (0 mM control, 10 mM, 20 mM, 30 mM, or 40 mM), followed by bilateral transfemoral amputation. Limbs were stored in 40 mL of the same perfusate at 4 °C for 48 h. Muscle punch biopsies were taken at set times over the 48 h cold-storage period and analyzed for caspase-3,7 activity, cytochrome C levels, and qualitative histology. A single 15 s perfusion of PrC-210-containing UW Solution conferred a dose-dependent reduction in CI-induced muscle cell death over 48 h. In the presence of PrC-210, muscle cell mitochondrial cytochrome C release was equivalent to 0 h controls, with profound reductions in the caspase-3,7 apoptotic marker that correlated with limb histology. PrC-210 conferred complete prevention of ROS-induced mitochondrial lysis in vitro, as measured by cytochrome C release. We conclude that the addition of 30 mM PrC210 to UW Solution conferred the most consistent reduction in CI limb damage, and it warrants further investigation for clinical application in the VCA setting.
Perinatal Use of Citrulline Rescues Hypertension in Adult Male Offspring Born to Pregnant Uremic Rats
Authors: Tain You-Lin , Hou Chih-Yao , Chang-Chien Guo-Ping , Lin Sufan , Hsu Chien-Ning
Published: January 2024

The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin–angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens. Citrulline’s ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats.
Oral Excretion Kinetics of Food-Additive Silicon Dioxides and Their Effect on In Vivo Macrophage Activation
Authors: Kwon Ri-Ye , Youn Su-Min , Choi Soo-Jin
Published: January 2024

A food additive, silicon dioxide (SiO2) is commonly used in the food industry as an anti-caking agent. The presence of nanoparticles (NPs) in commercial food-grade SiO2 has raised concerns regarding their potential toxicity related to nano size. While recent studies have demonstrated the oral absorption and tissue distribution of food-additive SiO2 particles, limited information is available about their excretion behaviors and potential impact on macrophage activation. In this study, the excretion kinetics of two differently manufactured (fumed and precipitated) SiO2 particles were evaluated following repeated oral administration to rats for 28 d. The excretion fate of their intact particles, decomposed forms, or ionic forms was investigated in feces and urine, respectively. Monocyte uptake, Kupffer cell activation, and cytokine release were assessed after the oral administration of SiO2 particles. Additionally, their intracellular fates were determined in Raw 264.7 cells. The results revealed that the majority of SiO2 particles were not absorbed but directly excreted via feces in intact particle forms. Only a small portion of SiO2 was eliminated via urine, predominantly in the form of bioconverted silicic acid and slightly decomposed ionic forms. SiO2 particles were mainly present in particle forms inside cells, followed by ionic and silicic acid forms, indicating their slow conversion into silicic acid after cellular uptake. No effects of the manufacturing method were observed on excretion and fates. Moreover, no in vivo monocyte uptake, Kupffer cell polarization, or cytokine release were induced by orally administered SiO2 particles. These finding contribute to understanding the oral toxicokinetics of food-additive SiO2 and provide valuable insights into its potential toxicity.
An Efficient Expression and Purification Protocol for SpCas9 Nuclease and Evaluation of Different Delivery Methods of Ribonucleoprotein
Authors: Evmenov Konstantin , Pustogarov Nikolay , Panteleev Dmitri , Safin Artur , Alkalaeva Elena
Published: January 2024

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system is a revolutionary tool for precise genome editing across various cell types. Ribonucleoproteins (RNPs), encompassing the Cas9 protein and guide RNA (gRNA), have emerged as a promising technique due to their increased specificity and reduced off-target effects. This method eliminates the need for plasmid DNA introduction, thereby preventing potential integration of foreign DNA into the target cell genome. Given the requirement for large quantities of highly purified protein in various Cas9 studies, we present an efficient and simple method for the preparation of recombinant Streptococcus pyogenes Cas9 (SpCas9) protein. This method leverages the Small Ubiquitin Like Modifier(SUMO) tag system, which includes metal-affinity chromatography followed by anion-exchange chromatography purification. Furthermore, we compare two methods of CRISPR-Cas9 system delivery into cells: transfection with plasmid DNA encoding the CRISPR-Cas9 system and RNP transfection with the Cas9-gRNA complex. We estimate the efficiency of genomic editing and protein lifespan post-transfection. Intriguingly, we found that RNP treatment of cells, even in the absence of a transfection system, is a relatively efficient method for RNP delivery into cell culture. This discovery is particularly promising as it can significantly reduce cytotoxicity, which is crucial for certain cell cultures such as induced pluripotent stem cells (iPSCs).
Identification and Expression Patterns of WOX Transcription Factors under Abiotic Stresses in Pinus massoniana
Authors: Wang Dengbao , Qiu Zimo , Xu Tao , Yao Sheng , Zhang Mengyang , Cheng Xiang , Zhao Yulu , Ji Kongshu
Published: January 2024

WUSCHEL-related homeobox (WOX) transcription factors (TFs) play a crucial role in regulating plant development and responding to various abiotic stresses. However, the members and functions of WOX proteins in Pinus massoniana remain unclear. In this study, a total of 11 WOX genes were identified, and bioinformatics methods were used for preliminary identification and analysis. The phylogenetic tree revealed that most PmWOXs were distributed in ancient and WUS clades, with only one member found in the intermediate clade. We selected four highly conserved WOX genes within plants for further expression analysis. These genes exhibited expressions across almost all tissues, while PmWOX2, PmWOX3, and PmWOX4 showed high expression levels in the callus, suggesting their potential involvement in specific functions during callus development. Expression patterns under different abiotic stresses indicated that PmWOXs could participate in resisting multiple stresses in P. massoniana. The identification and preliminary analysis of PmWOXs lay the foundation for further research on analyzing the resistance molecular mechanism of P. massoniana to abiotic stresses.
Onco-Breastomics: An Eco-Evo-Devo Holistic Approach
Authors: Neagu Anca-Narcisa , Whitham Danielle , Bruno Pathea , Arshad Aneeta , Seymour Logan , Morrissiey Hailey , Hukovic Angiolina I. , Darie Costel C.
Published: January 2024

Known as a diverse collection of neoplastic diseases, breast cancer (BC) can be hyperbolically characterized as a dynamic pseudo-organ, a living organism able to build a complex, open, hierarchically organized, self-sustainable, and self-renewable tumor system, a population, a species, a local community, a biocenosis, or an evolving dynamical ecosystem (i.e., immune or metabolic ecosystem) that emphasizes both developmental continuity and spatio-temporal change. Moreover, a cancer cell community, also known as an oncobiota, has been described as non-sexually reproducing species, as well as a migratory or invasive species that expresses intelligent behavior, or an endangered or parasite species that fights to survive, to optimize its features inside the host’s ecosystem, or that is able to exploit or to disrupt its host circadian cycle for improving the own proliferation and spreading. BC tumorigenesis has also been compared with the early embryo and placenta development that may suggest new strategies for research and therapy. Furthermore, BC has also been characterized as an environmental disease or as an ecological disorder. Many mechanisms of cancer progression have been explained by principles of ecology, developmental biology, and evolutionary paradigms. Many authors have discussed ecological, developmental, and evolutionary strategies for more successful anti-cancer therapies, or for understanding the ecological, developmental, and evolutionary bases of BC exploitable vulnerabilities. Herein, we used the integrated framework of three well known ecological theories: the Bronfenbrenner’s theory of human development, the Vannote’s River Continuum Concept (RCC), and the Ecological Evolutionary Developmental Biology (Eco-Evo-Devo) theory, to explain and understand several eco-evo-devo-based principles that govern BC progression. Multi-omics fields, taken together as onco-breastomics, offer better opportunities to integrate, analyze, and interpret large amounts of complex heterogeneous data, such as various and big-omics data obtained by multiple investigative modalities, for understanding the eco-evo-devo-based principles that drive BC progression and treatment. These integrative eco-evo-devo theories can help clinicians better diagnose and treat BC, for example, by using non-invasive biomarkers in liquid-biopsies that have emerged from integrated omics-based data that accurately reflect the biomolecular landscape of the primary tumor in order to avoid mutilating preventive surgery, like bilateral mastectomy. From the perspective of preventive, personalized, and participatory medicine, these hypotheses may help patients to think about this disease as a process governed by natural rules, to understand the possible causes of the disease, and to gain control on their own health.
Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives
Authors: Adamopoulos Christos , Cave Donatella Delle , Papavassiliou Athanasios G.
Published: January 2024

Pancreatic cancer represents a formidable challenge in oncology, primarily due to its aggressive nature and limited therapeutic options. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), the main form of pancreatic cancer, remains disappointingly poor with a 5-year overall survival of only 5%. Almost 95% of PDAC patients harbor Kirsten rat sarcoma virus (KRAS) oncogenic mutations. KRAS activates downstream intracellular pathways, most notably the rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling axis. Dysregulation of the RAF/MEK/ERK pathway is a crucial feature of pancreatic cancer and therefore its main components, RAF, MEK and ERK kinases, have been targeted pharmacologically, largely by small-molecule inhibitors. The recent advances in the development of inhibitors not only directly targeting the RAF/MEK/ERK pathway but also indirectly through inhibition of its regulators, such as Src homology-containing protein tyrosine phosphatase 2 (SHP2) and Son of sevenless homolog 1 (SOS1), provide new therapeutic opportunities. Moreover, the discovery of allele-specific small-molecule inhibitors against mutant KRAS variants has brought excitement for successful innovations in the battle against pancreatic cancer. Herein, we review the recent advances in targeted therapy and combinatorial strategies with focus on the current preclinical and clinical approaches, providing critical insight, underscoring the potential of these efforts and supporting their promise to improve the lives of patients with PDAC.
Breath Fingerprint of Colorectal Cancer Patients Based on the Gas Chromatography–Mass Spectrometry Analysis
Authors: Kononova Elīna , Mežmale Linda , Poļaka Inese , Veliks Viktors , Anarkulova Linda , Vilkoite Ilona , Tolmanis Ivars , Ļeščinska Anna Marija , Stonāns Ilmārs , Pčolkins Andrejs , Mochalski Pawel , Leja Mārcis
Published: January 2024

The human body emits a multitude of volatile organic compounds (VOCs) via tissues and various bodily fluids or exhaled breath. These compounds collectively create a distinctive chemical profile, which can potentially be employed to identify changes in human metabolism associated with colorectal cancer (CRC) and, consequently, facilitate the diagnosis of this disease. The main goal of this study was to investigate and characterize the VOCs’ chemical patterns associated with the breath of CRC patients and controls and identify potential expiratory markers of this disease. For this purpose, gas chromatography–mass spectrometry was applied. Collectively, 1656 distinct compounds were identified in the breath samples provided by 152 subjects. Twenty-two statistically significant VOCs (p-xylene; hexanal; 2-methyl-1,3-dioxolane; 2,2,4-trimethyl-1,3-pentanediol diisobutyrate; hexadecane; nonane; ethylbenzene; cyclohexanone; diethyl phthalate; 6-methyl-5-hepten-2-one; tetrahydro-2H-pyran-2-one; 2-butanone; benzaldehyde; dodecanal; benzothiazole; tetradecane; 1-dodecanol; 1-benzene; 3-methylcyclopentyl acetate; 1-nonene; toluene) were observed at higher concentrations in the exhaled breath of the CRC group. The elevated levels of these VOCs in CRC patients’ breath suggest the potential for these compounds to serve as biomarkers for CRC.
Edaravone: A Novel Possible Drug for Cancer Treatment?
Authors: Duranti Elisa , Cordani Nicoletta , Villa Chiara
Published: January 2024

Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.
Unveiling Familial Hypercholesterolemia—Review, Cardiovascular Complications, Lipid-Lowering Treatment and Its Efficacy
Authors: Fularski Piotr , Hajdys Joanna , Majchrowicz Gabriela , Stabrawa Magdalena , Młynarska Ewelina , Rysz Jacek , Franczyk Beata
Published: January 2024

Familial hypercholesterolemia (FH) is a genetic disorder primarily transmitted in an autosomal-dominant manner. We distinguish two main forms of FH, which differ in the severity of the disease, namely homozygous familial hypercholesterolemia (HoFH) and heterozygous familial hypercholesterolemia (HeFH). The characteristic feature of this disease is a high concentration of low-density lipoprotein cholesterol (LDL-C) in the blood. However, the level may significantly vary between the two mentioned types of FH, and it is decidedly higher in HoFH. A chronically elevated concentration of LDL-C in the plasma leads to the occurrence of certain abnormalities, such as xanthomas in the tendons and skin, as well as corneal arcus. Nevertheless, a significantly more severe phenomenon is leading to the premature onset of cardiovascular disease (CVD) and its clinical implications, such as cardiac events, stroke or vascular dementia, even at a relatively young age. Due to the danger posed by this medical condition, we have investigated how both non-pharmacological and selected pharmacological treatment impact the course of FH, thereby reducing or postponing the risk of clinical manifestations of CVD. The primary objective of this review is to provide a comprehensive summary of the current understanding of FH, the effectiveness of lipid-lowering therapy in FH and to explain the anatomopathological correlation between FH and premature CVD development, with its complications.
Host Subcellular Organelles: Targets of Viral Manipulation
Authors: Song Min Seok , Lee Dong-Kun , Lee Chung-Young , Park Sang-Cheol , Yang Jinsung
Published: January 2024

Viruses have evolved sophisticated mechanisms to manipulate host cell processes and utilize intracellular organelles to facilitate their replication. These complex interactions between viruses and cellular organelles allow them to hijack the cellular machinery and impair homeostasis. Moreover, viral infection alters the cell membrane’s structure and composition and induces vesicle formation to facilitate intracellular trafficking of viral components. However, the research focus has predominantly been on the immune response elicited by viruses, often overlooking the significant alterations that viruses induce in cellular organelles. Gaining a deeper understanding of these virus-induced cellular changes is crucial for elucidating the full life cycle of viruses and developing potent antiviral therapies. Exploring virus-induced cellular changes could substantially improve our understanding of viral infection mechanisms.
Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence
Authors: Carvalho Nuno , Carolino Elisabete , Ferreira Margarida , Coelho Hélder , Santos Catarina Rolo , Barreira Ana Lúcia , Henriques Susana , Cardoso Carlos , Moita Luís , Costa Paulo Matos
Published: January 2024

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1–980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6–1075.1) pg/mL) than in the control group (7.3 (4.5–10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.
Novel Epigenetic Modifiers of Histones Presenting Potent Inhibitory Effects on Adenoid Cystic Carcinoma Stemness and Invasive Properties
Authors: Pina Paulo S. S. , Jang Yeejin , Emerick Carolina , Scarini João Figueira , Sousa Suzana C. O. M. , Squarize Cristiane H. , Castilho Rogerio M.
Published: January 2024

Adenoid cystic carcinoma (ACC) is a rare neoplasm known for its indolent clinical course, risk of perineural invasion, and late onset of distant metastasis. Due to the scarcity of samples and the tumor’s rarity, progress in developing effective treatments has been historically limited. To tackle this issue, a high-throughput screening of epigenetic drugs was conducted to identify compounds capable of disrupting the invasive properties of the tumor and its cancer stem cells (CSCs). ACC cells were screened for changes in tumor viability, chromatin decondensation, Snail inhibition along tumor migration, and disruption of cancer stem cells. Seven compounds showed potential clinical interest, and further validation showed that Scriptaid emerged as a promising candidate for treating ACC invasion. Scriptaid demonstrated a favorable cellular toxicity index, effectively inhibited Snail expression, induced hyperacetylation of histone, reduced cell migration, and effectively disrupted tumorspheres. Additionally, LMK235 displayed encouraging results in four out of five validation assays, further highlighting its potential in combating tumor invasion in ACC. By targeting the invasive properties of the tumor and CSCs, Scriptaid and LMK235 hold promise as potential treatments for ACC, with the potential to improve patient outcomes and pave the way for further research in this critical area.
CXCL14 as a Key Regulator of Neuronal Development: Insights from Its Receptor and Multi-Omics Analysis
Authors: Zhang Yinjie , Jin Yue , Li Jingjing , Yan Yan , Wang Ting , Wang Xuanlin , Li Zhenyu , Qin Xuemei
Published: January 2024

CXCL14 is not only involved in the immune process but is also closely related to neurodevelopment according to its molecular evolution. However, what role it plays in neurodevelopment remains unclear. In the present research, we found that, by crossbreeding CXCL14+/− and CXCL14−/− mice, the number of CXCL14−/− mice in their offspring was lower than the Mendelian frequency; CXCL14−/− mice had significantly fewer neurons in the external pyramidal layer of cortex than CXCL14+/− mice; and CXCL14 may be involved in synaptic plasticity, neuron projection, and chemical synaptic transmission based on analysis of human clinical transcriptome data. The expression of CXCL14 was highest at day 14.5 in the embryonic phase and after birth in the mRNA and protein levels. Therefore, we hypothesized that CXCL14 promotes the development of neurons in the somatic layer of the pyramidal cells of mice cortex on embryonic day 14.5. In order to further explore its mechanism, CXCR4 and CXCR7 were suggested as receptors by Membrane-Anchored Ligand and Receptor Yeast Two-Hybrid technology. Through metabolomic techniques, we inferred that CXCL14 promotes the development of neurons by regulating fatty acid anabolism and glycerophospholipid anabolism.
Charcot–Marie–Tooth Disease with Myelin Protein Zero Mutation Presenting as Painful, Predominant Small-Fiber Neuropathy
Authors: Gemignani Franco , Percesepe Antonio , Gualandi Francesca , Allegri Isabella , Bellanova Maria Federica , Nuredini Andi , Saccani Elena , Ambrosini Enrico , Barili Valeria , Uliana Vera
Published: January 2024

Charcot–Marie–Tooth disease (CMT) rarely presents with painful symptoms, which mainly occur in association with myelin protein zero (MPZ) gene mutations. We aimed to further characterize the features of painful neuropathic phenotypes in MPZ-related CMT. We report on a 58-year-old woman with a longstanding history of intermittent migrant pain and dysesthesias. Examination showed minimal clinical signs of neuropathy along with mild changes upon electroneurographic examination, consistent with an intermediate pattern, and small-fiber loss upon skin biopsy. Genetic testing identified the heterozygous variant p.Trp101Ter in MPZ. We identified another 20 CMT patients in the literature who presented with neuropathic pain as a main feature in association with MPZ mutations, mostly in the extracellular MPZ domain; the majority of these patients showed late onset (14/20), with motor-nerve-conduction velocities predominantly in the intermediate range (12/20). It is hypothesized that some MPZ mutations could manifest with, or predispose to, neuropathic pain. However, the mechanisms linking MPZ mutations and pain-generating nerve changes are unclear, as are the possible role of modifier factors. This peculiar CMT presentation may be diagnostically misleading, as it is suggestive of an acquired pain syndrome rather than of an inherited neuropathy.
The Role of Protein Degradation in Estimation Postmortem Interval and Confirmation of Cause of Death in Forensic Pathology: A Literature Review
Authors: Huang Weisheng , Zhao Shuquan , Liu Huine , Pan Meichen , Dong Hongmei
Published: January 2024

It is well known that proteins are important bio-macromolecules in human organisms, and numerous proteins are widely used in the clinical practice, whereas their application in forensic science is currently limited. This limitation is mainly attributed to the postmortem degradation of targeted proteins, which can significantly impact final conclusions. In the last decade, numerous methods have been established to detect the protein from a forensic perspective, and some of the postmortem proteins have been applied in forensic practice. To better understand the emerging issues and challenges in postmortem proteins, we have reviewed the current application of protein technologies at postmortem in forensic practice. Meanwhile, we discuss the application of proteins in identifying the cause of death, and postmortem interval (PMI). Finally, we highlight the interpretability and limitations of postmortem protein challenges. We believe that utilizing the multi-omics method can enhance the comprehensiveness of applying proteins in forensic practice.
Polysaccharide from Artocarpus heterophyllus Lam. (Jackfruit) Pulp Ameliorates Dextran Sodium Sulfate-Induced Enteritis in Rats
Authors: Li Yunlong , Chen Yuzi , Li Chuan , Wu Gang , He Yanfu , Tan Lehe , Zhu Kexue
Published: January 2024

A polysaccharide from Artocarpus heterophyllus Lam. (jackfruit) pulp (JFP-Ps) is known for its excellent bioactivities. However, its impact on small intestinal barrier function is still largely unexplored. The study aimed to examine the protection effect of JFP-Ps against dextran sodium sulfate-induced enteritis and its underlying mechanism. This research revealed that JFP-Ps mitigated small intestinal tissue damage by reducing the expression of pro-inflammatory cytokines and promoting the expression of the anti-inflammatory cytokine interleukin-10 in the small intestine. JFP-Ps diminished oxidative stress by bolstering the activity of antioxidant enzymes and reducing the concentration of malondialdehyde in the small intestine. In addition, JFP-Ps may restore the mechanical barrier and inhibit intestinal structure damage by augmenting the expression of short-chain fatty acids (SCFAs) receptors (GPR41/43) and up-regulating the expression of tight junction proteins (occludin). In conclusion, JFP-Ps may positively influence intestinal health by relieving oxidative stress in the small intestine, improving mechanical barrier function, activating the SCFA-GPR41/GPR43 axis, and inhibiting TLR4/MAPK pathway activation. The results augment our comprehension of the bioactivities of JFP-Ps, corroborating its great potential as a functional food.
The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence
Authors: Atkinson Caroline , McInerney-Leo Aideen M. , Proctor Martina , Lanagan Catherine , Stevenson Alexander J. , Dehkhoda Farhad , Caole Mary , Maas Ellie , Ainger Stephen , Pritchard Antonia L. , Johansson Peter A. , Leo Paul , Hayward Nicholas K. , Sturm Richard A. , Duncan Emma L. , Gabrielli Brian
Published: January 2024

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.
Newborn Screening for Krabbe Disease: Status Quo and Recommendations for Improvements
Authors: Matern Dietrich , Basheeruddin Khaja , Klug Tracy L. , McKee Gwendolyn , Edge Patricia U. , Hall Patricia L. , Kurtzberg Joanne , Orsini Joseph J.
Published: January 2024

Krabbe disease (KD) is part of newborn screening (NBS) in 11 states with at least one additional state preparing to screen. In July 2021, KD was re-nominated for addition to the federal Recommended Uniform Screening Panel (RUSP) in the USA with a two-tiered strategy based on psychosine (PSY) as the determinant if an NBS result is positive or negative after a first-tier test revealed decreased galactocerebrosidase activity. Nine states currently screening for KD include PSY analysis in their screening strategy. However, the nomination was rejected in February 2023 because of perceived concerns about a high false positive rate, potential harm to newborns with an uncertain prognosis, and inadequate data on presymptomatic treatment benefit or harm. To address the concern about false positive NBS results, a survey was conducted of the eight NBS programs that use PSY and have been screening for KD for at least 1 year. Seven of eight states responded. We found that: (1) the use of PSY is variable; (2) when modeling the data based on the recommended screening strategy for KD, and applying different cutoffs for PSY, each state could virtually eliminate false positive results without major impact on sensitivity; (3) the reason for the diverse strategies appears to be primarily the difficulty of state programs to adjust screening algorithms due to the concern of possibly missing even an adult-onset case following a change that focuses on infantile and early infantile KD. Contracts with outside vendors and the effort/cost of making changes to a program’s information systems can be additional obstacles. We recommend that programs review their historical NBS outcomes for KD with their advisory committees and make transparent decisions on whether to accept false positive results for such a devastating condition or to adjust their procedures to ensure an efficient, effective, and manageable NBS program for KD.
Analysis of the Impact of New Generation Narrow-Body Aircraft on Flexible and Rigid Regional Airport Pavements
Authors: White Greg
Published: January 2024

Airport pavements have always evolved to keep pace with the demands of new aircraft. As aircraft weights and tyre pressures increase, stronger, new pavements are designed and existing pavements are rehabilitated or upgraded. The narrow-body commercial jet aircraft, including the A320 and B737 families, are examples of aircraft that have retained the same number of wheels, with the same wheel spacing and the same wingspan, but have increased in weight and tyre pressure by approximately 50%. This places significant demand on airport pavements that were designed for the lighter variants but now face the introduction of the newer, heavier and more demanding variants. This research quantified the impact of the new A320 and B737 narrow-body aircraft variants on rigid and flexible regional airport pavements, where these are the critical aircraft, as well as demonstrating the importance of understanding the operational weight limitations of these aircraft, which is often well below the published maximum weight. Within the context of the pavements considered, the additional pavement thickness required for the heaviest aircraft variants, compared to the lightest variants, was 51%. Based on four examples from real regional airports in Australia, it was found that the additional embodied carbon associated with these new aircraft variants was 2.1–85.3 kg·eCO2/m2 of pavement, while the additional financial cost was AUD 6–219/m2 of pavement. It was concluded that airport pavement thickness designers must challenge the weight of the design aircraft and not take the simple and conservative approach of adopting the maximum weight of the heaviest variant within each aircraft family. By doing so, significant additional pavement thickness will be constructed for no practical benefit, creating an environmental (embodied carbon) and economic (financial cost) burden.
Structural and Mechanical Properties of NbN Alloyed with Hf, In, and Zr for Orthopedic Applications: A First-Principles Study
Authors: Alruqi Adel Bandar , Ongwen Nicholas O.
Published: January 2024

The search for biocompatible, non-toxic, and wear-resistant materials for orthopedic implant applications is on the rise. Different materials have been investigated for this purpose, some of which have proved successful. However, one challenge that has proven difficult to overcome is the balance between ductility and hardness of these materials. This study employed ab initio calculations to investigate the structural and mechanical properties of niobium nitride (NbN) alloyed with hafnium, indium, and zirconium, with the aim of improving its hardness. The calculations made use of density function theory within the quantum espresso package’s generalized gradient approximation, with Perdew–Burke–Ernzerhof ultrasoft pseudopotentials in all the calculations. It was found that addition of the three metals led to an improvement in both the shear and Young’s moduli of the alloys compared to those of the NbN. However, both the bulk moduli and the Poisson’s ratios reduced with the introduction of the metals. The Young’s moduli of all the samples were found to be higher than that of bone. The Vickers hardness of the alloys were found to be significantly higher than that of NbN, with that of indium being the highest. The alloys are therefore good for wear-resistant artificial bone implants in ceramic acetabulum, and also in prosthetic heads.
The Effect of the Linking Unit on the Electronic and Magnetic Interactions in Copper(II) Porphyrin Dimers Linked by Metal Ions
Authors: Appleton Jordan L. , Le Breton Nolwenn , Choua Sylvie , Ruppert Romain
Published: January 2024

The syntheses of a series of copper(II) porphyrins and their dimers linked by palladium(II) or platinum(II) are reported. Their electronic properties and their magnetic properties were studied. In particular, the effect of the linking unit on these properties was evaluated. It was discovered that three factors influence the electronic and magnetic interactions between the two metalloporphyrins: the nature of the linking metal ion, the nature of the external coordination site of the porphyrin, and also the nature of the metal ion present in the central core of the aromatic macrocycle.