This work presents a linear smoothing scheme over high-order triangular elements in the framework of a cell-based strain smoothed finite element method for two-dimensional nonlinear problems. The main idea behind the proposed linear smoothing scheme for strain-smoothed finite element method (S-FEM) is no subdivision of finite element cells to sub-cells while the classical S-FEM needs sub-cells. Since the linear smoothing function is employed, S-FEM is able to use quadratic triangular or quadrilateral elements. The modified smoothed matrix obtained node-wise is evaluated. In the same manner with the computation of the strain-displacement matrix, the smoothed stiffness matrix and deformation graident are obtained over smoothing domains. A series of benchmark tests are investigated to demonstrate validity and stability of the proposed scheme. The validity and accuracy are confirmed by comparing the obtained numerical results with the standard FEM using 2nd-order triangular element and the exact solutions.

Botulinum neurotoxin (BoNT) intoxication can lead to the disease botulism, characterized by flaccid muscle paralysis that can cause respiratory failure and death. Due to the significant morbidity and mortality costs associated with BoNTs high toxicity, developing highly sensitive, rapid, and field-deployable assays are critically important to protect the nation’s food supply against either accidental or intentional contamination. We report here that the B-cell based biosensor assay (CANARY^® Zephyr) detects BoNT/A in buffer and various food matrices rapidly in ≤ 40 min, in small volumes ≈ 50 μL, with minimal processing of samples, and is extremely portable (suitcase-sized equipment). BoNT/A was detected at limits of detection (LOD) < 0.075 ng ± 0.02 in assay buffer while milk matrices (non-fat, 2 %, whole milk) increased the LOD to < 0.175 – 0.314 ng. Limits of detection for the assay in complex foods were < 1 ng ± 0.0 (neutralized acidic juices-carrot, orange and apple); < 16.7 ng ± 7.7 (liquid egg); and varied from < 0. 39 – 3.125 ng for solid complex foods (ground beef, green bean baby puree, smoked salmon). These results show that the CANARY^® Zephyr assay can be a highly useful tool in clinical, environmental, and food safety surveillance programs.

Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies has performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations — specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to ATG-G (7.5% vs. 38.3%, p=0.001). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p&lt;0.001), with a shorter time between transplant and CMV (&lt;61 days, 77.8% vs. 33.3%, p=0.008) and a higher median CMV copy number (1000 vs. 0, p=0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p=0.005). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year probability of relapse while comparing ATG-T and ATG-G (32.0% vs 40.3%, p=0.423; 63.9% vs 55.7%, p=0.438, respectively).

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.

Glucocorticoid administration is a common clinical practice in attempt to decrease inflammation associated with, and improve resectability of, canine mast cell tumors (MCTs). However, the impact of neoadjuvant glucocorticoids on histological features and proliferation indices of canine MCTs is unknown. The objective of this study was to evaluate changes in tumor grade, mitotic count, Ki67, AgNOR, and AgNORxKi67 scores following short-course, anti-inflammatory neoadjuvant prednisone in canine patients with MCTs. This was a prospective, single-arm pilot study. Client-owned dogs with treatment-naïve, cytologically-confirmed MCTs were enrolled. Patients underwent an initial incisional biopsy followed by a 10-14 day course of anti-inflammatory prednisone, and surgical resection. All histological samples were randomized, masked, and evaluated by a single pathologist. Unstained paired pre- and post-treatment samples were submitted to a commercial laboratory for Ki67 and AgNOR immunohistochemical analysis. There were 11 dogs enrolled with 11 tumors. There were no statistical differences between the pre- and post-treatment histological parameters of mitotic index, Ki67, AgNOR, or Ki67xAgNOR. There were no clinically-significant alterations between pre-treatment and post-treatment in the assignment of tumor grades. A short-course of anti-inflammatory prednisone does not appear to alter the histological parameters that affect grade-determination, nor significantly alter the proliferation indices in canine MCTs.

Published transcriptomic data from surgically removed metastatic clear cell renal cell carcinoma (ccRCC) samples were re-analyzed from the Genomic Fabric Perspective that considers the transcriptome a multi-dimensional mathematical object, constrained by a dynamic set of expression correlations among genes. Every gene in the chest wall metastasis (MET), two primary tumors (PTA, PTB) and the surrounding normal tissue (NOR) of the right kidney was characterized by three independent measures: average expression level (AVE), relative expression variation (REV) and expression correlation (COR) with each other gene. AVE was used to determine the regulation of the genomic fabrics of ccRCC, apoptosis, chemokine and VEGF signaling pathways. REV quantified the alteration of the transcripts’ abundances control, while COR determined the remodeling of the transcriptomic networks of chemokine signaling and oxidative phosphorylation genes. The gene hierarchy was established in based on Gene Commanding Height and the Gene Master Regulators (GMR) TASOR (PTA), FAM27C (PTB) and ALG13 (MET) and DAPK3 (NOR) were identified in each profiled region. We predict that TASOR overexpression would block transcription in PTA but not in PTB, while slightly stimulating it in NOR. Silencing of ALG3 would slow-down the cell-cycle in all three cancer regions with practically no effect in NOR.

The development of a rapid, sensitive, specific method for detecting foodborne pathogens is paramount in supplying safe food to enhance public health safety. Despite the significant improvement in pathogen detection methods, key issues are still associated with rapid methods, such as distinguishing living cells from dead, pathogenic potential or health risk of the analyte at the time of consumption, detection limit, and sample-to-result. The mammalian cell-based assays analyze pathogens' interaction with the host cells and are responsive to only live pathogens or active toxins. In this study, a human embryonic kidney (HEK293) cell line expressing Toll-Like Receptor 5 (TLR-5) and chromogenic reporter system (HEK dual hTLR5) was used for the detection of viable Salmonella in a 96-well tissue culture plate. This cell line responds to low concentrations of TLR5 agonist flagellin. Stimulation of TLR5 ligand activates nuclear factor-kB (NF-κB) - linked alkaline phosphatase (AP-1) signaling cascade inducing the production of secreted embryonic alkaline phosphatase (SEAP). With the addition of a ρ-nitrophenyl phosphate as a substrate, a colored end product representing a positive signal is quantified. The assay's specificity was validated with the top 20 Salmonella enterica serovars and 19 non-Salmonella spp. The performance of the assay was also validated with spiked food samples. The total detection time (sample-to-result), including shortened pre-enrichment (4 h) and selective enrichment (4 h) steps with artificially inoculated outbreak-implicated food samples (chicken, peanut kernel, peanut butter, black pepper, mayonnaise, and peach) was 15 h when inoculated at 1–100 CFU/25 g sample. These results show the potential of HEK-DualTM hTLR5 cell-based functional biosensors for rapid screening of Salmonella.

Cancer cells are believed to be recognized and controlled by the immune system of the host, especially the adaptive immune system. Cancers may be initiated by a single gene defect in stem cells or regenerating cells during the replacement of old or injured tissue cells, and additional gene defect(s) then occur. To compensate for missing proteins intracellular homeostasis systems, such as proteostasis, may work with activation of new genes. The risk or predisposing factors in cancers may be related to the number of tissue cell renewals (the turnover time) and the probability of gene defect(s). Oncological symptoms may be associated with substances that are derived from antigens expressed on cancer cells and those derived from damaged cancer cells with corresponding immune reactions. In patients with cancers or other conditions, inadequate immune components to control these substances may result in chronic inflammatory or autoimmune diseases. Cancer cells communicate with host cells, including the immune cells such as T cells, for survival and proliferation and may need assistance from immune cells against intracellular infections or physicochemical insults. T cell-based immune therapeutics have been developed and clinically used in some cancers, especially in advanced cancers. We further discuss the oncogenesis, pathophysiology of cancers, and unresolved issues in tumor immunology and reinterpret the effectiveness of T cell-based therapies under the protein-homeostasis-system hypothesis.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of death due to cancer. About 30% of patients with PCa who have been castrated develop a castration-resistant form of the disease (CRPC), which is incurable. In the last decade, new treatments that control the disease have emerged, slowing progression and spread, and prolonging survival while maintaining the quality of life. These include immunotherapies; however, we do not yet know the optimal combination and sequence of these therapies with the standard ones. All therapies are not always suitable for every patient due to co-morbidities or adverse effects of therapies or both, so there is an urgent need for further work on new therapeutic options. Advances in cancer immunotherapy with an immune checkpoint inhibition mechanism (e.g., ipilimumab, an anti-CTLA-4 inhibitor) have not shown a survival benefit in patients with CRPC. Other immunological approaches have also not given clear results, which has indirectly prevented breakthrough for this type of therapeutic strategy into clinical use. Currently, the only approved form of immunotherapy for patients with CRPC is a cell-based medicine, but it is only available to patients in some parts of the world. Based on the experience gained from recently completed clinical research on immunotherapy with dendritic cell-based immunohybridomas, the aHyC dendritic cell vaccine, for patients with CRPC, we highlight the current status, and possible alternatives that should be considered in the future.

Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with bamlanivimab/etesevimab (BAM/ETE), casirivimab/imdevimab (CAS/IMD) and sotrovimab (SOT) as well as the activity of remdesivir, nirmatrelvir and molnupiravir. mAbs and drug activity were defined as the serum dilution (ID50) and drug concentration (IC50), respectively, showing 50% protection of virus-induced cytopathic effect. All pre-infusion sera were negative for SARS-CoV-2 neutralizing activity. BAM/ETE, CAS/IMD and SOT showed activity against the WT (ID50 6,295 [4,355-8,075] for BAM/ETE; 18,214 [16,248-21,365] for CAS/IMD and 456 [265-592] for SOT) and the delta (14,780 [ID50 10,905-21,020] for BAM/ETE, 63,937 [47,211-79,971] for CAS/IMD and 1,103 [843-1,334] for SOT). Notably, only SOT was active against BA.1 (ID50 200 [37-233]) while BA.2 was neutralized by CAS/IMD (ID50 174 [134-209] ID50) and SOT (ID50 20 [9-31] ID50) but not by BAM/ETE. No significant inter-variant IC50 differences were observed for molnupiravir (1.5±0.1/1.5±0.7/1.0±0.5/0.8±0.01 μM for WT/delta/BA.1/BA.2, respectively); nirmatrelvir (0.05±0.02/0.06±0.01/0.04±0.02/0.04±0.01 μM) and remdesivir (0.08±0.04/0.11±0.08/0.05±0.04/0.08±0.01 μM). Continued evolution of SARS-CoV-2 requires updating the mAbs arsenal, however antivirals have so far remained unaffected.

As non-operative management (NOM) of esophageal and rectal cancer is becoming more prevalent, blood-biomarkers such as circulating tumor DNA (ctDNA) may provide clinical information in addition to endoscopy and imaging to aid in treatment decisions following chemotherapy and radiation therapy. In this feasibility study, we prospectively collected plasma samples from locally advanced esophageal (n=3) and rectal cancer (n=2) patients undergoing multimodal neoadjuvant therapy to assess the feasibility of serial ctDNA monitoring throughout neoadjuvant therapy. Using the DIDA-Seq error-correction method, we serially interrogated plasma cell-free DNA at 28-41 tumor-specific genomic loci throughout therapy and in surveillance with an average limit of detection of 0.016% mutant allele frequency. In both rectal cancer patients, ctDNA levels were persistently elevated following total neoadjuvant therapy with eventual detection of clinical recurrence prior to salvage surgery. Among the esophageal cancer patients, ctDNA levels closely correlated with tumor burden throughout and following neoadjuvant therapy, which was associated with a pathologic complete response in one patient. In this feasibility study, patient and tumor-specific ctDNA levels correlated with clinical outcomes throughout multi-modality therapy suggesting that serial monitoring of patient ctDNA has the potential to serve as a highly sensitive and specific biomarker to risk-stratify esophageal and rectal cancer patients eligible for NOM. Further prospective investigation is warranted.

CAR-T cell therapy has emerged as a groundbreaking approach in cancer treatment, leveraging the immune system to target and eliminate cancer cells. While currently focused on hematologic malignancies, the future holds promise for expanding CAR-T cell therapy to diverse cancers, enhancing its efficacy, and improving safety profiles. Recent advances in tumor immunology have propelled CAR-T cell therapy as a game-changer in treating diseases such as relapsed/refractory B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Six CAR-T cell products have received FDA approval for treating R/R B cell malignancies. However, challenges persist, including complications like cytokine release syndrome (CRS), coagulopathy, and cytopenias. Strategies to mitigate these complications involve targeting distinct antigens with dual- or multi-targeted CAR-T cells and enhancing immunogenicity. Additionally, γδ CAR-T cells show promise in recognizing antigen- negative leukemia cells in an MHC-independent manner while reducing the risk of inducing graft-versus-host disease (GVHD). As CAR-T cell therapy continues to evolve through innovation and discovery, it holds the potential to revolutionize cancer treatment, offering new hope to patients and reshaping the landscape of oncology with its precision and efficacy.

The adipose-derived mesenchymal stem cells are becoming the tool of choice for many clinical applications and nowadays, nearly 200 clinical trials are running worldwide to prove the efficacy of this cell type for many diseases and pathological conditions. To reach the goal of cell therapies and produce ATMPs as drugs for regenerative medicine, it is necessary to properly standardize the GMP processes and thus collection methods, transportation strategies, extraction protocols and characterization procedures without forgetting that all the tissues of the human body are characterized by a wide inter-individual variability genetically determined and acquired during life. Here we compare 302 samples processed under GMP rules to exclude the influence of the operator and of the anatomical site of collection. Variability in the age of patients, gender and laboratory parameters like total cell number, cell viability, stem cell number and other stromal vascular fraction cell sub-populations have been compared to each other. Results show that, when the laboratory protocol is standardized, the variability in quantifiable cell parameters is widely statistically non-significant, meaning that we can make a further step toward standardized advanced cell therapy products.

Background: This retrospective study evaluates the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. The significant differences of survival between the two groups were only observed in patients with positive EGFR expression. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

The thymus hosts the development of a specific type of adaptive immune cells called T cells. T cells orchestrate the adaptive immune response through recognition of antigen by the highly variable T-cell receptor (TCR). T-cell development is a tightly coordinated process comprising lineage commitment, somatic recombination of Tcr gene loci and selection for functional, but non-self-reactive TCRs, all interspersed with massive proliferation and cell death. Thus, the thymus produces a pool of T cells throughout life capable of responding to virtually any exogenous attack while preserving the body through self-tolerance. The thymus has been of considerable interest to both immunologists and theoretical biologists due to its multiscale quantitative properties, bridging molecular binding, population dynamics and polyclonal repertoire specificity. Here, we review mathematical modelling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations. Furthermore, we summarize the current challenges to estimating in vivo cellular dynamics and to reaching a next-generation multiscale picture of T-cell development.

Conventional biochemical methods for studying cellular signaling cascades have relied on destructive cell disruption. In contrast, live cell imaging of fluorescent-tagged transfected proteins offers a non-invasive approach to understanding signal transduction events. One strategy involves monitoring the phosphorylation-dependent shuttling of a fluorescent-labeled kinase between the nucleus and cytoplasm using nuclear localization, export signals, or both. This paper introduces a simple method to visualize intracellular signal transduction in live cells by exploring the translocation properties of PKC from the cytoplasm to the membrane. We fused bait protein to PKC, allowing the bait (RFP-labeled) and target (GFP-labeled) proteins to co-translocate from the cytoplasm to the membrane. However, in non-interacting protein pairs, only the bait protein was translocated to the plasma membrane. To verify our approach, we examined the Raf–MEK–ERK signaling cascade (ERK pathway) and directly observed the Raf1/MEK2 interaction. We also identified ternary complexes containing the KSR1 scaffold protein. Additionally, the MEK/ERK interaction was dependent on the exogenous expression of KSR1.

Persistent human papillomavirus (HPV) infection is responsible for practically all cervical and a high proportion of anogenital and oropharyngeal cancers. Therapeutic HPV vaccines in clinical development show great promise in improving outcomes for patients who mount an anti-HPV T cell response, but far from all patients elicit a sufficient immunological response. This witnesses a translational gap between animal models and human patients. Here, we investigated the potential of a new assay consisting of co-culturing vaccine-transduced dendritic cells (DCs) with syngeneic healthy human peripheral blood mononuclear cells (PBMCs) to mimic a human in vivo immunization. This new promising human ex vivo PBMC assay was evaluated using an innovative therapeutic adenovirus (Adv)-based HPV vaccine encoding the E1, E2, E6, and E7 HPV16 genes. This new method allowed us to show that vaccine-transduced DCs yielded functional effector T cells and unveiled information on immunohierarchy showing E1-specific T cell immunodominance over time. We suggest that this assay can be a valuable translational tool to complement the known animal models, not only for HPV therapeutic vaccines, and supports the use of E1 as an immunotherapeutic target. Nevertheless, the findings reported here need to be validated in a larger number of donors, and preferably in patient samples.

Background: Metabolic flux analysis (MFA) is an indispensable tool in metabolic engineering. The simplest variant of MFA relies on an overdetermined stoichiometric model of the cell’s metabolism under the pseudo-steady state assumption, to evaluate the intracellular flux distribution. Despite its long history, the issue of model error in the overdetermined MFA, particularly misspecifications of the stoichiometric matrix, has not received much attention. Method: We evaluated the performance of statistical tests from linear least square regressions, namely Ramsey RESET test, F-test and Lagrange multiplier test, in detecting model misspecifications in the overdetermined MFA, particularly missing reactions. We further proposed an iterative procedure using the F-test to correct such an issue. Result: Using Chinese hamster ovary and random metabolic networks, we demonstrated that: (1) a statistically significant regression does not guarantee high accuracy of the flux estimates, (2) the removal of a reaction with a low flux magnitude can cause disproportionately large biases in the flux estimates, (3) the F-test could efficiently detect missing reactions, and (4) the proposed iterative procedure could robustly resolve the omission of reactions. Conclusion: Our work demonstrated that statistical analysis and tests could be used to systematically assess, detect and resolve model misspecifications in the overdetermined MFA.

Traumatic brain injury (TBI) causes multiple cerebrovascular disruptions and oxidative stress, resulting in pathophysiological mechanisms. These are often accompanied by serious impairment in cerebral blood flow autoregulation, as well as neuronal and glial degeneration. Most currently available early antioxidant therapies lack sufficient efficacy. However, the application of a newly developed class of biologically compatible carbon-based nanoclusters, namely poly-ethylene-glycol-functionalized hydrophilic carbon clusters (PEG-HCCs), mitigate secondary injury after a TBI in early studies. In the present pilot study, we explore the efficacy of PEG-HCCs in an open blast rat model of TBI. Here we report on the neuroprotective efficacy of PEG-HCCs.

Background: This retrospective study evaluate the survival effects of metronomic maintenance therapy with fluoropyrimidine in patients with stage III colorectal cancer (CRC) according to epidermal growth factor receptor (EGFR) expression. Methods: We enrolled 197 patients with stage III CRC who had undergone radical resection and FOLFOX regimen adjuvant chemotherapy. The clinicopathological features and effects of metronomic maintenance therapy on survival according to treatment group and EGFR expression were analyzed. By conducting an in vitro cell line study and in vivo study through knockdout of EGFR gene, we analyzed the capacities of cell proliferation and migration. Results: Postoperative relapse and mortality were significantly more common in the FOLFOX group. Metronomic maintenance therapy was a significantly independent predictive factor of postoperative relapse and mortality, as well as a prognostic factor of disease-free survival and overall survival. We also demonstrated that EGFR-knockout Caco2 cells are more sensitive to the inhibition effect of fluoropyrimidine than the control those. Conclusions: The present study suggested EGFR expression as the prognostic factor in patients with stage III CRC receiving metronomic maintenance therapy. By analyzing EGFR expression and treatment strategies, we can identify the potential candidates with optimal survival benefit from metronomic maintenance therapy in patients with stage III CRC.

Our study explores the genetic mechanisms underlying the spotted leaf phenotype in rice, focusing on the rpt5a mutant characterized by persistent reddish-brown leaf spots from seedling stage to maturity, leading to extensive leaf necrosis. Through map-based cloning, we localized the responsible locus to a 330Kb region on chromosome 2 and identified LOC_Os02g56000 (named OsRPT5A) as the causative gene. A point mutation in OsRPT5A, substituting valine for glutamic acid, was identified as the critical factor for the phenotype. Functional complementation and generation of knockout lines in the IR64 background confirmed the central role of OsRPT5A in controlling this trait. Our study also revealed that OsRPT5A is constitutively expressed across various tissues, with its subcellular localization unaffected by mutations. Notably, we observed an abnormal accumulation of reactive oxygen species (ROS) in rpt5a mutants, suggesting a disruption in the ROS system. Complementation studies indicated OsRPT5A's involvement in ROS homeostasis and catalase activity regulation. Moreover, the rpt5a mutant exhibited enhanced resistance to Xanthomonas oryzae pv. oryzae (Xoo), highlighting OsRPT5A's role in rice's pathogen resistance mechanisms. These findings elucidate the genetic basis of the spotted leaf phenotype and emphasize the intricate interplay between plant defense responses and developmental pathways.

Regeneration is a fundamental process much attributed to functions of adult stem cells. In last decades delivery of suspended adult stem cells is widely adopted in regenerative medicine as a leading mean of cell therapy. However, adult stem cells can not complete the task of human body regeneration effectively by themselves as far as they need a receptive microenvironment (the niche) to engraft and perform properly. Understanding of mechanisms underlying mammalian regeneration lead us to an assumption that improved outcomes of cell therapy requires a specific microenvironment generated in damaged area prior to stem cell delivery. To certain extent it may be achieved by delivery of mesenchymal stromal cells (MSC), not in dispersed form, but rather self-organized in cell sheets (CS) – tissue-like structures comprising of viable cells and microenvironment components: extracellular matrix and soluble factors deposited in the matrix. In this communication we highlight a potential role of mesenchymal stromal cells (MSC) as regeneration organizers and speculate that this function emerges in CS. This concept shifts our understanding of therapeutic mechanism underlying a widely known CS-based delivery method for regenerative medicine.

Articular cartilage healing and repair is one of the biggest clinical challenges in trauma and orthopaedic medicine, leading to high economic loss due to athletic impairment in sport horses. Multipotent Mesenchymal stem/stromal cells are part of novel therapeutic arsenal aimed at tissue regeneration and restoring organ function. These cells release biomolecules and factors in the culture media, producing the so called conditioned medium, which have a pro-regenerative effect through paracrine mechanisms. Considering this, a therapeutic product combining equine synovial membrane derived Mesenchymal stem/stromal cells and equine umbilical cord stroma-derived Mesenchymal stem/stromal cells conditioned medium was employed. In this work the treatment of two articular defects, in the first phalanx and third metacarpus of the left front limb of a five-year-old horse, is described. Following surgical debridement of the lesions, the treatment comprised two intra-articular administrations of the above-mentioned therapeutic combination, 15 days apart. This was followed by a thorough rehabilitation program. A second-round treatment was performed 6 months later. Diagnostic imaging demonstrated significant improvement of the articular defects. The clinical outcome allowed a full return to the athletic performance demonstrating the safety and potential advantages of this approach when compared with other therapeutic options.

Regeneration is a fundamental perpetual tissue process much attributed to functions of adult stem cell. In last decades delivery of adult stem cells to restore tissue structure is widely adopted in regenerative medicine. However, delivery of stem cells can not complete the task of human body regeneration effectively as far as cells need a basis to form a tissue. Certain improvement can be achieved when cells are organized to cells sheets (CS) – primitive tissue-engineered structures comprising of viable cells and ECM proteins. This led us to an assumption that after damage an intermediate feeder is structure formed as a ground for future tissue resulting in gradients of stimuli required to attract other cells (vascular, neural, epithelial, parenchyma etc.) in an organized manner. This feeder acquires increasing heterogeneity and becomes a guiding feeder that provides basic level of organization to increase complexity of structure up to normal tissue. We also highlight potential role of adult mesenchymal stromal cells (MSC) as the main source of guiding feeder and support it by our recent knowledge of their biological function. Finally, we assume that CS known to be a feasible delivery tool in therapeutics resemble guiding feeder and show our own data indicating properties of MSC-based CS. Furthermore, this concept shifts our understanding of therapeutic mechanism underlying a widely known delivery method for regenerative medicine.

Ephrin type A receptor 2 (EphA2) binds to membrane-bound ligands, ephrin A1, A2, and A5, eliciting bidirectional signaling. This signaling regulates many physiological processes, such as tissue development, homeostasis, and regeneration. The dysregulation of the EphA2-ephrins axis contributes to various diseases, including cancers. The high expression of EphA2 is observed in various cancers, which promotes cancer malignancy, whereas its levels are relatively low in most normal adult tissues. Therefore, EphA2 is a promising target for cancer therapy. In this study, we developed anti-human EphA2 monoclonal antibodies using the Cell-Based Immunization and Screening method. Among them, a clone Ea₂Mab-7 (IgG₁, κ) exhibited a high affinity and sensitivity in flow cytometry. The dissociation constant values of Ea₂Mab-7 for CHO/EphA2 and MDA-MB-231 cells were determined as 7.7 × 10⁻⁹ M and 2.1 × 10⁻⁹ M, respectively. Furthermore, Ea₂Mab-7 can detect endogenous EphA2 in western blot and immunohistochemistry. Therefore, the Ea₂Mab-7 is highly versatile for basic research and is expected to contribute to clinical applications, such as antibody therapy and tumor diagnosis.

Infectivity assays are the key analytical technology for development of manufacturing processes for virus-based therapeutics. Here, we introduce a novel assay format that utilizes label-free bright field images to determine the kinetics of infection-dependent changes in cell morphology. In particular, cell rounding is directly proportional to the amount of infectious virus applied, enabling rapid determination of viral titers in relation to a standard curve. Our kinetic infectious virus titer (KIT) assay is stability-indicating and, due to its sensitive readout method, provides results within 24 hours post-infection. Compared to traditional infectivity assays, which depend on a single readout of an infection endpoint, cumulated analysis of kinetic data by a fit model results in precise results (CV &lt; 20%) based on only three wells per sample. This approach allows for a high throughput with ~400 samples processed by a single operator per week. We demonstrate the applicability of the KIT assay for VSV-GP and NDV, but it can potentially be extended to a wide range of viruses that induce morphological changes upon infection. The versatility of this assay, combined with its independence from specific instruments or software, makes it a promising solution to overcome the analytical bottleneck in infectivity assays within the pharmaceutical industry and as a routine method in academic research.

The cell concentration measurement on a culture assay using bioimpedance is a very useful tool, but it is complex to translate impedance to cell concentration values. The purpose of this work is to find a method to obtain in real time the cell concentration values for a given cell-culture assay using an oscillator as the measurement circuit. From a basic cell-electrode model, enhanced models of the cell culture immersed in a saline solution (culture medium) can be derived. These models can be used in a fitting routine to real time estimation of the cell concentration in a cell culture, using the oscillation frequency and amplitude delivered by measurement circuits proposed by the authors. Based on real experimental data (frequency and amplitude of oscillations) obtained by connecting the cell culture to an oscillator as a load, the fitting routine is simulated, and real time data of cell concentration is achieved. These results are compared with concentration data found by traditional optical methods for counting. In addition, the error obtained is divided and analyzed in two parts: in the first part of the experiment (when the few cells are adapting to the culture medium) and the second part of the experiment (when the cells grow exponentially until they completely cover the well).Low error values are obtained in the growth phase of the cell culture (the relevant phase), therefore the results obtained are considered to be promising, proving that the fitting routine is valid, and that the cell concentration can be measured in real time using an oscillator.

Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to IFN-ω and IFN-α2 allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.

Cloud Computing is a promising and emerging technology that is rapidly being adopted by many IT companies due to a number of benefits that it provides, such as large storage space, low investment cost, virtualization, resource sharing, etc. Users are able to store a vast amount of data and information in the cloud and access it from anywhere, anytime on a pay-per-use basis. Since many users are able to share the data and the resources stored in the cloud, there arises a need to provide access to the data to only those users who are authorized to access it. This can be done through access control schemes which allow the authenticated and authorized users to access the data and deny access to unauthorized users. In this paper, a comprehensive review of all the existing access control schemes has been discussed along with analysis. Keywords: role-based access control, attribute-based access control, attribute-based encryption

Tumour microenvironment, composed of pro- and anti-tumour immune cells, affects cancer cells behaviour. We aimed to evaluate if tumour-infiltrating lymphocyte (TIL) density and TILs subtypes in core biopsies at diagnosis of breast cancer patients could predict pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably anti-tumour (CD8+, CXCL13+) and pro-tumour (PD-1+, FOXP3+) immune cells. A prospective, non-interventional study including 171 participants undergoing NST was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p=0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p=0.232), Ki-67 (p=0.001), node-negative status (p=0.024), and HER2+/triple negative vs luminal B-like subtype (p&lt;0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

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.

Quantitative polymerase chain reaction (qPCR) has emerged as an important bioanalytical method for assessing the pharmacokinetics of human cell-based medicinal products after xenotransplantation into immunodeficient mice. A particular challenge in bioanalytical qPCR studies is that the different tissues of the host organism can affect amplification efficiency and amplicon detection to varying degrees, and ignoring these matrix effects can easily cause a significant underestimation of the true number of target cells in a sample. Here we describe the development and drug regulatory-compliant validation of a TaqMan® qPCR assay for quantification of mesenchymal stromal cells in the range of 125 to 20,000 cells/200 µl lysate by amplification of a human-specific, highly repetitive αsatellite DNA sequence of the chromosome 17 centromere region HSSATA17. Assessment of matrix effects in 14 different mouse tissues and blood revealed a wide range of spike recovery rates across the different tissue types from 11 to 174%. Based on these observations, we propose to perform systematic spike-and-recovery experiments during assay validation and to correct for the effects of the different tissue matrices on cell quantification in subsequent bioanalytical studies by multiplying the back-calculated cell number by tissue-specific factors derived from the inverse of the validated percent recovery rate.

Background: This practice guideline was developed by the Chronic Kidney Disease (CKD) Task Force, which was composed of clinical and methodological experts. The Saudi Arabian Ministry of Health and its Health Holding Company commissioned this guideline project to support the realization of the Vision 2030's healthcare transformation pillar. Methods: The guideline synthesis was guided by the GRADE-ADOLOPMENT methodology. Results: The final adoloped guideline addressed 12 clinical questions on blood pressure management in patients with CKD through a set of recommendations and performance measures. The recommendations included antihypertensive agents in children, non-renin angiotensin system inhibition (Non-RASi) vs RASi in adults, intensive vs standard blood pressure targets, early vs late assessment for kidney replacement therapy (KRT), late vs early preparation strategy for KRT, CKD symptoms during assessment for KRT or conservative management, initiation of KRT in patients with deteriorating CKD, choice of KRT modality or conservative management in certain CKD patient groups, changing or discontinuing KRT modalities, review frequency for KRT or conservative management, and Information, education and support. Conclusions: These conditional recommendations were based on low to very low certainty of evidence that highlights the need for high-quality randomized trials comparing different antihypertensive agents in patients with CKD.

The ever-growing student population and limited administrative resources strain traditional communication channels within educational institutions. Chatbot technology offers a promising solution, but current limitations can impede effective student-administration interaction. This paper proposes a hybrid chatbot model to enhance reliability in educational administration by addressing the limitations of generative models like ChatGPT. We investigate three individual chatbot approaches (rule-based, retrieval-based, and generative-based) to handle educational inquiries. An evaluation assessed their strengths, weaknesses, and user experience. Based on these findings, a hybrid model with an intelligent classifier for query routing was developed. This model leverages each approach's strengths and addresses uncertainty in the generative model to achieve increased accuracy and reliability. Our results demonstrate an accuracy improvement compared to individual models. This work contributes to developing adaptable chatbot systems capable of addressing a wider range of user inquiries, which is particularly beneficial in resource-constrained educational settings. Additionally, the proposed model demonstrates competitive performance when benchmarked against existing state-of-the-art administrative educational chatbots. Furthermore, by automating routine inquiries and offering 24/7 access to information and support, this model has the potential to reduce administrative workload and improve the overall student experience significantly. Moreover, the modular design of our hybrid model offers a foundation for future research on personalizing chatbot interactions and integrating domain-specific knowledge for enhanced communication within educational environments.

Treating central giant cell granuloma (CGCG) is challenging due to high recurrence rates and variable therapy responses. This study examines the efficacy of various treatments in reducing CGCG recurrence. A literature review explored outcomes of surgical excision, curettage, intralesional corticosteroid injection, and adjuvant therapy, considering factors like lesion location, size, and histological features. Aggressive surgical techniques such as en bloc resection were found to potentially lower recurrence rates compared to conservative approaches. However, treatment should be tailored to individual patient needs. Further research is needed to confirm these findings and improve treatment strategies. A concise literature review was conducted using PubMed, MEDLINE, and Google Scholar, focusing on papers published from 1986 to 2024. Search terms included "central giant cell granuloma," "recurrence," "treatment modalities," and "surgical excision". Studies reporting recurrence rates and treatment outcomes for CGCG were analyzed. Twenty-nine studies were reviewed, including six studies on surgical excision and curettage, eight studies on intralesional corticosteroid injections, six studies on calcitonin therapy, five studies on interferon alpha therapy and four studies on the therapy with denosumab. Analysis indicated that aggressive surgical treatments like en bloc resection were associated with lower recurrence rates compared to conservative methods. Predictors of recurrence included lesion size (&gt;3 cm), location (mandible), and aggressive histopathological features. Aggressive surgical excision combined with nonsurgical methods may lower recurrence rates, while conservative techniques remain viable in some cases. Further prospective research is needed to validate these findings and enhance CGCG treatment options.

Management of multiple primary cancers, a not so infrequent event in oncology practice, is a critical issue due to the lack of literature . In this study, we reported the case of a patient with metachronous double metastatic non small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. She achieved a progression free survival and an overall survival (OS) of 28 months for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapies treatments displayed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. it is interesting to note that two neoplasms shared a commune mutation of B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a putative justification of the long survival of the patient considered in this report.

Cellular locomotion is required for survival, fertility, proper embryonic development, regeneration, and wound healing. Cell migration is a major component of metastasis, which accounts for two-thirds of all solid tumor deaths. While many studies have demonstrated increased energy requirements, metabolic rates, and migration of cancer cells compared to normal cells, few have systematically compared normal and cancer cell migration as well as energy requirements side by side. Thus, we investigated how non-malignant and malignant cells migrate utilizing several cell lines from the breast and lung. Initial screening was done in an unbiased high-throughput manner for the ability to migrate/invade on collagen and/or Matrigel. We unexpectedly observed that all the non-malignant lung cells moved significantly faster than cells derived from lung tumors regardless of growth media used. Given the paradigm-shifting nature of our discovery, we pursued possible mechanisms responsible. Neither mass, cell doubling, nor volume, accounted for the individual speed and track length of the normal cells. Non-malignant cells had higher levels of ATP at premigratory-wound induction stages. Meanwhile, cancer cells also increased ATP at premigratory-wound induction – but not to the levels of the normal cells, indicating the possibility for further therapeutic investigation.

The loss or dysfunction of skeletal tissue often necessitates surgical intervention, particularly in cases involving trauma, tumors, or abnormal development leading to critical-sized defects. Despite autografts being considered the gold standard for bone grafts, their limitations and complications prompt the exploration of alternative approaches for bone repair and regeneration. Current advancements in bone tissue engineering have led to innovative strategies aiming to regenerate injured bone structures, providing viable alternatives to traditional autografts or allografts. Among these strategies, Hydrogel Microparticles (HMPs) have emerged as promising scaffolds due to their notable characteristics, including high porosity and mechanical tunability. HMPs play an important role in facilitating vasculature formation, mineral deposition, and overall bone tissue regeneration. HMPs, fabricated through various techniques, exhibit versatility in functions such as drug and cell delivery, structural scaffolding, and bioinks for 3D printing. In addition, these microgels can be injected for minimally invasive delivery and can display modular properties with different designs and configurations. This review exclusively focuses on the advancements in HMPs for bone regeneration, delving into synthesis and functionalization techniques while highlighting their diverse applications documented in the literature. Our aim is to shed light on the unique benefits and potential of HMPs in the intricate field of engineering bone tissue.

Most oral squamous cell carcinomas (OSCCs) arise from oral epithelial dysplasia; however, there is no useful marker for early OSCC detection, likely owing to the inability to continuously observe the carcinoma sequence. We aimed to establish an experimental model to observe changes in the sequential expression pattern of mRNA and protein in the same rat using liquid-based cytology techniques. Cytology specimens were collected from a 4-nitroquinoline 1-oxide-induced rat tongue cancer model at 2, 5, 8, 11, 14, 17, and 21 weeks. We examined candidate biomarker expression using immunocytochemistry and quantitative real-time PCR. The percentage of positively stained nuclei was calculated as the labeling index (LI). All rats had OSCC of the tongue at 21 weeks. Brd4 (Brd4), Myc (c-Myc), and Tp53 (p53) mRNA levels were upregulated during progression from negative for intraepithelial lesion or malignancy to SCC. Brd4- and c-Myc-LI were increased in low- and high-grade squamous intraepithelial lesions and SCC specimens. p53-LI was significantly increased in SCC specimens. Our experimental model allowed the observation of sequential morphological changes and mRNA and protein expression patterns in the same rat during carcinogenesis. By reducing the false negative rate, BRD4 and c-Myc can be useful markers for the early detection of OSCC.

Large lithium-ion batteries (LIBs) in electric vehicles and energy storage systems demonstrate different performance and lifetime compared to small LIB cells, owing to the size effects generated by the electrical configuration and property imbalance. However, the calculation time for performing life predictions with three-dimensional (3D) cell models is undesirably long. In this paper, a lumped cell model with equivalent resistances (LER cell model) is proposed as a reduced order model of the 3D cell model, which enables accurate and fast life predictions of large LIBs. The developed LER cell model is validated via the comparisons with results of the 3D cell models by simulating a 20-Ah commercial pouch cell (NCM/graphite) and the experimental values. In addition, the LER cell models are applied to different cell types and sizes, such as a 20-Ah cylindrical cell and a 60-Ah pouch cell.

The increasing adoption of student-centred learning environs by the institutions of higher education in business, has led to new mechanisms and methodologies such as the Simulation-Based Learning (SBL), Problem-Based Learning (PBL) and Challenge-Based Learning (CBL). Literature has shown evidence of raising interest in these methodologies towards a more experiential paradigm with regard to upcoming events from the surrounding real-world context. This paper presents a Systematic Bibliographic Literature Review (SBLR) with respect to the integration and application of these innovative and collaborative methodologies in higher education. It aimed to identify its relevant advantages, challenges, and consequences for the future of business education. Bibliographic databases were searched for documents published up to May 2024 to categorize key topics discussed in the literature on SBL, PBL and CBL. The review process identified 89 empirical and non-empirical papers on SBL, PBL and CBL, business related paperwork, which resulted from the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) method. PRISMA is a framework with evidence-based data designed to help authors perform a systematic literature review. Data analysis revealed diverse subthemes for those methodologies uses in business higher education institutions. The research questions “What are the advantages, challenges and implications of SBL, PBL and CBL altogether, in the training of business students?” guided the study. The central output of the research is the discovery of the varying uses of SBL, PBL and CBL overall, to cope with diverse demands arising within environmental context. Future research directions are suggested.

The Peripheral giant cell granuloma (PGCG) is an asymptomatic, non-neoplastic and proliferative lesion of unknown etiology. Some possible pre-disposing factors such as hormonal changes dur-ing pregnancy, have been suggested. However, the association between PGCG and pregnancy is controversial. There are few reported clinical cases of pregnancy-associated PGCG in the litera-ture, and they occurred only in the lower jaw. The present report is on a 35-year-old female pa-tient at 36 weeks of gestation who presented with a PGCG in the central and lateral incisors of the upper jaw. The management consisted of surgical excision, along with curettage of the affected bony walls. The diagnosis was based on clinical results and imaging examinations, and it was histopathologically confirmed. The patient underwent postoperative follow-up evaluations at 3, 6 and 12 months, and there were no signs of recurrence.

Plant stem cell cultures have so far been established in only a few plant species using cambial meristematic cells. The presence of stem cells or stem cell-like cells in other organs and tissues of the plant body, as well as the possibility of de novo generation of meristematic cells from differentiated cells, allows to consider the establishment of stem cell cultures in a broader range of species. Therefore, this study aimed to establish a stem cell culture of the medicinal plant Calendula officinalis L. Callus tissues were induced from explants taken from leaves and roots. Appropriate combinations of plant growth regulators and light parameters for in vitro cultivation were selected. Already at this stage, stem and dedifferentiated cells could be identified, and cell suspension cultures were established from specific parts of the formed callus. Cell suspension cultures with a high proportion of stem cells originating from roots (92–93%) or leaves (72–73%) were developed. The amount of stem cells derived from the roots in the cell suspension reached a plateau at a level of 5.60–5.72105.

Reduced-order electrothermal models play a key role in the design and control of lithium- ion cell stacks, calling for accurate model parameter calibration. This paper presents a complete electrical and thermal experimental characterization procedure for coupled modeling of cylindrical lithium-ion cells in order to implement them in a prototype Formula SAE hybrid racing car. The main 4goal of the tests is to determine cell capacity variations with temperatures and discharge currents, to predict the open circuit voltage of the cell and its entropic component. A simple approach for the characterization of the battery equivalent electrical circuit and a two-steps thermal characterization method are also shown. The investigations are carried out on four commercial 18650 NMC lithium cells. The model demonstrated to predict the battery voltage at a RMS error lower than 20mV and the temperature to a RMS error equal to 0.5 ◦C. The authors hope that this manuscript can contribute to the development of standardized characterization techniques for such cells, while offering experimental data and validated models that can be used by researchers and BMS designers in different applications.

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a crucial role in monocyte survival and differentiation. Its overexpression is associated with aggressive tumor characterized by an immunosuppressive microenvironment and poor prognosis. CSF-1R ligands, IL-34 and M-CSF, are produced by many cells in the tumor microenvironment (TME), suggesting a key role for the receptor in the crosstalk between tumor, immune and stromal cells in the TME. Recently, CSF-1R expression was reported at the cell membrane of cancer cell from different solid tumors, capturing the interest of various research group interested in investigating the role of this receptor in non-myeloid cells. This review summarizes current data available on the expression and activity of CSF-1R in different tumor types. Notably, CSF-1R+ cancer cells have been shown to produce CSF-1R ligands, indicating that CSF-1R signaling is positively regulated in autocrine manner in cancer cells. Recent research demonstrated that CSF-1R signaling enhances cell transformation by supporting tumor cell proliferation, invasion, stemness and drug resistance. In addition, this review covers recent therapeutic strategies, including monoclonal antibodies and small molecule inhibitors, targeting the CSF-1R and designed to block the pro-oncogenic role of CSF-1R in cancer cell.

This comprehensive review delves into the multifaceted aspects of ERK signaling and the intricate mechanisms underlying distinct cellular fates. ERK1 and ERK2 (ERK) govern proliferation, transformation, epithelial-mesenchymal transition, differentiation, senescence, or cell death, con-tingent upon activation strength, duration, and context. The biochemical mechanisms underlying these outcomes are inadequately understood, shaped by signaling feedback and the spatial localization of ERK activation. Generally, ERK activation aligns with the Goldilocks principle in cell fate determination. Excessive or insufficient ERK activity inhibits growth, whereas moderated activation supports proliferation and survival. Unraveling the intricacies of how the degree of ERK activation dictates cell fate requires deciphering mechanisms encompassing protein stability, transcription factors downstream of ERK, and the chromatin landscape.

This hypothesis demonstrates that the efficiency of Loop-Mediated Isothermal Amplification (LAMP) for nucleic acid detection can be positively influenced by preconcentration of microbial cells onto hydrophobic paper surfaces. The mechanism of this model is based on the high attraction of microbes towards hydrophobic surfaces. Extensive studies have demonstrated that hydrophobic surfaces exhibit enhanced bacterial and fungal adhesion. The preconcentration approach by exploiting this inherent affinity of hydrophobic paper substrates enables the adherence of a greater number of target cells, resulting in a higher concentration of target templates for amplification directly from urine samples. In contrast to conventional methods, which often involve complex procedures, this approach offers a simpler, cost-effective, and user-friendly alternative. Moreover, the integration of cell adhesion, LAMP amplification, and signal readout within paper origami-based devices can provide a portable, robust, and highly efficient platform for rapid nucleic acid detection. This innovative hypothesis holds significant potential for point-of-care (POC) diagnostics and field surveillance applications. Further research and development in this field will advance the implementation of this technology, contributing to improved healthcare systems and public health outcomes.

Background: Extensive-stage SCLC (ES-SCLC) treatment has recently been revolutionized by the advent of immune checkpoint inhibitors. This survey was conducted to evaluate the current pattern of care among Italian clinicians, in particular about the integration with radiation therapy (RT). Methods: In June 2023, 225 Italian cancer care professionals were invited to 21-question web-based survey about the ES-SCLC management through personal contacts and the Italian Association for Radiotherapy and Clinical Oncology (AIRO) network. Results: We received 90 responses, the majority were radiation oncologists (89%) with more than 10 years of experience (51%). Preferred management of ES-SCLC in patients with a good performance status was concomitant chemo-immunotherapy (84%). Almost all respondents recommended prophylactic cranial irradiation (PCI) (85%), taking into account age and thoracic response; PCI was performed mainly between the end of chemotherapy before starting immunotherapy (37%), with three-dimensional conformal technique (46%). Furthermore, 83% of respondents choose to deliver thoracic RT in case of both intrathoracic and extrathoracic response with a RT schedule of 30 Gy/10 fractions. Stereotactic RT is increasingly being used in oligoprogressions. Conclusions: Our analysis showed the variability of real-world management of ES-SCLC. Future clinical trials and developments are needed to improve the multidisciplinary treatment of these patients.

On using a 3D model to teach students a topic in astronomy, feedback was evaluated via a questionnaire. Analysis of students' responses to the questions revealed that user interface had a significant impact on their attitudes, which in turn could increase users' willingness to use immersive technology in e-learning. The results also showed that improving visual features through immersive technology and augmented reality tools were effective. The results confirm all hypotheses about positive relationships between facilitating conditions and usability of metaverse technology for students' attention and study motivation.

In recent years there has been an increasing interest in developing novel materials based on natural biopolymers as a renewable alternative of petroleum-based plastics. The availability of proteins derived from agricultural by-products, along with their favourable properties, has fostered a renewed interest in protein-based materials, promoting research in innovative technologies. In this study we propose the use of rapeseed protein-rich meal as main ingredient for the preparation of novel sustainable materials combining excellent environmental properties such as biodegradability and renewable origin. Application as sustainable products in the present high-tech society needs modification of basic native properties of these natural compounds. The original route proposed in this paper consists in the preparation via compression moulding of flexible biomaterials stabilized by crosslinkers/chain extenders. Investigation of the effects of different denaturing and disulfide bond reducing agents, crosslinkers, and preparation conditions on the material mechanical behaviour demonstrated that the novel materials have appreciable strength and stiffness. The results show the potential of utilizing full meal from vegetable by-products to prepare protein-based materials with granted ecofriendly characteristics and mechanical properties adequate to specific structural applications.

A sustainable, scalable source of energy‐dense chemical fuel is urgently needed to ensure the security of our energy supply for future generations. Solar energy is the only renewable energy source of sufficient scale to replace fossil fuels and meet rising environmental demand. Hydrogen is expected to play a key role as an energy carrier in future energy systems of the world. As fossil fuel supplies become scarcer and environmental concerns increase, hydrogen is likely to become an increasingly important chemical energy carrier and eventually may become the principal chemical energy carrier. When most of the world’s energy sources become non-fossil based, hydrogen and electricity are expected to be the two dominant energy carriers for the provision of end-use services. Photocatalytic hydrogen evolution from water by solar energy over semiconductors offers a promising way for clean and renewable production of hydrogen. The TiO2-based materials have received considerable attention in recent years due to their extensive application in photocatalysis for hydrogen evolution. Though TiO2 is the most widely investigated photocatalyst for hydrogen evolution, it still provides low photocatalytic activity due to the wide bandgap that results in photocatalytic activity only under ultraviolet (UV) irradiation. Modification of TiO2 photocatalysts with several transition metals has been extensively studied to extend the absorbance capacity of TiO2 into the visible range. The effect of different photocatalytic deposition and reaction parameters also play major roles in enhancing the photostability of photoanode and increasing the hydrogen gas output, respectively.

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming. iCMs exited cell cycle along the process of reprogramming with decreased percentage of EdU⁺/αMHC-GFP⁺ cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFP^high iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFP^low cells; however, S-phase synchronization didn’t enhance the polycistronic-MGT reprogramming, in which cell-cycle exit had been accelerated. In conclusion, post-infection synchronization of S-phase facilitated the early progression of GMT-reprogramming through a mechanism of enhanced cell-cycle exit.

Stem/progenitor cell transplantation is a potential novel therapeutic strategy to induce angiogenesis in ischemic tissue, which can prevent major amputation in patients with advanced peripheral artery disease (PAD). Thus, clinicians can use cell therapies worldwide to treat PAD. However, some cell therapy studies did not report beneficial outcomes. Clinical researchers suggested that classical risk factors and comorbidities may adversely affect the efficacy of cell therapy. Some studies have indicated that the response to stem cell therapy varies among patients even in those harboring limited risk factors. This suggested the role of undetermined risk factors, including genetic alterations, somatic mutations, and clonal hematopoiesis. Personalized stem cell-based therapy can be developed by analyzing individual risk factors. These approaches must consider several clinical biomarkers and perform studies (such as genome-wide association studies (GWAS)) on disease-related genetic traits and integrate the findings with those of transcriptome-wide association studies (TWAS) and whole-genome sequencing in PAD. Additional unbiased analyses with state-of-the-art computational methods, such as machine learning-based patient stratification, are suited for predictions in clinical investigations. The integration of these complex approaches into a unified analysis procedure for the identification of responders and non-responders before stem cell therapy, which can decrease treatment expenditure, is a major challenge to increase the efficacy of therapies.

Background: Cardiac development is a complex developmental process. The early cardiac straight tube is composed of an external myocardial layer and an internal endocardial lining. Soon after rightward looping, the embryonic heart becomes externally covered by a new epithelial lining, the embryonic epicardium. A subset of these embryonic epicardial cells migrate and colonize the embryonic myocardium, contributing to distinct cell types. In recent years, our understanding of the molecular mechanisms that govern proepicardium and embryonic epicardium formation has greatly increased. We have recently witnessed a novel layer of complexity governing gene regulation with the discovery of non-coding RNAs. Our laboratory recently identified three distinct lncRNAs, adjacent to the Wt1, Bmp4 and Fgf8 chicken gene loci, with enhanced expression in the proepicardium that are distinctly regulated by Bmp, Fgf and thymosin 4, providing support of their plausible implication in epicardial formation. Methods: Expression of lncRNAs was analyzed in different chicken and mouse tissues as well as their subcellular distribution in chicken proepicardial, epicardial, ventricle explants and in different murine cardiac cell types. lncRNA transcriptional regulation was analyzed by using siRNAs and expression vectors of different transcription factors in chicken and mouse. Antisense oligonucleotides were used to inhibit Gm14014 expression. Cardiac injury was induced ex vivo in mouse ventricle explants by cryoinjury. Furthermore, RT-qPCR, immunocytochemistry, RNA pulldown, Western blot, viability and cell migration assays were conducted to investigate the biological function of Wt1_76127 and Gm14014. Results: We demonstrated that Wt1_76127 in chicken and its evolutionarily conserved homologue Gm14014 in mice are widely distributed in different embryonic and adult tissues and distinctly regulated by cardiac enriched transcription factors, particularly Mef2c and Nkx2.5. Gm14014 is distinctly regulated in mouse ventricular cryoinjury ex vivo models, displaying a negative correlation with epicardial and epithelial to mesenchymal transition markers. Furthermore, silencing assays demonstrated that mouse Gm14014, but not chicken Wt1_76127, is essential for epicardial, but not endocardial or myocardial cell migration. Such process is governed by partnering with Myl9, promoting cytoskeletal remodeling. Conclusion: Our data evidence that Gm14014 plays a pivotal role in epicardial cell migration essential for heart regeneration.

Background. Currently, most of the research in breast cancer has been carried out in conventional two-dimensional (2D) cell culture due to its practical benefits, however, the three-dimensional (3D) cell culture is becoming the model of choice in cancer research because it allows cell-cell and cell-extracellular matrix (ECM) interactions, mimicking the native microenvironment of tumors in vivo. Methods. in this work, we evaluated the effect of 3D cell organization on the expression pattern of miRNAs (by Small-RNAseq) and mRNAs (by microarrays) in the breast cancer SKBR3 cell line and analyzed the biological processes and signaling pathways regulated by the differ-entially expressed protein-coding genes (DE-mRNAs) and miRNAs (DE-microRNAs) found in the organoids. Results. We obtained well-defined cell-aggregated organoids with a grape cluster-like morphology with a size up to 9.2×105 μm3. The transcriptomic assays showed that cell growth in organoids significantly affected (all p < 0.01) the gene expression patterns of both, miRNAs and mRNAs, finding 20 upregulated and 19 downregulated DE-microRNAs, as well as 49 upregulated and 123 downregulated DE-mRNAs. In silico analysis showed that a subset of 11 upregulated DE-microRNAs target 70 downregulated DE-mRNAs. These genes are involved in 150 gene on-tology (GO) biological processes such as regulation of cell morphogenesis, regulation of cell shape, regulation of canonical Wnt signaling pathway, morphogenesis of epithelium, regulation of cy-toskeleton organization, as well as in the MAPK and AGE-RAGE signaling KEGG-pathways. In-terestingly, hsa-mir-122-5p (Fold Change (FC)=15.4), hsa-mir-369-3p (FC=11.4), and hsa-mir-10b-5p (FC=20.1) regulated up to the 81 % of the 70 downregulated DE-mRNAs. Conclu-sion, the organotypic 3D cell-organization architecture of breast cancer SKBR3 cells impacts the expression pattern of miRNAs-mRNAs network mainly through overexpression of hsa-mir-122-5p, hsa-mir-369-3p, and hsa-mir-10b-5p. All these findings suggest that the interaction between cell-cell and cell-ECM as well as the change in the culture architecture impacts gene ex-pression, and therefore, support the pertinence of migrating breast cancer research from conven-tional cultures to 3D models.

Many theoretical models of iron-based superconductors have been proposed but Tc calculations based on the models are usually missing. We have chosen two models of iron-based superconductors in the literature and then compute the Tc values accordingly: Recently two models have been announced which suggest that superconducting electron concentration involved in the pairing mechanism of iron-based superconductors may have been underestimated, and that the antiferromagnetism and the induced xy potential may even have a dramatic amplification effect on electron-phonon coupling. We use bulk FeSe, LiFeAs and NaFeAs data to calculate the Tc based on these models and test if the combined model can predict the superconducting transition temperature (Tc) of the nanostructured FeSe monolayer well. To substantiate the recently announced xy potential in the literature, we create a two-channel model to separately superimpose the dynamics of the electron in the upper and lower tetrahedral plane. The results of our two-channel model support the literature data. While scientists are still searching for a universal DFT functional that can describe the pairing mechanism of all iron-based superconductors, we base on the ARPES data to propose an empirical combination of DFT functional for revising the electron-phonon scattering matrix in the superconducting state, which ensures that all electrons involved in iron-based superconductivity are included in the computation. Our computational model takes into account this amplifying effect of antiferromagnetism and the correction of the electron-phonon scattering matrix together with the abnormal soft out-of-plane lattice vibration of the layered structure, which allows us to calculate theoretical Tc values of LiFeAs, NaFeAs and FeSe as a function of pressure that correspond reasonably well to the experimental values. More importantly, by taking into account the interfacial effect between an FeSe monolayer and its SrTiO3 substrate as an additional gain factor, our calculated Tc value is up to 91 K high, and provides evidence that the strong Tc enhancement recently observed in such monolayers with Tc reaching 100 K may be contributed from the electrons within the ARPES range.

LCK, a member of the Scr kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibition of Lck has been mainly to treat hematologic malignancies with a high rate of success. They may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown inter-esting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs host disease. Drug repurposing and bioinformatics can aid in solving several unsolved is-sues on the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

Transfer factor is the name given to material derived from activated lymphocytes that is probably composed of a complex of a peptide and a short segment of RNA and which has the reported ability to transfer specific T cell immunity to uncommitted lymphocytes. Many independent groups around the world reported isolating transfer factors between 1955 and 1990 and demonstrating their ability to transfer passive immunity from one animal or individual to another, often within 24 hours of inoculation. Such activity is potentially revolutionary both in making T cell vaccines readily manufacturable and also because the existence of transfer factors would undermine the basic assumptions of the clonal selection theory, which currently dominates immunological theory. Unfortunately, lack of the microanalytical and synthetic techniques required to properly identify transfer factors, combined with safety factors associated with it derivation from blood sources susceptible to HIV and prion infections, put an end to transfer factor research after 1990. This paper reviews the evidence supporting transfer factor activity and suggests that this potentially revolutionary concept be resurrected and subjected to renewed scrutiny in light of CRISPR-Cas mechanisms and because of its potential to make possible T cell vaccination and provide a novel basis for understanding immunological function.

Coastal zones, although vital for human livelihoods and environmental services, are increasingly vulnerable to climate change, especially communities dependent on marine ecosystems. These areas face significant threats from urbanization, population growth, and climate impacts, leading to biodiversity loss and ecosystem degradation. Recognizing these challenges, the United Nations declared 2021--2030 the Decade for Ecosystem Restoration, led by the UNEP and FAO, with the aim of restoring degraded ecosystems to achieve sustainable development goals (SDGs). The link between healthy ecosystems and disaster risk reduction (DRR) has gained global prominence, especially through the Sendai Framework for Disaster Risk Reduction (SFDRR), which emphasizes the importance of ecosystems in mitigating risks. Despite this, many tools for assessing risks in different ecosystem scenarios remain inaccessible to key stakeholders in disaster management. Advances in spatial modelling have supported ecosystem management, policy-making, and ecosystem health assessment, particularly following the Millennium Ecosystem Assessment. These models have been applied in regions such as the Great Bahamas, Haiti, and the Republic of Congo, helping shape ecosystem-based approaches to development. Improving access to spatial tools and models is crucial to enabling effective ecosystem-based DRR and climate adaptation strategies.

One of the efficient data mining tools is density-based clustering, including the density grid-based clustering. However, a common drawback always existing in clusters made by the density grid-based method is the existence of weakly connected grids deriving mainly from noise. Appearing such an unwanted connection with a high frequency reduces the accuracy of the obtained cluster data space (CDS) and its application efficiency. Here, we present an essential improvement to overcome this problem. First, we describe a concept of the weak-connected grid cell (WCG) and present a fuzzy-type approximation to depict the density-based distribution of data points at grid nodes. Then, we propose a strategy of searching WCG for density grid-based clustering (SWCG-DGB) to set up a CDS, filter noise, and tune the created CDS. A buffer is deployed during this phase to collect border points and filter noise, which improves the computational time significantly, especially for noisy datasets. Results from numerical surveys reflected the compared efficiency of this method in clustering validity, including the accuracy of the number of clusters.

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that alt-hough preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance and an uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limit-ing factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bac-terial proteins are targeted being the biosynthesis of the cell wall and the energetic metabolism two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and how chemical probes for protein profiling enabled the identification of new targets and bi-omarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

Lake Rawapening, Semarang Regency, Indonesia, has incorporated a holistic plan in its management practices. However, despite successful target achievements, some limitations remain that a review of its management plan is needed. This paper identifies and analyzes existing lake management strategies as a standard specifically in Lake Rawapening by exploring various literature, both legal frameworks and scholarly articles indexed in Google Scholar and published in Water by MDPI about lake management in many countries. There are two major types of lake management, namely pillar-based and object-based. While the former is the foundation of a conceptual paradigm that does not comprehensively consider the roles of finance and technology in the lake management, the latter indicates the objects to manage so as to create standards or benchmarks for the implementation of various programs. Overall, Lake Rawapening management should include more programs on erosion-sedimentation control and monitoring of operational performance using information systems.

Nature-based solutions (NbS) are increasingly recognised for their potential to address both the climate and biodiversity crises. These outcomes are interdependent, and both rely on the capacity of NbS to support and enhance the health of an ecosystem: its biodiversity, the condition of its abiotic and biotic elements, and its capacity to function normally despite environmental change. However, while understanding of ecosystem health outcomes of nature-based interventions for climate change mitigation is growing, the outcomes of those implemented for adaptation remain poorly understood with evidence scattered across multiple disciplines. To address this, we conducted a systematic review of the outcomes of 109 nature-based interventions for climate change adaptation using 33 indicators of ecosystem health across eight broad categories (e.g. diversity, biomass, ecosystem functioning and population dynamics). We showed that 88% of interventions with positive outcomes for climate change adaptation also reported measurable benefits for ecosystem health. We also showed that interventions were associated with a 67% average increase in local species richness. All eight studies that reported benefits in terms of both climate change mitigation and adaptation also supported ecosystem health, leading to a triple win. However, there were also trade-offs, mainly for forest management and creation of novel ecosystems such as monoculture plantations of non-native species. Our review highlights two major limitations of research to date. First, only a limited selection of metrics are used to assess ecosystem health and these rarely include key aspects such as functional diversity and habitat connectivity. Second, taxonomic coverage is poor: 67% of outcomes assessed only plants and 57% did not distinguish between native and non-native species. Future research addressing these issues will allow the design and adaptive management of NbS to support healthy and resilient ecosystems, and thereby enhance their effectiveness for meeting both climate and biodiversity targets.

Background Glioblastoma (GBM) is a poor prognosis malignant grade 4 glioma. After surgical resection, standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. The DC vaccination increased the amount of intratumoral-activated cytotoxic T lymphocytes and decreased the number of FoxP3-positive regulatory T cells. Based on these da-ta, we have developed a phase II protocol with the DC vaccine concomitant to standard RT-CT in patients undergoing surgery for GBM. Methods This is a single-arm, monocentric, phase II trial evaluating progression-free survival (PFS) and the safety of a DC vaccination integrated with standard therapy in resected GBM patients. The vaccine administration begins at the end of the RT-CT (Induction Phase) and is subsequently al-ternated with TMZ cycles (Maintenance Phase). The primary endpoints are PFS and safety. Among the secondary endpoints, are the in vitro and in vivo Immune response evaluations. Results By December 2022 , nine patients had been enrolled in the first step. Two patients progressed within three months after leukapheresis and none had experienced DC vaccine-related G3-4 tox-icity. Five patients had a positive DTH test against KLH. By June 2023. The median OS from leu-kapheresis was 23.1 months and 24.7 from surgery. Conclusions This combination therapy is well-tolerated, and we have achieved the two endpoints required for the first step. Therefore, the study will proceed to enroll the remaining 19 patients.

Biological parameters extracted from electrical signals from various body parts have been used for many years to analyze the human body and its behavior. In addition, electrical signals from cancer cell lines, normal cells, and viruses, among others, have been widely used for the detection of various diseases. Single-cell parameters such as cell and cytoplasmic conductivity, relaxation frequency, and membrane capacitance are important. There are many techniques available to characterize biomaterials, such as scanning tunneling microscopy (STM), nanotechnology, microstrip cavity resonance measurement, dielectric impedance measurement (DEPIM), etc. This article reviews the single cell isolation and sorting techniques, summarizes the common single cell operations such as impedance flow cytometry, cell electrical impedance, electrical impedance sensing, and summarizes the current single cell analysis techniques and their applications.

A new longitudinal flow heat dissipation theory for cylindrical batteries is proposed in order to increase the energy density and uniform temperature performance of cylindrical lithium-ion battery packs while also shrinking their size by roughly 10%. First, a genetic algorithm is used to identify the single cell's thermal properties. Based on this, modeling and simulation are used to examine the thermal properties of the longitudinal flow-cooled battery pack. It is found that the best coolant flow scheme has one inlet and one outlet from the end face, taking into account the cooling effect of the battery pack and engineering viability. Lastly, Thermal Dummy Cells (TDC) is used to conduct a validation test of the liquid cooling strategy. Additionally, the simulation and test results demonstrated that the liquid cooling solution can keep the battery pack's maximum temperature rise under the static conditions of a continuous, high-current discharge at a rate of 3C to 20 °C and under the dynamic conditions of the New European Driving Cycle (NEDC) to 2 °C. In applications where the space requirements for the battery pack are quite severe, the longitudinal flow cooling method has some advantages.

CD8 T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signal, cytokine stimulation and nutrients availability. This integration is achieved by signaling hubs such as the mechanistic target of Rapamycin (mTOR). mTOR is a conserved protein kinase, controlling cellular growth and metabolism in eukaryotic cells and therefore is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model to comprehend metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here we review the signaling pathways leading to mTOR activation in CD8 T and NK cells, focusing on activation by cytokines. We also discussed how this knowledge can contribute to immunotherapy development for intracellular pathogen and cancer treatment.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Microbial symbioses exhibit astounding adaptations, yet all symbionts face the problem of how to reliably associate with host offspring every generation. A common strategy is vertical transmission, in which symbionts are directly transmitted from the female to her offspring. The diversity of symbionts and vertical transmission mechanisms is as expansive as the diversity of eukaryotic host taxa that house them. However, there are several common themes among these mechanisms based on the degree to which symbionts associate with the host germline during transmission. In this review, we detail three distinct vertical transmission strategies, starting with associations that are transmitted from host somatic cells to offspring somatic cells, either due to lacking a germline or avoiding it. A second strategy involves somatically-localized symbionts that migrate into the germline during host development. The third strategy we discuss is one in which the symbiont maintains continuous association with the germline throughout development. Unexpectedly, the vast majority of documented vertically inherited symbionts rely on the second strategy: soma-to-germline migration. Given that not all eukaryotes contain a sequestered germline and instead produce offspring from somatic stem cell lineages, this soma-to-germline migration is discussed in the context of multicellular evolution. Lastly, as recent genomics data have revealed an abundance of horizontal gene transfer events from symbiotic and non-symbiotic bacteria to host genomes, we discuss their impact on eukaryotic host evolution.

Here, we present a staged approach for an innovative repurposing of a portable infant humidicrib into a live cell growth, observation, and imaging system. Furthmore, humidicrib can support different variations of “umbilical” bioreactors, and can be used to conduct electrophysiology experiments and in situ immunohistochemistry. Modifications incorporate a closed loop carbon dioxide (CO₂) concentration control system with umbilical CO₂ and heating support for tailored bioreactors. The repurposing cost is inexpensive and allows for the continued observation and imaging of cells. This prototype unit has been used to continuously observe and image live primary neurons for up to 21 days. This demonstrates the repurposed units’ suitability for use in tissue culture based research, particularly where modifications to microscopes are required or where sensitive manipulation outside of a standard incubator is needed.

Horses are high performance athletes prone to sportive injuries such as tendonitis and desmitis. The formation of fibrous tissue in tendon repair becomes a therapeutic challenge to overcome. This impels regenerative medicine to develop innovative therapies that enhance tissue regenera-tion retrieving original tissue properties. Multipotent Mesenchymal Stem/ Stromal Cells (MSCs) have been successfully used to develop therapeutic products, as they secrete a variety of bioac-tive molecules that play a pivotal role in tissue regeneration. These factors are released in cul-ture media producing conditioned media (CM). The aforementioned assumptions led to the formulation of equine synovial membrane MSCs (eSM-MSCs) – the cellular pool that naturally regenerates joint tissue, combined with medium enriched in immunomodulatory factors (among other bioactive factors) produced by umbilical cord stroma-derived MSCs (eUC-MSCs), that nat-urally contribute to suppress the immune rejection in the maternal-fetal barrier. A clinical case of an equine acute desmitis, treated with this formulation is presented. Ultrasonographic ligament regeneration occurred in a reduced time frame, reducing stoppage time and allowing return to unrestricted competition after completion of a physical rehabilitation program. This study fo-cused on the determination of the formulation therapeutic potential and the evaluation of its synergistic effect in an equine desmitis treatment, utilizing the cells themselves and its secretome.

Horses are high performance athletes prone to sportive injuries such as tendonitis and desmitis. Fibrous tissue formation with loss of mechanical properties occurs in tendon repair, becoming a therapeutic challenge to overcome. This impels regenerative medicine to develop innovative therapies that enhance tissue regeneration retrieving original tissue properties. Mesenchymal stem cells (MSCs) have been successfully used to develop therapeutic products. They secrete a variety of bioactive molecules that play a pivotal role in tissue regeneration. These factors are released in culture media producing conditioned media (CM). The aforementioned assumptions impelled us to formulate equine synovial membrane stem cells (eSM-MSCs) – the cellular pool that naturally regenerates joint tissue, combined with medium enriched in immunomodulatory factors produced by umbilical cord stroma-derived MSCs (eUC-MSCs), that naturally contribute to suppress the immune rejection in the maternal-fetal frontier. A clinical case of an equine acute desmitis, treated with the abovementioned formulation is presented. Ligament regeneration occurred in a reduced time frame, reducing stoppage time, allowing return to unrestricted competition after completion of a physical rehabilitation program. This study focus was determination of the formulation therapeutic potential and the evaluation of its synergistic effect in an equine desmitis treatment, utilizing the cells themselves and its secretome.

This comprehensive overview of the historical milestones in cell culture underscores key breakthroughs that have shaped the field over time. It begins with Wilhelm Roux's seminal experiments in the 1880s, followed by the pioneering efforts of Ross Granville Harrison, who initiated groundbreaking experiments that fundamentally shaped the landscape of cell culture in the early 20th century. Carrel's influential contributions, notably the immortalization of chicken heart cells, mark a significant advancement in cell culture techniques. Holtfreter, Moscona, and Leighton introduced innovations such as 3D cell culture, laying the groundwork for further exploration. The advent of induced pluripotent stem cells by Takahashi and Yamanaka in 2006 was revolutionary, enabling the reprogramming of differentiated cells into a pluripotent state. Since then, recent innovations include spheroids, organoids, and organ-on-a-chip technologies, aiming to mimic the structure and function of tissues and organs in vitro, pushing the boundaries of biological modeling and disease understanding. In this review, we overview the history of cell culture shedding light on the main discoveries, pitfalls and hurdles that were overcome during the transition from 2D to 3D cell culture techniques. Finally, we discussed the future directions for cell culture research that may accelerate the development of more effective and personalized treatments.

Studies performed at single-cell resolution have demonstrated the physiological significance of cell-to-cell variability. Various types of mathematical models and systems analyses of biological networks have further been used to gain a better understanding of the sources and regulatory mechanisms of such variability. In this work, we present a novel sensitivity analysis method, called molecular density function perturbation (MDFP), for the dynamical analysis of cellular heterogeneity. The proposed analysis is based on introducing perturbations to the density or distribution function of the cellular state variables at specific time points, and quantifying how such perturbations affect the state distribution at later time points. We applied the MDFP analysis to a model of signal transduction pathway involved in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in HeLa cells. The MDFP analysis showed that caspase-8 activation regulates the timing of the switch-like increase of cPARP (cleaved poly(ADP-ribose) polymerase), an indicator of apoptosis. Meanwhile, the cell-to-cell variability in the commitment to apoptosis depended on mitochondrial outer membrane permeabilization (MOMP) and events following MOMP, including the release of Smac (second mitochondria-derived activator of caspases) and cytochrome-C from mitochondria, the inhibition of XIAP (X-linked inhibitor of apoptosis) by Smac and the formation of apoptosome.

Internet of thing (IoT) has been used in different aspect of life as industry, and daily life. Aligned with IoT, Quantum computers have been generated with high features that can accomplish complicated tasks with high speed. IoT and Quantum computers don’t match in resources and due to this collaboration between the two terms, it was found there are many challenges with quantum computers brought some security concerns. This paper will examine all challenges and future direction that face the use of IoT through using different quantum cryptograph methods. The first part on the paper discussed the vulnerabilities of existing cryptographic methods like RSA and ECC. these two methods were used as basic level for IoT security protocols. These cryptographic algorithms could be easily attacked by quantum computers so to ensure that IoT devices are secure must develop quantum resistant cryptographic algorithms. Next this paper will examine the challenges in implementing quantum resistant cryptographic algorithm in any IoT device through quantum resistant cryptographic algorithms such as lattice-based cryptography, code-based cryptography, multivariate cryptography, and hash-based signatures. Then, the paper discussed the future direction of securing IoT in quantum computing. In conclusion, securing IoT devices in quantum presents many challenges that require to be addressed where quantum resistant algorithms can be a solution that mitigate threats.

This study presents a comparative analysis of two advanced attention-based deep learning models—Attention-LSTM and Attention-GRU—for predicting cryptocurrency price movements. The models utilize historical OHLCV data, combined with four technical indicators: SMA, EMA, TEMA, and MACD, to enhance the accuracy of classification into three categories: uptrend, downtrend, and neutral. Both models aim to capture market dynamics through sequential data while incorporating attention mechanisms to focus on relevant time steps. Experimental results demonstrate that the inclusion of technical indicators significantly improves model performance, with MACD yielding the highest accuracy. The Attention-GRU model shows computational advantages, while the Attention-LSTM model excels in capturing long-term dependencies.

Due to their increased surface area, extent of swelling and active substance loading capacity and flexibility, nanogels made from natural and synthetic polymers have gained significant interest in the scientific and industrial areas. Especially, customized design and implementation of non-toxic, biocompatible, and biodegradable micro/nano carriers makes their usage very feasible for a range of biomedical applications, including drug delivery, tissue engineering, and bioimaging. The design and application methodologies of nanogels have been outlined in this review. Additionally, the most recent advancements in nanogel biomedical applications have been discussed, with a particular emphasis on applications for the delivery of drugs and biomolecules.

Vision-based tactile sensors (VBTS) have become the de facto method of giving robots the ability to obtain tactile feedback from their environment. Unlike other solutions to tactile sensing, VBTS offers high spatial resolution feedback without compromising on instrumentation costs or incurring additional maintenance expenses. However, conventional cameras used in VBTS have a fixed update rate and output redundant data, leading to computational overhead downstream. In this work, we present a neuromorphic vision-based tactile sensor (N-VBTS) that employs observations from an event-based camera for contact angle prediction. Particularly, we design and develop a novel graph neural network, dubbed TactiGraph, that asynchronously operates on graphs constructed from raw N-VBTS streams exploiting their spatiotemporal correlations to perform predictions. Although conventional VBTS uses an internal illumination source, TactiGraph is reported to perform efficiently in both scenarios, with and without an internal illumination source. Rigorous experimental results revealed that TactiGraph achieved a mean absolute error of 0.62∘ in predicting the contact angle and was faster and more efficient than both conventional VBTS and other N-VBTS, with lower instrumentation costs. Specifically, N-VBTS requires only 5.5% of the compute-time needed by VBTS when both are tested on the same scenario.

For disciplines like biological science, security, and the medical field, link prediction is a popular research area. To demonstrate the link prediction many methods have been proposed. Some of them that have been demonstrated through this review paper are TransE, Complex, DistMult, and DensE models. Each model defines link prediction with different perceptions. We argue that the practical performance potential of these methods, having similar parameter values, using the fine-tuning technique to evaluate their reliability and reproducibility of results. We describe those methods and experiments; provide theoretical proofs and experimental examples, demonstrating how current link prediction methods work in such settings. We use the standard evaluation metrics for testing the model's ability.

Zoos are increasingly putting in place formalized animal welfare assessment programs to allow monitoring of welfare over time, as well as to aid in resource prioritization. These programs tend to rely on assessment tools that incorporate resource-based and observational animal- focused measures since it is rarely feasible to obtain measures of physiology in zoo-housed animals. A range of assessment tools are available which commonly have a basis in the Five Domains framework. A comprehensive review of the literature was conducted to bring together recent studies examining welfare assessment methods in zoo animals. A summary of these methods is provided with advantages and limitations of the approach es presented. We then highlight practical considerations with respect to implementation of these tools into practice, for example scoring schemes, weighting of criteria, and innate animal factors for consideration. It is concluded that would be value in standardizing guidelines for development of welfare assessment tools since zoo accreditation bodies rarely prescribe these. There is also a need to develop taxon or species- specific assessment tools to inform welfare management.

Background/Objective: In this study, for the first time, we examined and compared the sensitivity of four patient-derived cutaneous melanoma cell lines to alpha radiation in vitro and analyzed it in view of cell nucleus area and the formation of double strand breaks (DSB). Melanoma cells sensitivity to alpha radiation was compared to photon radiation effects. Furthermore, we compared the sensitivity of the melanoma cells to squamous cell carcinoma. Methods: Human melanoma cell lines YDFR.C, DP.C, M12.C and M16.C, and the squamous cell carcinoma cell line, CAL 27, were irradiated in-vitro using Americium-241 as alpha-particle source. Cells were irradiated with doses of 0 to 2.8 gray (Gy). Cell viability, DNA DSB and nuclear size were measured. Results: 1. Alpha radiation caused death and proliferation arrest of all four melanoma cell lines, but inter-tumor heterogeneity was observed. 2. The most sensitive cell line (DP.C) had a significantly larger nucleus area (408 mM²) and the highest mean number of DSB per cell (9.61) compared to more resistant cells. 3. The most resistant cell, M16.C, had a much lower nucleus area (236.99 mM²) and DSB per cell (6.9). 4. Alpha radiation was more lethal than photon radiation for all melanoma cells. 5. The SCC cell, CAL 27, was more sensitive to alpha radiation than all melanoma cells, yet, had a similar number of DSB (6.67) and nucleus size (175.49 mM²) as the more resistant cells. 6. The cytotoxic effect of alpha radiation was not affected by proliferation arrest after serum starvation. 7. Killing of cells by alpha radiation was marginally elevated by ATR or topoisomerase 1 inhibition. Conclusions: This study demonstrates that various human melanoma cells can be killed by alpha radiation but exhibit variance in sensitivity to alpha radiation. Alpha radiation applied using Intra-tumoral Diffusing alpha-emitters Radiation Therapy (Alpha DaRT) methodology may serve as an efficient treatment for human melanoma.

With worsening environmental degradation and increasing international demand for human health, plant cell based technology will be more important. The aim of this review is to give an overview regarding key points of current progress and development trend of nature medical and edible plants from the framework of whole plant cell engineering including cell cultures, cell fusion and cell splitting derived biotechnology. Here we sum up three main application trends of medical plants cell cultures covering industrial output, technology upgrading and potential resource development. We also provide classification and typification insights to summarize the development of somatic hybridization in cereal, vegetables crops and other medicinal and edible plants as well as application of artificial polyploidy induction in major medicinal herbs. Development medicinal and edible homologous plants based on modern plant cell engineering will bring us a promising future.

Viruses can infect a cell via one or both routes viz. cell-to-cell (c-c) or cell-free (c-f) . Pathogenesis studies of various viruses, including HIV, have shown that c-c transmission yields a significantly higher infection magnitude than the c-f route. Expectedly, potent antibodies inhibited c-f infection more efficiently than with c-cell transmission. To achieve a one-step, synchronous infection cycle that provides amplified infection, we have studied a consistent and efficient c-c HIV infection model since 1992. H9 cells persistently infected with HTLV-IIIB (H3B cells) and uninfected target CD4+ lymphocyte line (HuT78) were mixed in a ratio of 1:4 respectively. We have recently used this model to produce HIV designer antigens that have been shown to elicit monoclonal as well as polyclonal specific antibodies against novel epitopes that are formed post virus-cell engagement, but prior to fusion. The model can be extended for HIV neutralizing antibody assays or drug inhibitors against high multiplicity of infection.

The human scalp is a common site of skin cancer in humans, with non-melanoma skin cancer being exceedingly common. In this review, two dermatologists with extensive experience in cutaneous oncology will discuss unique features of the epidemiology of cancer of the scalp. Clinical observations on these common skin cancers lead to insight into the pathogenesis and potential prevention and treatment of cutaneous scalp neoplasia. Our hypothesis is that the presence of hair protects against the development of skin cancer, but not by serving as a physical shield, but rather by providing a continuous IL-17 biased immunosurveillance. Loss of hair allow release from immunosurveillance, resulting in expansion of neoplastic cells towards skin cancer. Both hair follicles and metabolic changes in stroma allow permissiveness for tumor promotion.

Objective To investigate the functional and biological significance of telomere-related active genes in cholangiocarcinoma (CCA) using single-cell sequencing and cell communication analysis. Methods First, we identified and annotated different cell types in CCA samples using single-cell sequencing data. Pseudotime analysis revealed the transcriptional status and differentiation process of CCA cells. We then explored interactions between CCA cells and their regulatory pathways through cell communication analysis. 47 key genes related to telomere activity were identified, and GO and KEGG pathway enrichment analysis was performed. Additionally, we constructed a prognostic model and verified the model's predictive efficacy. Finally, we identified genes associated with drug sensitivity in CCA patients and identified pathways associated with CCA prognosis through tumor TMB analysis. Results We identified 452 active telomere-associated cells. Then, we assessed telomere associated gene activity, obtaining 47 differentially expressed telomere genes by intersecting with CCA differentially expressed genes. Major up-regulated signaling pathways, including MIF-(CD74+CXCR4) and HLA-A-CD8A, were identified through pseudotime analysis. Three telomere-associated prognostic genes were identified using LASSO analysis, and prognostic-related models were built. In addition, PBRM1 mutation load was found to be highest in the high-risk group, making it a potential diagnostic target. Finally, drug sensitivity analysis revealed higher sensitivity to certain therapeutic drugs in the high-risk group, providing guidance for tailored CCA treatment. Conclusion The MIF-(CD74+CXCR4) and HLA-A-CD8A signaling pathways appear to be major pathways for CCA cell proliferation. Prognostic models based on telomere-associated genes show promise for application, indicating the biological and clinical significance of telomere activity genes in CCA.

CD4+ T cells orchestrate and regulate immunity within jawed vertebrates, yet our understanding of their evolution, development, and cellular physiology has only begun to be unearthed in the past few decades. Discoveries of genetic diseases that ablate this cellular population have provided insight into their critical functions while transcriptomics, proteomics, and highresolution microscopy have recently revealed new insights into CD4+ T cell anatomy and physiology. This article compiles historical, microscopic, and multi omics data which can be used as a reference atlas to dissect cellular physiology within these influential cells and further understand pathologies like HIV infection that inflict human CD4+ T cells.

Novel Cellular Immunotherapy with engineered T cells has improved cancer treatment and established therapeutic promises to prevent tumor formation in clinical studies. Due to certain restrictions and difficulties, CAR and TCR T cells therapies were inadequate at points. CRISPR Cas9 genome-editing tool has a significant potential for these two cell-based therapies. As a specialized gene-editing technique, CRISPR Cas9 is used to repair genetic alternation with minimum damage. It is used as an adjunct to Immunotherapy to stimulate a more robust immune response. CRISPR has long outpaced other target-specific genome editing methods such as ZFNs and TALEN due to its high efficiency, competence in targeting, and stable operating condition. CRISPR can overcome the two major drawbacks of universal CAR T cells: allorejection and graft-vs-host disease. TCR-based T cell treatment can reduce inappropriate binding between endogenous and transgenic TCR, resulting in a reduction of severe toxicity. The CAR and TCR T based cell therapies uphold an excellent future for tumor malignancies This article has elucidated the administration of CRISPR Cas9 in Novel Cellular Immunotherapy, CAR, and TCR T cell therapy. However, this article did not fail to observe this technology's ethical concerns, limitations, and challenges. Furthermore, the article compares CRISPR-mediated allogeneic CAR T cell to TCR-T cell therapy.

The outbreak of the 2019 Novel Coronavirus (2019-nCoV) has rapidly spread from Wuhan, China to multiple countries, causing staggering number of infections and deaths. A systematic profiling of the immune vulnerability landscape of 2019-nCoV is lacking, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development. In this study, we predicted the potential of all the 2019-nCoV viral proteins to induce class I and II MHC presentation and form linear antibody epitopes. We showed that the enrichment for T cell and B cell epitopes is not uniform on the viral genome, with several focused regions that generate abundant epitopes and may be more targetable. We showed that genetic variations in 2019-nCoV, though fewer for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus, which should be considered in the development of therapies. We create an online database to broadly share our research outcome. Overall, we present an immunological resource for 2019-nCoV that could significantly promote both therapeutic development and mechanistic research.

As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl- 2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silybin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, a 17- to 52-fold improvement in potency as compared with silybin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

A flavonoid Astragalin (kaempferol-3-O-β-D-glucopyranoside, Ast) has several biological activities including anti-oxidant, anti-HIV, and anti-allergic effects. Nonetheless, its insolubility in hydrophilic solvents imposes restrictions on its therapeutic applications. In this study, we investigated the effects of water-soluble astragalin-galactoside (kaempferol-3-O- β-D-isomaltotrioside, Ast-Gal) on dendritic cell (DC) maturation and T helper (Th) cell-mediated immune responses. Ast-Gal significantly increased maturation and activation of DCs through up-regulation of surface markers, such as CD80, CD86, and MHC II in a dose-dependent manner, while Ast had little effects. Also, Ast-Gal-treated DCs markedly secreted immune-stimulating cytokines such as IL-1β, IL-6, and IL-12. Importantly, Ast-Gal strongly increased expression of IL-12, a polarizing cytokine of Th1 cells. In a co-culture system of DCs and CD4+ T cells, Ast-Gal-treated DCs preferentially differentiates naïve CD4+ T cells into Th1 cells. The addition of neutralizing IL-12 mAb to cultures of Ast-Gal-treated DCs and CD4+ T cells significantly increased IFN- γ production, thereby indicating that Ast-Gal-stimulated DCs enhance the Th1 response through IL-12 production by DCs. Injection with Ast-Gal-treated DCs in mice increased IFN-γ-secreting Th1 cell population. Collectively, these findings indicate that hydrophilically modified astragalin can enhance Th1-mediated immune responses via DCs, and point to a possible application of water-soluble astragalin-galactoside as an immune adjuvant.

Tumor microenvironment including cancer-associated fibroblasts (CAF) has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell – tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF into their pathological counterparts. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

Avian mutations in vaccine strains obtained from embryonated eggs could impair vaccine effec-tiveness. We performed a systematic review and meta-analysis of the adjusted relative vaccine effectiveness (arVE) of seed cell-cultured influenza vaccines (ccIV) compared to egg-based influ-enza vaccines (eIV) in preventing laboratory-confirmed influenza related outcomes (IRO) or IRO by clinical codes, in subjects 18 and over. We completed the literature search in January 2021; ap-plied exclusion criteria, evaluated risk of bias of the evidence, and performed heterogeneity, pub-lication bias, qualitative, quantitative and sensitivity analyses. All estimates were computed us-ing a random approach. International Prospective Register of Systematic Reviews, CRD42021228290. We identified 12 publications that reported 26 adjusted arVE results. Five publications reported 13 laboratory confirmed arVE and seven reported 13 code-ascertained arVE. Nine publications with 22 results were at low risk of bias. Heterogeneity was explained by season and risk of bias. We found a significant 11% (8 to 14%) adjusted arVE favoring ccIV in preventing any IRO in the 2017-2018 influenza season. The arVE was 3% (-01 to 7%) in the 2018-2019 influenza season. We found moderate evidence of a significant advantage of the ccIV in preventing IRO, compared to eIV, in a well-matched A(H3N2) predominant season.

Breast Cancer Associated Susceptibility Proteins Type 1/2 (BRCA1/2) promote cellular functioning by modulating NRF2-mediated antioxidant signaling. Redox failure in women with BRCA1/2 insufficiency increases the risk for breast/ovarian/uterine cancers. Risk‐reducing salpingo‐oophorectomy (RRSO) is a prophylactic surgery of the reproductive organs, which is frequently conducted by the age of 40 to lower the occurrence of cancer in women with BRCA1/2 mutations. However, abrupt estrogen decline following RRSO causes ovarian failure, which implicates various cellular physiological processes, resulting in increased release of free radicals and subsequent severe onset of menopausal symptoms. Comfort measures (e.g., hormonal replacement therapy (HRT) and mindfulness-based stress reduction (MBSR)) may improve chronological menopause-related quality of life, but their specific effects are not clear in women with gene mutations. Aiming to fill the gap, this study used path analysis to examine the effects of HRT and MBSR on menopausal symptoms among RRSO patients (N = 199, mean age = 50.5 ± 6.7 years). HRT alleviated menopausal symptoms in BRCA2 carriers and women who were physically active, premenopausal at the time of RRSO, had a high BMI, and had no history of breast cancer. It increased the severity of urogenital symptoms in those with a history of cancer. MBSR, on the other hand, was associated with increased intensity of most menopausal symptoms. The results suggest that young women undergoing recent RRSO may benefit from HRT at an individual level while their need for extensive measures to optimize their psychological wellbeing is ongoing. Adverse effects of MBSR, which are captured in the present study imply that MBSR may interfere with redox sensitivity associated with estradiol fluctuations in BRCA1/2 carriers. Investigations are needed to test this hypothesis and elaborate on the underlying mechanisms in those women.

The augmenting commitment in the entrepreneurial learning process, both at academic and industry level, has led to new mechanisms and methodologies. Entrepreneurship literature has shown evidence of raising interest in the problem-based learning (PBL) methodology with regard to upcoming events from the surrounding learning context. This paper presents a Systematic Bibliographic Literature Review (SBLR) with respect to the application of PBL throughout distinct entrepreneurial processes either in higher education, or in industry. It aimed to identify relevant entrepreneurial opportunities for PBL. Bibliographic databases were searched for documents published between 2002 and May 2024 to categorize key topics discussed in the literature on PBL and entrepreneurship. The review process identified 142 empirical and non-empirical papers on entrepreneurship related PBL. Data analysis revealed diverse subthemes for PBL uses in entrepreneurship in both higher education institutions and industry. The research questions “What is the interplay of problem-based learning methodology with entrepreneurship?” guided the study. The central output of the research is the discovery of the varying uses of PBL to cope with diverse events arising within entrepreneurship context. Future research directions are suggested.

Herein we report the expansion of the chemical space available from the chitin, accessible via the biogenic N-platforms 3A5AF, M4A2C and di-HAF. The biologically active heteroaromatics furo[3,2-d]pyrimidin-4-one and furo[3,2-d]pyrimidin-4-amine can be selectively accessed from 3A5AF and M4A2C, respectively. The chiral pool synthon di-HAF is a viable substrate for the Achmatowicz rearrangement, providing streamlined access to 2-aminosugars possessing a versatile hydroxymethyl group at C5.

Wild-type p53 cancer therapy-induced senescent cells frequently engulf and degrade neighboring ones inside a massive vacuole in their cytoplasm. After clearance of the internalized cell, the vacuole persists, seemingly empty, for several hours. Despite large vacuoles being associated with cell death, this process is known to confer a survival advantage to cancer engulfing cells, leading to therapy resistance and tumor relapse. Previous attempts to resolve the vacuolar structure and visualize their content using dyes were unsatisfying for lack of known targets and ineffective dye penetration and/or retain. Here, we overcame this problem by applying optical diffraction tomography and Raman spectroscopy to MCF7 doxorubicin-induced engulfing cells. We demonstrated a real ability of cell tomography and Raman to phenotype complex microstructures, such as cell-in-cells and vacuoles, and detect chemical species in extremely low concentrations within live cells in a completely label-free fashion. We show that vacuoles had a density indistinguishable to the medium, but were not empty, instead contained diluted cell-derived macromolecules, and we could discern vacuoles from medium and cells using their Raman fingerprint. Our approach is useful for the non-invasive investigation of senescent engulfing (and other peculiar) cells in unperturbed conditions, crucial for a better understanding of complex biological processes.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Human induced climate change led to the recognition of Community-Based Adaptation (CBA) as one of the remedies in building adaptive capacity and resilience of communities. It recognizes the resources and the skills as well as the agency of communities in shaping the optimal strategy. CBA interventions are vital in addressing community needs and contextual specificities, enable participatory and inclusive engagement and thereby facilitate more profound adaptation impacts. Agent-based modelling (ABM) harbors the potential to be the ideal tool to support developing of tailored adaptation strategies while considering capacities, resources, skills, priorities, needs and the cultural context of local communities. ABM allows to capture the complex relationships among various components within community decision making on CBA actions, the CBA actions themselves and the environment. There exist plenty of tools, however they provide for varying degrees of freedom in agent definition, sensitivity analysis, scalability, experiment design and output analysis to name a few. A set of required key criteria for CBA modelling is developed and all available ABM modelling and simulation tools are assessed for their suitability for CBA. NetLogo emerges as the most fitting tool for incorporating and handling the special features of CBA. It is closely followed by GAMA and Envision. The article provides insights and guidance to researchers and practitioners in selecting ABM tools aligned with the specific requirements of their CBA simulations and projects.

Due to the rapid growth of the Internet of Things (IoT), securing communications between a huge number of devices has become very difficult. Access controls and authentication secure the connection between IoT devices and protect sensitive data from unauthorized users or malicious attackers. In this paper, we provide a comprehensive review to emphasize the critical role of authentication and access control in securing IoT environments. This paper explores different types of access controls, like Attribute-Based Access Control and Role-Based Access Control. Furthermore, it demonstrates different authentication techniques, like passwords and biometrics. Based on the previous mechanisms, we discuss different IoT security challenges regarding authentication and access control mechanisms and highlight future directions. In addition, this paper investigates the integration between access control and authentication to safeguard IoT communications.

The evolution of photovoltaic cells is intrinsically linked to advancements in the materials from which they are fabricated. This review paper provides an in-depth analysis of the latest developments in silicon-based, organic, and perovskite solar cells, which are at the forefront of photovoltaic research. We scrutinize the unique characteristics, advantages, and limitations of each material class, emphasizing their contributions to efficiency, stability, and commercial viability. Silicon-based cells are explored for their enduring relevance and recent innovations in crystalline structures. Organic photovoltaic cells are examined for their flexibility and potential for low-cost production, while perovskites are highlighted for their remarkable efficiency gains and ease of fabrication. The paper also addresses the challenges of material stability, scalability, and environmental impact, offering a balanced perspective on the current state and future potential of these material technologies.