bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA Profile of Cell Bodies and Exosomes Released by Tumorigenic and Non-Tumorigenic Thyroid Cells
Authors: Maggisano Valentina , Capriglione Francesca , Mio Catia , Bulotta Stefania , Damante Giuseppe , Russo Diego , Celano Marilena
Published: January 2024

Tumor cells release exosomes, extracellular vesicle containing various bioactive molecules such as protein, DNA and RNA. The analysis of RNA molecules packaged in exosomes may provide new potential diagnostic or prognostic tumor biomarkers. The treatment of radioiodine-refractory aggressive thyroid cancer is still an unresolved clinical challenge, and the search for biomarkers that are detectable in early phase of the disease has become a fundamental goal for thyroid cancer research. By using transcriptome analysis, this study aimed to analyze the gene expression profiles of exosomes secreted by a non-tumorigenic thyroid cell line (Nthy-ori 3.1-exo) and a papillary thyroid cancer (TPC-1-exo) cell line, comparing them with those of cell bodies (Nthy-ori 3.1-cells and TPC-1-cells). A total of 9107 transcripts were identified as differentially expressed when comparing TPC-1-exo with TPC-1-cells and 5861 when comparing Nthy-ori 3.1-exo with Nthy-ori 3.1-cells. Among them, Sialic acid-binding immunoglobulin-like lectins 10 and 11 (SIGLEC10, SIGLEC11) and Keratin-associated protein 5 (KRTAP5-3) transcripts, genes known to be involved in cancer progression, turned out to be up-regulated only in TPC-1-exo. Gene ontology analysis revealed significantly enriched pathways, and only in TPC-1-exo were the differential expressed genes associated with an up-regulation in epigenetic processes. These findings provide a proof of concept that some mRNA species are specifically packaged in tumor-cell-derived exosomes and may constitute a starting point for the identification of new biomarkers for thyroid tumors.
The Roles and Regulatory Mechanisms of Tight Junction Protein Cingulin and Transcription Factor Forkhead Box Protein O1 in Human Lung Adenocarcinoma A549 Cells and Normal Lung Epithelial Cells
Authors: Ishii Daichi , Shindo Yuma , Arai Wataru , Konno Takumi , Kohno Takayuki , Honda Kazuya , Miyajima Masahiro , Watanabe Atsushi , Kojima Takashi
Published: January 2024

Tight junction (TJ) protein cingulin (CGN) and transcription factor forkhead box protein O1 (FOXO1) contribute to the development of various cancers. Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for some cancers. HDAC inhibitors affect the expression of both CGN and FOXO1. However, the roles and regulatory mechanisms of CGN and FOXO1 are unknown in non-small cell lung cancer (NSCLC) and normal human lung epithelial (HLE) cells. In the present study, to investigate the effects of CGN and FOXO1 on the malignancy of NSCLC, we used A549 cells as human lung adenocarcinoma and primary human lung epithelial (HLE) cells as normal lung tissues and performed the knockdown of CGN and FOXO1 by siRNAs. Furthermore, to investigate the detailed mechanisms in the antitumor effects of HDAC inhibitors for NSCLC via CGN and FOXO1, A549 cells and HLE cells were treated with the HDAC inhibitors trichostatin A (TSA) and Quisinostat (JNJ-2648158). In A549 cells, the knockdown of CGN increased bicellular TJ protein claudin-2 (CLDN-2) via mitogen-activated protein kinase/adenosine monophosphate-activated protein kinase (MAPK/AMPK) pathways and induced cell migration, while the knockdown of FOXO1 increased claudin-4 (CLDN-4), decreased CGN, and induced cell proliferation. The knockdown of CGN and FOXO1 induced cell metabolism in A549 cells. TSA and Quisinostat increased CGN and tricellular TJ protein angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) in A549. In normal HLE cells, the knockdown of CGN and FOXO1 increased CLDN-4, while HDAC inhibitors increased CGN and CLDN-4. In conclusion, the knockdown of CGN via FOXO1 contributes to the malignancy of NSCLC. Both HDAC inhibitors, TSA and Quisinostat, may have potential for use in therapy for lung adenocarcinoma via changes in the expression of CGN and FOXO1.
Opioid Analgesic as a Positive Allosteric Modulator of Acid-Sensing Ion Channels
Authors: Osmakov Dmitry I. , Onoprienko Lyudmila V. , Kalinovskii Aleksandr P. , Koshelev Sergey G. , Stepanenko Vasiliy N. , Andreev Yaroslav A. , Kozlov Sergey A.
Published: January 2024

Tafalgin (Taf) is a tetrapeptide opioid used in clinical practice in Russia as an analgesic drug for subcutaneous administration as a solution (4 mg/mL; concentration of 9 mM). We found that the acid-sensing ion channels (ASICs) are another molecular target for this molecule. ASICs are proton-gated sodium channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Using electrophysiological methods, we demonstrated that Taf could increase the integral current through heterologically expressed ASIC with half-maximal effective concentration values of 0.09 mM and 0.3 mM for rat and human ASIC3, respectively, and 1 mM for ASIC1a. The molecular mechanism of Taf action was shown to be binding to the channel in the resting state and slowing down the rate of desensitization. Taf did not compete for binding sites with both protons and ASIC3 antagonists, such as APETx2 and amiloride (Ami). Moreover, Taf and Ami together caused an unusual synergistic effect, which was manifested itself as the development of a pronounced second desensitizing component. Thus, the ability of Taf to act as a positive allosteric modulator of these channels could potentially cause promiscuous effects in clinical practice. This fact must be considered in patients’ treatment.
The Gárdos Channel and Piezo1 Revisited: Comparison between Reticulocytes and Mature Red Blood Cells
Authors: Petkova-Kirova Polina , Murciano Nicoletta , Iacono Giulia , Jansen Julia , Simionato Greta , Qiao Min , van der Zwaan Carmen , Rotordam Maria Giustina , John Thomas , Hertz Laura , Hoogendijk Arjan J. , Becker Nadine , Wagner Christian , von Lindern Marieke , Egee Stephane , van den Akker Emile , Kaestner Lars
Published: January 2024

The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the abundance of the channels in RBCs. Furthermore, we utilize automated patch clamp, based on planar chips, to compare the activity of the two channels in reticulocytes and mature RBCs. In addition to this characterization, we performed membrane potential measurements to demonstrate the effect of channel activity and interplay on the RBC properties. Both the Gárdos channel and Piezo1, albeit their average copy number of activatable channels per cell is in the single-digit range, can be detected through transcriptome analysis of reticulocytes. Proteomics analysis of reticulocytes and mature RBCs could only detect Piezo1 but not the Gárdos channel. Furthermore, they can be reliably measured in the whole-cell configuration of the patch clamp method. While for the Gárdos channel, the activity in terms of ion currents is higher in reticulocytes compared to mature RBCs, for Piezo1, the tendency is the opposite. While the interplay between Piezo1 and Gárdos channel cannot be followed using the patch clamp measurements, it could be proved based on membrane potential measurements in populations of intact RBCs. We discuss the Gárdos channel and Piezo1 abundance, interdependencies and interactions in the context of their proposed physiological and pathophysiological functions, which are the passing of small constrictions, e.g., in the spleen, and their active participation in blood clot formation and thrombosis.
Red Blood Cell Contribution to Thrombosis in Polycythemia Vera and Essential Thrombocythemia
Authors: Grenier Julien M. P. , El Nemer Wassim , De Grandis Maria
Published: January 2024

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.
Circulating miRNAs and Preeclampsia: From Implantation to Epigenetics
Authors: Giannubilo Stefano Raffaele , Cecati Monia , Marzioni Daniela , Ciavattini Andrea
Published: January 2024

In this review, we comprehensively present the literature on circulating microRNAs (miRNAs) associated with preeclampsia, a pregnancy-specific disease considered the primary reason for maternal and fetal mortality and morbidity. miRNAs are single-stranded non-coding RNAs, 20–24 nt long, which control mRNA expression. Changes in miRNA expression can induce a variation in the relative mRNA level and influence cellular homeostasis, and the strong presence of miRNAs in all body fluids has made them useful biomarkers of several diseases. Preeclampsia is a multifactorial disease, but the etiopathogenesis remains unclear. The functions of trophoblasts, including differentiation, proliferation, migration, invasion and apoptosis, are essential for a successful pregnancy. During the early stages of placental development, trophoblasts are strictly regulated by several molecular pathways; however, an imbalance in these molecular pathways can lead to severe placental lesions and pregnancy complications. We then discuss the role of miRNAs in trophoblast invasion and in the pathogenesis, diagnosis and prediction of preeclampsia. We also discuss the potential role of miRNAs from an epigenetic perspective with possible future therapeutic implications.
Association of Plasma Claudin-5 with Age and Alzheimer Disease
Authors: Tachibana Keisuke , Hirayama Ryuichi , Sato Naoyuki , Hattori Kotaro , Kato Takashi , Takeda Hiroyuki , Kondoh Masuo
Published: January 2024

The blood–brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL). Plasma levels of phosphorylated tau (pTau181), a biomarker of pathological tau, were elevated in patients with MCI or AD (2.86 and 4.20 pg/mL, respectively) compared with control subjects (1.81 pg/mL). In patients with MCI or AD, plasma levels of CLDN-5—but not pTau181—decreased with age, suggesting some age-dependent BBB changes in MCI and AD. These findings suggest that plasma CLDN-5 may a potential biochemical marker for the diagnosis of AD.
Evolution and Dynamic Transcriptome of Key Genes of Photoperiodic Flowering Pathway in Water Spinach (Ipomoea aquatica)
Authors: Wang Xin , Hao Yuanyuan , Altaf Muhammad Ahsan , Shu Huangying , Cheng Shanhan , Wang Zhiwei , Zhu Guopeng
Published: January 2024

The photoperiod is a major environmental factor in flowering control. Water spinach flowering under the inductive short-day condition decreases the yield of vegetative tissues and the eating quality. To obtain an insight into the molecular mechanism of the photoperiod-dependent regulation of the flowering time in water spinach, we performed transcriptome sequencing on water spinach under long- and short-day conditions with eight time points. Our results indicated that there were 6615 circadian-rhythm-related genes under the long-day condition and 8691 under the short-day condition. The three key circadian-rhythm genes, IaCCA1, IaLHY, and IaTOC1, still maintained single copies and similar IaCCA1, IaLHY, and IaTOC1 feedback expression patterns, indicating the conservation of reverse feedback. In the photoperiod pathway, highly conserved GI genes were amplified into two copies (IaGI1 and IaGI2) in water spinach. The significant difference in the expression of the two genes indicates functional diversity. Although the photoperiod core gene FT was duplicated to three copies in water spinach, only IaFT1 was highly expressed and strongly responsive to the photoperiod and circadian rhythms, and the almost complete inhibition of IaFT1 in water spinach may be the reason why water spinach does not bloom, no matter how long it lasts under the long-day condition. Differing from other species (I. nil, I. triloba, I. trifida) of the Ipomoea genus that have three CO members, water spinach lacks one of them, and the other two CO genes (IaCO1 and IaCO2) encode only one CCT domain. In addition, through weighted correlation network analysis (WGCNA), some transcription factors closely related to the photoperiod pathway were obtained. This work provides valuable data for further in-depth analyses of the molecular regulation of the flowering time in water spinach and the Ipomoea genus.
Biomarkers of Response to Venetoclax Therapy in Acute Myeloid Leukemia
Authors: Rodríguez-Medina Carlos , Stuckey Ruth , Bilbao-Sieyro Cristina , Gómez-Casares María Teresa
Published: January 2024

Recent progress in the use of massive sequencing technologies has greatly enhanced our understanding of acute myeloid leukemia (AML) pathology. This knowledge has in turn driven the development of targeted therapies, such as venetoclax, a BCL-2 inhibitor approved for use in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed adult patients with AML who are not eligible for intensive chemotherapy. However, a significant number of AML patients still face the challenge of disease relapse. In this review, we will explore biomarkers that may predict disease progression in patients receiving venetoclax-based therapy, considering both clinical factors and genetic changes. Despite the many advances, we conclude that the identification of molecular profiles for AML patients who will respond optimally to venetoclax therapy remains an unmet clinical need.
Using 8-Hydroxy-2′-Deoxiguanosine (8-OHdG) as a Reliable Biomarker for Assessing Periodontal Disease Associated with Diabetes
Authors: Goriuc Ancuta , Cojocaru Karina-Alexandra , Luchian Ionut , Ursu Ramona-Garbriela , Butnaru Oana , Foia Liliana
Published: January 2024

In recent years, research has shown that oxidative stress plays a significant role in chronic inflammatory conditions. The alteration of the oxidant/antioxidant balance leads to the appearance of free radicals, important molecules involved in both diabetes mellitus and periodontal disease. Diabetes is considered to be one of the major risk factors of periodontal disease and the inflammation characterizing this condition is associated with oxidative stress, implicitly resulting in oxidative damage to DNA. 8-Hydroxydeoxyguanosine (8-OHdG) is the most common stable product of oxidative DNA damage caused by reactive oxygen species, and its levels have been reported to increase in body fluids and tissues during inflammatory conditions. 8-OHdG emerges as a pivotal biomarker for assessing oxidative DNA damage, demonstrating its relevance across diverse health conditions, including neurodegenerative disorders, cancers, inflammatory conditions, and periodontal disease. Continued research in this field is crucial for developing more precise treatments and understanding the detailed link between oxidative stress and the progression of periodontitis. The use of the 8-OHdG biomarker in assessing and managing chronic periodontitis is an area of increased interest in dental research, with the potential to provide crucial information for diagnosis and treatment.
Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells
Authors: Borghini Andrea , Ndreu Rudina , Canale Paola , Campolo Jonica , Marinaro Irene , Mercuri Antonella , Turchi Stefano , Andreassi Maria Grazia
Published: January 2024

Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 μM and 200 μM of hydrogen peroxide (H2O2) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H2O2 and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H2O2 was also found. In PBMCs treated with 200 µM H2O2, a significant inverse correlation was found between TL and MN (r = −0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = −0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere–mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs.
How the ‘Aerobic/Anaerobic Glycolysis’ Meme Formed a ‘Habit of Mind’ Which Impedes Progress in the Field of Brain Energy Metabolism
Authors: Schurr Avital
Published: January 2024

The division of glycolysis into two separate pathways, aerobic and anaerobic, depending on the presence or absence of oxygen, respectively, was formulated over eight decades ago. The former ends with pyruvate, while the latter ends with lactate. Today, this division is confusing and misleading as research over the past 35 years clearly has demonstrated that glycolysis ends with lactate not only in cancerous cells but also in healthy tissues and cells. The present essay offers a review of the history of said division and the more recent knowledge that has been gained about glycolysis and its end-product, lactate. Then, it presents arguments in an attempt to explain why separating glycolysis into aerobic and anaerobic pathways persists among scientists, clinicians and teachers alike, despite convincing evidence that such division is not only wrong scientifically but also hinders progress in the field of energy metabolism.
Special Issue “From Basic Science to Treatment Strategies: Personalized Cancer Therapy”
Authors: Muminovic Meri , Hussein Atif , Raez Luis E.
Published: January 2024

Molecular testing has created a revolution in cancer [...]
NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration
Authors: Antuña Eduardo , Potes Yaiza , Baena-Huerta Francisco Javier , Cachán-Vega Cristina , Menéndez-Coto Nerea , Álvarez Darriba Eva , Fernández-Fernández Marta , Burgos Bencosme Natalie , Bermúdez Manuel , López Álvarez Eva María , Gutiérrez-Rodríguez José , Boga José Antonio , Caballero Beatriz , Vega-Naredo Ignacio , Coto-Montes Ana , Garcia-Gonzalez Claudia
Published: January 2024

Sarcopenia, a complex and debilitating condition characterized by progressive deterioration of skeletal muscle, is the primary cause of age-associated disability and significantly impacts healthspan in elderly patients. Despite its prevalence among the aging population, the underlying molecular mechanisms are still under investigation. The NLRP3 inflammasome is crucial in the innate immune response and has a significant impact on diseases related to inflammation and aging. Here, we investigated the expression of the NLRP3 inflammasome pathway and pro-inflammatory cytokines in skeletal muscle and peripheral blood of dependent and independent patients who underwent hip surgery. Patients were categorized into independent and dependent individuals based on their Barthel Index. The expression of NLRP3 inflammasome components was significantly upregulated in sarcopenic muscle from dependent patients, accompanied by higher levels of Caspase-1, IL-1β and IL-6. Among older dependent individuals with sarcopenia, there was a significant increase in the MYH3/MYH2 ratio, indicating a transcriptional shift in expression from mature to developmental myosin isoforms. Creatine kinase levels and senescence markers were also higher in dependent patients, altogether resembling dystrophic diseases and indicating muscle degeneration. In summary, we present evidence for the involvement of the NLRP3/ASC/NEK7/Caspase-1 inflammasome pathway with activation of pro-inflammatory SASP in the outcome of sarcopenia in the elderly.
Understanding the Molecular Regulatory Networks of Seed Size in Soybean
Authors: Zhang Ye , Bhat Javaid Akhter , Zhang Yaohua , Yang Suxin
Published: January 2024

Soybean being a major cash crop provides half of the vegetable oil and a quarter of the plant proteins to the global population. Seed size traits are the most important agronomic traits determining the soybean yield. These are complex traits governed by polygenes with low heritability as well as are highly influenced by the environment as well as by genotype x environment interactions. Although, extensive efforts have been made to unravel the genetic basis and molecular mechanism of seed size in soybean. But most of these efforts were majorly limited to QTL identification, and only a few genes for seed size were isolated and their molecular mechanism was elucidated. Hence, elucidating the detailed molecular regulatory networks controlling seed size in soybeans has been an important area of research in soybeans from the past decades. This paper describes the current progress of genetic architecture, molecular mechanisms, and regulatory networks for seed sizes of soybeans. Additionally, the main problems and bottlenecks/challenges soybean researchers currently face in seed size research are also discussed. This review summarizes the comprehensive and systematic information to the soybean researchers regarding the molecular understanding of seed size in soybeans and will help future research work on seed size in soybeans.
The Cellular and Organismal Effects of Nitroxides and Nitroxide-Containing Nanoparticles
Authors: Sadowska-Bartosz Izabela , Bartosz Grzegorz
Published: January 2024

Nitroxides are stable free radicals that have antioxidant properties. They react with many types of radicals, including alkyl and peroxyl radicals. They act as mimics of superoxide dismutase and stimulate the catalase activity of hemoproteins. In some situations, they may exhibit pro-oxidant activity, mainly due to the formation of oxoammonium cations as products of their oxidation. In this review, the cellular effects of nitroxides and their effects in animal experiments and clinical trials are discussed, including the beneficial effects in various pathological situations involving oxidative stress, protective effects against UV and ionizing radiation, and prolongation of the life span of cancer-prone mice. Nitroxides were used as active components of various types of nanoparticles. The application of these nanoparticles in cellular and animal experiments is also discussed.
Scarring Skin: Mechanisms and Therapies
Authors: Lin Xinye , Lai Yuping
Published: January 2024

Skin injury always results in fibrotic, non-functional scars in adults. Although multiple factors are well-known contributors to scar formation, the precise underlying mechanisms remain elusive. This review aims to elucidate the intricacies of the wound healing process, summarize the known factors driving skin cells in wounds toward a scarring fate, and particularly to discuss the impact of fibroblast heterogeneity on scar formation. To the end, we explore potential therapeutic interventions used in the treatment of scarring wounds.
Variation of the 2D Pattern of Brain Proteins in Mice Infected with Taenia crassiceps ORF Strain
Authors: Díaz-Zaragoza Mariana , Hernández-Ávila Ricardo , Landa Abraham , Ostoa-Saloma Pedro
Published: January 2024

Some parasites are known to influence brain proteins or induce changes in the functioning of the nervous system. In this study, our objective is to demonstrate how the two-dimensional gel technique is valuable for detecting differences in protein expression and providing detailed information on changes in the brain proteome during a parasitic infection. Subsequently, we seek to understand how the parasitic infection affects the protein composition in the brain and how this may be related to changes in brain function. By analyzing de novo-expressed proteins at 2, 4, and 8 weeks post-infection compared to the brains of the control mice, we observed that proteins expressed at 2 weeks are primarily associated with neuroprotection or the initial response of the mouse brain to the infection. At 8 weeks, parasitic infection can induce oxidative stress in the brain, potentially activating signaling pathways related to the response to cellular damage. Proteins expressed at 8 weeks exhibit a pattern indicating that, as the host fails to balance the Neuro-Immuno-Endocrine network of the organism, the brain begins to undergo an apoptotic process and consequently experiences brain damage.
Functionalization of Bacterial Cellulose with the Antimicrobial Peptide KR-12 via Chimerical Cellulose-Binding Peptides
Authors: van Zyl Elizabeth M. , Coburn Jeannine M.
Published: January 2024

Bacterial-derived cellulose (BC) has been studied as a promising material for biomedical applications, including wound care, due to its biocompatibility, water-holding capacity, liquid/gas permeability, and handleability properties. Although BC has been studied as a dressing material for cutaneous wounds, to date, BC inherently lacks antibacterial properties. The current research utilizes bifunctional chimeric peptides containing carbohydrate binding peptides (CBP; either a short version or a long version) and an antimicrobial peptide (AMP), KR-12. The secondary structure of the chimeric peptides was evaluated and confirmed that the α-helix structure of KR-12 was retained for both chimeric peptides evaluated (Long-CBP-KR12 and Short-CBP-KR12). Chimeric peptides and their individual components were assessed for cytotoxicity, where only higher concentrations of Short-CBP and longer timepoints of Short-CBP-KR12 exposure exhibited negative effects on metabolic activity, which was attributed to solubility issues. All KR-12-containing peptides exhibited antibacterial activity in solution against Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). The lipopolysaccharide (LPS) binding capability of the peptides was evaluated and the Short-CBP-KR12 peptide exhibited enhanced LPS-binding capabilities compared to KR-12 alone. Both chimeric peptides were able to bind to BC and were observed to be retained on the surface over a 7-day period. All functionalized materials exhibited no adverse effects on the metabolic activity of both normal human dermal fibroblasts (NHDFs) and human epidermal keratinocyte (HaCaT) epithelial cells. Additionally, the BC tethered chimeric peptides exhibited antibacterial activity against E. coli. Overall, this research outlines the design and evaluation of chimeric CBP-KR12 peptides for developing antimicrobial BC membranes with potential applications in wound care.
CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in TCF3::PBX1 ALL
Authors: Gutierrez-Camino Angela , Caron Maxime , Richer Chantal , Fuchs Claire , Illarregi Unai , Poncelet Lucas , St-Onge Pascal , Bataille Alain R. , Tremblay-Dauphinais Pascal , Lopez-Lopez Elixabet , Camos Mireia , Ramirez-Orellana Manuel , Astigarraga Itziar , Lécuyer Éric , Bourque Guillaume , Martin-Guerrero Idoia , Sinnett Daniel
Published: January 2024

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis of each subtype vs. controls, 156 overexpressed and 134 underexpressed circRNAs were identified consistently in at least one subtype, most of them with subtype-specific expression. TCF3::PBX1 subtype was the one with the highest number of unique and overexpressed circRNAs, and the circRNA signature could effectively discriminate new patients with TCF3::PBX1 subtype from others. Our results indicated that NUDT21, an RNA-binding protein (RBP) involved in circRNA biogenesis, may contribute to this circRNA enrichment in TCF3::PBX1 ALL. Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1, overexpressed in TCF3::PBX1 patients and regulated by NUDT21, might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p. Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.
Revisiting the Role of Serotonin in Sleep-Disordered Breathing
Authors: Aung O , Amorim Mateus R. , Mendelowitz David , Polotsky Vsevolod Y.
Published: January 2024

Serotonin or 5-hydroxytryptamine (5-HT) is a ubiquitous neuro-modulator–transmitter that acts in the central nervous system, playing a major role in the control of breathing and other physiological functions. The midbrain, pons, and medulla regions contain several serotonergic nuclei with distinct physiological roles, including regulating the hypercapnic ventilatory response, upper airway patency, and sleep–wake states. Obesity is a major risk factor in the development of sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), recurrent closure of the upper airway during sleep, and obesity hypoventilation syndrome (OHS), a condition characterized by daytime hypercapnia and hypoventilation during sleep. Approximately 936 million adults have OSA, and 32 million have OHS worldwide. 5-HT acts on 5-HT receptor subtypes that modulate neural control of breathing and upper airway patency. This article reviews the role of 5-HT in SDB and the current advances in 5-HT-targeted treatments for SDB.
Semaglutide Modulates Extracellular Matrix Production of LX-2 Cells via Exosomes and Improves Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Authors: Scavo Maria Principia , Lisco Giuseppe , Depalo Nicoletta , Rizzi Federica , Volpe Sara , Arrè Valentina , Carrieri Livianna , Notarnicola Maria , De Nunzio Valentina , Curri Maria Lucia , De Pergola Giovanni , Piazzolla Giuseppina , Giannelli Gianluigi
Published: January 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to some metabolic disorders, such as central obesity and type 2 diabetes (T2D). Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, may have therapeutic roles in MASLD associated with T2D. This study aims to investigate the molecular mechanisms underlying the effectiveness of semaglutide on MASLD in terms of progression from liver steatosis to fibrosis. We characterized exosomes from ten patients with type 2 diabetes (T2D) before (T0) and after 12 months (T12) of treatment with once-weekly subcutaneous semaglutide. Six of ten patients were considered responders to therapy (R) based on MASLD severity downgrading by at least one class according to a validated ultrasonographic (US) score. Normal hepatocytes (HEPA-RG) and stellate (LX-2) cells were challenged with exosomes from R and NR patients, isolated before and after 12 months of therapy. Exosomes from both R and NR patients isolated at T0 significantly affected LX-2 viability. After 12 months of treatment, only those isolated from R patients restored cell viability, whereas those from NR patients did not. No effects were observed on HEPA-RG cells. Exosomes at T12 from R but not from NR patients significantly decreased the production of α-SMA, a marker of LX-2 activation, a liver stellate cell model, and ph-SMAD2 and CTGF, involved in fibrosis processes. TGF-β1 was not modulated by the exosomes of R and NR patients. As a downstream effect, Vimentin, Collagen 1A1, and Fibronectin extracellular matrix components were also downregulated, as measured by droplets digital PCR. In conclusion, these results shed light on the potential effectiveness of semaglutide in improving liver fibrosis in MASLD.
Establishment of a Pilot Newborn Screening Program for Spinal Muscular Atrophy in Saint Petersburg
Authors: Kiselev Anton , Maretina Marianna , Shtykalova Sofia , Al-Hilal Haya , Maslyanyuk Natalia , Plokhih Mariya , Serebryakova Elena , Frolova Marina , Shved Natalia , Krylova Nadezhda , Il’ina Arina , Freund Svetlana , Osinovskaya Natalia , Sultanov Iskender , Egorova Anna , Lobenskaya Anastasia , Koroteev Alexander , Sosnina Irina , Gorelik Yulia , Bespalova Olesya , Baranov Vladislav , Kogan Igor , Glotov Andrey
Published: January 2024

Spinal muscular atrophy 5q (SMA) is one of the most common neuromuscular inherited diseases and is the most common genetic cause of infant mortality. SMA is associated with homozygous deletion of exon 7 in the SMN1 gene. Recently developed drugs can improve the motor functions of infants with SMA when they are treated in the pre-symptomatic stage. With aim of providing an early diagnosis, newborn screening (NBS) for SMA using a real-time PCR assay with dried blood spots (DBS) was performed from January 2022 through November 2022 in Saint Petersburg, which is a representative Russian megapolis. Here, 36,140 newborns were screened by the GenomeX real-time PCR-based screening test, and three genotypes were identified: homozygous deletion carriers (4 newborns), heterozygous carriers (772 newborns), and wild-type individuals (35,364 newborns). The disease status of all four newborns that screened positive for the homozygous SMN1 deletion was confirmed by alternate methods. Two of the newborns had two copies of SMN2, and two of the newborns had three copies. We determined the incidence of spinal muscular atrophy in Saint Petersburg to be 1 in 9035 and the SMA carrier frequency to be 1 in 47. In conclusion, providing timely information regarding SMN1, confirmation of disease status, and SMN2 copy number as part of the SMA newborn-screening algorithm can significantly improve clinical follow-up, testing of family members, and treatment of patients with SMA.
Minoan Cryptanalysis: Computational Approaches to Deciphering Linear A and Assessing Its Connections with Language Families from the Mediterranean and the Black Sea Areas
Authors: Nepal Aaradh , Perono Cacciafoco Francesco
Published: January 2024

During the Bronze Age, the inhabitants of regions of Crete, mainland Greece, and Cyprus inscribed their languages using, among other scripts, a writing system called Linear A. These symbols, mainly characterized by combinations of lines, have, since their discovery, remained a mystery. Not only is the corpus very small, but it is challenging to link Minoan, the language behind Linear A, to any known language. Most decipherment attempts involve using the phonetic values of Linear B, a grammatological offspring of Linear A, to ‘read’ Linear A. However, this yields meaningless words. Recently, novel approaches to deciphering the script have emerged which involve a computational component. In this paper, two such approaches are combined to account for the biases involved in provisionally assigning Linear B phonetic values to Linear A and to shed more light on the possible connections of Linear A with other scripts and languages from the region. Additionally, the limitations inherent in such approaches are discussed. Firstly, a feature-based similarity measure is used to compare Linear A with the Carian Alphabet and the Cypriot Syllabary. A few Linear A symbols are matched with symbols from the Carian Alphabet and the Cypriot Syllabary. Finally, using the derived phonetic values, Linear A is compared with Ancient Egyptian, Luwian, Hittite, Proto-Celtic, and Uralic using a consonantal approach. Some possible word matches are identified from each language.
Implementation of Kidney Biopsy in One of the Poorest Countries in the World: Experience from Zinder Hospital (Niger)
Authors: Diongolé Hassane Moussa , Tondi Zeinabou Maiga Moussa , Garba Abdoulazize , Ganiou Kabirou , Chaibou Laouali , Bonkano Djibrilla , Aboubacar Illiassou , Seribah Abdoul Aziz , Abdoulaye Idrissa Abdoul Madjid , Atanda Akinfenwa , Rostaing Lionel
Published: January 2024

Kidney biopsy (KB) has become essential in the nephrologist’s approach to kidney diseases, both for diagnosis, treatment, and prognosis. Our objective is to describe the preliminary results of KBs in Niger, one of the poorest countries in the world. This is a descriptive cross-sectional study that took place over 36 months in the nephrology/dialysis department of the Zinder National Hospital. Biopsy results were obtained in less than 5 working days. Patients were responsible for covering the cost of the kidney biopsy. The data collected were analyzed using Epi Info V7 software. We performed 120 kidney biopsies during the study period. The average age of the patients was 35 years ± 15.4 [5–68]. The male/female sex ratio was 2:1. Patients’ medical history included herbal medicine use in 33% of cases and high blood pressure in 27.5% of cases. Proteinuria was present at a rate of ≥3 g/24 h in 46.6% of them. The primary indication for kidney biopsy was glomerular syndrome in 62.5% of cases, including 50% with nephrotic syndrome. All kidney biopsies were performed with real-time ultrasound guidance, using an automatic gun fitted with a 16G needle. Regarding complications, macroscopic hematuria was present in 12.5% of cases. Inadequate kidney biopsy was infrequent (5.8% of cases). The most common findings were (i) glomerular diseases (58.4%), such as membranoproliferative glomerulonephritis (13.3%), focal-segmental glomerulosclerosis (10.6%), lupus nephritis (8.8%), minimal change disease (8%), and membranous nephropathy (2.7%), and (ii) tubulointerstitial changes (31.8%). Diabetic nephropathy was rare (2.6%), as was IgA nephropathy (0.9%). We have demonstrated that implementing a sustainable kidney biopsy program in a very poor country is feasible, thanks to the dedication of a specialized renal pathologist. Having a clear diagnosis can assist in properly treating these renal patients according to international guidelines, thereby delaying the progression to end-stage kidney disease.
Vertical Dentofacial Skeletal Divergency Is Not Linked with Oral Health-Related Quality of Life
Authors: Pereira Dinis , Machado Vanessa , Botelho João , Lemos Carolina , Mendes José João , Delgado Ana Sintra
Published: January 2024

The aim of this study is to assess how vertical skeletal malocclusion affects oral health-related quality of life (OHRQoL) among a sample of individuals comprising adolescents, young adults, and adults seeking orthodontic treatment. From January 2019 to March 2020, participants were consecutively enrolled. The assessment of OHRQoL involved measurement using the oral health impact profile (OHIP-14). Lateral cephalograms were performed to measure the vertical skeletal divergency with four cephalometric measurements. Descriptive and inferential statistical analyses were performed. The Mann–Whitney test was applied to compare OHRQoL scores according to the vertical dimension category. The mean age of the participants ranged between 30.3 ± 14.9 and 29.9 ± 14.4 and there was a majority of female participants, between 64.1% and 65.9%. There were no statistically significant differences observed between hyperdivergent and normodivergent groups in either the total score or any domain of the OHIP-14 questionnaire. Individuals with hyperdivergent facial morphology did not show a reduced OHRQoL compared with a normodivergent facial type.
Combined Anterior–Posterior vs. Posterior-Only Approach in Adult Spinal Deformity Surgery: Which Strategy Is Superior?
Authors: Younus Iyan , Chanbour Hani , Chen Jeffrey W. , Johnson Graham W. , Metcalf Tyler , Lyons Alexander T. , Jonzzon Soren , Liles Campbell , Roth Steven G. , Abtahi Amir M. , Stephens Byron F. , Zuckerman Scott L.
Published: January 2024

Introduction: Whether a combined anterior–posterior (AP) approach offers additional benefits over the posterior-only (P) approach in adult spinal deformity (ASD) surgery remains unknown. In a cohort of patients undergoing ASD surgery, we compared the combined AP vs. the P-only approach in: (1) preoperative/perioperative variables, (2) radiographic measurements, and (3) postoperative outcomes. Methods: A single-institution, retrospective cohort study was performed for patients undergoing ASD surgery from 2009 to 2021. Inclusion criteria were ≥5-level fusion, sagittal/coronal deformity, and 2-year follow-up. The primary exposure was the operative approach: a combined AP approach or P alone. Postoperative outcomes included mechanical complications, reoperation, and minimal clinically important difference (MCID), defined as 30% of patient-reported outcome measures (PROMs). Multivariable linear regression was controlled for age, BMI, and previous fusion. Results: Among 238 patients undergoing ASD surgery, 34 (14.3%) patients underwent the AP approach and 204 (85.7%) underwent the P-only approach. The AP group consisted mostly of anterior lumbar interbody fusion (ALIF) at L5/S1 (73.5%) and/or L4/L5 (38.0%). Preoperatively, the AP group had more previous fusions (64.7% vs. 28.9%, p < 0.001), higher pelvic tilt (PT) (29.6 ± 11.6° vs. 24.6 ± 11.4°, p = 0.037), higher T1 pelvic angle (T1PA) (31.8 ± 12.7° vs. 24.0 ± 13.9°, p = 0.003), less L1-S1 lordosis (−14.7 ± 28.4° vs. −24.3 ± 33.4°, p < 0.039), less L4-S1 lordosis (−25.4 ± 14.7° vs. 31.6 ± 15.5°, p = 0.042), and higher sagittal vertical axis (SVA) (102.6 ± 51.9 vs. 66.4 ± 71.2 mm, p = 0.005). Perioperatively, the AP approach had longer operative time (553.9 ± 177.4 vs. 397.4 ± 129.0 min, p < 0.001), more interbodies placed (100% vs. 17.6%, p < 0.001), and longer length of stay (8.4 ± 10.7 vs. 7.0 ± 9.6 days, p = 0.026). Radiographically, the AP group had more improvement in T1PA (13.4 ± 8.7° vs. 9.5 ± 8.6°, p = 0.005), L1-S1 lordosis (−14.3 ± 25.6° vs. −3.2 ± 20.2°, p < 0.001), L4-S1 lordosis (−4.7 ± 16.4° vs. 3.2 ± 13.7°, p = 0.008), and SVA (65.3 ± 44.8 vs. 44.8 ± 47.7 mm, p = 0.007). These outcomes remained statistically significant in the multivariable analysis controlling for age, BMI, and previous fusion. Postoperatively, no significant differences were found in mechanical complications, reoperations, or MCID of PROMs. Conclusions: Preoperatively, patients undergoing the combined anterior–posterior approach had higher PT, T1PA, and SVA and lower L1-S1 and L4-S1 lordosis than the posterior-only approach. Despite increased operative time and length of stay, the anterior–posterior approach provided greater sagittal correction without any difference in mechanical complications or PROMs.
Identification of a Chondrocyte-Specific Enhancer in the Hoxc8 Gene
Authors: Cormier Stephania A. , Kappen Claudia
Published: January 2024

Hox genes encode transcription factors whose roles in patterning animal body plans during embryonic development are well-documented. Multiple studies demonstrate that Hox genes continue to act in adult cells, in normal differentiation, in regenerative processes, and, with abnormal expression, in diverse types of cancers. However, surprisingly little is known about the regulatory mechanisms that govern Hox gene expression in specific cell types, as they differentiate during late embryonic development, and in the adult organism. The murine Hoxc8 gene determines the identity of multiple skeletal elements in the lower thoracic and lumbar region and continues to play a role in the proliferation and differentiation of cells in cartilage as the skeleton matures. This study was undertaken to identify regulatory elements in the Hoxc8 gene that control transcriptional activity, specifically in cartilage-producing chondrocytes. We report that an enhancer comprising two 416 and 224 bps long interacting DNA elements produces reporter gene activity when assayed on a heterologous transcriptional promoter in transgenic mice. This enhancer is distinct in spatial, temporal, and molecular regulation from previously identified regulatory sequences in the Hoxc8 gene that control its expression in early development. The identification of a tissue-specific Hox gene regulatory element now allows mechanistic investigations into Hox transcription factor expression and function in differentiating cell types and adult tissues and to specifically target these cells during repair processes and regeneration.
Simplified Design Method of Laterally Loaded Rigid Monopiles in Cohesionless Soil
Authors: Luo Ruping , Wang Anhui , Li Jie , Ding Wenyun , Zhu Bitang
Published: January 2024

This paper presents a simplified design method for laterally loaded rigid monopiles in cohesionless soil. The proposed design method is based on a constant depth of the rotation point and a bi-linear distribution of soil lateral reaction along the embedded length of the monopile. Furthermore, a mobilization coefficient of soil resistance is introduced to quantify the magnitude of the soil reaction mobilized under a certain load level applied at the pile head. The mobilization coefficient is found to be directly related to the pile head rotation by back-analyzing test results measured from 13 laterally loaded piles in the published literature. The feasibility and reliability of the proposed design method are evaluated with another 23 laterally loaded piles, which are compiled in a database. The results show that the proposed design method yields relatively satisfactory predictions of the nonlinear load-deformation responses of these piles. Furthermore, comparison of soil lateral reaction profiles between those measured and calculated with the proposed method proves the validity of the assumed soil reaction profiles. As the mobilization coefficient is back-analyzed from piles mostly embedded in uniform ground and the pile bending and translational deformations are neglected in this study, the proposed method is suitable for monopile designs in uniform sites with medium~medium-dense sand, in which the pile bending and translational deformations can be ignored.