Fucoidan is a brown algae-derived polysaccharide having several biomedical applications. This study simultaneously compares the anticancer activities of crude fucoidans from Fucus vesiculosus and Sargassum filipendula, and effects of low (LMW, 10-50kDa), medium (MMW, 50-100kDa) and high (HMW, >100kDa) molecular weight fractions of S. filipendula fucoidan against osteosarcoma cells. Glucose, fucose and acid levels were lower and sulphation was higher in F. vesiculosus crude fucoidan compared to S. filipendula crude fucoidan. MMW had highest the levels of sugars, acids and sulphation among molecular weight fractions. There was a dose dependent drop in focal adhesion formation and proliferation of cells for all fucoidan-types, but F. vesiculosus fucoidan and HMW had the strongest effects. G1-phase arrest was induced by F. vesiculosus fucoidan, MMW and HMW, however F. vesiculosus fucoidan treatment also caused accumulation in sub G1-phase. Mitochondrial damage occurred for all fucoidan-types, however F. vesiculosus fucoidan led to mitochondrial fragmentation. Annexin V/PI, TUNEL and cytochrome c staining confirmed stress induced apoptosis-like cell death for F. vesiculosus fucoidan but features of stress-induced necrosis-like cell death for S. filipendula fucoidans. There was also variation in penetrability of different fucoidans inside the cell. These differences in anti-cancer activity of fucoidans are applicable for osteosarcoma treatment.

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM.

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of Coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in cardiovascular system, the clinical applications centered on the NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process based on the clinical images and mathematical modeling to assess the endothelial function and vulnerability of atherosclerotic plaque. Then, the emerging bioimaging technologies that have the potential to directly measure the arterial NO concentration were discussed, including the Raman spectroscopy and electrochemical sensor. Aside from the diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the inhaled NO therapy to treat the pulmonary hypertension and COVID-19, stem cell therapy and NO-releasing platform to treat endothelial dysfunction and atherosclerosis.

COVID-19 sepsis immune response remains unclear. Here we propose a new perspective in host response against pathogenic proteins that may lead to a vaccine design by polymerization of antigens of <70 kDa. In COVID-19, initial Th1 response kills infected cells releasing viral proteins. SARS-CoV-2 viral structural proteins are Spike (140 kDa), Nucleocapsid (50 kDa), Membrane (25 kDa) and Envelope (10 kDa). B cell receptor cannot capture antigens >70 kDa. The Spike protein (140 kDa) cannot be captured by B cells and triggers inflammatory Th1 response via the macrophages. Only proteins with a size <70 kDa can activate B cell receptor and trigger Th2 adaptative humoral response. Moreover, M-25 kDa and E-12 kDa glycoproteins can activate IgM-BCR like oligovalent or monovalent antigens. The sustained infected cells lysis overfeeds high levels of viral proteins <70 kDa, increases B cells activation and, in the shift from Th1 to Th2 immune response, triggers the cytokine storm. The continuous BCR activation increases IL-10 releasing and may lead to immune paralysis.

It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis.

Phelipanche ramosa is a root parasitic plant fully dependent on host plants for nutrition and development. Once germinated, the parasitic seedling develops inside of the infected roots a specific organ, the haustorium, thanks to notably cell wall degrading enzymes of haustorial intrusive cells and induced modifications in host’s cell walls. The model plant Arabidopsis thaliana is susceptible to P. ramosa, thus mutants in cell wall metabolism, notably in pectin remodeling like Atpme3-1, are of interest in studying the involvement of cell wall degrading host’s enzymes in establishment of the plant-plant interaction. Host-parasite co-cultures in mini-rhizotrons systems revealed that parasite attachments are twice more numerous and tubercle growth is quicker on Atpme3-1 roots than on WT roots. When compared to the WT, increase in susceptibility in the mutant is associated to reduction in PME activity in roots and to lowering in the degree of pectin methylation at the host-parasite interface, as detected immunohistochemically in infected roots. In addition, both WT and Atpme3-1 responded to infestation by modulations in expression of PAE and PME encoding genes and in global related enzymes activities in roots, before and after parasite attachment. However, modulations differ in WT and Atpme3-1 and this may contribute to different pectin remodeling in roots and contrasted susceptibility to P. ramosa. By this integrative study, we could define a model of the cell wall response to this particular biotic stress and indicate for the first time the role of PME3 in this parasitic plant-plant interaction.

Ageing may be characterized by progressive loss of cognitive function as well as decrease in physical activities, in addition to change in appearance. Previously, we reported that intracerebroventricular transplantation of a human neural stem cell (NSC) line (F3) over-expressing choline acetyltransferase (F3.ChAT) gene, an enzyme responsible for acetylcholine synthesis, markedly improved cognitive function and physical activity of aged animals by enhancing acetylcholine and growth factors (GFs) and neurotrophic factors (NFs). In the present study, 10-month-old F344 rats were intravenously transplanted with F3 or F3.ChAT NSCs (1 x 106 cells) once a month to 21st month of age when the cumulative mortality reached 20%, and physical activity and learning/memory function were investigated, in addition to the analyses of brain acetylcholine concentration, and cholinergic and dopaminergic system restoration. Neuroprotective and neuroregenerative activities of stem cells were also confirmed by analyzing oxidative damages, neuronal skeletal protein, angiogenesis, brain and muscle weights, and proliferating host stem cells. Stem cells markedly improved both the cognitive (passive avoidance and water-maze performances) and physical (locomotor and rota-rod activities) functions, in parallel with the elevation of acetylcholine levels in cerebrospinal fluid and in muscles, in which F3.ChAT cells were superior to F3 parental cells. Stem cell transplantation down-regulated CCL11, leading to restoration of microtubule-associated protein 2 as well as functional markers of cholinergic and dopaminergic systems, and preserved brain and muscular capillaries, recovering muscle mass. In addition, stem cells enhanced antioxidative capacity, attenuating oxidative damage of multiple organs including muscles and the brain. The results indicate that NSCs over-expressing ChAT gene improve cognitive function and physical activity of ageing animals by protecting and recovering functions of multiple organs including cholinergic and dopaminergic systems as well as muscles from oxidative injuries through secretion of acetylcholine and GFs/NFs, increased antioxidant elements, and enhanced blood flow.

Abstract The relationship between cancer and neurodegeneration has spurred extensive scientific discourse, challenging their historical classification as distinct disorders. While cancer signifies uncontrolled cellular proliferation and neurodegeneration marks progressive neuronal loss, recent insights highlight intriguing interconnections between these seemingly disparate conditions. Cancer entails perpetual signaling for growth, evasion of growth inhibitors, resistance to cell death, acquisition of replicative immortality, stimulation of blood vessel growth (angiogenesis), and initiation of invasion and metastasis. Conversely, investigations emphasize disrupted cellular energy regulation and evasion of immune surveillance as key traits arising from genome instability, mutations, and inflammation driving tumorigenesis. Neurodegeneration involves neuronal malfunction and depletion, synaptic impairment, and protein abnormalities aggregations contributing to muscle atrophy and cognitive deficits. Varied clinical studies underscore contrasting correlations between cancer and neurodegeneration, hinting at mirrored molecular pathways that foster cell resilience or vulnerability. Research explores cellular signaling in tumorigenesis, shared with neurodegenerative disorders. Aberrant expression or mutations in crucial genes implicated in neurodegeneration also surface in cancer contexts. Debates persist on the nature of the relationship between cancer and neurodegeneration, contemplating inverse associations or shared pathways. Understanding their complex interplay, encompassing genetics, cellular mechanisms, and environmental influences, remains pivotal in unraveling their connections. This review explores the intriguing perspective that neurodegeneration and cancer might share fundamental genetic links, delving into potential implications for their onset and progression.

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in close vicinity as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.

The aim of the study was to gain deeper insights in the potential for polyclonal stimulation of PBMC from cows and pigs with banana lectin (BanLec) from Musa paradisiaca. BanLec induced a marked proliferative response in cow and pig PBMC. The response in pigs was even higher than to Concanavalin A. Molecular processes associated with respective responses were examined with differential proteome analyses. Discovery proteomic experiments was applied to BanLec stimulated PBMC and cellular and secretome responses were analyzed with label free LC-MS/MS. In PBMC, 3955 proteins were identified. After polyclonal stimulation with BanLec, 459 proteins showed significantly changed abundance in PBMC. In respective PBMC secretomes, 2867 proteins were identified with 231 differentially expressed candidates as reaction to BanLec stimulation. The transcription factor `E74 like ETS transcription factor 1 (ELF1)` was solely enriched in BanLec stimulated PBMC. BanLec induced secretion of several immune regulators, amongst them positive regulators of activated T cell proliferation and Jak-STAT signaling pathway. Top changed immune proteins were CD226, CD27, IFNG, IL18, IL2, CXCL10, LAT, ICOS, IL2RA, LAG3 and CD300C. BanLec stimulates PBMC of cows and pigs polyclonally and induces IL2 pathway and further proinflammatory cytokines. Proteomics data are available via ProteomeXchange with identifier PXD027505.

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cells transplantation, may hold promise as stroke therapy because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria, potentially transferrable into ischemic cells, may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells, to critically evaluate the potential of mitochondria-based stem cell therapy for stroke.

Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD associated cardiopulmonary complications in recent mechanistic and observational studies. In this review, we discuss recent cellular and molecular mechanisms of cardiopulmonary complications in SCD and summarize the most recent evidence from clinical and laboratory studies. We emphasize the role of inflammation in the onset and progression of these complications to better understand the underlying pathobiological processes. We also discuss future basic and translational research in addressing questions about the complex role of inflammation in the development of SCD cardiopulmonary complications, which may lead to promising therapies and reduce morbidity and mortality in this vulnerable population.

Hydroperoxides (ROOH) are known as damaging agents capable of mediating mutation, while a role as signaling agents through oxidation of protein sulfhydryls that can alter cancer-related pathways has gained traction. Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme that reduces ROOH at the expense of glutathione (GSH). GPX2 is noted for a tendency of large in-creases or decreases in expression levels during tumorigenesis that leads to investigators focusing on its role in cancer. However, GPX2 is only one component of multiple enzyme families that metabolize ROOH and GPX2 levels are often very low in the context of these other ROOH reducing activities. Colorectal cancer (CRC) was selected as a case study for examining GPX2 function as colorectal tissues and cancers are sites where GPX2 is highly expressed. A case can be made for a significant impact of changes in expression levels. There is also a link between GPX2 and NADPH oxidase 1 (NOX1) from earlier studies that is seldom addressed and is discussed, presenting data on a unique association in colon and CRC. Tumor-derived cell lines are quite commonly used for pre-clinical studies involving the role of GPX2 in CRC. Generally, selection for this type of work is limited to identifying cell lines based on high and low GPX2 expression with the standard re-search scheme of overexpression in low expressing lines and suppression in high expressing lines to identify impacted pathways. This overlooks CRC subtypes among cell lines involving a wide range of gene expression profiles and a variety of driver mutation differences along with a large difference in GPX2 expression levels. A trend for low and high GPX2 expressing cell lines to segregate into different CRC subclasses, indicated in this report, suggests that choices based solely on GPX2 levels may provide misleading and conflicting results by disregarding other properties of cell lines and failing to factor in differences in potential protein targets of ROOH. CRC and cell line classification schemes are presented here that were intended to assist workers in performing pre-clinical studies but are largely unnoted in work on GPX2 and CRC. Studies are often initiated on the premise that the transition from normal to CRC is associated with up-regulation of GPX2. This is probably correct. However, the source normal cells for CRC could be almost any colon cell type, some with very high GPX2 levels. These factors are addressed in this study.

Amino acid sequences of native proteins are generally not palindromic. The protein molecule obtained as a result of reading the amino acid sequence backwards, i.e., a retro-protein, having the same amino acid composition and the same hydrophobicity profile as the native sequence may behave as a different molecule. Here we have used R4, a directed evolution product of Scfv-13, a protein that binds β-galactosidase, and report the properties of the retro-R4 (rR4). rR4 remains a binding protein and its new target is Glutamine-fructose-6-phosphate aminotransferase (GLMS), a native E. coli protein. Additionally, a tight junction immunoglobulin domain- containing membrane protein, junctional adhesion molecule A (JAMA) retro-protein retains the ability to drive cell-cell interactions. Thus, protein engineering suggests a new potential application to retro-proteins of the immunoglobulin superfamily.

Three types of double perovskite La1-xPrxBa0.5Sr0.5Co1.5Fe0.5O5+δ(x=1,0.3,0) are prepared using the EDTA-citrate method and identified as solid oxide fuel cell (SOFC) cathodes. The microstructures, as well as electrochemical performances of La1-xPrxBa0.5Sr0.5Co1.5Fe0.5O5+δ (LPBSCF) and La2NiO4-impregnated LPBSCF (LN-LPBSCF) cathodes, are investigated in detail. An optimum impregnation amount of LN-LPBSCF (LN loading of 0.64 mg/cm2) electrode exhibits relatively lower electrode polarization resistance (Rp) and better stable performance as compared to that of pure LPBSCF electrode in symmetrical SOFCs. The maximum power density of LN-LPBSCF single cells is 800 mW/cm2 at 800 °C and demonstrates good stability for 100 h in short-term testing.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare severe hereditary skin disease characterized by skin and mucosa fragility, resulting in blister formation. The most severe complication in RDEB patients is the development of cutaneous squamous cell carcinoma (SCC) leading to premature death. Multiple evidences suggest a permissive tumor micro-environment (TME) as driver of SCC development in RDEB patients. In a cohort of RDEB patients, we characterized the immune profiles of RDEB-SCCs and compared them with clinical, histopathological, and prognostic features. RDEB-SCCs were subdivided into 4 groups based on their occurrence (first onset or recurrences) and grading according to their clinical-histopathological parameters of aggressiveness. Thirty-eight SCCs from 20 RDEB patients were analysed. Five RDEB patients experienced an unfavorable course af-ter the diagnosis of the first SCC, with early recurrence or metastasis, whereas 15 pa-tients developed multiple SCCs without metastasis. High-risk primary RDEB-SCCs showed a higher neutrophil-to-lymphocyte ratio in the tumor microenvironment, and an increased proportion of neutrophil extracellular traps (NET). Additionally, citrullinated histone H3, a marker of NETs, was increased in the serum of RDEB patients with high-risk primary SCC, suggesting that this modified form of histone H3 may serve as a potential blood marker of unfavorable prognosis in RDEB-SCCs.

Members of the SOX (SRY-related HMG-box) family of transcription factors are crucial for embryonic development and cell fate determination. This review investigates the role of SOX3 in cancer, as aberrations in SOX3 expression have been implicated in several cancers, including osteosarcoma, breast, esophageal, endometrial, ovarian, gastric, hepatocellular carcinomas, glioblastoma, and leukemia. These dysregulations modulate key cancer outcomes such as apoptosis, epithelial-mesenchymal transition (EMT), invasion, migration, cell cycle, and proliferation, contributing to cancer development. SOX3 exhibits varied expression patterns correlated with clinicopathological parameters in diverse tumor types. This review aims to elucidate the nuanced role of SOX3 in tumorigenesis, correlating its expression with clinical and pathological characteristics in cancer patients and cellular models. By providing a comprehensive exploration of SOX3 involvement in cancer, this review underscores the multifaceted role of SOX3 across distinct tumor types. The complexity uncovered in SOX3 function emphasizes the need for further research to unravel its full potential in cancer therapeutics.

Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is the most prevalent form, accounting for nearly 95% of laryngeal cancer. This study evaluates the effectiveness of chemotherapy and radiation therapy combined for treating LSCC, along with exploring miR-449a as a potential biomarker for predicting treatment response and prognosis in LSCC patients. Patients and Methods: The study had 81 patients with advanced laryngeal cancer and 50 healthy controls. Chemotherapy was given for two cycles, followed by an evaluation of the response. Disease progression cases had surgical resection and radiation therapy. Positive responders had radiation therapy after a third cycle. The study also assessed miR-449a expression levels in tumor tissue, normal tissue, and serum samples from control subjects. Results: 31% achieved a complete response, and 49% showed a partial response. 31% of complete response participants maintained laryngeal integrity and vocal function. After radiation therapy, 74% of 65 patients responded completely and preserved laryngeal functions. Lower MiR-449a levels found in LSCC tissues and serum samples were correlated with aggressive tumor behavior, poor prognostic markers, and decreased survival. Conversely, elevated levels were seen in treatment responders. Conclusions: Combined chemo and radiotherapy preserve vocal function and improve outcomes in LSCC. MiR-449a is a promising indicator for diagnosis and treatment efficacy in LSCC.

Multiple sclerosis is an autoinflammatory condition that results in damage of myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing remittent disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting opportunity to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

Neuroblastoma is an embryonal tumor arising from the sympathetic central nervous system. The epidermal growth factor (EGF) plays a role in neuroblastoma growth and metastatic behavior. Recently, we have demonstrated that cathepsin D (CD) contrasts EGF-induced neuroblastoma cell growth in 2D by downregulating EGFR/MAPK signaling. Aggressive NB is highly metastatic to the bone and the brain. In the metastatic process, adherent cells detach to form clusters of suspended cells that once reached the metastatic site adhere and form secondary colonies. Whether CD involves in survival of metastatic NB clones is not known. Therefore, in this study we addressed how CD differentially affects cell growth in suspension versus adherent condition. To mimic tumor heterogeneity, we co-cultured transgenic clones silenced for or overexpressing CD. We compared the growth kinetics of such mixed clones in 2D and 3D models in response to EGF, and we found that Over CD clone was advantaged for the growth in suspension, while the CD knocked-down clone was favored for the adherent growth as 2D. The fact that CD plays a dual role in cancer cell growth in 2D and 3D conditions indicates that during clonal evolution subclones expressing different level of CD may arise, which confers survival and growth advantages depending on the metastatic step. Whether CD involves in survival of metastatic NB clones is not known. We propose that epigenetic regulation of CD expression could be an additional strategy to prevent NB metastases.

Primary bone lymphoma of the scapula is a rare tumor that usually causes local pain. Presented patient suffered for two years from paresthesia, tingling, numbness, and edema of the little and ring finger. The 45-year-old man underwent several radiological and neurological assessments of the palm, elbow and neck prior to radiographs revealing the tumor of the left shoulder. Once diffuse large B cell lymphoma was confirmed, immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and methylprednisolone (R-CHOP) started. The treatment was accompanied by antiviral treatment with lamivudine due to positive hepatitis B virus serology and with bisphosphonate treatment for the prevention of bone resorption. Once immunochemotherapy was finished, the treatment was supplemented by radiotherapy of the shoulder. After more than three years of accomplishing remission, the patient had an ischemic stroke manifesting with right-sided hemiparesis. Following the physical therapy, the patient is currently in the process of evaluation for thrombophilia, as well as further cardiac assessment due to the positive transcranial Doppler bubble test setting high suspicion for the presence of patent foramen ovale.

[Objective] To investigate the expression of ALDH2 in hepatocellular carcinoma and its correlation with macrophage infiltration and with the activation of specific subtypes of macrophages. [Methods] Transcriptome and clinical data from patients with hepatocellular carcinoma were downloaded from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases and analyzed and collated using R and Perl software. In the TCGA hepatocellular carcinoma dataset, the Wilcoxon test was used to identify macrophage activation-related gene sets that show differential expression between hepatocellular carcinoma and normal tissues. Single-cell sequencing combined with bulk data was used to analyze macrophage infiltration of hepatocellular carcinoma immune cells and the activation and recruitment of different subtypes of macrophages. Single-factor Cox regression and minimum absolute convergence and selection operator (Lasso) were used to identify survival-related genes and construct prognostic models of HCC. The patients were divided into two groups based on their model scores. The Wilcoxon test was used to identify differentially expressed genes (DEGs) between the two groups, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of the DEGs were performed. Single-sample gene set enrichment analysis (ssGSEA) was performed to explore the possible mechanism underlying the differences in prognosis. The reliability of the model was verified using the ICGC hepatocellular carcinoma dataset. A Kaplan‒Meier curve was constructed and used to analyze the influence of macrophage activation-related gene expression on survival and prognosis in patients with hepatocellular carcinoma. The log-rank test and the independent t test were used to analyze survival time data and to compare immune cell infiltration in the two groups. [Results] In a comparison of hepatocellular carcinoma and paracancerous tissues, the expression of six of 137 macrophage activation-related genes (ALDH2, CCNB2, CYP2C9, CYP3A4, F9 and KLKB1) was found to be significantly correlated with overall survival time (OS) in patients with hepatocellular carcinoma. Based on this finding, a prognosis assessment model for hepatocellular carcinoma was constructed. The OS of the patients in the high-scoring group was significantly shorter than the OS of the patients in the low-scoring group (P<0.05), and the model predicted the prognosis of patients with hepatocellular carcinoma independently of sex, age, tumor grade and stage. The area under the receiver operating characteristic (ROC) curve of the model used to predict 1-, 2-, and 3-year survival was greater than 0.7 in both the test set and the validation set. GO enrichment of DEGs between the high- and low-scoring groups of the model suggested that the DEGs are mainly related to immune function. GSEA suggested that the tumor-infiltrating immune cells in the high-scoring group were macrophages, Th2 cells and Treg cells and showed that the number of tumor-infiltrating immune cells, including NK cells, was lower in the high-scoring group than in the low-scoring group. With respect to immune function, the immune checkpoint of the high-scoring group was higher than that of the low-scoring group. Single-cell sequencing data indicated the recruitment of B cells, M0 cells, M1 cells and M2 cells to the hepatocellular carcinoma microenvironment and suggested that ALDH2 regulates related signaling pathways in a way that promotes the differentiation of macrophages into M2-type macrophages. [Conclusion] M2-type macrophages are the dominant type of macrophages associated with immune infiltration in hepatocellular carcinoma. The macrophage-associated activation gene ALDH2 activates the macrophage polarization signaling pathway and negatively regulates the differentiation of macrophages into M2-type macrophages.

Oral squamous cell carcinoma (OSCC) remains an under-studied and significant global cancer killer and dismal survival rates have not changed in decades. A better understanding of the molecular basis of OSCC progression and metastasis is needed to develop new approaches for treating this disease. The supportive network surrounding cancer tumor cells known as the tumor microenvironment (TME) has gained increasing interest lately since it performs essential pro-tumorigenic functions. Cancer-associated fibroblasts (CAFs) are one of the main cell types in the TME and are known to play a key role in influencing the biological behavior of tumors. CAFs present a heterogeneity both in phenotype as well as functions, leading to the suggestion of different CAF subtypes in several cancer forms. The task to subtype CAFs in OSCC has however just begun and there is today no united way of subtyping CAFs in this disease. This review aims to define the features of CAFs and to summarize CAF subtype research in OSCC including aspects as disease prognosis and therapeutic opportunities.

The research presents a novel synthetic photosensitizer for photodynamic therapy (PDT) of malignant tumors - meso-tetra(3-pyridyl) bacteriochlorin, which absorbs at 747 nm (in the long-wavelength region of the spectrum) and is stable when stored in the dark. H2Py4BC demonstrates pronounced photoinduced activity in vitro against tumor cells of various genesis (IC50 varies from 21 to 68 nM for НЕр2, EJ, S37, CТ26, and LLC cultured cells) and provides in vivo pronounced antitumor efficacy in the treatment of mice bearing small or large S37, Colo26, and LLC metastatic tumors, as well as in the treatment of rats bearing RS-1 liver cholangioma. As a result, total regress of primary tumor nodules and cure of 40 to 100% of the animals were proved by the experiment criteria, MRI, and histological analysis. Meso-tetra(3-pyridyl) bacteriochlorin quickly penetrates and accumulates in the tumor tissue and internal organs of mice, and after 24 hours 80% of the dye is excreted from skin as well as 87% - 92% from liver, kidneys, and spleen.

The development of the ovarian antral follicle is a complex, highly regulated process. Oocytes orchestrate and coordinate the development of mammalian ovarian follicles, and the rate of follicular development is governed by a developmental program intrinsic to the oocyte. Characterizing oocyte signatures during this dynamic process is critical for understanding oocyte maturation and follicular development. Although the transcriptional signature of sheep oocytes matured in vitro and preovulatory oocytes have been previously described, the transcriptional changes of oocytes in antral follicles have not. Here, we used single-cell transcriptomics (SmartSeq2) to characterize sheep oocytes from small, medium, and large antral follicles. We characterized the transcriptomic landscape of sheep oocytes during antral follicle development, identifying unique features in the transcriptional atlas, stage-specific molecular signatures, oocyte-secreted factors, and transcription factor networks. Notably, we identified specific gene and signaling pathways in each antral follicle stage that may reflect oocyte quality and in vitro maturation competency. Additionally, we discovered key biological processes that drive the transition from small to large antral follicles, revealing hub genes involved in follicle recruitment and selection. Thus, our work provides a comprehensive characterization of the single-oocyte transcriptome, filling a gap in the mapping of the molecular landscape of sheep oogenesis. We also provide key insights into the transcriptional regulation of the critical stages of antral follicular development, which is essential for understanding how the oocyte orchestrates follicular development.

Chromium poisoning strongly influences the performance of solid oxide fuel cell (SOFC) stacks. A three-dimensional, time-dependent, computational fluid dynamics model of a single channel of a F10 SOFC stack in Forschungszentrum Jülich GmbH is developed to investigate chromium poisoning for different stack designs, temperatures and absolute air humidities. The model takes into account both chemical and electrochemical mechanisms of chromium poisoning and is able to predict the spatial distribution of SrCrO4 and Cr2O3. The voltage degradation over 100 kh can be simulated quantitatively. According to the simulation results, chromium poisoning is almost eliminated by the application of the protective coating fabricated by the atmospheric plasma-spraying (APS) technology. Besides, with the help of the APS protective coating, operating a SOFC stack with less dehumidified air at 650 oC is possible according to the simulation.

Recent successes in the field of evolutionary cancer cell biology (ECCB) have brought to a head two of the most important controversies regarding cancer origin. The first concerns the question of whether carcinogenesis is initiated only by genetic alterations, mutations, and driver genes, as the mutational theory teaches. The ECCB, claims that a large number of polyploidy-related cancers (PGCC cancers) are not due to mutations, but rather to inadequate ancient repair mechanisms used by DNA-damaged stem cells for their repair. Somatic mutations are merely secondary. The second controversy, described in the previous article, concerns the non-mutational theory itself: Are non-mutational polyploid cancers an atavism - as previously thought - or rather the effect of an ancient gene regulatory network aGRN that controls genome reprogramming in precancerous DNA-damaged cells as well in the transformed cells. Finally, the unicellular gene module of cancer, of which the aGRN is a part, has evolved along with the multicellular genome during the last 1000 My of evolution. and non-mutated cancer cell systems are under the control of the aGRN. The atavistic theory relies on phylostratigraphic evidence to determine the age of cancer genes. It states that most cancer-like genes arose during the transition period from unicellularity to multicellularity, but also during the early metazoan era. In our opinion, the atavistic theory is flawed and suffers from many misunderstandings. It provides little insight into the origin and coevolution of the cancer cell system and its control by the ancient gene regulatory network aGRN.

Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been associated with poor cardiovascular disease (CVD) outcomes, supporting its role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1 release or interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs), but the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from a inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β overexpression in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest that diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease particularly in diabetes, holds significant therapeutic potential.

: Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions which would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. For the 36 patients identified, best overall response (BOR) to ICI was partial response (PR) in 41.7%, complete response (CR) in 27.8%, and stable disease in (SD) 13.9% of patients. The PFS rate at 1 year was 63%; median PFS was not reached (NR). The median OS was 38.6 months (95% CI 25.4-NR). Immune compromised patients, ECOG performance 2-3, and age ≥75 years were not significantly associated with PFS or OS. IrAE grade 3-4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefit with ICI regardless of age, immune status or ECOG performance status.

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations, and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 enters the host by infecting nasal ciliated cells. Then, the virus can spread towards the oropharyngeal cavity and the pulmonary tissues. The antiviral adaptive immunity is promptly induced in response to virus detection, with virus-specific T lymphocytes appearing before antiviral antibodies. Both breadth and potency of the antiviral CD8+ T cell immunity have a key role in containing viral spread and disease severity. Current anti-SARS-CoV-2 vaccines do not impede the virus replication in the upper respiratory tract, and there is consensus on the fact that the best potency of the antiviral immune response in both blood and upper respiratory tract can be reached upon infection in vaccinees (i.e., breakthrough infection). However, whether the antiviral CD8+ T cells developing in response to the breakthrough infection in the upper respiratory tract diffuse to the lungs also is still largely unknown. To fill the gap, we checked the CD8+ T cell immunity elicited after infection of K18-hACE2 transgenic mice both 3 weeks and 3 months after anti-Spike vaccination. The virus-specific CD8+ T cell immunity was monitored in both blood and the lungs before and after infection. By investigating the de novo generation of CD8+ T cells specific for SARS-CoV-2 viral proteins, we found that both membrane (M) and/or nucleocapsid (N)-specific CD8+ T cells were induced at comparable levels in blood of both unvaccinated and vaccinated mice. Conversely, N-specific CD8+ T cells were readily found in the lungs of control mice, but were either rare or absent in those of vaccinated mice. These results support the idea that the hybrid cell immunity developing after asymptomatic/mild breakthrough infection strengthens the antiviral cell immunity at lungs only marginally, implying that the direct exposition of the viral antigens is required for the induction of an efficient antiviral cell immunity in the lungs.

Post-translational modifications (PTMs) represent a cornerstone in the complexity of the proteome, significantly contributing to diversifying protein structure and function. PTMs can significantly influence protein function, stability, localization, and interactions with other molecules. Therefore, it is important when choosing a protein expression system to ensure the precise incorporation of PTMs during protein synthesis, which is paramount for producing biologically active proteins. Cell-free protein synthesis (CFPS) system has emerged as a powerful protein synthesis platform and research toolkit in synthetic biology. The open nature of the system allows the reaction environment to be tailored to any protein of interest to promote specific PTMs, thus allowing for the production of a protein with the desired modifications. This review presents various PTMs achieved in the CFPS systems, providing insights into the current challenges, successes, and future prospects.

Blood-based circulating cell free DNA(cfDNA) detection offers a non-invasive and easily accessible way for early cancer detection. Despite the extensive utility of cfDNA, there are still many challenges to develop the clinical biomarkers. For example, cfDNA with genetic alterations often compose a small portion of the DNA circulating in plasma, which can be confounded by cfDNA contributed by normal cells. Therefore, filtering out the potential false-positive cfDNA mutations from health population will be important for the cancer-based biomarkers. Additionally, many low-frequency genetic alterations are easily overlooked in small amount of cfDNA-based cancer test. We hypothesize that, the combination of diverse types of cancer studies on cfDNA can provide us a new insight to identify low-frequency genetic variant across cancer types for early clinical detection of cancers. By building a standardized computational pipeline for 1358 cfDNA samples across seven cancer types, we prioritize 129 shard genetic variants in the major cancer types. Further functional analysis of the 129 variants found that they are mainly enriched in ribosome pathways such as cotranslational protein targeting to membrane, some of which are tumor suppressor, oncogene and related to cancer initiation. In summary, our integrative analysis revealed the important roles of ribosome proteins as the common biomarkers in early cancer diagnosis.

Cell-free massive multiple input multiple output (MIMO) has the potential of providing joint services including joint initial access, efficient clustering of access points (APs) and pilot allocation to user equipments (UEs) over large coverage area with reduced interference. In cell-free massive MIMO, large coverage area corresponds to provision and maintenance of scalable quality of service requirements for infinitely large number of UEs. The research in cell free massive MIMO is mostly focused on time division duplex mode due to availability of channel reciprocity which aids in avoiding feedback overhead. However, frequency division duplex (FDD) protocol still dominates the current wireless standards and the provision of angle reciprocity aids in reducing this overhead. The challenge of providing a scalable cell-free massive MIMO system in FDD setting is also prevalent, since computational complexity regarding signal processing tasks such as channel estimation, precoding/combining and power allocation, becomes prohibitively high with increase in number of UEs. In this work, we consider an FDD based scalable cell-free network with angular reciprocity and dynamic cooperation clustering approach. We have proposed scalability for our FDD cell-free and perform comparative analysis with reference to channel estimation, power allocation and precoding/combining techniques. We present expressions for scalable spectral efficiency, angle based precoding/combining schemes and provide comparison of overhead between conventional and scalable angle based estimation as well as combining schemes. Simulations confirm that the proposed scalable cell-free network based on FDD scheme outperforms the conventional matched filtering scheme based on non-scalable precoding/combiming schemes. The angle based LP-MMSE in FDD cell-free network provides 14.3% improvement in spectral efficiency and 11.11% improvement in energy efficiency compared to non-scalable MF scheme.

CAR-T therapy has achieved considerable treatment success in hematologic tumors by using patient derived autologous αβ T cells. There is an impetus to broaden the applicability of this approach by using a third-party donor derived CAR-T cell product which has a potent anti-tumor function but a constrained GVHD property. In this study, CAR-T cells were prepared from Vγ9Vδ2 T cells expanded by using a novel prodrug PTA and their anti-tumor functions were assessed in conjunction with persistency, localization, and phenotype. γδ T cells were successfully transduced with a CAR specific to CEA with signaling domains of CD3ζ and CD28 (CEA.CAR-γδ T cells), and exhibited potent tumor killing function in vitro. In a xenograft mouse model, CEA.CAR-γδ T cells suppressed CEA+ tumor growth though a limited time window. CEA.CAR-γδ T cells persisted and accumulated in the tumor even after tumor progression, however, ex vivo analysis revealed that those recovered at different time points from PBMC, spleen and tumors gradually lost tumor reactivity as assessed by IFN-γ production. Provision of GITR co-stimulation enhanced anti-tumor function of CEA.CAR-γδ T cells, the result of which imposes additional measurers to be adopted in CAR-γδ T cells for an allogeneic adoptive immunotherapy.

Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported melanoma actives that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2. In a separate study, we reported that these compounds were non-toxic to Balb/C mice at 50 mg/kg suggesting their utility in in vivo studies. In the present study, we aimed to determine the therapeutic potential of these compounds by testing them in A375 cell-line derived xenograft in nu/nu mice. Animals were randomized into four groups (n=12/group) to receive subcutaneous administration of vehicle, 10 mg/kg vemurafenib, and 25 mg/kg 2155-14 and 2155-18 three times per week for 15 days along with a control group. The results revealed that both 2155-14 and 2155-18 significantly decreased the growth of A375 tumors, which was comparable to vemurafenib. These results were confirmed by tumor volume, weight, and histopathological examination. In conclusion, these results suggest a therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2.

Cell therapy has used mesenchymal stem cells (MSCs) which in cell culture are multipotent progenitors, capable of producing a variety of cells limited to the mesoderm layer. There are two types of MSCs sources: 1) adult MSCs, which are obtained from the bone marrow, adipose tissue, peripheral blood, and dental pulp; and 2) neonatal tissue-derived MSCs, obtained from extra-embryonic tissues such as the placenta, amnion, and umbilical cord. Until April 2023, there are 1,120 registered clinical trials using MSCs therapies worldwide, but there are only 12 MSCs therapies that have been approved by regulatory agencies for commercialization. Nine of the twelve approved MSCs products are from Asia, with South Korea being the country with the most approved therapies. In the future, MSCs will play an important role in the treatment of many diseases. However, there are many issues to deal with before their application and usage in medical practice. Some strategies have been proposed to face these problems with the hope of reaching the objective of applying these MSCs therapies at optimal therapeutic levels.

ATP-dependent chromatin remodeling complexes are involved in nucleosomes sliding, eviction and/or histone variants incorporation into chromatin to facilitate several cellular and biological processes, including DNA transcription, replication and repair. The DOM/TIP60 chromatin remodeling complex of Drosophila melanogaster contains 18 subunits, including the DOMINO (DOM), an ATPase that catalyzes the ex-change of the canonical H2A with its variant (H2A.V); and TIP60, a lysine-acetyltransferase that acetylates H4, H2A and H2A.V histones. In the last decade, different experimental evidence showed that ATP-dependent chromatin remodeling factors, in addition to their role in chromatin organization, have a functional relevance in cell division. In particular, emerging studies suggested direct roles of ATP-dependent chromatin remodeling complex subunits in controlling mitosis and cytokinesis in both humans and D. melanogaster. However, little is known about their possible involvement during meiosis Meiotic chromosomes non-disjunction led to aneuploid offspring, which are often inviable/poorly viable or sterile due to gene dosage imbalance. Therefore, studying the role of DOM/TIP60 complex in D. melanogaster meiosis can provide new insights on our understanding of the molecular mechanisms underlying cell division control in gametogenesis.

Mesenchymal stem cells (MSCs) have the tumor-homing capacity, and therefore MSCs are considered to be a promising drug delivery carrier for cancer therapy. To maintain the viability and activity of MSCs, anti-cancer drugs are preferably modified on the surface of MSCs, rather than directly introduced into MSCs. In this study, we attempted to construct surface-modified MSCs with liposomes as a drug carrier by using magnetic anionic liposome/atelocollagen complexes we previously developed. We observed that large-sized magnetic anionic liposome/atelocollagen complexes were abundantly associated with MSCs via electrostatic interactions under a magnetic field, and its cellular internalization was lower than that of the small-sized complexes. Moreover, the complexes with higher atelocollagen concentration showed lower cellular internalization than the complexes with lower atelocollagen concentration. Based on these results, we succeeded in the efficient surface modification of MSCs with liposome by using large-sized magnetic anionic liposomes complexed with high concentration of atelocollagen. The constructed liposome-modified MSCs showed comparable proliferation rate and differentiation potential to unmodified MSCs. Furthermore, liposome-modified MSCs efficiently adhered to vascular endothelial cells and migrated toward the conditioned medium from cancer cells in vitro. These findings suggest that liposome-modified MSCs could serve as an efficient cell-based drug carrier for tumor targeted delivery.

Altered expression of microRNAs (miRNAs) after spinal cord injury (SCI) has been described as being responsible for the main secondary responses, such as apoptosis. X-linked inhibitor apoptosis protein (XIAP) is a key apoptotic component involved in the progression of apoptotic programmed cell death. Several regulators have been described to modulate the XIAP's function, including the post-transcriptional regulator's miRNAs. The main aim of the present work is to identify miRNAs with altered expression after SCI which can regulate XIAP expression. Our bioinformatic analyses identified several candidate miRNAs that may regulate XIAP, among which miR-199a-5p may be involved in the downregulation of XIAP after SCI. Gene reporter assays and in vitro analyses in the neural C6 cell line confirmed the targeting of miR-199a-5p on the 3-UTR of the rat XIAP and its post-transcriptional regulation of XIAP protein level, but not at mRNA level. Analyses in a rat model of SCI revealed a trend towards increased expression of miR-199a-5p and a decrease in XIAP protein level at 3 days after injury. Finally, using a specific fluorescent in situ hybridization (FISH) probe for miR-199a-5p, we characterized the expression pattern of miR-199a-5p in cells of uninjured and rat-contused spinal cords. These findings provide new insights into apoptotic miRNA-mediated mechanisms after SCI, which will help us develop therapeutic strategies based on miRNAs for treating SCI.

We evaluated hexadecyltrimethylammonium bromide (HTAB) for use in radio frequency (RF) applications in which liquid crystals (LCs) are used in layered structures that have various cell gap conditions. HTAB is a surfactant that can self-align vertically on the surface of indium tin oxide (ITO) substrates, and can induce homeotropic alignment of the LCs. For implementing RF devices with HTAB and LCs, we should consider limitations caused by the design conditions which are different from conventional liquid crystal displays such as cell gap. We quantified the concentration of HTAB ([HTAB]) that is necessary to form and maintain a sufficiently dense vertical alignment of 5CB (4-Cyano-4'-pentylbiphenyl). The required [HTAB] for full-homeotropic alignment was proportional to the cell gap until it was too large to support the transfer of the surface alignment to the LC, due to the weak anchoring nature of HTAB. We also showed the phase-change characteristic of the LC mixture depended on [HTAB] for the design of RF devices driven by light or heat. This work may help to guide the development of new approaches to designing efficient RF devices that use LCs.

Separation and detection of cells and particles in a suspension are essential for various applications, including biomedical investigations and clinical diagnostics. Microfluidics realizes the miniaturization of analytical devices by controlling the motion of a small volume of fluids in microchannels and microchambers. Accordingly, microfluidic devices have been widely used in particle/ cell manipulation processes. Different microfluidic methods for particle separation include dielectrophoretic, magnetic, optical, acoustic, hydrodynamic, and chemical techniques. Dielectrophoresis (DEP) is a method for manipulating polarizable particles’ trajectories in non-uniform electric fields using unique dielectric characteristics. It provides several advantages for dealing with neutral bioparticles owing to its sensitivity, selectivity, and noninvasive nature. This review provides a detailed study on the signal-based DEP methods that use the applied signal parameters, including frequency, amplitude, phase, and shape for cell/particle separation and manipulation. Rather than employing complex channels or time-consuming fabrication procedures, these methods realize sorting and detecting the cells/particles by modifying the signal parameters while using a simple device. In addition, these methods can significantly impact clinical diagnostics by making low-cost and rapid separation possible.

The production of vaccines of biological origin presents a tremendous challenge for researchers. In this context, animal cell cultures are an excellent alternative for the isolation and production of biologicals against several viruses since they have an affinity with viruses and a great capacity for their replicability. Different variables have been studied to know the system's ideal parameters, allowing it to obtain profitable and competitive products. Consequently, this work focuses its efforts on evaluating an alternative for producing an anti-influenza biological from MDCK cells using SuperPro Designer v8.0 software. The process uses the DMEN culture medium supplemented with nutrients as raw material for cell development; the MDCK cells were obtained from a potential scale-up with a final working volume of 500 L, four days of residence time, inoculum volume of 10%, and continuous working mode with up to a total of 7400 h/Yr of work. The scheme has the necessary equipment for the vaccine's production, infection, and manufacture with yields of up to 416,698 units/h. In addition, it was estimated to be economically viable to produce recombinant vaccines with competitive prices of up to 0.31 USD/unit.

Abstract: Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53‑dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53‑dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on p53. Furthermore, p53 does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, p53 accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are p53-independent. In embryonic fibroblasts, p53 induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage.

Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.

PG9, PG16, PGT121, and PGT145 antibodies were identified from culture media of activated memory B-cells of an infected donor and shown to neutralize many HIV-1 strains. Since HIV-1 spreads via both free virions and cell-cell fusion, we examined the effect of the antibodies on HIV-1 Env-mediated cell-cell fusion. Clone69TRevEnv cells that express Env in the absence of tetracycline were labeled with Calcein-AM Green, and incubated with CD4+ SupT1 cells labeled with CellTrace™ Calcein Red-Orange, with or without antibodies. Monoclonal antibodies PG9, PG16, 2G12, PGT121, and PGT145 (at up to 50 µg/mL) had little or no inhibitory effect on fusion between HIV-Env and SupT1 cells. By contrast, Hippeastrum hybrid agglutinin completely inhibited fusion. Our results indicate that transmission of the virus or viral genetic material would not be inhibited by these broadly neutralizing antibodies. Thus, antibodies generated by HIV-1 vaccines should be screened for their inhibitory effect on Env-mediated cell-cell fusion.

Cancer immunotherapies are gaining a large popularity and many of them have been approved as standard second-line or in some cases even as first-line treatment for a wide range of cancers. However, immunotherapy has not shown a clinically relevant success in glioblastoma (GBM), principally due to the brain’s “immune-privileged” status and the peculiar tumor microenvironment (TME) of GBM featured by lack of presence of tumor-infiltrating lymphocytes and the establishment of immunosuppressive mechanisms. Emerging evidence has highlighted the key role played by innate immune cells in immunosurveillance and in initiating and driving immune responses against GBM. Immunogenic cell death (ICD) is a promising approach to elicit direct activation of the innate immune system by inducing in target cancer cells the expression of molecular signatures recognized through a repertoire of innate immune cell pattern recognition receptors (PRRs) by effector innate immune cells. Herein, we explored local mild thermal treatment, generated by using ultrasmall (size ~ 17 nm) cubic-shaped iron oxide nanoparticles exposed to an external alternating magnetic field (AMF), to induce ICD in U87 glioblastoma cells. In accordance with what has been previously observed with other types of tumors, we found that mild hyperthermia modulates the immunological profile of U87 glioblastoma cells by inducing stress-associated signals leading to enhanced phagocytosis and killing of U87 cells by macrophages. Finally, we demonstrated that mild magnetic hyperthermia has a modulatory effect on the expression of inhibitory and activating NK cell ligands on target cells. Interestingly, alteration in the expression of NK ligands, caused by mild hyperthermia treatment, in U87 glioblastoma cells, increased their susceptibility to NK cell killing and NK cell functionality. The overall findings demonstrate that mild magnetic hyperthermia stimulates ICD and sensitizes GBM cells to NK-mediated killing by inducing the upregulation of specific stress ligands, providing a novel immunotherapeutic approach for GBM treatment, with potential to synergize with existing NK cell-based therapies thus improving their therapeutic outcomes.

Visceral Leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we have designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from 3 previously identified antigen genes of Leishmania donovani from our lab, by immune-informatic approach using IFNepiotpe, NET-MHC-1 and NET MHC-2 webservers. We have tested the protective potential of these three multiepitope proteins as vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th-1 biased protective immune response in-vivo in a hamster model of experimental visceral Leishmaniasis, with one of the candidates inducing a sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of designed candidates.

Candida albicans is a major fungal pathogen of humans, accounting for 15% of nosocomial infections with an estimated attributable mortality of 47%. C. albicans is usually a benign member of the human microbiome in healthy people. Under constant exposure to highly dynamic environmental cues in diverse host niches, C. albicans has successfully evolved to adapt to both commensal and pathogenic lifestyles. The ability of C. albicans to undergo a reversible morphological transition from yeast to filamentous forms is a well-established virulent trait. Over the past few decades, a significant amount of research has been carried out to understand the underlying regulatory mechanisms, signaling pathways, and transcription factors that govern the C. albicans yeast-to-hyphal transition. This review will summarize our current understanding of well-elucidated signal transduction pathways that activate C. albicans hyphal morphogenesis in response to various environmental cues and the cell cycle machinery involved in the subsequent regulation and maintenance of hyphal morphogenesis.

Bone marrow derived adult human mesenchymal stem cells (hMSCs) possess therapeutic qualities that enable them to enhance wound repair. However, the mechanisms by which this occurs remains poorly understood. Basic mechanisms may include the directed migration of delivered cells to target sites and/or the production and release of soluble factors that act at a distance. Allogeneic and even xenogeneic cells may effectively participate in wound repair. Labeled hMSCs were delivered to full-thickness skin wounds that were created in immunologically competent mice. The delivery occurred on day 3 post-wounding using two different carriers; one which released cells and one which retained cells. The fates of the delivered cells were tracked for up to 25 days. During this period, released cells migrated as a tight cohort deep into the wound to reach the subdermal vascular plexus. Simultaneously, enhanced formation of granulation tissue was evident. This migration of hMSCs was not essential in that enhanced granulation tissue formation and wound contraction occurred when cells were retained in the carrier matrix. This provided further evidence for the release of therapeutic factors by hMSCs to sites of injury.

The cellular model we teach and have theorized assumes that the cell is the basic unit of multicellular living beings. This fundamental element has been the subject of many theories concerning its properties and the exchanges that exist with its environment. In this article, we demonstrate that certain functional aspects, in particular the electrical aspects related to diffusion, have not been correctly assumed or that certain initial conditions have been purely ignored and are in contradiction with physics, chemistry and thermodynamics.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells and CAR T cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T cells and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load and tumor burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenging technology of regenerative medicine for damaged myocardium. Efforts have been focused on improving the efficiency by understanding fundamental mechanisms. One of the major challenges is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed that a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in the primary cell culture of tissues. Both forskolin, which activates adenylyl cyclase and increases cAMP concentration, and TGFbeta inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of iCM reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblast could improve their plasticity for reprogramming, and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold amount of reprogrammed iCMs compared to that of untreated control cells. In conclusion, suppression of cAMP/PKA/CREB signaling axis improves fibroblast plasticity for direct cardiac reprogramming.

Multicellularity evolved repeatedly in the history of life, but how it unfolded varies greatly between different lineages. Dictyostelid social amoebas offer a good system to study the evolution of multicellular complexity, with a well-resolved phylogeny and molecular genetic tools being available. We compare the life cycles of the Dictyostelids with closely related amoebozoans to show that complex life cycles were already present in the unicellular common ancestor of Dictyostelids. We propose frost resistance as an early driver of multicellular evolution in Dictyostelids and show that the cell signalling pathways for differentiating spore and stalk cells evolved from that for encystation. The stalk cell differentiation program was further modified, possibly through gene duplication, to evolve a new cell type, cup cells, in Group 4 Dictyostelids. Studies in various multicellular organisms including Dictyostelids, volvocine algae, and metazoans suggest as a common principle in the evolution of multicellular complexity that unicellular regulatory programs for adapting to environmental change serve as “proto-cell types” for subsequent evolution of multicellular organisms. Later, new cell types could further evolve by duplicating and diversifying the “proto-cell type” gene regulatory networks.

Growing evidence has revealed the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of putatively disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment of 26 genes in germline protein truncating variants (PTVs), affecting cell signaling (MET, JAK2, ANGPT2), energy metabolism (ACO1) and nucleic acid metabolism and repair pathways (NT5E, DCK). Interestingly, some of these variants were restricted to either chronic lymphocytic leukemia (CLL) (i.e., ANGPT2 and AKR1C3) or B-cell lymphoma cases (PNMT, TPT1 and IGHMBP2). Additionally, we detected 1,675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were PTVs. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A and TSC2. Homozygous or compound heterozygous variants were detected in 28 cases; and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D and MYC. Finally, we observed that variants in the helicase gene WRN were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis, clinical presentation and disease outcome of B-cell lymphoid neoplasms.

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found in silico evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway through interaction with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51 binding sites in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-binding sites in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway were significantly occupied by RAD51 in all four cell lines. Taken together, these results predicted a novel role of RAD51 that had not been addressed previously, and provided evidence that RAD51 could possibly be involved in regulating genes associated with the autophagy pathway, through interaction with E-box binding proteins.

This review provides a snapshot of chronic bacterial infections through the lens of Burkholderia pseudomallei; detailing its ability to establish multi-nucleated giant cells (MNGC) within the host, leading to the formation of pyogranulomatous lesions. We explore the role of MNGC in melioidosis disease progression and pathology by comparing the similarities and differences of melioidosis to tuberculosis, outlining the concerted events in pathogenesis that lead to MNGC formation, discussing the factors that influence MNGC formation and how they fit into clinical findings reported in chronic cases. Finally, we speculate about future models and techniques that can be used to delineate the mechanisms of MNGC formation and function.

A major parameter controlling the extent and rate of oral drug absorption is permeability through the lipid bilayer of intestinal epithelial cells. Here, a biomimetic artificial membrane permeability assay (Franz-Bampa) was validated using Franz cells apparatus. Both high and low permeability drugs (metoprolol and mannitol, respectively) were used as external standards. Biomimetic properties of Franz-Bampa were also characterized by electron paramagnetic resonance spectroscopy (EPR). Moreover, the permeation profile for the 14 BCS class I-IV drugs cited in the FDA guidance (including other drugs as acyclovir, cimetidine, diclofenac, ibuprofen, piroxicam, and trimethoprim) were measured across Franz-Bampa. Apparent permeability (Papp) was compared to literature fraction dose absorbed in humans (Fa%). Papp in Caco-2 cells and Corti artificial membrane were likewise compared to Fa% to assess Franz-Bampa performance. Mannitol and metoprolol Papp values across Franz-Bampa were lower (3.20 x 10-7 and 1.61 x 10-5 cm/s, respectively) than those obtained across non-impregnated membrane (2.27 x 10-5 and 2.55 x 10-5 cm/s, respectively), confirming lipidic barrier resistivity. Performance of the Franz cell permeation apparatus using an artificial membrane showed similar log linear correlation (R2 = 0.664) with Fa%, as seen for Papp in Caco-2 cells (R2 = 0.805). Data support the validation of the Franz-Bampa method for use during drug discovery process.

Importance: The COVID-19 pandemic is currently accelerating. Patients with locally advanced non-small cell lung cancer (LA-NSCLC) may require treatment in locations where resources are limited and the prevalence of infection is high. Patients with LA-NSCLC frequently present with comorbidities that increase the risk for severe morbidity and mortality from COVID-19. These risks may be further increased by treatments for LA-NSCLC. Observation: We present expert thoracic oncology multidisciplinary (radiation oncology, medical oncology, surgical oncology) consensus of alternative strategies for the treatment of LA-NSCLC during a pandemic. The overarching goals of these approaches are to reduce the number of visits to a healthcare facility, reduce the risk of SARS-CoV-2 exposure, and attenuate the immunocompromising effects of lung cancer therapies. Patients with resectable disease can be treated with definitive non-operative management if surgical resources are limited or the risks of perioperative care are high. Non-operative options include chemotherapy, chemoimmunotherapy, and radiation therapy with sequential schedules. The order of treatments may be based on patient factors and clinical resources. Whenever radiation therapy is delivered without concurrent chemotherapy, hypofractionated schedules are appropriate. For patients who are confirmed to have COVID-19, usually cancer therapies may be withheld until symptoms have resolved with negative viral test results. Conclusions and Relevance: The risk of severe treatment-related morbidity and mortality is significantly elevated for patients undergoing treatment for LA-NSCLC during the COVID-19 pandemic. Adapting alternative treatment strategies as quickly as possible may save lives and should be implemented through communication with the multidisciplinary cancer team.

The most prevalent Ca2+-buffer proteins (CaBPs: parvalbumin—PV; calbindin—CaB; calretinin—CaR) are widely expressed by various neurons throughout the brain, including the retinal ganglion cells (RGCs). Even though their retinal expression has been extensively studied, a coherent assessment of topographical variations is missing. To examine this, we performed immunohistochemistry (IHC) in the mouse retina. We found variability in the expression levels and cell numbers for CaR, with stronger and more numerous labels in the dorso-central area. CaBP+ cells contributed to RGCs with all soma sizes, indicating heterogeneity. We separated 4-9 RGC clusters in each area based on expression levels and soma sizes. Besides the overall high variety in cluster number and size, the peripheral half of the temporal retina showed the greatest cluster number, indicating a better separation of RGC subtypes there. Multiple labels showed that 39% of the RGCs showed positivity for a single CaBP, 30% expressed two CaBPs, 25% showed no CaBP expression and 6% expressed all three proteins. Finally, we observed an inverse relation between CaB and CaR expression levels in CaB/CaR dually- and CaB/CaR/PV triple labeled RGCs, suggesting a mutual complementary function.

We remind about the dogma initially established with the nucleic acid double helix, i.e. the DNA structure as the primary source of life. However, we bring into the discussion those additional processes that were crucial to enable life and cell evolution. Studying chemosensory proteins (CSPs) and odor binding proteins (OBPs) of insects, we have found a high level of pinpoint mutations on the RNA and peptide sequences. Many of these mutations are found to be tissue-specific and induce subtle changes in the protein structure, leading to a new theory of cell multifunction and life evolution. Here, attention is given to RNA and peptide mutations in small soluble protein families known for carrying lipids and fatty acids as fuel for moth cells. A new phylogenetic analysis of mutations is presented and provides even more support to the pioneer work, i.e. the finding that mutations in binding proteins have spread through moths and various groups of insects. Then, focus is given to specific mechanisms of mutations that are not random, change α-helical profilings and bring new functions at the protein level. In conclusion, RNA and peptide mutations are not seen as representative of a multitude of diseases, but rather as an alternative way by which protocells developed to acquire multifunction and totipotency. This provides a basis for the theory of RNA/peptide mutations for birth and evolution of life on earth’s crust proposed here.

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the widely practiced treatment; however, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to high blood glucose level. However, determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for treatment of diabetes is still debated upon. While hPSC-derived beta cells are perceived as the ultimate candidate, the efficiency needs further improvement in order to obtain a sufficient number of glucose responsive β-cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address co-generation of functionally relevant islet cell subpopulations and structural properties contributing to glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.

Incident rates of neurodegenerative diseases have steadily increased globally, but there is no therapeutic access available. We newly prescribed medicinal herbal remedy including five different herbal plants called, Chen-Ma-Dan-Sam-Ga-Mi-Bang (CMST), purposed to prove for pharmacological properties and corresponded actions on hippocampus neuronal cell injury by hypoxia-induced mice model. Mice were adapted to normoxia or hypoxia with or without CMST for 5 days. We gathered pharmacological effects of CMST on cell injury by enhancement of dihydroethidium and 4-hydroxynonenal signals which were correlated with abnormal redox status in the protein or gene expression levels (abnormal elevations of nitric oxide, reactive oxygen species, lipid peroxidation and deteriorations of total glutathione, total antioxidant capacity, and activities of superoxide dismutase and catalase) due to hypoxia. CMST also notably exerted to attenuates molecules for neuronal cell injury markers such as p-tau, cleaved caspase-3 due to DNA oxidations (53bp1and phosphor-histone H2AX), inflammatory cytokines, and hemeoxigenase-1. We further figured out the underlying actions of CMST by in vitro experiment through inactivation of microglial cell which can mediate neuronal cell injury. Collectively, CMST prevented from hippocampal neuronal cells via inactivation of microglial cell with normalization of redox status on hypoxia-induced hippocampus neuronal cell injury.

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to cause severe complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to control programmed cell death whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

3D city models are being extensively used in applications such as evacuation scenarios and energy consumption estimation. The main standard for 3D city models is the CityGML data model which can be encoded through the CityJSON data format. CityGML and CityJSON use polygonal modelling in order to represent geometries. True topological data structures have proven to be more computationally efficient for geometric analysis compared to polygonal modelling. In a previous study, we have introduced a method to topologically reconstruct CityGML models while maintaining the semantic information of the dataset, based solely on the combinatorial map (C-Map) data structure. As a result of the limitations of C-Map's semantic representation mechanism, the resulting datasets could suffer either from semantic information loss or the redundant repetition of them. In this article, we propose a solution for a more efficient representation of both geometry, topology and semantics by incorporating the C-Map data structure in the CityGML data model and implementing a CityJSON extension to encode the C-Map data. In addition, we provide an algorithm for the topological reconstruction of CityJSON datasets to append them according to this extension. Finally, we apply our methodology to three open datasets in order to validate our approach when applied to real-world data. Our results show that the proposed CityJSON extension can represent all geometric information of a city model in a lossless way, providing additional topological information for the objects of the model.

Bioelectrochemical systems (BES) encompass a group of biobased technologies capable of directly converting organic matter into electricity. In these systems, which are derived from conventional electrochemical systems, the ion exchange membrane represents a key element because of its influence on the economic feasibility and on the performance of BES. This study examines the impact of long-term operation of a BES on the mechanical, chemical and electrochemical properties of five different kind of cation exchange membranes (Nafion-117, CMI-7001, Zirfon UTP 500, FKE and FKB) through several techniques: (i) scanning electron microscopy (SEM) and atomic force microscopy (AFM) to assess the changes on the membranes surface, (ii) thermogravimetric analysis (TGA) to evaluate the structural stability of the membranes, and (iii) ion exchange capacity (IEC) to monitor any change in their electrochemical properties. Results confirmed that there is not an ideal membrane for BES. While Nafion and CMI-7000 exhibited the strongest chemical structure, they also underwent the highest fouling as revealed by a fast increase in surface roughness.

Mechanism of traffic congestion generation is more than complicated, due to complex geometric road design and complicated driving behavior at urban expressway in China. We employ Cell transmission model (CTM) to simulate traffic flow spatiotemporal evolution process along the expressway, and reveal the characteristics of traffic congestion occurrence and propagation. Here we apply the variable-length-cell CTM to adapt the complicated road geometry and configuration, and propose the merge section CTM considering drivers' mandatory lane-changing and other unreasonable behavior at on-ramp merge section, and propose the diverge section CTM considering queue length end extending expressway mainline to generate dynamic bottleneck at diverge section. In the new improved CTM model, we introduce merge ratio and diverge ratio to describe the effect of driver behavior at merge and diverge section. We conduct simulation on the real urban expressway in China, results show that merge section and diverge section are the original location of expressway traffic congestion generation, on/off-ramp traffic flow has great effect on expressway mainline operation. When on-ramp traffic volume increases by 40%, merge section delay increases by 35%. And when off-ramp capacity increases by 100 veh/hr, diverge section delay decreases about by 10%, which proves the strong interaction between expressway and adjacent road networks . Our results provide the underlying insights of traffic congestion mechanism in urban expressway in China, which can be used to better understand and manage this issue.

The conversion of C1 gas feedstock, such as carbon monoxide (CO), into useful platform chemicals has attracted considerable interest in industrial biotechnology. One conversion method is electrode-based electron transfer to microorganisms using bioelectrochemical systems (BESs). In this BES system, acetate is the predominant component of various volatile fatty acids (VFAs). To appropriately separate and concentrate the produced acetate, a BES type electrodialysis cell with an anion exchange membrane was constructed and evaluated under various operational conditions, such as the applied external current. The higher acetate flux of 23.9 mmol/m2∙hr was observed under -15 mA current in an electrodialysis-based bioelectrochemical system. In addition, the initial acetate concentration affects the separation efficiency and transportation rate. The maximum flux appeared at 48.6 mmol/m2∙hr when the acetate concentration was 100mM, whereas the effect of the initial pH of the anolyte was negligible. The acetate flux was 14.9 mmol/m2∙hr when actual fermentation broth from BES based CO fermentation, was used as a catholyte. A comparison of the synthetic medium with the actual fermentation medium suggests that unknown substances and metabolites in the actual medium interfere with electrodialysis in the BES. These results provide information on the separation and optimal concentration for VFAs produced by C1 gas fermentation through electrodialysis, and a combination of a BES and electrodialysis.

Filamentous fungi such as Aspergillus spp. are opportunistic pathogens, which cause highly invasive infections, especially in immunocompromised individuals. Control of such fungal pathogens is increasingly problematic due to the small number of effective drugs available for treatment. Moreover, the increased incidence of fungal resistance to antifungal agents makes this problem a global human health issue. The cell wall integrity system of fungi is the target of antimycotic drugs echinocandins, such as caspofungin (CAS). However, echinocandins cannot completely inhibit the growth of filamentous fungal pathogens, which results in survival/escape of fungi during treatment. Chemosensitization was developed as an alternative intervention strategy, where co-application of CAS with the intervention catalyst octyl gallate (OG; chemosensitizer) greatly enhanced CAS efficacy, thus achieved ≥ 99.9% elimination of filamentous fungi in vitro. Based on hypersensitive responses of Aspergillus antioxidant mutants to OG, it is hypothesized that, besides destabilizing cell wall integrity, the redox-active characteristic of OG may further debilitate fungal antioxidant system.

Arthropod-borne flaviviruses represent human pathogens of global medical importance, against which no effective small molecule-based antiviral therapy is currently available. Arbidol (umifenovir) is a broad spectrum antiviral compound approved in Russia and China for prophylaxis and treatment of influenza. This compound showed activity against numerous DNA and RNA viruses. Its mode of action is based predominantly on the impairment of critical steps of virus-cell interaction. Here we demonstrate that arbidol possesses a micromolar inhibition activity (EC50 values ranging from 10.57 ± 0.74 to 19.16 ± 0.29 µM) in Vero cells infected with Zika virus, West Nile virus, and tick-borne encephalitis virus, three medically important representatives of arthropod-borne flaviviruses. Interestingly, no antiviral effect of arbidol is observed in porcine stable kidney cells (PS), human neuroblastoma cells (UKF-NB-6), human hepatoma cells (Huh-7 cells) indicating that the antiviral effect of arbidol is strongly cell-type dependent. Arbidol presents a significant increasing in cytotoxicity profiles when tested in various cell lines in the order: Huh-7 < HBCA < PS < UKF-NB-6 < Vero with CC50 values ranging from 18.69 ± 0.1 to 89.72 ± 0.19 µM. Antiviral activity and acceptable cytotoxicity profiles suggest that arbidol could be a promising candidate for further investigation as a potential therapeutic agent in treating flaviviral infections.

In this work commercial 18650 lithium-ion cells with LiMn₂O₄, LiFePO₄ and Li(Ni_0.33Mn_0.33Co_0.33)O₂ cathodes were exposed to external heating in an Accelerating Rate Calorimeter (es-ARC, THT Company) to investigate the thermal behavior under abuse conditions. New procedures for measuring external and internal pressure change of cells were developed. The external pressure was measured utilizing a gas-tight cylinder inside the calorimeter chamber in order to detect venting of the cells. For internal pressure measurements, a pressure line connected to a pressure transducer was directly inserted into the cell. During the thermal runaway experiments, three stages (low rate, medium rate and high rate reaction) have been observed. Both pressure and temperature change indicated different stages of exothermic reactions, which produced gases or/and heat. The onset temperature of thermal runaway was estimated according to temperature and pressure changes. Moreover, the different activation energies for the exothermic reactions could be derived from Arrhenius plots.

Hydrogen plays an important role in the implementation of Australia’s Net-Zero Strategy. It competes with lithium-ion rechargeable batteries in the electrification of Australian land transportation sector, and can provide an alternative energy storage medium for the greening of the country’s electrical grid system. This paper reviews the role hydrogen plays in the current government’s Net-Zero strategy, and investigates the potential role of other bioenergy sources. It is found that hydrogen and batteries play essentially complementary roles in reducing transport emissions, and that the former energy source is more suited to the operation of long-distance commercial service vehicles than batteries. It is suggested that bioenergy fuels such as biomethane, second generation biofuels and HVO can provide suitable bridging alternatives in the event that Australia’s EV strategy is unable to meet the 2030 target.

This paper defines the two main causes of global warming in the UK and seeks to cut climate change using green hydrogen made from renewable electricity sources. Combustion vehicles powered by fossil gasoline and diesel emit a third of UK climate-warming CO2 while buildings heated by natural gas provide a quarter. First, current UK grid problems are defined: Electricity grid, gas grid and petroleum grid. Then experiments on the private energy community of Keele University allow electrolysis demonstrations producing green hydrogen for buildings and vehicle refueling. Next, the model supply chain is planned and tested. Finally, experiments and calculations are outlined, analyzing the optimum system design criteria proposed. We conclude that economic green hydrogen can displace diesel and gasoline in vehicle transport, while also displacing natural gas for combined heat and power in buildings. In addition, the prospect in 2023 is that profits can now be made all along the green hydrogen supply chain, such that new businesses involved in clean communities can beat the National Grid monopoly and other large dominant fossil grid companies.

Wingless-type MMTV integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation, axonal extension, synapse formation, neurogenesis and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as Lymphoid Enhancer Factor (LEF) and T Cell Factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. Here I focus on a “Wnt/β-catenin-glial connection” in Parkinson’s disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. I will summarize the work of the last decade documenting that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every levels in the regulation of nigrostriatal DAergic neuronal health, protection and regeneration in the MPTP mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well-documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well-understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1-4 to provide context for past and current efforts to translate STEAP1-4 into the clinic.

Environmental pollution is becoming ubiquitous; it has a negative impact on the ecosystem diversity and worsens the quality of human life. This review discusses the possibility of applying the Plant Microbial Fuel Cells (PMFC) technology for concurrent processes of electricity generation, purification of water and soil ecosystems from organic pollutants, in particular, from synthetic surfactants and heavy metals. The review describes the PMFC functioning mechanisms and highlights the issues of the PMFC environmental application. Generally, this work summarizes different approaches to the PMFC development and to the potential usage of such hybrid bioelectrochemical systems for the environmental protection.

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat Shock Protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane-Hsp70 positive tumor cells actively release Hsp70 into lipid microvesicles termed exosomes into the blood. Due to conformational changes of Hsp70 in the lipid environment, most commercially available antibodies fail to detect membrane-bound and exosomal Hsp70. To fill this gap and to assess the role of exosomal Hsp70 in the circulation as a potential tumor biomarker, we established the novel complete Hsp70 (compHsp70) sandwich ELISA using two monoclonal antibodies (mAbs) that are able to recognize both, free and lipid-associated Hsp70 on the cell surface of viable tumor cells and exosomes. The epitopes of the mAbs cmHsp70.1 (aa 451-461) and cmHsp70.2 (aa 614-623) that are conserved among different species reside in the substrate-binding domain of Hsp70, with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/ml, high recovery rates of ‘spiked’ liposomal Hsp70 (>84%), comparable values between human serum and plasma samples, and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy volunteers. Hsp70 concentrations dropped concomitantly with the decrease in viable tumor mass on irradiation of patients with approximately 20 Gy (range 18 – 22.5 Gy) or after completion of radiotherapy (60 - 70 Gy). In summary, the compHsp70 ELISA presented herein provides a highly sensitive and reliable tool for measuring free and exosomal Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a predictive tumor-specific biomarker, risk assessment and for monitoring therapeutic outcome.

Hepatitis D virus (HDV) infection represents the most severe form of chronic viral hepatitis. We have shown that the delivery of HDV replication-competent genomes to the hepatocytes using adenoassociated virus (AAV-HDV) as gene delivery vehicles offers a unique platform to investi-gate the molecular aspects of HDV and associated liver damage. Here, we generated HDV ge-nomes modified by site directed mutagenesis aimed to: i) prevent some post-translational modi-fications of HDV antigens (HDAgs) such as Large-HDAg (L-HDAg) isoprenylation or Short-HDAg (S-HDAg) phosphorylation ii) alter the localization of HDAgs within the subcellular compartments and iii) inhibit the right conformation of the delta ribozyme. First, the different HDV mutants were tested in vitro using plasmid-transfected Huh-7 cells and then in vivo in C57BL/6 mice using AAV vectors. We found that Ser 177 phosphorylation and the ribozymal ac-tivity are essential for HDV replication and HDAg expression. Mutation of the isoprenylation domain prevent the formation of infectious particles and increase cellular toxicity and liver dam-age. Finally, altering the intracellular localization od HDAg have a profound on viral replication in vivo but liver toxicity is maintained. Mutation in the nuclear export signal impair the for-mation of infectious viral particles. These findings contribute valuable insights into the intricate mechanisms of HDV biology and have implications for therapeutic considerations

This work aims to study and analyze a hybrid power system for electric vehicles consisting of a dual low and high-rate lithium battery block and a fuel cell. In this configuration, the high-rate lithium battery powers the electric vehicle in high power demand processes like acceleration mode or on an uphill road; the low-rate battery operates at a low output power range, servicing the auxiliary systems and low power loads and the fuel cell supplies energy at intermediate power demand conditions, normal driving mode, constant velocity, or flat and downhill terrain. The dual power system improves global efficiency since every power unit operates optimally depending on driving conditions. Power sharing optimizes the lithium battery performance and fuel cell capacity, minimizing the size and weight of each energy system and enlarging the driving range. A comparative study between different lithium battery configurations and fuel cell shows an efficiency improvement of 31.4% for the hybrid dual battery block and fuel cell operating in low, high, and intermediate output power ranges, respectively. The study bases on a simulation process recreating current driving conditions for electric cars in urban, peripheral, and intercity routes. An alternative solution consisting of a hybrid system, fuel cell and a high rate lithium battery produces a 29 % power gain.

The cellular cytoskeleton provides the cell with a mechanical rigidity which allows mechanical interaction between cells and the extracellular environment. The actin structure plays a key role in mechanical events like motility, or establishment of cell polarity. From the earliest stages of development, as represented by ex vivo expansion of naïve embryonic stem cells (ESCs), the critical mechanical role of the actin structure is becoming recognized as a vital cue for correct segregation and lineage control of cells and as a regulatory structure that controls several transcription factors. Naïve ESCs have a characteristic morphology and the ultrastructure that underlies this condition remains to be further investigated. Here, we investigate the 3D actin cytoskeleton of naïve mouse ESCs using super resolution optical reconstruction microscopy (STORM). We investigate the morphological, cytoskeletal and mechanical changes in cells cultured in 2i or Serum/LIF media reflecting a homogenous preimplantation cell state and a state that is closer to embarking on differentiation. STORM imaging showed that the peripheral actin structure undergoes a dramatic change between the two media conditions. We also detected micro-rheological differences in the cell periphery between the cells cultured in these two media correlating well with the observed nano-architecture of the ESCs in the two different culture conditions. These results pave the way for linking physical properties and cytoskeletal architecture to cell morphology during early development.

The high level of dengue virus (DENV) seroprevalence in areas where Zika virus (ZIKV) is circulating and the cross-reactivity between these two viruses have raised concerns on the risk of increased ZIKV disease severity for patients with a history of previous DENV infection. To determine the role of DENV pre-immunity in ZIKV infection, we analysed the T and B cell responses against ZIKV in donors with or without previous DENV infection. Using PBMCs from donors living in an endemic area in Colombia, we have identified, by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, most of the immunodominant ZIKV T-cell epitopes in the non-structural proteins NS1, NS3 and NS5. Analyses of the T and B-cell responses in the same donors revealed a stronger T-cell response against peptides conserved between DENV and ZIKV, with a higher level of ZIKV-neutralizing antibodies in DENV-immune donors, in comparison with DENV-naïve donors. Strikingly, the potential for antibody mediated enhancement of ZIKV infection was reduced in donors with sequential DENV and ZIKV infection in comparison with donors with DENV infection only. Altogether, these data suggest that individuals with DENV immunity present improved immune responses against ZIKV.

Vascular endothelial growth factors (VEGFs) are regarded as the key vasculogenic mediators in the human body, of which VEGF-A is considered as one of the important types. It is the major growth factor possessing increasing vascular permeability as well as angiogenesis properties. This article provides intuition into the different effects of VEGF-A on vessels in ovarian hyper stimulation syndrome (OHSS) which is defined as a complication of in-vitro fertilization for infertility treatment, and obesity, a universally health problem. These are two dissimilar pathways outcomes for VEGF-A effects, thereby This article reviews updated information about the mentioned disorders and reveals that how this kind of growth factor yields different results on vasculature by activating distinct intracellular signaling in endothelial cells.

Terrestrial algae are the group of photosynthetic organisms, which can survive in extreme conditions. pH is one of the most important factor, influencing on distribution of algae, both in aquatic and terrestrial ecosystems. The influence of different pH levels on cell volume and other morphological characters of authentic and reference strains of Chlorella vulgaris, Bracteacoccus minor, Pseudoccomyxa simplex, Chlorococcum infusionum, and Vischeria magna were studied. Chlorella vulgaris and Pseudoccomyxa simplex were the most resistant species, retaining its morphology in range of pH 4-11,5. The change of pH towards acidic and alkaline levels caused the increase of volume of Pseudoccomixa simplex and Vischeria magna cells according to polynomial regression model. Volume of Chlorella vulgaris cells increased from low to high pH according to linear regression model. Changes of pH levels did not have a significant impact on volume of Bracteacoccus minor and Chlorococcum infusionum cells. Low and high levels of pH caused thickening of cell walls of Chlorococcum infusionum and increase of oil containing substances in Vischeria magna and Bracteacoccus minor cells. Our study revealed a high resistance of studied species to extreme level of pH, which allow recommend these strains for broader use in biotechnology and natures protection.

The streptavidin and biotin interaction is one of the strongest non-covalent interactions in nature. As a result, this non-covalent interaction has been of great interest when it comes to biochemical assays, diagnosis of diseases, and cell-targeted drug delivery. Past research has proven that biotin-streptavidin is useful in biosensor development to improve the detection of a system when conjugated to nanoparticles. This study aims to prove that streptavidin-coated nanoparticles can be conjugated with biotinylated antibodies using the primary-secondary method to non-invasively detect adenocarcinoma in-vitro. While the use of nanoparticles is not uncommon to the diagnostics area of scientific research, the technique this research aims to investigate is a non-invasive one, utilizing the primary-secondary method. Specifically, the increased stability of fluorophores when bound to antibodies as opposed to nanoparticles directly can be indicative of the particles conjugated through the primary-secondary method’s ability to specifically bind to overexpressed transferrin receptors in the A549 cell line. In this paper, streptavidin-coated nanoparticles were conjugated with biotinylated anti-transferrin receptor antibodies and AlexaFluor-488 secondary antibodies were used to enable fluorescence-based detection. The efficiency of these particles were observed quantitatively through a plate reader and qualitatively through a fluorescence microscope. I demonstrated that these nanoparticles are able to specifically bind to the target proteins in this study. These findings contribute to the field of nanoparticle diagnostics and can be extended to different diseases caused by overexpression of proteins in the future. While this was conducted in-vitro, conjugates can be prepared to detect cancer in-vivo and can be tested with magnetic relaxometry in the future.

In this paper, we redefine the boundaries of blood cell classification, expanding from 5 to 11 distinct blood cell types using the challenging 11-class PBC dataset. This shift enables a deeper understanding of blood cell diversity, overcoming previous limitations in medical image analysis. Our approach combines state-of-the-art deep learning techniques, including pre-trained ConvNets, ViTb16 models, and custom CNN architectures. We employ transfer learning, fine-tuning, and ensemble strategies, such as CBAM and Averaging ensembles, to achieve unprecedented accuracy and interpretability. Our fully fine-tuned EfficientNetV2 B0 model sets a new standard, with a macro-average precision, recall, and F1-score of 91%, 90%, and 90%, respectively, and an average accuracy of 93%. This breakthrough underscores the transformative potential of 11-class blood cell classification for more precise medical diagnoses. Moreover, our groundbreaking "Naturalize" augmentation technique produces remarkable results. The 2K-PBC dataset generated with "Naturalize" boasts a macro-average precision, recall, and F1-score of 97%, along with an average accuracy of 96% when leveraging the fully fine-tuned EfficientNetV2 B0 model. This innovation not only elevates classification performance but also addresses data scarcity and bias in medical deep learning. Our research marks a paradigm shift in blood cell classification, enabling more nuanced and insightful medical analyses. The "Naturalize" technique’s impact extends beyond blood cell classification, emphasizing the vital role of diverse and comprehensive datasets in advancing healthcare applications through deep learning.

Activation of the NLRP3 inflammasome plays a crucial role in innate immune response. During cell division, the NLRP3 inflammasome activation must be strictly controlled. Here, we discovered the anaphase promoting complex subunit 10 (Anapc10, APC10), a substrate recognition protein of the anaphase promoting complex/cyclosome (APC/C), is a critical mediator of the NLRP3 inflammasome activation. APC10 protein interacts with NLRP3, and co-localizes with NLRP3 protein in the cytoplasm. During interphase, APC10 interacts with NLRP3 to promote the NLRP3 inflammasome activation. During mitosis, APC10 disassociates from the NLRP3 inflammasome to inhibit the inflammatory responses. This study reveals a distinct mechanism by which APC10 serves as a switch of the NLRP3 inflammasome activation during cell cycle.

This paper presents a demonstration of a linearly-polarized transmit-arrays antenna with high-efficiency and wideband operating in X-band. The topology of the unit cell consists of two identical patch antennas loaded by C-loop slot and interconnected by a metalized via through a ground plane sandwiched between two identical substrates [18]. A waveguide measurement system WGMS has been used for single cell characterization (reflection/transmission coefficients). Good results have been demonstrated in terms of matching performances; the reflection coefficient S11 is under 10-dB in the 9.4-10.4 GHz band (i.e. 10.1% around 9.9 GHz) and with only 0.35 dB-insertion loss at 10 GHz. The transmit-arrays prototype permitted to achieve 22.4 dBi of directivity and 20.1 dBi of gain. The aperture and radiation efficiencies are about 28.2% and 58.3%, respectively. With a focal ratio (F/D) of 1/2 the spill-over loss is less than 2 dB. Beam-scanning up to ± 35° has been achieved with the same phase quantization (passive) and less than 3 dB of gain losses.

The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic mutations, epigenetic alterations, and changes in selection dynamics. Myeloid leukemia associated with DS (ML-DS) is preceded by a preleukemic phase called transient abnormal myelopoiesis driven by GATA1 gene mutations and progresses to ML-DS through additional mutations in cohesin genes, CTCF, RAS, or JAK/STAT pathway genes. DS-related ALL (ALL-DS) differs from non-DS ALL in terms of cytogenetic subgroups and genetic driver events and aberrant expression of CRLF2, JAK2 mutations, and RAS pathway activating mutations are frequent in ALL-DS. Recent advancements in single-cell multi-omics technologies have provided unprecedented insights into the cellular and molecular heterogeneity of DS-associated hematologic neoplasms. Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment's role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies.

Numerous dynamic and complicated processes characterize development from the oocyte to the embryo. However, given the importance of functional transcriptome profiles, long non-coding RNAs, single-nucleotide polymorphisms, and alternative splicing during embryonic development, the effect that these features have on the blastomeres of 2-, 4-, 8-, 16-cell, and morula stages of development have not been studied. Here, we conducted a scRNA-seq survey of cells from sheep from the oocyte to the blastocyst developmental stages. We then carried out experiments to identify and functionally analyze the transcriptome profiles, long non-coding RNAs, single-nucleotide polymorphisms (SNPs), and alternative splicing (AS). We founded that between the oocyte and zygote groups significantly down-regulated genes and the second-largest change in gene expression occurred between the 8- and 16-cell stages. We used various methods to construct a profile to characterize cellular and molecular features and systematically analyze the related GO and KEGG profile of cells of all stages from the oocyte to the blastocyst. This large-scale, single-cell atlas provides key cellular information and will likely assist clinical studies in improving preimplantation genetic diagnosis.

The main focus of this work is to extend the knowledge about the complexity of issues of oxidative stress. Natural compounds play a serious role in multiple aspects of both human, leading to clear health-promoting effects. This work is focused on the potential application cosmetic formulations containing including but not limited to of clove water and isolated clove oils on their aid in the control of the diseases. The aim of our work was to prepare to evaluate cosmetic formulations containing clove oil, eugenol or new eugenol ester derivative (eugenyl dichloroacetate - EDChA) but also cosmetic formulations containing the aqueous phase obtained after separation of essential oil following the clove buds steam distillation. To evaluate the antioxidants transdermal delivery system, in vitro permeation experiments in a Franz diffusion cell were performed using pig skin. The antioxidative capacity of the cosmetic formulations obtained was determined by the DPPH free radical reduction method. In the next stage, the antioxidant activity (DPPH, ABTS, and Folin–Ciocalteu methods) of the fluid that penetrated through pig skin and of the fluid obtained after skin extraction, were also evaluated. For comparison, studies of cosmetic formulation containing alone dichloroacetic acid (DChAA) were as well carried out. The obtained cosmetic formulations were characterized by of antioxidant activity estimated after 24 hours of conducting the experiment, which indicates long-term protection against reactive oxygen species (ROS) in the deeper layers of the skin. The results of this work contribute to the development of cosmetic formulations with antioxidant potential, emphasizing that the water phases are waste from the process of cloves steam distillation and are not used to prepare cosmetic formulations. The use of waste water from the clove buds steam distillation process is environmentally friendly and not allows us to waste, containing however valuable biologically active compounds (furfural, methyl salicylate, 4-allilofenol, eugenol, α- and β-caryophyllene, eugenyl acetate, β-caryophyllene oxide). Together, these results suggest that cosmetic formulations may be potential drug candidates for chemopreventive, antineoplastic and antimutagenic therapy.

Abstract: Epigenetic approaches in direct correlation with assessment of critical genetic mutations in non-small cell lung cancer (NSCLC) are currently very intensive, as the epigenetic components in NSCLC development and progression have attained high recognition. In this level of research, established human NSCLC cell lines as well as experimental animals are widely used to detect novel biomarkers and pharmacological targets to treat NSCLC. The epigenetic background of NSCLC is highly complex and requires precise definition as these phenomena are variable between NSCLC subtypes and systems origin. We engaged an in-depth characterization of non-coding (nc)RNAs prevalent in human KRAS-mutant NSCLC cell lines A549 and H460 and mouse KRAS-mutant NSCLC tissue by Next Generation Sequencing (NGS) and quantitative Real Time PCRs (qPCRs). Also, the effect of transcription factor (TF) LRF, a known epigenetic silencer, was examined on the epigenome modulation. Finally, interacting networks underlying epigenetic variations in NSCLC subtypes were created. Data derived from our study highlights the divergent epigenetic profiles of NSCLC of human and mouse origin, as well as the significant contribution of 12qf1: 109,709,060-109,747,960 mouse chromosomal region to micro-RNA upregulated species. Fur-thermore, the novel epigenetic miR-148b-3p/PVT1/ZBTB7A axis was identified, which differentiates lung adenocarcinoma from large cell lung carcinoma, two characteristic NSCLC subtypes. The detailed recording of epigenetic events in NSCLC and combinational studies including networking between ncRNAs and TFs validate the identification of significant epigenetic features, prevailing in NSCLC subtypes and among experimental models. Our results enrich knowledge in the field and empower research on the epigenetic prognostic biomarkers of the disease and patient-tailored treatments.

Neuronal cell fate is predominantly controlled by the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised, due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, lacking endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role on inducing cell specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, leading towards the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates for the first time the expression of p75NTR in human induced Pluripotent Stem Cells - derived Neural Progenitor Cells (hiPSCs - derived NPCs) and receptor-dependent cell death induced by ENT-A044 treatment. In conclusion, ENT-A044 could be proven a lead molecule for the development of novel pharmacological agents, aiming on new therapeutic approaches and research tools, by controlling p75NTR actions.

: The primary objective of this study was to investigate the association of certain genetic alterations and intraoperative fluorescent activity of 5-aminolevulinic acid (ALA) in brain metastasis (BM) of lung adenocarcinoma. A retrospective cohort study was conducted among 72 patients who underwent surgical resection of BM from lung adenocarcinoma at our institute for 5 years. Cancer cell infiltration was estimated by the intraoperative fluorescent activity of 5-ALA, and genetic alterations were analyzed by next-generation sequencing (NGS). The sensitivity and specificity for detecting cancer cell infiltration using 5-ALA were 87.5% and 96.4%, respectively. Genes associated with cell cycle regulation (p = 0.003) and cell proliferation (p = 0.044) were significantly associated with positive fluorescence activity of 5-ALA in the adjacent brain tissue. Genetic alterations in cell cycle regulation and cell proliferation were also associated with shorter recurrence-free survival (p = 0.013 and p = 0.042, respectively) and overall survival (p = 0.026 and p = 0.042, respectively) in the multivariate analysis. The results suggest that genetic alterations in cell cycle regulation and cell proliferation are associated with positive fluorescence activity of 5-ALA in the adjacent infiltrative brain tissue and influence the clinical outcome of BM of lung adenocarcinoma.

This study propounds a sustainable alternative to petroleum-based polyurethane (PU) foams aiming to curtail this nonrenewable resource's continued and uncontrolled use. Coconut fatty acid distillate (CFAD) and crude glycerol (CG), both wastes from vegetable oil processes, were utilized for bio-based polyol production for rigid PU foam application. The raw materials were subjected to catalyzed glycerolysis with alkaline-alcohol neutralization and bleaching. The resulting polyol possessed properties suitable for rigid foam application with an average OH number of 215 mg KOH/g, acid number of 7.2983 mg KOH/g, and Gardner color value of 18. The polyol was used to prepare rigid PU foam, and its properties were determined using FTIR, TGA/DTA, and UTM. Additionally, the cell foam morphology was investigated by scanning electron microscope (SEM) in which most of its structure revealed an open-celled network and quantified at 92.71% open cell content using pycnometric testing. The PU foam thermal and mechanical analysis results showed an average compressive strength of 70.59 kPa, thermal conductivity of 46.50 mWm-1K-1, and density of 32.79 kgm-3. These properties showed its applicability as thermal insulating foam, thus, demonstrating the potential use of CFAD and CG in commercial polyol and PU foam production.

The association between autoimmune diseases, mostly rheumatoid arthritis, systemic lupus erythematous, celiac disease and Sjögren syndrome, and lymphoma has been widely demonstrated by several epidemiologic studies. By a not yet entirely elucidated mechanism, chronic activation/stimulation of the immune system, along with the administration of specific treatments, may lead to persistent stimulation of both of B- and T-cells, and to the onset of different types of lymphoma in such patients. Specifically, patients affected by may develop lymphomas may years after the original diagnosis. Several epidemiologic, hematologic and histological factors may anticipate the progression from Sjögren syndrome into lymphoma but, to the best of our knowledge, a definite pathogenetic mechanism for such progression is still missing. In fact, while the association between Sjögren syndrome and non-Hodgkin lymphoma, mostly diffuse large B-cell and extranodal marginal zone lymphomas is well established, many other variables, such as time of onset, gender predilection, sites of occurrence, subtype of lymphoma and predictive factors still remain unclear. We report on a rare case of primary breast lymphoma occurring three years after the diagnosis of Sjögren syndrome in a 57 y.o. patient. The diagnostic work-up, including radiograms, core needle biopsy and histological examination are discussed, along with emerging data from the recent literature, thus highlighting the usefulness of breast surveillance in Sjögren syndrome patients.

The potential of metallic lithium to become the anode material for next-generation batteries is hampered by significant challenges, chief among which is dendrite growth during battery charging. These dendritic structures not only impair battery performance but also pose safety risks. Among the non-destructive analytical techniques in battery research, Magnetic Resonance Imaging (MRI) stands out as a promising tool. However, the direct imaging of lithium by 7Li MRI is hindered by its low sensitivity and spatial resolution, making its use for of dendritic growth imaging very difficult. Instead, a recently introduced indirect imaging approach based on 1H MRI of the electrolyte was used in this study. This method was used for sequential 3D imaging to monitor the charging process of lithium metal symmetric cells in three different electrical circuits: single cell, four cells in parallel, four cells in series. The measured sequential images allowed measurement of dendrite growth in each cell using volumetric analysis. The growth results confirmed the theoretical expectation that growth across cells is uneven in a parallel circuit and even in a series circuit. The methods presented in this study can be applied also to many other dendrite-related issues in batteries.

Background: Penile squamous cell carcinoma (PSCC) is classified into two prognostically distinct types: human papillomavirus (HPV)-associated and HPV-independent. Conversely, the impact of p53 status on prognosis remains controversial. We correlated HPV and p53 status with prognosis in a large series of PSCC patients. p53 was analysed according to a recently described immunohistochemical (IHC) pattern-based framework that includes two normal (scattered, mid-epithelial) and four abnormal patterns (diffuse, basal overexpression, cytoplasmic and null) and closely correlates with TP53 mutational status. Methods: A total of 122 patients with surgically treated PSCC in three hospitals in Barcelona, Spain, were included. Based on HPV in situ hybridization and p16 and p53 IHC expression, the tumors were classified into three molecular types: HPV-associated, HPV-independent/p53 normal, and HPV-independent/p53 abnormal. All patients were followed for at least 22 months (median 56.9 months), and disease-specific survival (DSS) was analysed. Results: Thirty-six tumors (29%) were HPV-associated, 35 (29%) were HPV-independent/p53 normal, and 51 (42%) were HPV-independent/p53 abnormal. Disease-related deaths were observed in 3/36 (8%), 0/35 (0%) and 14/51 (27%) of the patients, respectively (p&lt;0.001). A total of 7/14 deaths in the latter group were patients with tumors showing p53 patterns not recognized in the classical p53 IHC interpretation (basal, null, cytoplasmic). According to our multivariate analysis, HPV-independent/p53 abnormal tumors and advanced stage were associated with impaired DSS (hazard ratio=23.4, 95% confidence interval [CI]= 2.7-3095.3; p=0.001 and 16.3, 95% CI=1.8-2151.5; p=0.008, respectively). CONCLUSION: Compared with patients with HPV-associated and HPV-independent/p53-normal PSCC, patients with HPV-independent/p53 abnormal PSCC have worse clinical outcomes. p53 IHC results define two prognostic categories in HPV-independent PSCC: HPV-independent/p53-normal tumors as low-risk tumors, whereas HPV-independent/p53-abnormal tumors as aggressive neoplasms.

B-1 cells, a subtype of B lymphocytes, are found in lymphoid tissues and peritoneal and pleural cavities. They play diverse roles, releasing cytokines, generating antibodies, regulating the immune response, engaging in phagocytosis, and moving to inflammatory sites. However, their physiology remains partially understood, especially in stressful conditions like sleep restriction. This study aimed to investigate murine B-1 cell activation and differentiation under sleep restriction. Male C57BL/6J mice underwent an 18-hour sleep restriction for 21 days, followed by Candida albicans or Paracoccidioides brasiliensis infection. Purified peritoneal B-1 cells were evaluated for activation markers, microbicidal molecules, cytokine gene expression, Toll-like receptors, and commitment factors. Results showed that sleep restriction minimally influenced activation marker expression in B-1 cells across infection models. However, under sleep restriction, microbicidal molecule production increased in P. brasiliensis (NO) and C. albicans (ROS) infections. Gene expression revealed elevated TLR-2 and cytokines (IL-12, IL-6, TNF-α) in sleep-restricted animals. Lineage commitment analysis indicated myeloid polarization in sleep-restricted B-1 cells for all infection models. These findings underscore the impact of sleep restriction on B-1 cell activation and differentiation, with outcomes varying based on infection type. This study highlights the importance of investigating immunological changes resulting from sleep restriction.

The ubiquitous deployment of Li-ion batteries (LIBs) in more demanding applications has reinforced the need to understand root-causes of thermal runaway. Herein we perform a forensic simulation of a real-case failure scenario, using localised heating of Li(Ni0.5Mn0.3Co0.2)O2 versus graphite 18650 cylindrical cells. This study determined the localised temperatures that would lead to venting and thermal runaway of these cells, as well as correlating the gases produced as a function of degradation pathway. Catastrophic failure, involving melting (with internal cell temperatures exceeding 1085°C), deformation and ejection of cell componentry, was induced by locally applying 200 °C and 250 °C to a fully charged cell. Conversely, catastrophic failure was not observed when the same temperatures were applied to the cells at lower state of charge (SOC). This work highlights the importance of SOC, chemistry and heat in driving the thermal failure mode of Ni-rich LIB cells, allowing for a better understanding of battery safety and associated design improvements.

Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than smoking. The intestinal absorption of Cd involves the transporters for iron, zinc, copper, and calcium. These metal transporters essentially determine the body burden of Cd because only 0.001-0.005% of Cd accumulated in the body can be excreted in urine each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen. Current evidence, however, suggests that environmental Cd may increase the prevalence of many types of cancer, notably lung, liver, breast, pancreas, and kidney. A two-year bioassay that mimics a lifelong exposure demonstrates Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cell lines underwent malignant cell transformation, when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it can profoundly affect gene expression through its interactions with various proteins, and Cd can thus be viewed as a transcription modulator. The present review highlights epidemiological studies that connected an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is on the impact of body iron stores on the absorption rate of Cd, and its implications for breast cancer prevention in highly susceptible subpopulation groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer-cell transformation, under in vitro conditions, are briefly discussed. The potential role for ZnT1 efflux transporter in cellular acquisition of tolerance to Cd cytotoxicity are highlighted.