bluuebunny/crossref_metadata_2025 huggingface dataset:
CD44 Expression in Clear Cell Renal Cell Carcinoma (ccRCC) Correlates with Tumor Grade and Patient Survival and Is Affected by Gene Methylation
Authors: Papanastasiou Anastasios D. , Peroukidis Stavros , Sirinian Chaido , Arkoumani Elisavet , Chaniotis Dimitrios , Zizi-Sermpetzoglou Adamantia
Published: April 2024

Clear cell RCC (ccRCC) represents the most common type of kidney cancer, with surgery being the only potential curative treatment. Almost one-third of ccRCC patients relapse either locally or as cases of distant metastases. Several biomarkers have been employed in order to separate ccRCC patients with better prognosis or to predict treatment outcomes, with limited results. CD44 is a membrane glycoprotein with multiple roles in normal development but also cancer. Recently, the CD44 standard isoform has been implicated in tumor progression and the metastasis cascade through microenvironment interactions. Here, through CD44 immunohistochemical staining of ccRCC patient samples and TCGA data analysis, we sought to elucidate the expression patterns (mRNA and protein) of CD44 in clear cell RCC and correlate its expression with clinicopathological parameters. We were able to show that CD44 expression presents a positive association with tumor grade and overall survival, predicting a worse patient outcome in ccRCC. In addition, our data indicate that the CD44 mRNA upregulation can be attributed to reduced gene methylation, implicating epigenetic gene regulation in ccRCC development and progression.
Colorectal Cancer: Genetic Underpinning and Molecular Therapeutics for Precision Medicine
Authors: Dosunmu Gideon T. , Shergill Ardaman
Published: April 2024

Colorectal cancer (CRC) accounts for about 10% of all cancer cases and 9% of cancer-related deaths globally. In the United States alone, CRC represents approximately 12.6% of all cancer cases, with a mortality rate of about 8%. CRC is now the first leading cause of cancer death in men younger than age 50 and second in women younger than age 50. This review delves into the genetic landscape of CRC, highlighting key mutations and their implications in disease progression and treatment. We provide an overview of the current and emerging therapeutic strategies tailored to individual genomic profiles.
Characterization of the Apoptotic and Antimicrobial Activities of Two Initiator Caspases of Sea Cucumber Apostichopus japonicus
Authors: Zhu Hanshuo , Yuan Zihao , Xu Hang , Sun Li
Published: April 2024

Caspase (CASP) is a protease family that plays a vital role in apoptosis, development, and immune response. Herein, we reported the identification and characterization of two CASPs, AjCASPX1 and AjCASPX2, from the sea cucumber Apostichopus japonicus, an important aquaculture species. AjCASPX1/2 share similar domain organizations with the vertebrate initiator caspases CASP2/9, including the CARD domain and the p20/p10 subunits with conserved functional motifs. However, compared with human CASP2/9, AjCASPX1/2 possess unique structural features in the linker region between p20 and p10. AjCASPX1, but not AjCASPX2, induced marked apoptosis of human cells by activating CASP3/7. The recombinant proteins of AjCASPX2 and the CARD domain of AjCASPX2 were able to bind to a wide range of bacteria, as well as bacterial cell wall components, and inhibit bacterial growth. AjCASPX1, when expressed in Escherichia coli, was able to kill the host bacteria. Under normal conditions, AjCASPX1 and AjCASPX2 expressions were most abundant in sea cucumber muscle and coelomocytes, respectively. After bacterial infection, both AjCASPX1 and AjCASPX2 expressions were significantly upregulated in sea cucumber tissues and cells. Together, these results indicated that AjCASPX1 and AjCASPX2 were initiator caspases with antimicrobial activity and likely functioned in apoptosis and immune defense against pathogen infection.
Non-Specific Epileptic Activity, EEG, and Brain Imaging in Loss of Function Variants in SATB1: A New Case Report and Review of the Literature
Authors: Privitera Flavia , Pagano Stefano , Meossi Camilla , Battini Roberta , Bartolini Emanuele , Montanaro Domenico , Santorelli Filippo Maria
Published: April 2024

SATB1 (MIM #602075) is a relatively new gene reported only in recent years in association with neurodevelopmental disorders characterized by variable facial dysmorphisms, global developmental delay, poor or absent speech, altered electroencephalogram (EEG), and brain abnormalities on imaging. To date about thirty variants in forty-four patients/children have been described, with a heterogeneous spectrum of clinical manifestations. In the present study, we describe a new patient affected by mild intellectual disability, speech disorder, and non-specific abnormalities on EEG and neuroimaging. Family studies identified a new de novo frameshift variant c.1818delG (p.(Gln606Hisfs*101)) in SATB1. To better define genotype–phenotype associations in the different types of reported SATB1 variants, we reviewed clinical data from our patient and from the literature and compared manifestations (epileptic activity, EEG abnormalities and abnormal brain imaging) due to missense variants versus those attributable to loss-of-function/premature termination variants. Our analyses showed that the latter variants are associated with less severe, non-specific clinical features when compared with the more severe phenotypes due to missense variants. These findings provide new insights into SATB1-related disorders.
A Bidirectional Non-Coding RNA Promoter Mediates Long-Range Gene Expression Regulation
Authors: Peralta-Alvarez Carlos Alberto , Núñez-Martínez Hober Nelson , Cerecedo-Castillo Ángel Josué , Poot-Hernández Augusto César , Tapia-Urzúa Gustavo , Garza-Manero Sylvia , Guerrero Georgina , Recillas-Targa Félix
Published: April 2024

Recent evidence suggests that human gene promoters display gene expression regulatory mechanisms beyond the typical single gene local transcription modulation. In mammalian genomes, genes with an associated bidirectional promoter are abundant; bidirectional promoter architecture serves as a regulatory hub for a gene pair expression. However, it has been suggested that its contribution to transcriptional regulation might exceed local transcription initiation modulation. Despite their abundance, the functional consequences of bidirectional promoter architecture remain largely unexplored. This work studies the long-range gene expression regulatory role of a long non-coding RNA gene promoter using chromosome conformation capture methods. We found that this particular bidirectional promoter contributes to distal gene expression regulation in a target-specific manner by establishing promoter–promoter interactions. In particular, we validated that the promoter–promoter interactions of this regulatory element with the promoter of distal gene BBX contribute to modulating the transcription rate of this gene; removing the bidirectional promoter from its genomic context leads to a rearrangement of BBX promoter–enhancer interactions and to increased gene expression. Moreover, long-range regulatory functionality is not directly dependent on its associated non-coding gene pair expression levels.
Exploring the Role of the MUTYH Gene in Breast, Ovarian and Endometrial Cancer
Authors: Lintas Carla , Canalis Benedetta , Azzarà Alessia , Sabarese Giovanna , Perrone Giuseppe , Gurrieri Fiorella
Published: April 2024

Background: MUTYH germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue. Methods: we used Sanger sequencing and immunohistochemistry to search for a second MUTYH variant in the tumoral DNA and to assess protein expression, respectively. Results: we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the MUTYH protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced. Conclusions: our results fail to demonstrate that germinal monoallelic MUTYH variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the MUTYH protein in many tumors suggests its dysregulation regardless of MUTYH genetic status.
Substantial Increases in Healthcare Students’ State Empathy Scores Owing to Participation in a Single Improvisation Session
Authors: Schwartz Brian D. , Rogers Shane L. , Michels Nicole , Van Winkle Lon J.
Published: April 2024

Purpose: To determine whether the 12-item state empathy scale could be modified reliably to measure empathy in healthcare professions students and to detect changes in their empathy owing to a single improvisation (improv) session. Methods: Three cohorts of students from two healthcare professions programs (total = 165 students) participated in an improv session. During the session, one of the researchers (BS) tasked the students with several improv activities. Participants’ self-reported state empathy scores were assessed at three time points (pre-improv, post-improv, and end of semester) using revised, in-class paper versions of the State Empathy Scale. Results: The exploratory factor analysis revealed a single factor solution for the revised scale, justifying the creation of an overall state empathy score from the questionnaire. Cronbach’s alpha reliability values averaged 0.87. Students’ mean empathy scores were higher directly after the improv session than directly prior to the session (p < 0.0001; effect size = r = 0.67, 0.55, and 0.79 for cohorts 1, 2, and 3, respectively). Conclusions: These findings show that a single one- or two-hour improv session can foster substantial increases in healthcare professional students’ state empathy for one another. Greater healthcare professional empathy and compassion foster better healthcare team cooperation and patient outcomes, so healthcare professionals and their students should engage in such empathy-enhancing activities at regular intervals throughout their training and careers.
Healthy Habits, Physical Activity, Stress, and Food Consumption Trends in Chilean Adults with Irritable Bowel Syndrome during the COVID-19 Pandemic
Authors: Mandiola-Palma Carolina , Leiva Camila , Moya-Salazar María Jesús , Goicochea-Palomino Eliane A. , Contreras-Pulache Hans , Moya-Salazar Jeel
Published: April 2024

The COVID-19 pandemic has increased stress levels in the population due to radical lifestyle changes caused by containment measures. Studies suggest that high levels of stress may be related to the development of irritable bowel syndrome (IBS). This study aims to explain how quarantine habits and lifestyles acted as risk factors for the frequency of this syndrome during the COVID-19 pandemic. An observational study was conducted with 34 Chilean participants (average age 24.5 ± 3.85 years), of whom 21 (62%) were female. Surveys on consumption trends and lifestyles created by the authors were administered. Additionally, we used the global physical activity questionnaire (GPAQ) and the depression anxiety stress scales (DASS-21) to assess psychological stress and the Rome IV criteria to assess IBS. Significant differences were found between individuals with better healthy habits compared to those with poor healthy habits. The former showed lower sedentary activity (32%, p = 0.005), only 27% were fast eaters (vs. 44%, p = 0.001), had shorter nap intervals (14% vs. 28%, p = 0.03), and higher vegetable consumption (p = 0.02). There were 20 cases (59%) of IBS, with a strong association with the female sex (p = 0.004), where females were 15 times more likely to develop it compared to males (p = 0.008). Additionally, when alcohol consumption was added to females, there was a higher likelihood of developing this syndrome (p = 0.009), as individuals who consumed alcohol were 12 times more likely to develop it compared to those who did not (p = 0.02). Among other factors, it was observed that 57% of those with the syndrome consumed drinks more often (p = 0.02) but consumed fewer nuts (p = 0.009). In conclusion, IBS has a multifactorial etiology, and correcting individual habits such as alcohol consumption could potentially prevent or delay its development. Therefore, it is important to maintain healthy lifestyles, regardless of non-modifiable factors such as gender, in order to better cope with this syndrome.
Clinical and Neuroimaging Predictors of Alzheimer’s Dementia Conversion in Patients with Mild Cognitive Impairment Using Amyloid Positron Emission Tomography by Quantitative Analysis over 2 Years
Authors: Kim Seonjeong , Yoon Daye , Seong Junho , Jeong Young Jin , Kang Do-Young , Park Kyung Won
Published: April 2024

Patients with mild cognitive impairment (MCI) have a relatively high risk of developing Alzheimer’s dementia (AD), so early identification of the risk for AD conversion can lessen the socioeconomic burden. In this study, 18F-Florapronol, newly developed in Korea, was used for qualitative and quantitative analyses to assess amyloid positivity. We also investigated the clinical predictors of the progression from MCI to dementia over 2 years. From December 2019 to December 2022, 50 patients with MCI were recruited at a single center, and 34 patients were included finally. Based on visual analysis, 13 (38.2%) of 34 participants were amyloid-positive, and 12 (35.3%) were positive by quantitative analysis. Moreover, 6 of 34 participants (17.6%) converted to dementia after a 2-year follow-up (p = 0.173). Among the 15 participants who were positive for amyloid in the posterior cingulate region, 5 (33.3%) patients developed dementia (p = 0.066). The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) at baseline was significantly associated with AD conversion in multivariate Cox regression analyses (p = 0.043). In conclusion, these results suggest that amyloid positivity in the posterior cingulate region and higher CDR-SOB scores at baseline can be useful predictors of AD conversion in patients with MCI.
Clinical Outcomes from the Alaska Native Tribal Health Consortium Colorectal Cancer Control Program: 2009–2015
Authors: Nash Sarah H. , Verhage Elizabeth , Flanagan Christie , Haverkamp Donald , Roik Elena , Zimpelman Garrett , Redwood Diana
Published: April 2024

The Alaska Native Tribal Health Consortium (ANTHC) participated in the United States Centers for Disease Control and Prevention Colorectal Cancer Control Program (CRCCP) from 2009 to 2015. We conducted a descriptive evaluation of ANTHC CRCCP demographics, quality measures, and clinical outcomes, including screening methods employed within the program and screening outcomes. There were 6981 program screenings completed, with the majority (81.3%) of people screened in the 50–75 year age group. Colonoscopy was the primary screening test used, accounting for 6704 (96.9%) of the screening tests. Quality of colonoscopy was high: adequate bowel preparation was reported in 98.2% of colonoscopies, cecal intubation rate was 98.9%, and the adenoma detection rate was 38.9%. A high proportion (58.9%) of colonoscopies had an initial finding of polyps or lesions suspicious for cancer; 41.2% of all colonoscopies had histological confirmation of either adenomatous polyps (40.6%) or cancer (0.5%). The ANTHC CRCCP successfully increased CRC screening among American Indian and Alaska Native peoples living in Alaska; this was achieved primarily through high-quality colonoscopy metrics. These data support a continued focus by the Alaska Native Tribal Health Consortium and its tribal health partners on increasing CRC screening and reducing cancer mortality among Alaska Native peoples.
CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis
Authors: Szukiewicz Dariusz
Published: April 2024

The chemotactic cytokine fractalkine (FKN, chemokine CX3CL1) has unique properties resulting from the combination of chemoattractants and adhesion molecules. The soluble form (sFKN) has chemotactic properties and strongly attracts T cells and monocytes. The membrane-bound form (mFKN) facilitates diapedesis and is responsible for cell-to-cell adhesion, especially by promoting the strong adhesion of leukocytes (monocytes) to activated endothelial cells with the subsequent formation of an extracellular matrix and angiogenesis. FKN signaling occurs via CX3CR1, which is the only known member of the CX3C chemokine receptor subfamily. Signaling within the FKN-CX3CR1 axis plays an important role in many processes related to inflammation and the immune response, which often occur simultaneously and overlap. FKN is strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokine release, and it may act locally as a key angiogenic factor in the highly hypoxic tumor microenvironment. The importance of the FKN/CX3CR1 signaling pathway in tumorigenesis and cancer metastasis results from its influence on cell adhesion, apoptosis, and cell migration. This review presents the role of the FKN signaling pathway in the context of angiogenesis in inflammation and cancer. The mechanisms determining the pro- or anti-tumor effects are presented, which are the cause of the seemingly contradictory results that create confusion regarding the therapeutic goals.
New Insights on Solvent-Induced Changes in Refractivity and Specific Rotation of Poly(propylene oxide) Systems Extracted from Channeled Spectra
Authors: Zara Alexandru , Albu Raluca Marinica , Stoica Iuliana , Barzic Andreea Irina , Dimitriu Dan Gheorghe , Dorohoi Dana Ortansa
Published: April 2024

Investigation of chiroptical polymers in the solution phase is paramount for designing supramolecular architectures for photonic or biomedical devices. This work is devoted to the case study of poly(propylene oxide) (PPO) optical activity in several solvents: benzonitrile, carbon disulfide, chloroform, ethyl acetate, and p-dioxane. To attain information on the interactions in these systems, rheological testing was undertaken, showing distinct variations of the rheological parameters as a function of the solvent type. These aspects are also reflected in the refractive index dispersive behavior, from which linear and non-linear optical properties are extracted. To determine the circular birefringence and specific rotation of the PPO solutions, the alternative method of the channeled spectra was employed. The spectral data were correlated with the molecular modeling of the PPO structural unit in the selected solvents. Density functional theory (DFT) computational data indicated that the torsional potential energy—related to the O1-C2-C3-O4 dihedral angle from the polymer repeating unit—was hindered in solvation environments characterized by high polarity and the ability to interact via hydrogen bonding. This was in agreement with the optical characterization of the samples, which indicated a lower circular birefringence and specific rotation for the solutions of PPO in ethyl acetate and p-dioxane. Also, the shape of optical rotatory dispersion curves was slightly modified for PPO in these solvents compared with the other ones.
Single-Cell Transcriptional Profile Construction of Rat Pituitary Glands before and after Sexual Maturation and Identification of Novel Marker Spp1 in Gonadotropes
Authors: Huang Qing-Hua , Zhao Guo-Kun , Wang Hao-Qi , Wei Fan-Hao , Zhang Jin-Yu , Zhang Jia-Bao , Gao Fei , Yuan Bao
Published: April 2024

The mammalian pituitary gland drives highly conserved physiological processes such as somatic cell growth, pubertal transformation, fertility, and metabolism by secreting a variety of hormones. Recently, single-cell transcriptomics techniques have been used in pituitary gland research. However, more studies have focused on adult pituitary gland tissues from different species or different sexes, and no research has yet resolved cellular differences in pituitary gland tissue before and after sexual maturation. Here, we identified a total of 15 cell clusters and constructed single-cell transcriptional profiles of rats before and after sexual maturation. Furthermore, focusing on the gonadotrope cluster, 106 genes were found to be differentially expressed before and after sexual maturation. It was verified that Spp1, which is specifically expressed in gonadotrope cells, could serve as a novel marker for this cell cluster and has a promotional effect on the synthesis and secretion of follicle-stimulating hormone. The results provide a new resource for further resolving the regulatory mechanism of pituitary gland development and pituitary hormone synthesis and secretion.
HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology
Authors: Thompson Landon John-Patrick , Genovese Jessica , Hong Zhenzi , Singh Meera Vir , Singh Vir Bahadur
Published: April 2024

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood–brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.
Anti-Obesity Therapeutic Targets Studied In Silico and In Vivo: A Systematic Review
Authors: de Medeiros Wendjilla F. , Gomes Ana Francisca T. , Aguiar Ana Júlia F. C. , de Queiroz Jaluza Luana C. , Bezerra Ingrid Wilza L. , da Silva-Maia Juliana Kelly , Piuvezam Grasiela , Morais Ana Heloneida de A.
Published: April 2024

In the age of information technology and the additional computational search tools and software available, this systematic review aimed to identify potential therapeutic targets for obesity, evaluated in silico and subsequently validated in vivo. The systematic review was initially guided by the research question “What therapeutic targets have been used in in silico analysis for the treatment of obesity?” and structured based on the acronym PECo (P, problem; E, exposure; Co, context). The systematic review protocol was formulated and registered in PROSPERO (CRD42022353808) in accordance with the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA was followed for the systematic review. The studies were selected according to the eligibility criteria, aligned with PECo, in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. The search strategy yielded 1142 articles, from which, based on the evaluation criteria, 12 were included in the systematic review. Only seven these articles allowed the identification of both in silico and in vivo reassessed therapeutic targets. Among these targets, five were exclusively experimental, one was exclusively theoretical, and one of the targets presented an experimental portion and a portion obtained by modeling. The predominant methodology used was molecular docking and the most studied target was Human Pancreatic Lipase (HPL) (n = 4). The lack of methodological details resulted in more than 50% of the papers being categorized with an “unclear risk of bias” across eight out of the eleven evaluated criteria. From the current systematic review, it seems evident that integrating in silico methodologies into studies of potential drug targets for the exploration of new therapeutic agents provides an important tool, given the ongoing challenges in controlling obesity.
Mixed-Lineage Leukaemia Gene Regulates Glucose-Sensitive Gene Expression and Insulin Secretion in Pancreatic Beta Cells
Authors: Yoshino Satoshi , Ishida Emi , Horiguchi Kazuhiko , Matsumoto Shunichi , Nakajima Yasuyo , Ozawa Atsushi , Yamada Masanobu , Yamada Eijiro
Published: April 2024

The escalating prevalence of diabetes mellitus underscores the need for a comprehensive understanding of pancreatic beta cell function. Interest in glucose effectiveness has prompted the exploration of novel regulatory factors. The myeloid/lymphoid or mixed-lineage leukaemia gene (MLL) is widely recognised for its role in leukemogenesis and nuclear regulatory mechanisms through its histone methyltransferase activity in active chromatin. However, its function within pancreatic endocrine tissues remains elusive. Herein, we unveil a novel role of MLL in glucose metabolism and insulin secretion. MLL knockdown in βHC-9 pancreatic beta cells diminished insulin secretion in response to glucose loading, paralleled by the downregulation of the glucose-sensitive genes SLC2a1 and SLC2a2. Similar observations were made in MLL heterozygous knockout mice (MLL+/−), which exhibited impaired glucose tolerance and reduced insulin secretion without morphological anomalies in pancreatic endocrine cells. The reduction in insulin secretion was independent of changes in beta cell mass or insulin granule morphology, suggesting the regulatory role of MLL in glucose-sensitive gene expression. The current results suggest that MLL interacts with circadian-related complexes to modulate the expression of glucose transporter genes, thereby regulating glucose sensing and insulin secretion. Our findings shed light on insulin secretion control, providing potential avenues for therapeutics against diabetes.
(2,6-Dimethylphenyl)arsonic Acid Induces Apoptosis through the Mitochondrial Pathway, Downregulates XIAP, and Overcomes Multidrug Resistance to Cytostatic Drugs in Leukemia and Lymphoma Cells In Vitro
Authors: Wilke Nathalie , Frias Corazon , Berkessel Albrecht , Prokop Aram
Published: April 2024

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.
Cytotoxicity of Quantum Dots in Receptor-Mediated Endocytic and Pinocytic Pathways in Yeast
Authors: Okafor Onyinye , Kim Kyoungtae
Published: April 2024

Despite the promising applications of the use of quantum dots (QDs) in the biomedical field, the long-lasting effects of QDs on the cell remain poorly understood. To comprehend the mechanisms underlying the toxic effects of QDs in yeast, we characterized defects associated with receptor-mediated endocytosis (RME) as well as pinocytosis using Saccharomyces cerevisiae as a model in the presence of cadmium selenide/zinc sulfide (CdSe/ZnS) QDs. Our findings revealed that QDs led to an inefficient RME at the early, intermediate, and late stages of endocytic patch maturation at the endocytic site, with the prolonged lifespan of GFP fused yeast fimbrin (Sac6-GFP), a late marker of endocytosis. The transit of FM1-43, a lipophilic dye from the plasma membrane to the vacuole, was severely retarded in the presence of QDs. Finally, QDs caused an accumulation of monomeric red fluorescent protein fused carbamoyl phosphate synthetase 1 (mRFP-Cps1), a vacuolar lumen marker in the vacuole. In summary, the present study provides novel insights into the possible impact of CdSe/ZnS QDs on the endocytic machinery, enabling a deeper comprehension of QD toxicity.
An Explainable Deep Learning Classifier of Bovine Mastitis Based on Whole-Genome Sequence Data—Circumventing the p >> n Problem
Authors: Kotlarz Krzysztof , Mielczarek Magda , Biecek Przemysław , Wojdak-Maksymiec Katarzyna , Suchocki Tomasz , Topolski Piotr , Jagusiak Wojciech , Szyda Joanna
Published: April 2024

The serious drawback underlying the biological annotation of whole-genome sequence data is the p >> n problem, which means that the number of polymorphic variants (p) is much larger than the number of available phenotypic records (n). We propose a way to circumvent the problem by combining a LASSO logistic regression with deep learning to classify cows as susceptible or resistant to mastitis, based on single nucleotide polymorphism (SNP) genotypes. Among several architectures, the one with 204,642 SNPs was selected as the best. This architecture was composed of two layers with, respectively, 7 and 46 units per layer implementing respective drop-out rates of 0.210 and 0.358. The classification of the test data resulted in AUC = 0.750, accuracy = 0.650, sensitivity = 0.600, and specificity = 0.700. Significant SNPs were selected based on the SHapley Additive exPlanation (SHAP). As a final result, one GO term related to the biological process and thirteen GO terms related to molecular function were significantly enriched in the gene set that corresponded to the significant SNPs. Our findings revealed that the optimal approach can correctly predict susceptibility or resistance status for approximately 65% of cows. Genes marked by the most significant SNPs are related to the immune response and protein synthesis.
Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders
Authors: Ung Trong Thuan , Starr Christopher R. , Zhylkibayev Assylbek , Saltykova Irina , Gorbatyuk Marina
Published: April 2024

Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a diverse spectrum of cellular signaling, with the unfolded protein response (UPR) identified as a common signaling pathway chronically activated in degenerating retinas. TRIB3 has been recognized as a key mediator of the PERK UPR arm, influencing various metabolic pathways, such as insulin signaling, lipid metabolism, and glucose homeostasis, by acting as an AKT pseudokinase that prevents the activation of the AKT → mTOR axis. This study aimed to develop a gene-independent approach targeting the UPR TRIB3 mediator previously tested by our group using a genetic approach in mice with RD. The goal was to validate a therapeutic approach targeting TRIB3 interactomes through the pharmacological targeting of EGFR-TRIB3 and delivering cell-penetrating peptides targeting TRIB3 → AKT. The study employed rd10 and P23H RHO mice, with afatinib treatment conducted in p15 rd10 mice through daily intraperitoneal injections. P15 P23H RHO mice received intraocular injections of cell-penetrating peptides twice at a 2-week interval. Our study revealed that both strategies successfully targeted TRIB3 interactomes, leading to an improvement in scotopic A- and B-wave ERG recordings. Additionally, the afatinib-treated mice manifested enhanced photopic ERG amplitudes accompanied by a delay in photoreceptor cell loss. The treated rd10 retinas also showed increased PDE6β and RHO staining, along with an elevation in total PDE activity in the retinas. Consequently, our study demonstrated the feasibility of a gene-independent strategy to target common signaling in degenerating retinas by employing a TRIB3-based therapeutic approach that delays retinal function and photoreceptor cell loss in two RD models.
Thiacalixarene Carboxylic Acid Derivatives as Inhibitors of Lysozyme Fibrillation
Authors: Nazarova Anastasia , Shiabiev Igor , Shibaeva Ksenia , Mostovaya Olga , Mukhametzyanov Timur , Khannanov Arthur , Evtugyn Vladimir , Zelenikhin Pavel , Shi Xiangyang , Shen Mingwu , Padnya Pavel , Stoikov Ivan
Published: April 2024

Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05–5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29–45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5–250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.
Mitochondrial DNA and Electron Transport Chain Protein Levels Are Altered in Peripheral Nerve Tissues from Donors with HIV Sensory Neuropathy: A Pilot Study
Authors: Boustani Ali , Kulbe Jacqueline R. , Andalibi Mohammadsobhan Sheikh , Pérez-Santiago Josué , Mehta Sanjay R. , Ellis Ronald J. , Fields Jerel Adam
Published: April 2024

Distal sensory polyneuropathy (DSP) and distal neuropathic pain (DNP) remain significant challenges for older people with HIV (PWH), necessitating enhanced clinical attention. HIV and certain antiretroviral therapies (ARTs) can compromise mitochondrial function and impact mitochondrial DNA (mtDNA) replication, which is linked to DSP in ART-treated PWH. This study investigated mtDNA, mitochondrial fission and fusion proteins, and mitochondrial electron transport chain protein changes in the dorsal root ganglions (DRGs) and sural nerves (SuNs) of 11 autopsied PWH. In antemortem standardized assessments, six had no or one sign of DSP, while five exhibited two or more DSP signs. Digital droplet polymerase chain reaction was used to measure mtDNA quantity and the common deletions in isolated DNA. We found lower mtDNA copy numbers in DSP+ donors. SuNs exhibited a higher proportion of mtDNA common deletion than DRGs in both groups. Mitochondrial electron transport chain (ETC) proteins were altered in the DRGs of DSP+ compared to DSP− donors, particularly Complex I. These findings suggest that reduced mtDNA quantity and increased common deletion abundance may contribute to DSP in PWH, indicating diminished mitochondrial activity in the sensory neurons. Accumulated ETC proteins in the DRG imply impaired mitochondrial transport to the sensory neuron’s distal portion. Identifying molecules to safeguard mitochondrial integrity could aid in treating or preventing HIV-associated peripheral neuropathy.
Effect of Helichrysum italicum in Promoting Collagen Deposition and Skin Regeneration in a New Dynamic Model of Skin Wound Healing
Authors: Serra Diletta , Cruciani Sara , Garroni Giuseppe , Sarais Giorgia , Kavak Fikriye Fulya , Satta Rosanna , Montesu Maria Antonietta , Floris Matteo , Ventura Carlo , Maioli Margherita
Published: April 2024

Natural products have many healing effects on the skin with minimal or no adverse effects. In this study, we analyzed the regenerative properties of a waste product (hydrolate) derived from Helichrysum italicum (HH) on scratch-tested skin cell populations seeded on a fluidic culture system. Helichrysum italicum has always been recognized in the traditional medicine of Mediterranean countries for its wide pharmacological activities. We recreated skin physiology with a bioreactor that mimics skin stem cell (SSCs) and fibroblast (HFF1) communication as in vivo skin layers. Dynamic culture models represent an essential instrument for recreating and preserving the complex multicellular organization and interactions of the cellular microenvironment. Both cell types were exposed to two different concentrations of HH after the scratch assay and were compared to untreated control cells. Collagen is the constituent of many wound care products that act directly on the damaged wound environment. We analyzed the role played by HH in stimulating collagen production during tissue repair, both in static and dynamic culture conditions, by a confocal microscopic analysis. In addition, we performed a gene expression analysis that revealed the activation of a molecular program of stemness in treated skin stem cells. Altogether, our results indicate a future translational application of this natural extract to support skin regeneration and define a new protocol to recreate a dynamic process of healing.
Biosynthetic Pathways of Tryptophan Metabolites in Saccharomyces cerevisiae Strain: Insights and Implications
Authors: Kung Hsin-Chieh , Bui Ngoc-Han , Huang Bo-Wun , Cheruiyot Nicholas Kiprotich , Chang-Chien Guo-Ping
Published: April 2024

Tryptophan metabolites, such as 5-hydroxytryptophan (5-HTP), serotonin, and melatonin, hold significant promise as supplements for managing various mood-related disorders, including depression and insomnia. However, their chemical production via chemical synthesis and phytochemical extraction presents drawbacks, such as the generation of toxic byproducts and low yields. In this study, we explore an alternative approach utilizing S. cerevisiae STG S101 for biosynthesis. Through a series of eleven experiments employing different combinations of tryptophan supplementation, Tween 20, and HEPES buffer, we investigated the production of these indolamines. The tryptophan metabolites were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Notably, setups replacing peptone in the YPD media with tryptophan (Run 3) and incorporating tryptophan along with 25 mM HEPES buffer (Run 4) demonstrated successful biosynthesis of 5-HTP and serotonin. The highest 5-HTP and serotonin concentrations were 58.9 ± 16.0 mg L−1 and 0.0650 ± 0.00211 mg L−1, respectively. Melatonin concentrations were undetected in all the setups. These findings underscore the potential of using probiotic yeast strains as a safer and conceivably more cost-effective alternative for indolamine synthesis. The utilization of probiotic strains presents a promising avenue, potentially offering scalability, sustainability, reduced environmental impact, and feasibility for large-scale production.
β1-Integrin-Mediated Uptake of Chondrocyte Extracellular Vesicles Regulates Chondrocyte Homeostasis
Authors: Hussain Mohammed Tayab , Austin-Williams Shani , Wright Thomas Dudley , Dhawan Umesh Kumar , Pinto Andreia L. , Cooper Dianne , Norling Lucy V.
Published: April 2024

Osteoarthritis (OA) is the most prevalent age-related degenerative disorder, which severely reduces the quality of life of those affected. Whilst management strategies exist, no cures are currently available. Virtually all joint resident cells generate extracellular vesicles (EVs), and alterations in chondrocyte EVs during OA have previously been reported. Herein, we investigated factors influencing chondrocyte EV release and the functional role that these EVs exhibit. Both 2D and 3D models of culturing C28I/2 chondrocytes were used for generating chondrocyte EVs. We assessed the effect of these EVs on chondrogenic gene expression as well as their uptake by chondrocytes. Collectively, the data demonstrated that chondrocyte EVs are sequestered within the cartilage ECM and that a bi-directional relationship exists between chondrocyte EV release and changes in chondrogenic differentiation. Finally, we demonstrated that the uptake of chondrocyte EVs is at least partially dependent on β1-integrin. These results indicate that chondrocyte EVs have an autocrine homeostatic role that maintains chondrocyte phenotype. How this role is perturbed under OA conditions remains the subject of future work.
The Impact of Conservative Surgical Treatment of Adenomyosis on Fertility and Perinatal Outcomes
Authors: Moawad Gaby , Youssef Youssef , Fruscalzo Arrigo , Faysal Hani , Merida Manuel , Pirtea Paul , Guani Benedetta , Ayoubi Jean Marc , Feki Anis
Published: April 2024

Adenomyosis is a benign condition commonly encountered in patients with infertility. While the definitive surgical management is hysterectomy, conservative surgical management is gaining attention in patients desiring future fertility. This review explores whether the surgical treatment of adenomyosis affects fertility outcomes for patients trying to conceive. The PubMed and Medline databases were searched using the keywords: “adenomyosis”, “surgery”, “radiofrequency”, “infertility”, “pregnancy”, “sterility”, “conception”, “miscarriage”, and “endometrial receptivity”. Abstracts were screened, and relevant articles were selected for review. This review reveals that surgery appears to improve fertility outcomes with or without medical therapy; however, the risk of uterine rupture remains high and the best technique to reduce this risk is still not known. More studies are needed to formulate the best surgical approach for preserving fertility in treating adenomyosis and to establish standardized guidelines.
No Changes in Keratometry Readings and Anterior Chamber Depth after XEN Gel Implantation in Patients with Glaucoma
Authors: Tatti Filippo , Tronci Claudia , Lixi Filippo , Demarinis Giuseppe , Kuzmich Sviatlana , Peiretti Enrico , Fossarello Maurizio , Giannaccare Giuseppe
Published: April 2024

Background: This study aimed to compare keratometry and anterior chamber depth (ACD) changes after XEN implantation in primary open-angle glaucoma (POAG) cases over a 3-month follow-up period. Methods: Twenty patients with POAG who underwent XEN63 implantation, either standalone or combined with cataract surgery, were included. Preoperative data, including best-corrected visual acuity (BCVA), refraction, gonioscopy, ophthalmoscopy, intraocular pressure (IOP) evaluation, and axial length, were collected. Corneal topography and ACD measurements were assessed preoperatively and at postoperative days 1, 7, 15, 30, 60, and 90. Each patient’s eye that underwent XEN surgery was included in the study group, with the fellow eye serving as a control. Results: In the study group, there was a significant decrease in IOP after XEN stent implantation at all investigated time intervals (p < 0.05). However, changes in mean ACD did not show statistically significant differences at any follow-up examination in both the study and control groups. Additionally, keratometry readings revealed no significant changes in total astigmatism or steep keratometry values in either group. Conclusions: XEN implantation in POAG cases resulted in a significant decrease in IOP over the 3-month follow-up period. However, there were no significant changes observed in mean ACD or keratometry readings, indicating stability in these parameters post-XEN implantation. These findings suggest that XEN implantation may be an effective option for IOP reduction without affecting corneal curvature or ACD in POAG patients.
Five-Year Trends of Vascular Disease-Related Amputations in Romania: A Retrospective Database Study
Authors: Coman Horațiu F. , Stancu Bogdan , Andercou Octavian A. , Ciocan Razvan , Gherman Claudia D. , Rusu Adriana , Gavan Norina A. , Bondor Cosmina I. , Gavan Alexandru D. , Bala Cornelia G. , Necula Alexandru , Ana Trif , Tatiana Trif , Haldenwang Peter L.
Published: April 2024

Background/Objectives: Lower extremity amputations (LEAs) are a burdensome complication of peripheral artery disease (PAD) and/or arterial embolism and thrombosis (AET). We assessed the trends in PAD- and/or AET-related LEAs in Romania. Methods: This retrospective study (2015–2019) analyzed data on minor and major LEAs in hospitalized patients recorded in the National School for Public Health, Management, and Health Education database. The absolute numbers and incidences of LEAs were analyzed by diagnosis type, year, age, sex, and amputation level. Results: Of 38,590 vascular disease-related amputations recorded nationwide, 36,162 were in PAD and 2428 in AET patients. The average LEA incidence in the general population was 34.73 (minimum: 31.96 in 2015; maximum: 36.57 in 2019). The average incidence of major amputations, amputations above the knee, hip amputations, amputations below the knee, and minor amputations was 16.21 (15.62 in 2015; 16.84 in 2018), 13.76 (13.33 in 2015; 14.28 in 2018), 0.29 (0.22 in 2017; 0.35 in 2019), 2.15 (2.00 in 2015; 2.28 in 2019), and 18.52 (16.34 in 2015; 20.12 in 2019), respectively. Yearly PAD- and/or AET-related amputations were significantly higher in men versus women. The overall number of LEAs increased with age, particularly in patients ≥ 70 years. The increase in the total number of amputations was mainly due to a constant rise in minor amputations for both groups, regardless of gender. Conclusions: PAD- and/or AET-related LEAs in Romania increased from 2015 to 2019, with men having a greater incidence than women. Raising awareness and effective management strategies are needed to prevent LEAs.