Human Papillomavirus (HPV) related cancers account for a large percentage of cancers. The tumor microenvironment (TME) is a complex structure and contributes significantly to tumor development, progression, and invasion. The TME is particularly pronounced in HPV-related cancers and HPV is known to influence the TME. In cancer research, there is an urgent need for new models to deepen our understanding of the pathophysiology of the disease and to facilitate the development of innovative therapies. In this context, 3D cell culture has emerged as a promising method in cancer research, that offers significant potential compared to conventional approaches. 3D modelling can produce results that are more consistent with clinical outcomes without the ethical concerns and problems of animal models. In this review, our aim is to discuss the tumor microenvironment in HPV-related cancers and demonstrate the importance of advancing 3D cell culture models for this purpose.

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study was aimed to analyze USP1 expression and study its roles in bladder cancer. Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1 function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic-inactive mutant) used to overexpress USP1 in T24 cells. CCK8, colony formation, and transwell assays were used to assess cell viability, proliferation and migration. RNA sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Coimmunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. Xenograft mouse model was used to study the role of USP1 in bladder cancer. Results: USP1 expression is upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration; this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1- deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could directly interact with c-MYC. and increase c-MYC stability depending on the catalytic activity of USP1. Conclusions: Our results suggest that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 it may serve as a novel therapeutic target for treating bladder cancer.

Silver nanoparticles (AgNPs) have arisen as promising specialists in malignant growth treatment, especially in further developing radiotherapy results. In vitro examinations feature AgNPs' capacity to increment radiosensitivity in disease cell lines, prompting uplifted cell demise and decreased clonogenic endurance. Outstandingly, AgNPs display insignificant poisonousness to ordinary cells, recommending potential for specific focusing of disease cells during radiotherapy. The blend of AgNPs with cisplatin shows huge cytotoxicity and oxidative pressure, particularly in tumoral cells, underscoring the requirement for additional investigation of this therapeutic methodology. AgNPs likewise show guarantee in prompting oxidative pressure in pancreatic disease cells, recommending an expected application in pancreatic malignant growth treatment. In co-openness situations, AgNPs, when joined with cadmium, prompt metabolic variation, showing compromised cell safeguard systems. Moreover, AgNPs display potential in tweaking ABC carrier action, offering a procedure to defeat multidrug obstruction in disease cells. While featuring the significant capability of AgNPs in disease treatment, the rundown highlights the need for continuous exploration to clarify their components, well-being profiles, and clinical applications. Combining AgNPs with radiotherapy presents a promising road, tending to limits in ordinary disease therapies and underlining their multifunctionality in forming the eventual fate of malignant growth therapeutics.

Dendritic cells (DCs) are known as major antigen-presenting cells, and lymph nodes (LNs) play an important role in the DC-mediated immune response. This study focused on infiltration of CD1a-positive DCs (CD1a-DCs) in regional LNs in 70 cases of gallbladder cancer (GBC). The results showed that LNs infiltration by CD1a-DCs was associated with unfavorable clinical outcomes in patients with GBC in univariate analyses, but all cases categorized as CD1a-DCs high group at regional LNs had nodal metastasis. Therefore, LNs infiltration by CD1a-DCs was not an independent prognostic factor identified by multivariate analyses. The subgroup analyses in cases with LN metastasis group (n = 32), significant impact of CD1a-DCs infiltration into metastatic LNs was not observed. In contrast, CD1a-DCs infiltration into primary tumor had a significant impact on surgical outcomes. As the results of previous reports that focused on CD1a-DCs infiltration in regional LNs of other organs were varied, the role and significance of CD1a-DCs infiltration in regional LNs may be different according to the tumor histology or primary site. Accumulation of further studies is needed to clarify the role and significance of CD1a-DCs infiltration into regional LNs of solid cancers.

This paper deals with the formulation of a Cobot kinematic model by developing both the direct and inverse kinematics and choosing the noa transformation matrix for defining the end-effector position and orientation with respect to the base frame. These algorithms have been validated via software in Matlab environment and by means of suitable experimental tests, which have been carried out by using a UR5e Cobot. Moreover, a specific industrial application regarding the robotized assembling of a multi-cylinder IC engine, has been designed in terms of layout and corresponding automatic cycle that is intended as a sequence of the robot elementary actions. In particular, the proposed robotized cell is composed by the UR5e Cobot along with its controller and a suitable electropneumatic circuit that includes a PLC with its user interface, which are both governed by means of a specific electronic board and a switch control box. The IC engine in scale of 1:5 and specific parts of the end-effector, which takes the role of vacuum gripper and torque limiting screwdriver, have been designed and manufactured by using a 3D printer.

Recent advancements in nanotechnology have led to the development of multifunctional iron oxide nanoparticles, presenting new opportunities in cancer therapy. This study aimed to synthesize and evaluate citric acid-coated/ folic acid conjugated nanoparticles loaded with doxorubi-cin and investigate their efficacy in experimental tumor models. For synthesis, controlled co-precipitation method was employed to produce highly dispersive, multifunctional nanofluids with a narrow size distribution of iron oxide nanoparticles. Nanoparticles were characterized using Dynamic Light Scattering (DLS) and Electrophoretic Light Scattering (ELS) for size distribution and zeta potential, X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) for structure and morphology, Vibrating Sample Magnetometry (VSM) for magnetic properties, and UV-Visible (UV-Vis) and Fourier-Transform Infra-red (FTIR) spectroscopy for modification confirmation. In vitro experiments employed RM1 (prostate cancer) and MEC1 (Chronic lymphocytic leukemia) cell lines to assess cytotoxicity and drug delivery efficiency. Fluorescence microscopy confirmed the intracellular delivery of doxorubicin by these nanoparticles, highlighting their potential for targeted therapy. As a result, nanoparticles conjugated with folic acid showed reduced efficacy over time. This study underscores the critical role of nanoparticle modifications in optimizing therapeutic outcomes. Future research should focus on further refining nanoparticle formulations and long-term effects in vivo, for development of effective and safe agents for targeted cancer treatment.

The mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates ribosome biogenesis and the transcription of ribosomal genes. Its inactivation impacts protein synthesis necessary for transport of cell adhesion molecule. In Dictyostelium discoideum, the activity of mechanistic Target of Rapamycin Complex 2 (mTORC2) is crucial for cAMP synthesis and relay, processes that depend on heterotrimeric G-proteins and Ras GTPases. Mutants lacking rip3 or lst-8 genes exhibit impaired adenyl cyclase activation and cAMP signaling, resulting in deficient expression of the cell adhesion protein CsaA. Despite this, rip3^- cells, which have impaired mTORC2, upregulate Cad-1 expression, a cell adhesion protein regulated by Ras-GTPases, to compensate for the loss of CsaA. lst-8^- cells, which have both mTORC1 and mTORC2 inactivated, show reduced nutrient sensing, premature CsaA expression and solitary cell behavior. These cells also show defective transport of adhesion proteins to the cell surface, impeding aggregation. Similar defects are observed with caffeine treatment, suggesting both mTORC1 and mTORC2 inhibition. This study highlights the interplay between mTORC1 and mTORC2 in regulating cell adhesion and aggregation through cAMP signaling and protein synthesis pathways in Dictyostelium.

Equine laminitis is a debilitating condition characterized by the breakdown of the dermal–epidermal junction, resulting in severe lameness and pain, often requiring euthanasia. This study aimed to establish an in vitro model of laminitis using a continuous keratinocyte cell line exposed to anoxia-reoxygenation and activated neutrophil supernatant. A significant decrease in keratinocytes metabolism was noted during the reoxygenation period, indicative of cellular stress. Adding muscle-derived mesenchymal stem/stroma cells during reoxygenation demonstrated a protective effect, restoring keratinocytes metabolic activity. Moreover, incubation of keratinocytes with activated neutrophil supernatant or myeloperoxidase alone induced increased keratinocyte myeloperoxidase activity, which was modulated by stem cells. These findings underscore the potential of muscle-derived mesenchymal stem/stroma cells in mitigating inflammation and restoring keratinocyte metabolism, offering insights for future cell therapy research in laminitis treatment.

Vegetative desiccation tolerance has evolved within the genus Craterostigma and Lindernia. A centre of endemism and diversification for these plants appears to occur in ancient tropical montane rainforests of east Africa in Kenya and Tanzania. Lindernia subracemosa, a desiccation-sensitive relative of C. plantagineum, occurs in these rainforests and experiences adequate rainfall and thus does not require desiccation tolerance. However, sharing this inselberg habitat, another species Lindernia brevidens does retain vegetative desiccation tolerance and is also related to the resurrection plant C. plantagineum found in South Africa. Leaf material was collected from all three species at different stages of hydration: fully hydrated, half-dry (ca. 45% relative water content), and fully desiccated. Cell wall monosaccharide datasets were collected from all three species. Comprehensive microarray polymer profiling (CoMPP) was performed using ca. 27 plant cell wall specific antibody and carbohydrate binding module probes. Global datasets do not show significant differences between the selected species suggesting that cell wall modifications in response to vegetative desiccation involve subtle cell wall remodelling not reflected by compositional analysis and that the plants and their walls are constitutively protected against desiccation.

The objective of this paper was to study the expression pattern of the GLOD4 gene in the testis and its regulatory effect on testicular cells. Currently, the regulated mechanism through are unclear. Here, we explored how GLOD4 functions in goat leydig cells to enhance our understanding of spermatogenesis and improve reproduction in breeding rams. In this study, we demonstrated that the localization of GLOD4 in testicular cells using immunohistochemistry and subcellular localization analyses. Subsequently, we analyzed the GLOD4 expression pattern in 4 age-based groups (0, 6, 12, and 18 months old) using real-time quantitative polymerase chain reaction (qRT‒PCR) and protein blotting. Finally, we performed GLOD4 gene silencing and overexpression studies in testicular cells from goats and explored the effects of GLOD4 on cell proliferation, the cell cycle, steroid hormone secretion and the expression of candidate testosterone hormone-regulated genes. GLOD4 was mainly expressed in testicular leydig cells, and the subcellular localization results showed that the GLOD4 protein was mainly localized in the cytoplasm and nucleus. Silencing of GLOD4 significantly suppressed the mRNA expression levels of the testosterone secretion-related genes CYP11A1, 3β-HSD and CYP17A1 and the mRNA expression levels of cell-cycle related genes CDK6, PCNA, and Cyclin E. Moreover, the cell cycle was blocked at the G2/M phase after GLOD4 silencing, which significantly suppressed testosterone secretion. In contrast, GLOD4 overexpression significantly increased the mRNA expression levels of the testosterone secretion-related genes CYP11A1, 3β-HSD, and CYP17A1 and increased the expression of the cell-cycle related genes CDK6, PCNA, and Cyclin E. Moreover, GLOD4 overexpression promoted the cell cycle from G0/G1 phases to enter the S phase and G2/M phases,promoted the secretion of testosterone. Taken together, our experimental results indicate that GLOD4 may affect the development of cells in Qianbei Ma goats of different ages by influencing the cell cycle, Proliferation and testosterone hormone synthesis. These findings enhance our understanding of the functions of GLOD4 in the cells of goats.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas.

Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine and oncology applications, Ad based platforms offer advantages including ease of genetic manipulation, scale of production and well established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that may need to be overcome for adenovirus based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects upon the downstream impact of an adenovirus-based therapeutic. This review focusses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, both in context of the innate and adaptive immune responses. We summarize different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and pre-scribed off-label for several neurological conditions like neuropathic pain, migraine and anxiety. Amitriptyline potentiates the monoaminergic transmission by blocking the reuptake of norepi-nephrine and serotonin. However, antidepressants also act on additional targets that contribute to either therapeutic or adverse effects and may suggest new indications for their repurposing. Furthermore, since depression is often a co-morbidity in patients with chronic conditions (i.e. cancer, neurodegenerative diseases) the use of antidepressants interfering with pathways in-volved in cell homeostasis may affect the progression and outcome of these pathologies. Here we investigate the effects of amitriptyline on proliferation and autophagy in human SH-SY5Y neuroblastoma cells. Dose and time-dependent upregulation of the autophagy markers LC3II and autophagy receptor p62, with accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to amitriptyline. Alteration of autophagy was accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5 -/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine suggesting that the amitriptyline’s effects on cell proliferation were not caused by the modulation of autophagy. Our findings demonstrate that amitriptyline acts on pathways that are crucial for cell and tissue homeostasis and pose the basis for further studies on the potential application of these effects and the consequences during long-term antidepressant treatment.

Fine dust causes various disorders, including cardiovascular, neurological, renal, reproductive, motor, systemic, respiratory, and cancerous diseases. Therefore, it is necessary to study functional materials to prevent these problems. In this study we used various methods, including quantitative PCR, flow cytometry, ELISA, and Alizarin O staining, to study the beneficial effects of erucic acid against fine dust. Erucic acid and erucic acid-induced exosomes (EIE) strongly suppress the attenuation of osteocytic differentiation and inflammation induced by fine dust. Erucic acid effectively suppresses inflammation in fibroblasts exposed to fine dust. Notably, despite exposure to fine dust, EIE promoted osteocytic differentiation in adipose-derived stem cells (ASC) and osteogenesis in macrophages, in addition to phagocytosis. Dramatic upregulation of RunX2 and BMP7 by EIE indicates that it is a strong activator of osteocytic differentiation in ASC and protects them from the effects of fine dust. Moreover, EIE induces immune activity and acts as an osteogenic trigger for macrophages. Therefore, this study suggests the potential use of erucic acid and erucic acid-induced exosomes (EIE) as biomaterials to prevent environment-borne diseases.

This study explores the use of remote ultrasound vibration to enhance welding strength. It examines the effects of 20 kHz, and 40 kHz High Power Ultrasound Transducers (HPUT) in contact and contactless modes during ultrasonic assistance laser welding. Employing shear tests and microscopy for assessment, the research evaluates ultrasound's impact on welding strength and identifies the optimal transducer. Theoretical and numerical analyses investigate vibration transmission into the welding area, particularly examining the vibration distribution and cavitation initiation within the molten pool area. Results indicate that ultrasound-assisted welding increases pull test performance, including the resistance force and strain, and improves microscopic structural integrity. Numerical simulations suggest that narrow-band vibration intensifies pressure in specific welding zones. Contactless ultrasound application also shows enhanced welding quality, offering a promising alternative to current methods. This work contributes to electric car technology by suggesting improvements in welding techniques for power battery systems.

Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS), arise due to numerous causes like protein accumulation and autoimmunity, characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform a critical role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. MiRNA participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlighted miRNA as therapy.

The mechanisms underlying the establishment of asymmetric structures during development remain elusive. The wing of Drosophila is asymmetric along the Anterior-Posterior (AP) axis, despite that its growth signals that drive its growth are presumably symmetric. Here, we investigated the contribution of cell recruitment, a process that drives wing fate differentiation in Drosophila, to the asymmetric shape and pattern of the adult wing. Genetic impairment of cell recruitment results in a significant reduction in adult wing asymmetry, primarily affecting the region between longitudinal vein 5 and the wing margin (L5-M). Morphometric analysis reveals that the lack of cell recruitment results in a more symmetric wing with respect to the AP, suggesting a contribution of cell recruitment to the establishment of asymmetry in the adult wing. A close examination of the expression of the wing selector gene vestigial (vg) in wing disc does not support this hypothesis. However, the circularity of the Vg pattern significantly increase in recruitment-impaired wing disc, suggesting that while the decrease of the L5-M region in the adult wing may not be attributed to cell recruitment, it could contribute to the overall asymmetry of the adult wing. We conclude that cell recruitment, a widespread mechanism that participates in growth and patterning of several developing systems, could drive, at least partially, the asymmetric shape of the Drosophila wing.

Background and objectives: sickle cell disease is the most common hemoglobinopathy in the world. It is considered to be a real public health problem. Sickle cell patients are subjected to several factors causing inflammation such as iron metabolism. The study aimed to look for inflammation in children with sickle cell disease in Cameroon, identify the factors associated with inflammation, and raise the consequences for the patient including the iron profile and the profile of the hemogram. Materials and methods: We conducted an analytical cross-sectional study for 03 months. The sickle cell disease patients coming and/or followed at the Hematology Department of the Regional Hospital of Bafoussam and the Central Hospital of Yaoundé have been recruited. The exploration of inflammation was made by determining CRP, IL6, and ferritin concentrations. The hematological parameters and iron profile were evaluated using standard methods. Statistical analysis of the data was performed; Univariate and multivariate logistic regression analyses allowed to identification of factors associated with inflammation in patients, using the statistical tool R version 4.1.1.. The proportions were compared with the chi-square test when the expected numbers were greater than 5 and the Fisher test when not. Results: The frequency of inflammation in the population was 42.3%. Hyperferritinemia was significantly greater (p<0.001) in patients with inflammation compared to the non-inflammatory patients (96.8% and 76.7% respectively). Patients with inflammation showed a significant elevation of iron parameters (p<0.05). In addition, ferritin and IL6 elevation were associated with inflammation during sickle cell disease respectively (Or = 4.96; 95% CI [1.15-36.42]; p=0.056) and (Or =6.23; 95% CI [1.43-45.96]; p=0.030). Conclusions: The elevated iron in plasma is an effect of inflammation in sickle cell patients. Hence the need of controlling inflammation and iron in the latter is necessary.

To elucidate the cellular immune response to coronavirus disease (COVID-19) among children, we assessed cellular immunity in 8 children post-vaccination for COVID-19 and 11 children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, using the T-SPOT®.COVID assay for both the spike (S) and nucleocapsid (N) proteins. In the vaccinated group, the T-SPOT®.COVID assay for the S protein yielded positive results in all eight children. In contrast, in the post-infection group, the assay for the N protein was positive in 5 of 11 children, with 3 of these 5 children requiring hospital admission, including 2 who needed mechanical ventilation. Therefore, the T-SPOT®.COVID assay is valuable for assessing cellular immunity against COVID-19, and most children infected with COVID-19 may not develop such immunity unless the disease severity is significant.

Vibrio parahaemolyticus is an important human pathogen that is currently the leading cause of shellfish-borne gastroenteritis in the world. Particularly, the pandemic strain has the capacity to induce cytotoxicity and enterotoxicity through its Type 3 Secretion System (T3SS2) that leads to massive cell death. However, the specific mechanism by which T3SS2 induces cell death remain unclear and the contribution in mitochondrial stress is not fully understood. In this work, we evaluated the contribution of T3SS2 of V. parahaemolyticus to generate mitochondrial stress and cell death during infection in human intestinal HT-29 cells. To evaluate this, infection assays were carried out to evaluate mitochondrial transition pore opening, mitochondrial fragmentation, ATP quantification, and cell viability during infection. Our results showed that the Δvscn1 (T3SS2+) mutant strain contributes to generating the sustained opening of the mitochondrial transition pore. Furthermore, it generates perturbations in the ATP production in infected cells, leading to a significant decrease in cell viability and loss of membrane integrity. Our results suggest that T3SS2 from V. parahaemolyticus plays a role in generating mitochondrial stress and cell death in human intestinal HT-29 cells. It is important to highlight that this study represents the first report indicating the involvement of T3SS2 from V. parahaemolyticus in generating mitochondrial stress, its impact on the mitochondrial pore, and its effect on ATP production in human cells.

Background: Large-cell neuroendocrine carcinoma presents significant treatment challenges owing to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. Methods: In this non-randomized study, patients with metastatic LCNEC were treated with ei-ther standard chemotherapy plus atezolizumab or standard chemotherapy alone. The primary outcomes measured were progression-free survival (PFS) and overall survival (OS), with an ex-ploratory analysis of miR375 in plasma as a potential biomarker. Results: Of the 22 screened patients, 17 met the inclusion criteria and were stratified into the atezolizumab and chemotherapy (n=10) or chemotherapy alone(n=7) groups. After a median follow-up of 23.3 months, the 12-month survival rate for the atezolizumab group was 57.1% (95% CI: 32.6%-100%) and 45.7% at 24 months (95% CI: 22.4%-93.2%). In contrast, the chemotherapy group had a 14.3% survival rate at both 12 and 24 months (95% CI: 2.33%-87.7%). The log-rank test for survival showed a statistically significant difference in the atezolizumab-treated group (chi-squared = 4, df = 1, p = 0.04). A non-significant correlation was found between disease pro-gression and elevated levels of miR375. Conclusions: This pilot study suggests that atezolizumab combined with chemotherapy may be effective in treating metastatic LCNEC. The non-significant correlation between plasma miR375 levels and disease progression suggests its biomarker potential, warranting further validation research.

MicroRNAs, short non-protein coding RNAs, are overexpressed in GCTs. Circulating levels of germ cell tumor (GCT)- associated miRNAs, such as miR-371a-3p, can be utilized as efficient and cost-effective alternatives in diagnosing and managing patients presenting with GCTs. This quality of miRNAs has demonstrated favorable performance characteristics as a reliable blood-based biomarker with high diagnostic accuracy compared to current serum tumor markers (STMs) including α-fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH). The conventional STMs exhibit limited specificity and sensitivity. Potential clinical implications of miRNAs include impact on de-escalating or intensifying treatment, detecting recurrence at earlier stages, and lessening the necessity of cross-sectional imaging or invasive tissue biopsy for non-teratomatous GCTs. Here we also highlight the outstanding issues that must be addressed prior to clinical implementation. Standards for measuring circulating miRNAs and determining ideal cutoff values are essential for integration into current clinical guidelines.

52 years have passed since President Nixon launched the "War on Cancer". The goals outlined by the President were not achieved because cancer treatment applied such as chemotherapy, radiotherapy, and targeted therapy have not fully met expectations. We suggest a new chemotherapeutic strategy: disrupting the communication between cancer cells and their microenvironment by chemical means. Immunological synapses that form between cancer cells and immune or other stromal cells provide an attractive target for this approach. Synapses form ligand-receptor clusters within interface of the interacting cells. Despite their differences, synapses share common properties: intercellular protein clusters; the proximity of these proteins; and their cooperative interaction making a synapse an unified functional unit. Synapses provide the limited space for the focused intercellular exchange of signaling molecules and particles. Therefore, destruction of synapses is expected to cause collapse of various tumor types. Additionally, the clustered arrangement of synapse components offers opportunities to increase treatment safety by reducing the concentration of cell impermeable agents used, to enhance its specificity applying cross-linking reagents, thus restricting modifications of surface-exposed molecules. By attaching a cleavable cell permeable toxic agent to a crosslinker should further enhance a killing potential in treating cancer. The proposed approach promises to be simple, universal, and less expensive than existing cancer therapy methods.

Apoptotic cells possess immunomodulatory effects that can be utilized to treat imbalanced immune conditions. Information on the preclinical safety of such treatment is sparse. In this study, the safety of apoptotic cells (Allocetra-OTS) was assessed in a GLP toxicological study on Sprague Dawley rats. Three doses of Allocetra-OTS or vehicle were administered intravenously (IV) for 3 consecutive days. Animals in the Main study were sacrificed on day 4, while animals from the Recovery groups were kept for 14 or 28 days. Allocetra-OTS was well tolerated, and no adverse effects were observed in body weight, clinical signs, food consumption or ophthalmologic observation. Thus, the No Observed Adverse Effect Level (NOAEL) dose was determined as the highest dose administered. An observed elevation in immune cells was suspected to be due to Allocetra-OTS; similarly to other clinical chemistry parameters, however, it was resolved in the Recovery phases. Splenomegaly and a dose-related Extramedullary Hematopoiesis (EMH) in the red pulp were observed, with no adverse events, and were considered to be a normal and expected reaction following IV administration of cell-based therapies. In conclusion, under the conditions of this study Allocetra-OTS was concluded to be safe, further supporting its potential candidacy for clinical studies

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exist e.g. in Parkinson’s disease or Alzheimer’s disease, there are only few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disorder characterized by progressive motor neuron degeneration. Initial studies, however, highlight that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, mitochondrial and dysfunction alterations in mitochondrial morphology, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2 and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc- and GPX4 activity, respectively, yielding in lipid peroxidation and cellular demise. Mutations in Fused in Sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as putative cell death pathway in motor neuron demise. However, mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated ferroptosis vulnerability in a FUS-ALS cell model, revealing mitochondrial disturbance and increased susceptibility for ferroptosis in cells harboring the mutant FUS variant. This was accompanied by altered expression of ferroptosis-associated proteins, particularly by dramatic reduction of xCT expression, leading to cellular imbalance of the redox system and increased lipid peroxidation. Iron chelation with deferoxamine as well as inhibition of the mitochondrial calcium uniporter (MCU) significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential therapeutic targets.

Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) signaling pathway. Notably, its active site harbors a cysteine residue that is susceptible to oxidation by hydrogen peroxide (H2O2). This oxidation inhibits the phosphatase function of PTEN, critically contributing to the activation of the PI3K/AKT pathway. Upon stimulation of cell surface receptors, the activity of NADPH oxidase 2 (NOX2) generates a transient amount of H2O2, serving as a mediator in this pathway by oxidizing PTEN. The mechanism underlying this oxidation, occurring despite the presence of highly efficient and abundant cellular oxidant-protecting and reducing systems, continues to pose a perplexing conundrum. Here, we demonstrate that the presence of bicarbonate (HCO3-) promoted the rate of H2O2-mediated PTEN oxidation, probably through the formation of peroxymonocarbonate (HCO4-), consequently potentiated the phosphorylation of AKT. In essence, our findings consolidate the crucial role of HCO3- in the redox regulation of PTEN by H2O2, lead to the presumption regarding HCO4- as a signaling molecule during cellular physiological processes.

The receptor Tyrosine Kinase (RTK) pathway and the downstream related Mitogen Activated Protein Kinase (MAPK) cascades are crucial signal transduction pathways that preside over various cellular processes, including proliferation, differentiation, apoptosis, and responses to stressors. They are well described in solid malignancies, where many of the involved factors are used as prognostic molecular markers or targets for precision therapy. Germ cell tumors (GCTs) are relatively rare. However, they are the most diagnosed malignancies occurring in the testis (TGCT) among men aged between 15 and 40 years. Despite high aneuploidy and a paucity of somatic mutations, several genomic and transcriptomic assays have identified few significantly mutated somatic genes, primarily KIT and K-RAS, so affecting, at various levels, the KIT–RAS–RAF–MEK–ERK cascade. This review focuses on the most recent investigations about this signaling pathway in TGCTs concerning their development, natural history, response to standard chemotherapy protocols (i.e., cisplatin-based), and on the efforts being made to identify targetable markers for possible precision medicine approaches.

Phosphatase and tensin homolog (PTEN) is a tumor suppressor due to its ability to regulate cell survival, growth and proliferation by down-regulating PI3K/AKT signaling pathway. In addition, PTEN plays an essential role in other physiological events associated with cell growth demands, such as ischemia-reperfusion, nerve injury and immune response. Therefore, recently PTEN inhibition has emerged as a potential therapeutic intervention in these situations. Increasing evidence demonstrates that reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), are produced and required for the signaling in many important cellular processes under such physiological conditions. ROS have been shown to oxidize PTEN at the cysteine residue of its active site, consequently inhibiting its function. Here we provide an overview of studies that highlight the role of oxidative inhibition of PTEN in physiological processes.

Cytokinesis, as the last stage of the cell division cycle, is a tightly controlled process amongst all eukaryotes, and defective division can lead to severe cellular consequences, and is implicated in serious human diseases and conditions such as cancer. Both mammalian cells and the fission yeast Schizosaccharomyces pombe use binary fission to divide into two equal sized daughter cells. Similar to mammalian cells, in S. pombe such cytokinetic division is driven by the assembly of an actin-myosin contractile ring (ACR) at the cell equator between the two cell tips. The ACR is composed of a complex network of membrane scaffold proteins, actin filaments, myosin motors, and other cytokinesis regulators. Contraction of the ACR leads to the formation of a cleavage furrow which is severed by the endosomal sorting complex required for transport (ESCRT) proteins leading to the final cell separation during the last stage of cytokinesis, abscission. This review describes recent findings defining the three phases to establish cytokinesis in S. pombe: ACR assembly, ACR constriction, and its coordination with septation. Collectively, we provide an overview of current understanding of the mechanisms regulating the ACR-mediated cytokinesis in S. pombe with a potential role of ESCRT proteins in this process.

Hepatocellular carcinoma (HCC) is characterized by uncontrolled cellular proliferation driven by aberrant signal transduction. Cells respond to potential carcinogenic signals by inducing cellular senescence (CS) as a defense mechanism. However, assessing CS levels in various tumors is challenging due to heterogeneity and the lack of universal CS markers. This study integrates single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from HCC samples to analyze gene expression profiles. HCC-specific senescence-related pathways are identified, and genes from these pathways distinguish molecular subtypes associated with senescence in HCC. These subtypes exhibit significant variations in biological and clinical attributes. A specific CS risk model is developed, revealing associations between CS scores and prognosis, clinical staging, immune infiltration, immunotherapy response, and drug sensitivity. The key gene G6PD is identified as a potential senescence-related target in liver cancer. Molecular experiments confirm the effective suppression of HepG2 cell proliferation, invasion, and migration upon G6PD knockdown. In summary, this analysis enhances our understanding of HCC-specific senescence molecular features and introduces a novel senescence-related biomarker, offering promising implications for future research.

Localized jawbone invasion is a milestone in the progression of oral squamous cell carcinoma (OSCC). The factors that promote this process are not well understood. Sclerostin is known to be involved in bone metabolism and there are preliminary reports of its involvement in bone tumors and metastasis. To identify a possible involvement of sclerostin in the bone invasion process of OSCC, sclerostin expression was analyzed in vitro in two different human OSCC tumor cell lines by qRT-PCR, and the effect of recombinant human (rh)-sclerostin treatment on tumor cell capabil-ities was evaluated using proliferation, migration, and invasion assays. Undifferentiated human mesenchymal stem cells (hMSCs) were osteogenically differentiated and co-cultured with OSCC tumor cells to demonstrate potential interactions on migration characteristics. Sclerostin expres-sion was evaluated in clinical cases by immunohistochemistry at the OSCC jawbone interface in a cohort of 15 patients. Sclerostin expression was detected in both OSCC tumor cell lines in vitro and was also detected at the OSCC jawbone interface in clinical cases. Tumor cell proliferation rate, migration and invasion ability were increased by rh-sclerostin treatment. The migration rate of tumor cells co-cultured with osteogenically differentiated hMSCs was increased. The re-sults presented are the first data suggesting a possible involvement of sclerostin in the bone inva-sion process of OSCC, which needs to be further investigated

(1) Background: China holds the highest esophageal squamous cell carcinoma (ESCC) incidence areas in the world, with some areas of incidence over 100 per 100,000. Despite extensive public health efforts, its etiology is still poorly understood. This study aims to review and summarize past research into potential etiologic factors for ESCC in China. (2) Methods: Relevant observational and intervention studies were systematically extracted from four databases using key terms, reviewed using Rayyan software, and summarized into Excel tables. (3) Results: Among the 207 studies included in this review, 130 studies were focused on genetic etiologic factors, followed by 22 studies focused on dietary-related factors, 18 studies focused on HPV-related factors, and 37 studies focused on other factors. (4) Conclusions: ESCC in China involves a variety of factors including genetic variations, gene-environment interactions, dietary factors like alcohol, tobacco use, pickled vegetables, and salted meat, dietary behavior such as hot food/drink consumption, infections like HPV, poor oral health, gastric atrophy, and socioeconomic factors. Public health measures should prioritize genetic screening for relevant polymorphisms, conduct comprehensive investigations into environmental, dietary, and HPV influences, enhance oral health education, and consider socioeconomic factors overall as integral strategies to reduce ESCC in high-risk areas of China.

A study was conducted on the power system of a forklift equipped with PEM fuel cells. A fuel cell assembly relies on several components for proper functioning, and among these, the air compressor holds paramount importance due to its significant energy consumption when compared to other Balance of Plant components. The air supply system, in turn, plays a critical role in ensuring the stable and efficient operation of the entire fuel cell system. To enhance system efficiency, we delved into the impact of varying the stoichiometric ratio of air and air pressure on the validated and optimized power module model. This investigation was carried out under real loading conditions, replicating the conditions experienced by the power module when fuel cells are in use within a forklift. The air compressor, being a pivotal component of a PEM fuel cell system, can be oper-ated at different excess air and pressure ratios, which in turn influence both the fuel cell's performance and the overall efficiency of the power module system. Our research focused on assessing the performance of polymer electrolyte membrane (PEM) fuel cells under different load cycles, adhering to the VDI60 requirements for forklift applications. This comprehensive examination encompassed the system's minimum and maximum load scenarios, with the primary goal of optimizing excess air and pressure ratio parameters, especially under dynamic load conditions. The results revealed that higher air pressures and lower excess air ratios were con-ducive to increasing system efficiency, shedding light on potential avenues for enhancing the performance of PEM fuel cell systems in forklift applications.

Chronic rhinosinusitis (CRS) can have a significant impact on quality of life. With persistent symptoms and the failure of initial medical treatments, surgical management is indicated. Despite the excellent results of endoscopic sinus surgery for persistent CRS, it is quite a challenging procedure for frontal sinusitis given the complex anatomy and location of the frontal sinus. Frontal sinus cells significantly contribute to the complexity of the frontal sinus, and numerous studies have sought to establish their association with sinusitis. This review offers a comprehensive understanding of the frontal sinus cells, their different classifications, their prevalence among different populations, and their relationship to sinusitis. After an extensive review of the current literature, the International Frontal Sinus Anatomy Classification (IFAC) is the most recent classification method and a preferred practical preoperative assessment tool. Although the Agger Nasi Cell is the most prevalent cell among all reported populations, ethnic variations are still influencing the other cells' distribution. Studies are inconsistent in reporting a relationship between frontal sinus cells and sinusitis, and that is mainly because of the difference in the classification method used. More research using a standardized classification method is needed to understand the association between frontal sinus cells and sinusitis.

Ferroptosis is a recent form of non-apoptotic cell death, which occurs due to imbalance of iron homeostasis (iron overload). Oxidative stress due to the impairment of the antioxidant system is a major pathophysiology during ferroptosis, which eventually results in lipid peroxidation. The cellular and physiological biomarker of ferroptotic cell death includes major alteration in the glutathione peroxidase 4 (GPX4) antioxidant system and lipid peroxidation induced loss of plasma membrane integrity. This review elaborates the mechanism of oxidative stress which triggers ferroptosis.

The continuous growth of roots depends on their ability to maintain a balanced ratio between cell production and cell differentiation at the tip. This process was reported to be regulated by the hormonal balance of cytokinin and auxin. However, other important regulators, such as plant folates, have also been reported to play a regulatory role. In this study, we investigated the impact of the folate precursor PABA on root development. Using pharmacological, genetic, and imaging approaches, we show that the growth of Arabidopsis thaliana roots is repressed by either supplementing the growth medium with PABA or overexpressing the PABA synthesis gene GAT-ADCS. This is associated with a smaller root meristem size, which consists of fewer cells. Conversely, reducing the levels of free root endogenous PABA results in longer roots with extended meristems and increased cell numbers. We provide evidence that PABA represses Arabidopsis root growth in a folate-independent manner and likely acts through two mechanisms: (i) the G2/M transition of cell division in the root apical meristem and (ii) promoting premature cell differentiation in the transition zone. These data collectively suggest that PABA plays a role in Arabidopsis root growth at the point where cell division and cell differentiation intersect.

In this study, we aimed to identify blood lymphocytes as a prognostic factor for survival in patients with locally advanced stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT). We conducted a secondary analysis of 196 patients enrolled in the Korean Radiation Oncology Group 0903 phase III clinical trial to evaluate the prognostic significance of circulating blood lymphocyte levels. The median total lymphocyte count (TLC) reduction ratio during CCRT was 0.74 (range: 0.29 – 0.97). In multivariate analysis, patient age (p = 0.014) and gross tumor volume (GTV, p = 0.031) were significant factors associated with overall survival, while TLC reduction (p = 0.018) and pretreatment neutrophil-to-lymphocyte ratio (NLR; p = 0.010) were associated with progression-free survival (PFS). In multivariate logistic regression analysis, pretreatment NLR, GTV, and heart V20 were significantly associated with TLC reduction. TLC reduction during CCRT is a significant prognostic factor for PFS, and heart V20 is significantly associated with TLC reduction. Thus, constraining the volume of the radiation dose to the whole heart must be prioritized to reduce TLC.

The high protein content of several microalgal species makes them attractive and unconventional for applications in the food and pharmaceutical industries. Due to microalgae's robust cell wall, cell rupture is necessary to improve the extraction of their intracellular proteins. Thus, choosing a suitable cell-breaking treatment before protein extraction is a vital downstream processing step. Additionally, it is necessary to use an effective technique for monitoring and measuring the impact of rupture treatments on microalgal cell walls. In our study, Tetradesmus obliquus cells were disrupted by three different mechanical rupture methods: high-pressure homogenization (HPH), ultrasound (US), and ball milling (BM). The ruptured biomass cells were counted, and soluble proteins were extracted and quantified. The cell counting technique did not detect differences between intact and damaged cells after BM treatment because the dye (erythrosine B) did not permeate the microalgae biomass accurately. The US treatment promoted the highest yield of total protein extraction (19.95%). The yields of protein extraction of T. obliquus with HPH (15.68%) and BM (14.11%) were significantly (p value ≤ 0.05) lower than that achieved in the US treatment. The increase in the number of extraction steps increased the protein recovery. Thus, the content of extracted soluble protein was a reliable indirect index for a quantitative comparison of the cell disruption level.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system caused by myelin-specific autoreactive T cells. We previously demonstrated intestinal barrier disruption and signs of inflammation in experimental autoimmune encephalomyelitis (EAE), a model of MS. Fecal calprotectin is a disease activity biomarker in inflammatory bowel diseases, released by neutrophils in response to inflammation. We aimed to further investigate EAE manifestations in the gastrointestinal tract, and to determine whether calprotectin is a useful biomarker of intestinal inflammation in EAE. Calprotectin was analyzed in feces, cecal contents, and plasma of EAE mice. Infiltrating neutrophils and goblet cells were investigated in different parts of the gastrointestinal tract, before onset of neurological symptoms and during established disease. We found increased calprotectin levels in feces, cecal content and plasma, preceding EAE onset that further escalated during disease progression. Increased neutrophil infiltration in the intestinal tissue concomitant with IL-17 expression and myeloperoxidase activity was found correlating well with clinical activity. Increased goblet cells in intestine similar to irritable bowel syndrome (IBS) were also observed. The results suggest calprotectin as a good biomarker of gastrointestinal inflammation in EAE, also the potential of this model as a useful animal model for IBS.

EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, remission is transient, and no further effective treatment options are available for EGFR-TKI-advanced EGFR-mutant NSCLCs. Immunotherapy with immune checkpoint inhibitors (ICIs) induces sustained cancer remission in a subset of NSCLCs. However, ICI therapy exhibits limited activity in most EGFR-mutant NSCLCs. Mechanistically, the strong oncogenic EGFR signaling in EGFR-mutant NSCLCs contributes to the non-inflamed tumor immune microenvironment (TIME), characterized by a limited number of CD8+ T cell infiltration, a high number of regulatory CD4+ T cells and a high number of inactivated infiltrated T cells. Besides, EGFR-mutant NSCLC patients are generally non-smokers with low levels of PD-L1 expression and tumor mutation burden. However, current understanding only partially explains why a small population of EGFR-mutant NSCLCs durably respond to ICI therapy, resulting in many researchers actively working in this field. This review reviews the hope seen from pre-clinical studies and clinical trials which may be adopted to improve the outcome of ICI therapy in EGFR-mutant NSCLCs. Besides, the underlying mechanisms leading to the inferior clinical outcome of ICI therapy in EGFR-mutant NSCLCs are discussed.

Currently, multiple studies have indicated that CD8+ T lymphocytes play a role in causing damage to the exocrine glands through acinar injury in Primary Sjogren’s syndrome (pSS). The aim of this research was to assess the imbalance of subsets within CD8+ cells in peripheral blood. We examined blood samples from 34 patients with pSS and 34 healthy individuals as controls. We used flow cytometry to enumerate CD8+ T cell maturation stages using as markers CD62L, CD28, CD27, CD4, CD8, CD3, CD45RA, and CD45. For immunophenotyping of ‘polarized’ CD8+ T cell subsets we used the following monoclonal antibodies:CXCR5, CCR6,CXCR3 and CCR4. The findings revealed that both the relative and absolute numbers of 'naïve' CD8+ T cells were higher in pSS patients compared to the healthy volunteers. Conversely, the proportions of effector memory CD8+ T cells were notably lower. Furthermore, our data suggested that among patients with pSS, the levels of cytotoxic Tc1 CD8+ T cells were reduced, while the frequencies of regulatory cytokine-producing Tc2 and Tc17 CD8+ T cells were significantly elevated. Simultaneously, the Tc1 cell subsets displayed a negative correlation with immunoglobulin G, Rheumatoid factor, the Schirmer test, and unstimulated saliva flow. On the other hand, the Tc2 cell subsets exhibited a positive correlation with these parameters. In summary, our study indicated that immune dysfunction within CD8+ T cells, including alterations in Tc1 cells, plays a significant role in the development of pSS.

Background Multilineage-differentiating stress-enduring (Muse) cells are newly established pluripotent stem cells. The aim of the present study was to examine the potential of the systemic administration of Muse cells as an effective treatment for subacute SCI. Methods: We intravenously administered the clinical product “CL2020” containing Muse cells to a rat model two weeks after mid-thoracic spinal cord contusion. Eight experimental animals received CL2020 and 12 received the vehicle. Behavioral analyses were conducted over 20 weeks. Histological evaluations were performed. After 20 weeks of observation, diphtheria toxin was administered to 3 CL2020-treated animals to selectively ablate human cell functions. Results: Hindlimb motor functions significantly improved from 6 to 20 weeks after the administration of CL2020. The cystic cavity was smaller in the CL2020 group. Furthermore, larger numbers of descending 5-HT fibers were preserved in the distal spinal cord. Muse cells in CL2020 were considered to have differentiated into neuronal and neural cells in the injured spinal cord. Neuronal and neural cells were identified in the gray and white matter, respectively. Importantly, these effects were reversed by the selective ablation of human cells by diphtheria toxin. Conclusions: Intravenously administered Muse cells facilitated the therapeutic potential of CL2020 for severe subacute spinal cord injury.

Ebola virus disease (EVD) represents a global health threat. The etiological agents of EVD are 6 species of Orthoebolaviruses, with Orthoebolavirus zairense (EBOV) having the greatest public health and medical significance. EVD disease pathogenesis occurs as a result of broad cellular tropism of the virus, robust viral replication and a potent and dysregulated production of cytokines. In vivo, tissue macrophages are some of the earliest cells infected and contribute significantly to virus load and cytokine production. While EBOV is known to infect macrophages and to generate high titer virus in the liver, EBOV infection of liver macrophages, Kupffer cells, has not previously been examined in tissue culture or experimentally manipulated in vivo. Here, we employed primary murine Kupffer cells (KC) and an immortalized murine Kupffer cell line (ImKC) to assess EBOV-eGFP replication in liver macrophages. KCs and ImKCs were highly permissive for EBOV infection and IFN-γ polarization of these cells suppressed their permissiveness to infection. The kinetics of IFN-γ-elicited antiviral responses were examined using a biologically-contained model of EBOV infection termed EBOV ΔVP30. The antiviral activity of IFN-γ was transient, but a modest ~3-fold reduction of infection persisted for as long as 6 days post treatment. To assess the interferon stimulated gene products (ISGs) responsible for protection, the efficacy of secreted ISGs induced by IFN-γ were evaluated. Secreted ISGs blocked recombinant VSV expressing EBOV GP (rVSV/EBOV GP) infection, but failed to block EBOV ΔVP30. Our studies define new cellular tools for the study of EBOV infection that can potentially aid the development of new antiviral therapies. Furthermore, our data underscore the importance of macrophages in EVD pathogenesis and those IFN-γ-elicited ISGs that help to control EBOV infection.

The overexploitation of fossil fuels and their negative environmental impact has attracted the attention of researchers worldwide to propose alternatives to produce bioenergy. Microbial fuel cells (MFCs) systems are sustainable biotechnologies that use bacterial activity to break down organic matter while generating bioelectricity. MFCs have bioelectricity from domestic wastewater (DWW), municipal wastewater (MWW), and potato and fruit waste, reducing environmental contamination and decreasing energy consumption and treatment cost. This review focuses on the recent advancements regarding the designs and configurations, the operation mode of MFCs, and their capacity to produce bioelectricity (e.g., 2203 mW/m2) and fuels (i.e., H2: 438.7 mL/g and CH4: 358.7 mL/g, respectively). Besides, this review highlights practical applications, challenges, techno-economic, and life cycle assessments (LCA) of MFCs. Despite MFC's promising biotechnology, great efforts should be made to implement it in real-time and commercialization.

Acute kidney injury (AKI) is a clinical syndrome where a rapid decrease in kidney function and/or urine output is observed, which may result in the imbalance of water, electrolyte and acid base, and is associated with poor prognosis and prolonged hospitalization. Therefore, early diagnosis and treatment to avoid the severe AKI stage is important. While several biomarkers, such as urinary L-FABP and NGAL, can be clinically useful, there is still no gold standard for early detection of AKI and there are limited therapeutic options against AKI. miRNAs are non-coding and single-stranded RNAs that silence their target genes in the post-transcriptional process and are involved in a wide range of biological processes. Recent accumulated evidence has revealed that miRNAs may be potential biomarkers and therapeutic targets for AKI. In this review article, we summarize the current knowledge about miRNAs as promising biomarkers and potential therapeutic targets for AKI, as well as the challenges in their clinical use.

Vertical III-V semiconductor nanowires have shown promising absorption of light for solar cell and photodetector applications. The absorption properties can be tuned through the choice of III-V materials and geometry of the nanowires. Here, we review recent progress in the design of the absorption properties of both individual nanowires and nanowire arrays. Future directions for the research field are proposed.

Acute promyelocytic leukemia (APL) currently represents one of the malignant hemopathies with the best therapeutic responses following the introduction of all-trans retinoic acid (ATRA) and later of arsenic trioxide (ATO) treatment. As a result, patients with APL achieve long-term responses in a large proportion after first-line therapy, so that performing hematopoietic stem cell transplant as consolidation of first complete remission is no longer necessary. Even in the case of relapses, most patients obtain a new remission thanks to the therapy with ATO and ATRA, but to maintain it, a consolidation treatment as effective as possible is necessary. The experience accumulated from studies published in the last two decades shows the effectiveness of hematopoietic stem cell transplantation (HSCT) in improving the evolution of patients who achieve a new complete re-mission. Thus, the recommendations of expert groups indicate transplantation as consolidation therapy in patients with a second complete remission with the mention of the use of autologous HSCT in cases with complete molecular remission and allogeneic HSCT for patients with the persistence of minimal residual disease or early relapse. However, there is a variety of contro-versial aspects related to the role of HSCT in APL, from obtaining outcome data almost exclusively from retrospective studies and historical analyzes to questions related to the type of transplanta-tion, the impact of minimal residual disease, conditioning regimens, or the role of other thera-peutic options. All these questions justify the performance of controlled prospective studies in the following years.

Canine lymphoma (CL) is one of the most common malignant tumors in dogs. The cause of CL remains unclear. Genetic mutations that have been suggested as possible causes of CL are not fully understood. Whole-exome sequencing (WES) is a time- and cost-effective method for detecting genetic variants targeting only protein-coding regions (exons) that are part of the entire genome region. A total of eight patients with B-cell lymphomas were recruited, and WES analysis was performed on whole blood and lymph node aspirate samples from each patient. A total of 17 somatic variants (GOLIM4, ITM2B, STN1, UNC79, PLEKHG4, BRF1, ENSCAFG00845007156, SEMA6B, DSC1, TNFAIP1, MYLK3, WAPL, ADORA2B, LOXHD1, GP6, AZIN1, and NCSTN) with moderate to high impact were identified by WES analysis. Through a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of 17 genes with somatic mutations, a total of 16 pathways were identified. Overall, the somatic mutations identified in this study suggest novel candidate mutations for CL, and further studies are needed to confirm the role of these mutations.

The study of the mechanisms underlying stem cell differentiation is under intensive research, and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has still strengthened the interest for the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission and mitophagy processes, as well as to emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate.

This work reports the influence of reduced graphene oxide (rGO) support on the catalytic performance of Cu@PtRu/rGO catalysts towards methanol oxidation in acidic medium. These core-shell catalysts are synthesized by the reduction method in two steps being the first using ethylene glycol to obtain Cu/rGO and the second, the reduction of copper atoms synthesized in the previous step to produce Cu@PtRu/rGO. In order to compare the catalytic performance of the prepared catalysts, Pt/C, PtRu/C, Cu@PtRu/C catalysts are also synthesized on Vulcan XC-72R carbon. The theoretical loading of Pt used in the Vulcan XC-72R carbon supported catalysts is equal to that utilized in Cu@PtRu/rGO, and higher in the other prepared catalysts. The surface composition of the nanoparticles, as well as their sizes, particle size distribution and morphology of the catalyst particles are characterized by X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM). Cyclic voltammetry (CV) and chronoamperometry (CA) are employed to measure the electrochemical performance of the prepared catalysts. The anodic scans show that for the region of technological interest (0.1 to 0.4 V), the Cu@PtRu/rGO-16 electrocatalyst exhibits higher current density value than the others as a result of its lower starting oxidation potential (0.250V against 0.437V for Pt/C) and its higher ratio between forward (iF) and reverse (iR) current densities (iF/iR 1.45 against 0.93 for Pt/C). Chronoamperometric tests depict that the current density value of Cu@PtRu/rGO-16 catalyst is about 4 times higher than that of Cu@PtRu/C-16 and Cu@PtRu/C-18 catalysts, ca. 4.8 times higher than that of PtRu/C-30 catalyst and around 6 times higher than that of Pt/C-30. These results suggest that Cu@PtRu/rGO-16 exhibits high bulk activity for the electrooxidation of methanol, high stability and high tolerance to CO poisoning, making it possible to reduce the platinum loading in proton exchange membrane fuel cells (PEMFCs).

Background: Cell-free plasma DNA (cfDNA) is composed of circulating extracellular DNA originating from apoptosis or cell necrosis. It is generally present in healthy individuals, but its levels increase in different clinical conditions, such as kidney disease, sepsis, myocardial infarction, trauma and cancer. Caspase-3 plays a central role in apoptosis, a mechanism of programmed cell death involved in the pathogenesis of chronic kidney disease (CKD). Methods: We compared cfDNA and caspase-3 levels in 25 CKD patients and in 10 healthy subjects, evaluating the modification of their concentrations according to CKD stage. We also analyzed the correlation between cfDNA and caspase-3 levels in CKD patients and the correlation between cfDNA and caspase-3 levels and creatinine and urea. Results: CfDNA and caspase-3 levels were higher in CKD patients compared to healthy subjects, in particular in patients with advanced renal disease. A positive correlation between cfDNA and caspase-3 levels and between cfDNA and caspase-3 and creatinine and urea was also observed. Conclusion: Patients with chronic kidney disease present higher levels of cfDNA and caspase-3 levels compared with healthy subjects. The worsening of renal damage and the increase in uremic toxin concentration are associated to higher levels of cfDNA and caspase-3 levels, thus reflecting a central role of apoptosis in the pathogenesis of CKD.

Age-related macular degeneration (AMD) is a complex, progressive degenerative retinal disease. Retinal pigment epithelial (RPE) cells play an important role in the immune defense of the eye, and their dysfunction leads to the progressive irreversible degeneration of photoreceptors. Genetic factors, chronic inflammation, and oxidative stress have been implicated in AMD pathogenesis. Oxidative stress causes RPE injury, resulting in a chronic inflammatory response and cell death. The Y402H polymorphism in the complement factor H (CFH) protein is an important risk factor for AMD. However, the functional significance of CFH Y402H polymorphism remains unclear. In the present study, we investigated the role of CFH in the proinflammatory response using an in vitro model of oxidative stress in the RPE with the at-risk CFH Y402H variant. : ARPE-19 cells with the at-risk CFH Y402H variant were highly susceptible to damage caused by oxidative stress, with increased levels of inflammatory mediators and pro-apoptotic factors that lead to cell death. Pretreatment of ARPE-19 cell cultures with exogenous CFH prior to the induction of oxidative stress prevented damage and cell death. This protective affect may be related to the negative regulation of pro-inflammatory cytokines. CFH contributes to cell homeostasis and is required to modulate the pro-inflammatory cytokine response under oxidative stress in the ARPE-19 cells with the at-risk CFH Y402H variant.

No abstract available

Cell identity is determined by chromatin structure and the profiles of gene expression, which are dependent on chromatin accessibility and DNA methylation of regions critical for gene expression, such as enhancers and promoters. These epigenetic modifications are required for mammalian development and are essential for the establishment and the maintenance of the cellular identity. DNA methylation was once thought to be a permanent repressive epigenetic mark, but systematic analysis in various genomic contexts reveals a more dynamic regulation than previously thought. In fact, both active DNA methylation and demethylation occur during cell fate commitment and terminal differentiation. To link methylation signatures of specific genes to their expression profiles, we have determined the methyl-CpG configurations of the promoters of five genes switched on and off during murine postnatal brain differentiation by bisulfite-targeted sequencing. We report here the structure of significant, dynamic and stable methyl-CpG profiles associated with silencing or activation of expression of genes during neural stem cell and brain postnatal differentiation. Strikingly, these methylation cores mark different mouse brain areas and cell types derived from the same areas during differentiation.

A wide variety of renal neoplasms can have cystic areas. It happens for different reasons: some tumors have an intrinsic cystic architecture, others have a pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated to low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway and they are more frequent in patients suffering from VHL disease. The differential diagnosis with multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and it requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumors include cystic forms, a knowledge of criteria for a differential diagnosis is mandatory.

Bananas and plantains (Musa spp.) cultivation holds significant global economic importance, but it faces numerous challenges, which may include diverse abiotic and biotic factors such as drought and various diseases caused by fungi, viruses, and bacteria. The genetic and asexual nature of cultivated banana varieties makes them unattractive for improvement via traditional breeding. To overcome these constraints, modern biotechnological approaches like genetic modification and genome editing have become essential for banana improvement. However, these techniques rely on somatic embryogenesis, which has only been successfully achieved in a limited number of banana cultivars. Therefore, developing new strategies for improving somatic embryogenesis in banana is crucial. This review article focuses on advancements in banana somatic embryogenesis, highlighting the progress, the various stages involved, cryopreservation techniques, and the molecular mechanisms underlying the process. Furthermore, the article discusses the factors that could influence somatic embryogenesis and explores the prospects for improving the process, especially in recalcitrant banana cultivars. By addressing these challenges and exploring potential solutions, researchers aim to unlock the full potential of somatic embryogenesis as a tool for banana improvement, ultimately benefiting the global banana industry.

Recently, a database of human piRNAs has been created, which allows studying the binding of many piRNAs to mRNAs of genes involved in many diseases, including cancer. In the present work, we investigated what piRNAs can interact with candidate esophageal squamous cell carcinoma (ESCC) genes. The binding of 480 thousand piRNAs with mRNAs of 66 candidate ESCC genes was studied. Bioinformatic studies found that piRNAs bind only to the mRNAs of nine candidate genes: AURKA, BMP7, GCOM1, ERCC1, MTHFR, SASH1, SIX4, SULT1A1, and TP53. It has been shown that piRNAs can bind to mRNA by overlapping nucleotide sequences in limited 3'UTR and 5'UTR regions called clusters of binding sites (BSs). The existence of clusters of piRNA BSs significantly reduces the proportion of nucleotide sequences of these sites in the mRNA of target genes. Competition between piRNAs occurs for binding to the mRNA of target genes. Individual piRNAs and groups of piRNAs that have separate BSs and clusters of BSs in the mRNAs of two or more candidate genes have been identified in the mRNAs of these genes. This organization of piRNAs BSs indicates the interdependence of the expression of candidate genes through piRNAs. Significant differences in the ability of genes to interact with piRNAs avoid the side effects of piRNAs on genes with the lack of binding of such piRNAs. Individual piRNAs and sets of piRNAs are proposed and recommended for the diagnosis and therapy of ESCC.

Liquid biopsy has been developed to diagnose and monitor cancer. Despite the recent advances in investigating early cancer detection and diagnosis strategies, there is still a lack of improvements in capturing (CTCs). To archive this, we developed an efficient CTC detection system by integrating gold nanoparticles and a microfluidic platform, which can achieve CTC capture within 120 min. The microdevice was functionalized by immobilizing antibodies specific to the target cells. The method was tested with spiked tumor cells in whole human blood with three pancreatic cancer cell lines and compared with purified cancer cells suspended in a phosphate buffer solution. Our results captured pancreatic cancer cells spiked in blood samples with efficiency (90±3.2)% and were used to isolate CTCs from patients with metastatic pancreatic cancer. This methodology will enable the production of functionalized, patterned surfaces that interact with tumor cells, enhancing the selective capture of CTCs from biological assays.

Platinum-resistant high-grade serous ovarian cancer (HGSOC) is invariably a fatal disease, so a central goal in ovarian cancer research is to develop novel strategies to overcome platinum resistance. Treatment is thus moving towards personalized therapy. However, validated molecular biomarkers to predict patients’ risk of developing platinum resistance are still lacking. Extracellular vesicles (EVs) are promising candidates for biomarkers. EpCAM-specific EVs are largely unexplored biomarkers in predicting chemoresistance. Using transmission electron microscopy, nanoparticle tracking analysis and flow cytometry, we compared the characteristics of EVs released from a cell line derived from a clinically confirmed cisplatin-resistant patient (OAW28) and EVs released from two cell lines from tumors sensitive to platinum-based chemotherapy (PEO1, OAW42). We showed that characteristics of EVs released from the HGSOC cell line of chemoresistant patients had higher heterogeneity in size, a larger proportion of medium/large (&gt;200nm) EVs and a higher number of released EpCAM-positive EVs of different sizes, although expression of EpCAM predominated, especially on those larger than 400 nm. We also determined a strong positive correlation between the concentration of EpCAM-positive EVs and expression of cellular EpCAM. These results may contribute to prediction of platinum resistance in the future, although they should first be validated in clinical samples.

This study investigates the use of Au-doped Pd anodic electrocatalysts on ATO support for the conversion of methane to methanol. The study involves cyclic voltammetry, in-situ Raman spectra, polarization curves, and FTIR analysis to determine the optimal composition of gold and palladium for enhancing the conversion process. The results demonstrate the potential for utilizing methane as a feedstock for producing sustainable energy sources. Pd75Au25/ATO electrode exhibited the highest OCP value, and Pd50Au50/ATO had the highest methanol production value at a potential of 0.05 V. Therefore, it can be concluded that an optimal composition of gold and palladium exists to enhance the conversion of methane to methanol. The findings contribute to the development of efficient and sustainable energy sources, highlighting the importance of exploring alternative ways to produce methanol.

Viruses with encephalitogenic potential can cause neurological conditions of clinical and epidemiological importance, such as Saint Louis encephalitis virus, Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, dengue virus, Zika virus, Chikungunya virus, Mayaro virus and West Nile virus. The objective of the present study was to determine the number of arboviruses with neuroinvasive potential isolated in Brazil that corresponds to the collection of viral samples belonging to the Section of Arbovirology and Hemorrhagic Fevers (SAARB/IEC) of the Laboratory Network of National Reference for Arbovirus Diagnosis from 1954 to 2022. A total of 1,090 arbovirus samples with encephalitogenic potential were isolated from mice. From a total of 7,054 samples intended for cell culture. The isolates from mosquitoes totaled 659 viruses. The emergence of new arboviruses may be responsible for diseases still unknown to humans, making the Amazon region a hotspot for infectious diseases due to its fauna and flora species characteristics. The detection of circulating arboviruses with the potential to cause neuroinvasive diseases is constant, which justifies the continuation of active epidemiological surveillance work that offers adequate support to the public health system regarding the virological diagnosis of circulating arboviruses in Brazil.

Previous research suggests that the senescence and death of the replaceable bud in chestnut cultivar (cv.) ‘Tima Zhenzhu’ involves programmed cell death (PCD). However, the molecular network responsible for regulating replaceable bud PCD is poorly characterized. Here, we performed transcriptomic profiling of the chestnut cv. ‘Tima Zhenzhu’ replaceable bud before (S20), during (S25), and after PCD (S30) to ascertain the molecular mechanism underlying the PCD process. A total of 5,779, 9,867, and 2,674 differentially expressed genes (DEGs) were discovered upon comparison of S20 vs. S25, S20 vs. S30, and S25 vs. S30, respectively. Approximately 6,137 DEGs common to at least two comparisons were selected for GO and KEGG enrichment analyses to interrogate the main corresponding biological functions and pathways. GO analysis showed that these common DEGs could be divided into three functional categories, including 15 cellular components, 14 molecular functions, and 19 biological processes. KEGG analysis found that “plant hormone signal transduction” included 93 DEGs. Overall, 441 DEGs were identified as related to the process of PCD. Most of these were found to be genes associated with ethylene signaling, as well as initiation and execution of various PCD processes. A hypothetical model, consisting of three overlapping processes, is proposed for the replaceable bud PCD: First, ethylene signaling is activated during preparation for PCD, in order to regulate the activity of downstream targets. Next, during PCD initiation, the up-regulation of several TFs (including MYB, MADS-box, bHLH, and NAC TFs) induces an increase in cytochrome c expression and in the cytosolic Ca2+ content, activating the Ca2+-dependent signaling cascade. Finally, during PCD execution, the process of autophagy and the activity of proteases (i.e., cysteine proteinases RD21A-like, metacaspase-9-like, vacuolar-processing enzyme-like, and senescence-associated proteins for hydrolysis) work synergistically to clear the cell of cellular components. When this process is complete, the replaceable bud senesces and dies.

Renal Cell Carcinoma (RCC) is generally represented by low-FDG avidity, and [18F]FDG-PET/CT is not recommended to stage the primary tumor. However, its role to assess metastases is still unclear. The aim of this study was to evaluate the diagnostic accuracy of [18F]FDG-PET/CT to correctly identify RCC lung metastases using histology as standard of truth. Records of 350 patients affected by RCC and with CT evidence of at least one lung nodule, were retrospectively analyzed. Inclusion criteria were: a) histologically proven RCC; b) [18F]FDG-PET/CT performed prior to lung surgery; c) lung surgery with histological analysis of surgical specimens; d) complete follow-up available. A per-lesion analysis was performed, and diagnostic accuracy was reported as sensitivity and specificity, using histology as standard of truth. [18F]FDG-PET/CT semiquantitative parameters (Standardized Uptake Value [SUVmax], Metabolic Tumor Volume [MTV] and Total Lesion Glycolysis [TLG]) were collected for each lesion. Sixty-seven (n=67) patients with a total of 107 lesions were included: lung metastases from RCC were detected in 57/107 of cases, while 50/107 lesions were related to others lung malignancies. Applying a cut-off of SUVmax ≥2, the sensitivity and the specificity of [18F]FDG-PET/CT for detect RCC lung metastases were 33.3% (95% CI: 21.4% - 47.1%) and 26% (95%CI: 14.6% - 40.3%), respectively. The analysis demonstrated sub-optimal diagnostic accuracy of [18F]FDG-PET/CT to discriminate between RCC lung metastases versus other malignancies. However, semiquantitative analysis including also volumetric parameters (MTV and TLG) can support [18F]FDG-PET/CT image interpretation.

Herein we foremost detailed the numerical modeling of the double absorber layer- methyl ammonium lead iodide– carbon nitride layer solar cell and subsequently provided in-depth insight on the active layer associated with dominant radiative and non-radiative recombination losses limiting the efficiency ( ) of the solar cell. Under recombination kinetics phenomena, we explored the influence of Radiative recombination, Auger recombination, Shockley Read Hall recombination, the energy distribution of defects; Band Tail recombination (Hoping Model), Gaussian distribution, metastable defect states including single donor (0/+), single acceptor (-/0), Double Donor (0/+/2+), double acceptor (2/-/0-), and the interface layer defects on the output characteristics of the solar cell. Setting defect (or trap) density to with uniform energy distribution of defects for all the layers, we achieved the of 24. 16 %. A considerable enhancement in power conversion efficiency was perceived as we reduced the trap density to for the absorber layers. Further, it was observed that for the absorber layer with double donor defect states, the active layer should be carefully synthesized to reduce crystal order defects to keep the total defect density as low as to achieve efficient device characteristics

Excessive activation of frog eggs (overactivation) is a pathological process that renders eggs unfertilizable. Its physiological inducers are unknown. Previously, oxidative stress was shown to cause time- and dose-dependent overactivation of Xenopus laevis frog eggs [1]. Here, we demonstrate that the oxidative stress-induced egg overactivation is a calcium-dependent phe-nomenon which can be attenuated in the presence of the selective calcium chelator BAPTA. Degradation of cyclin B2, which is known to be initiated by calcium transient in fertilized or parthenogenetically activated eggs, can also be observed in the overactivated eggs. Decline in mitochondrial membrane potential, ATP depletion and termination of protein synthesis manifest in the eggs within one hour of triggering overactivation. These intracellular events occur in the absence of caspase activation. Furthermore, plasma membrane integrity is compromised in the overactivated eggs, as evidenced by ATP leakage and egg swelling. In sum, our data demonstrate that oxidative stress-induced overactivation of frog eggs causes fast and dramatic disruption of cellular homeostasis, resulting in robust and expedited cell death by a calcium-dependent non-apoptotic mechanism.

Cannabidiol (CBD) is an active diterpenoid compound that is extracted from the leaves and stem of Cannabis sativa. Previous studies show that CBD is a non-psychotropic compound with significant anti-cancer effects. This study determines its cytotoxic effect on oral cancer cells and OECM1 cells and compares the outcomes with a chemotherapeutic drug, cisplatin. This study determines the effect of CBD on the viability, apoptosis, morphology and migration of OECM1 cells. Electric cell-substrate impedance sensing (ECIS) is used to measure the change in cell impedance for cells that are treated with a series concentration of CBD for 24 hours. AlamarBlue and annexin V/7-AAD staining assays show that CBD has a cytotoxic effect on cell viability and induces cell apoptosis. ECIS analysis shows that CBD decreases the overall resistance and morphological parameters at 4 kHz in a concentration-dependent manner. There is a significant reduction in the wound-healing recovery rate for cells that are treated with 30 μM CBD. This study demonstrates that ECIS can be used for in vitro screening of anticancer drugs and is more sensitive, functional and comprehensive than traditional biochemical assays. CBD also increases cytotoxicity on cell survival and the migration of oral cancer cells, so it may be a therapeutic drug for oral cancer

The main objective of this study is to demonstrate proof of principle that computational fluid dynamics (CFD) modeling is a tool for studying the contribution of covert and overt vascular architecture to the risk of cerebrovascular disease in in sickle cell disease (SCD) as well as uncover one or more mechanism of response to therapy such as chronic red blood cell (cRBC) transfusion. We analyzed baseline (screening), pre-randomization and study exit magnetic resonance angiogram (MRA) images from 10 (5 each from the transfusion and observation arms) pediatric sickle SCD participants in the silent cerebral infarct transfusion (SIT) trial, using CFD modeling. We reconstructed the intracranial portion of the internal carotid artery and branches and extracted the geometry using 3D Slicer. We cut specific potions of the large intracranial artery to include segments of the internal carotid, middle, anterior, and posterior cerebral artery such that the vessel segment analyzed extended from the intracranial beginning of the internal carotid artery up to immediately after (~0.25 inches) the middle cerebral artery branching point. Cut models were imported into Ansys 2021R2/2022R1 and laminar and time-dependent flow simulation was performed. Change in time averaged mean velocity, wall shear stress, and vessel tortuosity were compared between the observation and cRBC arm. We did not observe a correlation between time averaged mean velocity (TAMV) and mean transcranial doppler (TCD) velocity at study entry. There was also no difference in change in time average mean velocity, wall shear stress (WSS), and vessel tortuosity between the observation and cRBC transfusion arms. WSS and TAMV were abnormal for 2 (developed TIA) out of the 3 participants (one participant had SCI) that developed neurovascular outcomes. CFD approaches allows for the evaluation of vascular topology and hemodynamics in SCD using MRA images. In this proof of principle study, we show that CFD could be a useful tool and we intend to carry out future studies with a larger sample to enable more robust conclusions.

There is a growing appreciation in the fields of Cell and Developmental Biology that cells collectively process information in time and space. While many powerful molecular tools exist to observe biophysical dynamics biologists must find ways to quantitatively understand these phenomena at the systems level. Here, we present a guide for application of well-established information theory metrics to biological datasets and explain these metrics using examples from cell, developmental and regenerative biology. We introduce a novel computational tool (CAIM) for simple, rigorous application of these metrics to timeseries datasets. Finally, we use CAIM to study calcium and cytoskeletal Actin information flow patterns between Xenopus laevis embryonic animal cap stem cells. The tools that we present here will enable biologists to apply information theory to develop systems level understanding of a diverse array of experimental systems.

Attempts to find and quantify the supposed low entropy of organisms and its preservation are revised. Absolute entropy of the mixed components of non-living biomass (around -1.6 x 103 J K-1 L-1) is the reference to which other entropy decreases would be ascribed to life. Compartmentation of metabolites and departure from the equilibrium of metabolic reactions account for 1 and 40-50 J K-1 L-1, respectively, decreases of entropy and, though small, are distinctive features of living tissues. DNA and proteins do not supply significant decreases of thermodynamic entropy, but their low informational entropy is relevant for life and its evolution. No other living feature contributes significantly to the low entropy associated to life. The photosynthetic conversion of radiant energy to biomass energy accounts for the most of entropy (2.8 x 105 J K-1 carbon kg-1) produced by living beings. The comparative very low entropy produced in other processes (around 4.8 x102 J K-1 L-1 day-1 in human body) must be rapidly exported outside as heat to preserve the low entropy decreases due to compartmentation and non-equilibrium metabolism. Enzymes and genes are described whose control minimize the rate of production of entropy and could explain selective pressures in biological evolution and the rapid proliferation of cancer cells.

Cytochrome P450 (CYPs) is a functionally diversified third-largest gene family that exploded in the plant kingdom. Their role in different organ development has been illustrated by the intervention of phytohormone. Cotton is a model organism for cell differentiation and cell elongation. To decipher the participation of CYPs in different cotton fiber developmental stages, we identified and characterized 2460 CYPs in three diploids and two allotetraploid cottons. Furthermore, In-silico expression and cluster analysis of cotton CYPs was conducted to distinguish the fiber stage-specific clusters that have the determining role in different stages of fiber development. The subgenome expression of two conserved Gossypium hirsutum CYPs, namely, GhCYP78A197 and GhCYP78A198 contributed to fiber initiation at an early stage of fiber development, governed by the co-occurrence of TATA and MYB TFs binding sites. Coexpression network partners of these two GhCYP78A annotated as auxin, kinases, chromatin remodeler, epigenetic regulator and cyclin-related genes that possibly induce the endoreduplication and cell proliferation for fiber cell initiation to define the high yield and biomass.

Tumor cells evolve in a complex and heterogeneous environment composed of different cell types and an extracellular matrix. Current 2D culture methods are very limited in their ability to mimic the cancer cell environment. In recent years, various 3D models of cancer cells have been developed, notably in the form of spheroids/organoids, using scaffold or cancer-on-chip devices. However, these models have the disadvantage of not being able to precisely control the organization of multiple cell types in complex architecture and are sometimes not very reproducible in their production, and this is especially true for spheroids. Three-dimensional bioprinting can produce complex, multi-cellular, and reproducible constructs in which the matrix composition and rigidity can be adapted locally or globally to the tumor model studied. For these reasons, 3D bioprinting seems to be the technique of choice to mimic the tumor microenvironment in vivo as closely as possible. In this review, we discuss different 3D-bioprinting technologies, including bioinks and crosslinkers that can be used for in vitro cancer models, and the techniques used to study cells grown in hydrogels; finally, we provide some applications of bioprinted cancer models.

Gap junctions (GJ) and connexins play integral roles in cellular physiology and have been found to be involved in multiple pathophysiological states from cancer to cardiovascular disease. Studies over the last 60 years have demonstrated the utility of altering GJ signaling pathways in experimental models, which has led to them being attractive targets for therapeutic intervention. A number of different mechanisms have been proposed to regulate GJ signaling, including channel blocking, enhancing channel open state, and disrupting protein-protein interactions. The primary mechanism for this has been through the design of numerous peptides as therapeutics, that are either currently in early development or are in various stages of clinical trials. Despite over 25 years of research into connexin targeting peptides, the overall mechanisms of action are still poorly understood. In this overview, we discuss published connexin targeting peptides, their reported mechanisms of action and the potential for these molecules in the treatment of disease.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma is possibly derived from nodal T-cell/histiocyte-rich large B-cell lymphoma; however, a transition between the nodal and splenic micronodular forms has not been described to date. Of note, the only lymph nodes to be involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes, and that, with partial involvement only. Kan et al, in their series of articles, have raised the possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations (apoptosis, necrosis, tissue shrinkage), which modify or even obscure the diagnostic morphological features. The indications for glucocorticoid therapy are either related to the suspected lymphoma, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic, rather than nodal subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved tissue, causing disparate morphologies in the spleen. Apoptosis, as induced by corticosteroids, is hypothesized as the major mechanism initiating the histopa-thological and functional changes in the splenic micronodular variant of our patients.

Staphylococcus aureus mastitis remains a major challenge for dairy farming. Here, 24 mice were immunized and divided into four groups: G1: control; G2: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) DNA vaccine; G3: F0F1 ATP synthase subunit α (SAS), succinyl-diaminopimelate (SDD), and cysteinyl-tRNA synthetase (CTS) recombinant proteins; and G4: SAS+SDD+CTS plus GM-CSF DNA vaccine. The lymphocyte subpopulations and the intracellular interleukin-17A (IL-17A) and interferon-γ production in the draining lymph node cells were immunophenotyped by flow cytometry. The immunophenotyping and lymphocyte proliferation was determined in spleen cells cultured with and without S. aureus stimulus. Immunization with S. aureus recombinant proteins generated memory cells in draining lymph nodes. Immunization with the three recombinant proteins plus GM-CSF DNA led to an increase in the percentage of IL-17A+ cells among overall CD44+ (memory), T CD4+, CD4+ T CD44+ CD27-, γδ TCR, γδ TCR+ CD44+ CD27+ and TCRVγ4+ cells. Vaccination with S. aureus recombinant proteins associated with GM-CSF DNA vaccine downregulates TH2 immunity. Immunization with the three recombinant proteins plus the GM-CSF DNA led to a proliferation of overall memory T, CD4+ and CD4+ TEM cells upon S. aureus stimulus. This approach fostered type 3 immunity, suggesting the development of a protective immune response against S. aureus.

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.

In this paper, we use three different experimental methods (particle method, grid method and hybrid method) to model and simulate the smoke from the perspective of fluid dynamics. Through the comparison of different methods, we conclude: The particle method can avoid the numerical dissipation problem caused by grid calculation, but it also brings problems such as the distortion of the trajectory of the example. The grid method is accurate in calculation, but it is prone to numerical dissipation and loss of details. Finally, we choose the hybrid method to store the vorticity in the form of particles in vortex particles, avoiding the numerical dissipation problem caused by the use of grids, and including rich turbulence, which perfectly shows the simulation effect of smoke.

Because of their low cost and easy production silica nanoparticles (NPs) are amply used in multiple manufactures as anti-caking, densifying and hydrophobic agents. However, this has increased the exposure levels of the general population and has raised concerns about possible toxicity of this nanomaterial. NPs are known to affect the function of the airway epithelium, but the biochemical pathways targeted by these particles remain largely unknown. Here we investigated the effects of NPs on the responses of cultured human bronchial epithelial (16HBE) cells to the damage-associated molecular pattern ATP, using fluorometric measurements of intracellular Ca2+ concentration. Upon stimulation with extracellular ATP these cells displayed a concentration-dependent increase in intracellular Ca2+, which was mediated by release from intracellular stores. Silica NPs inhibited the Ca2+ responses to ATP within minutes of application and at low micromolar concentrations, which are significantly faster and more potent than those previously reported for the induction of cellular toxicity and pro-inflammatory responses. NPs-induced inhibition appeared to be independent from the increase in intracellular Ca2+ they produce, and via a non-competitive mechanism. These findings suggest that NPs reduce the ability of airway epithelial cells to mount ATP-dependent protective responses such as the increase in mucociliary clearance and cough.

The application of electrode-based microfluidic devices in biological entity often imposes a problem due to joule heating. The strong applied potentials or micro channels having narrow cross sections generate undesirable temperature inside the microfluidic channels leading to strong thermal distribution inside the micro channel. When intrinsic distribution of temperature, if not fix with threshold value, causes device damage or cell loss. In this work, we investigate the effects of temperature generated due to joules heating effects and we attempt to address the design constraints for minimizing the joule heating effects in the microfluidic device for developing effective microfluidic device. The device reliability was analyzed under different parametric constraints for various types of substrate materials (PDMS, PMMA, Polyimide and glass). We also attempt to investigate the effects of cell reliability due to strong temperature gradients generated through different applied potentials on different cell types. Furthermore, the response of the device performance due to different electrode configuration and different conductivity of the medium was also studied. Our investigation will eventually provide guidelines for microfluidic researchers to fabricate efficient electrode based microfluidic device which will ultimately help to choose a critical channel dimensions, threshold potentials, and conductivity of solutions in order to avoid device damage and cell loss.

In clinical guidelines, such as National Comprehensive Cancer Network guidelines, it is embodied as first therapeutic option the combination of erlotinib and bevacizumab, based on a small clinical trial which included patients with HLRCC. With this case report we bring out another treatment option, not described before, with extraordinary results based on the combination of a check-point inhibitor and a tyrosine-kinase inhibitor, based on theoretical tumor immunogenic environment.

A recent study from our lab revealed that inhibition of cyclooxygenase-2 exclusively reduces the level of PGE2 amongst the prostanoids and hamper the normal development of several structures, strikingly the cranial vault, in chick embryos. In order to unearth the mechanism behind the deviant development of cranial features, the expression pattern of various factors that are known to influence the cranial neural crest cell (CNCC) migration were checked in chick embryo after inhibiting the COX-2 activity using etoricoxib. The compromised level of cell adhesion molecules and their upstream regulators, namely CDH1, CDH2, MSX1, and TGF-β, observed in the etoricoxib treated embryos indicate that COX-2, through its downstream effector PGE2, regulates the expression of these factors perhaps to aid the migration of CNCC. The histological features and levels of FoxD3 as well as PCNA further consolidates the role of COX-2 in migration and survival of CNCC in developing embryo. The results of the current study indicate that the COX-2 plays a pivotal role in orchestrating the proliferation and migration of CNCC during embryonic development of chick.

The present study is aimed at designing anti-reflective (AR) engraving on the Input-Output surfaces of a rectangular light-guide. We estimate AR efficiency, by the transmittance level in the angular range, determined by the light-guide. Using nano-engraving, we achieve a uniform high transmission over a wide range of wavelengths. In the past, we used smoothed conical pins or indentations on the faces of light-guide crystal as the engraved structure. Here, we widen the class of pins under consideration, following the physical model developed in the previous paper. We analyze the smoothed pyramidal pins with different base shapes. The possible effect of randomization of the pins parameters is also examined. The results obtained demonstrate optimized engraved structure with parameters depending on the required spectral range and facet format. The predicted level of transmittance is close to 99\%, and its flatness (estimated by the standard deviation) in the required wavelength range is 0.2\%. The theoretical analysis and numerical calculations indicate that the obtained results demonstrate the best transmission (reflection) we can expect for a facet with the given shape and size for the required spectral band. The approach is equally useful for any other form and of the facet. We also discuss a simple way of comparing experimental and theoretical results for a light-guide with the designed input and output features. In this study, as well as in our previous work, we restrict ourselves to rectangular facets. We also consider the limitations on maximal transmission produced by the size and shape of the light-guide facets. The theoretical analysis is performed for an infinite structure and serves as an upper bound on the transmittance for smaller-size apertures.

Epithelial-mesenchymal transition (EMT) plays an important role in the acquisition of cancer stem cell (CSC) feature and drug resistance, which are the main hallmarks of cancer malignancy. Although previous findings have shown that several signaling pathways are activated in cancer progression, the precise mechanism of signaling pathways in EMT and CSCs are not fully understood. In this study, we focused on the intestinal and diffuse-type gastric cancer (GC), and analyzed the gene expression of public RNAseq data to understand the molecular pathway regulation in different subtypes of gastric cancer. Network pathway analysis was performed by Ingenuity Pathway Analysis (IPA). Total 2815 probe set IDs were significantly different between intestinal- and diffuse-type GC data in cBioPortal Cancer Genomics. The 10 genes including male-specific lethal 3 homolog (Drosophila) pseudogene 1 (MSL3P1), CDC28 protein kinase regulatory subunit 1B (CKS1B), DEAD-box helicase 27 (DDX27), golgi to ER traffic protein 4 (GET4), chromosome segregation 1 like (CSE1L), translocase of outer mitochondrial membrane 34 (TOMM34), YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), ribonucleic acid export 1 (RAE1), par-6 family cell polarity regulator beta (PARD6B), and MRG domain binding protein (MRGBP) were found to have difference in gene expression in intestinal- and diffuse-type GC. Total 463 direct relationships with 3 molecules (MYC, NTRK1, UBE2M) were found in the biomarker-filtered network generated by network pathway analysis. The networks and features in intestinal- and diffuse-type GC have been investigated and profiled in bioinformatics. Our results revealed the signaling pathways networks in intestinal- and diffuse-type GC, bringing new light for the elucidation of drug resistance mechanisms in CSCs.

Bone innate ability to repair without scaring is surpassed by major bone damage. Current gold-standard strategies do not achieve a full recovery of bone biomechanical properties. To bypass these limitations, tissue engineering techniques based on hybrid materials made up of osteoprogenitor cells, like mesenchymal stem cells (MSCs), and bioactive ceramic scaffolds, like calcium phosphate-based (CaPs), are promising. Biological properties of the MSCs, are influenced by the tissue source. The aim of this study is to define the MSC source and construct (MSC and scaffold combination) most interesting for its clinical application in bone regeneration. iTRAQ generated the hypothesis that anatomical proximity to bone has a direct effect on MSC phenotype. MSCs were isolated from adipose tissue, bone marrow and dental pulp. MSCs were cultured both on plastic surface and on CaPs (hydroxyapatite and β-tricalcium phosphate) to compare their biological features. On plastic, MSCs isolated from dental pulp (DPSCs) were the MSCs with the highest proliferation capacity and the greatest osteogenic potential. On both CaPs, DPSCs are the MSCs with the greatest capacity to colonize bioceramics. Furthermore, results show a trend for DPSCs are the MSCs with the most robust increase in the ALP activity. We propose DPSCs as a suitable MSCs for bone regeneration cell-based strategies.What do you want to do ?New mailCopy

Biologic scaffolds have become an attractive approach for repairing the infarcted myocardium and have been shown to facilitate constructive remodeling in injured tissues. This study aimed to investigate the possible utilization of bacterial cellulose membrane patch containing cocultured cells to limit the myocardium's post-infarction pathology. Myocardial infarction was induced by ligating the left anterior descending coronary artery in 45 Wistar rats, and patches with or without cells were attached to the hearts. After one week, the animals underwent echocardiography for assessing ejection fraction and left ventricular end-diastolic and end-systolic volumes. Following the patch formation, cocultured cells retained viability of >90% over 14 days in culture. The patch was applied to the myocardial surface of the infarcted area after staying 14 days in culture. Interestingly, the bacterial cellulose membrane without cellular treatment showed higher preservation of cardiac dimensions; however, we did not observe improvement in the left ventricular ejection fraction of this group compared to coculture treated membranes. Our results demonstrated an important role for bacterial cellulose in supporting cells known to produce cardioprotective soluble factors and may thus provide effective future therapeutic outcomes for patients suffering from ischemic heart disease.

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

Achieving devices to be transparent is the task considered in the last time in many aspects and for different purposes. One issue of these problems is making anti-reflective surfaces in a wide wavelength range and keeping it flat enough. The authors of the previous publication showed that one could enhance a flat facet's transmission efficiency by suitable engraving. They used smoothed conical fingers and holes. Here, we widen the class of anti-reflective metasurfaces under consideration, following the requirements of the model developed in the previous paper. We involve also smoothed pyramidal fingers. The obtained results provide the improved engraved structure, with parameters dependent on the required spectral range, and the facet format. The predicted level of transmittance is close to 99\%, and the flatness(estimated by the standard deviation) as 0.2\%. This improvement is significant enough for high and broadband transmittance. In this work, we show that the randomization of the engraving parameters does not provide any significant effect for small facets. We also discuss a simple way of comparing experimental and theoretical results for a waveguide with the considered input and output features. In this study, as well as in our previous work, we restrict ourselves by rectangular facets. We also discuss the limitations that originated from the size and shape of the waveguide facets.

Many species of the Asteraceae family are used in traditional Mexican medicine for possessing healing properties. Ageratina pichinchensis (Asteraceae) is a plant used for the treatment of gastric ulcers, deep wounds and for its antifungal effects. The aim of this study was to establish a cell suspension culture of A. pichinchensis, quantify the anti-inflammatory constituents 2,3-dihydrobenzofuran and 3-epilupeol, to evaluate the anti-inflammatory potential of its extracts and perform a phytochemical analysis. Cell suspension cultures were established in MS culture medium supplemented with 30 g L-1 sucrose and 1.0 g L-1 α-naphthaleneacetic acid (NAA) plus 0.1 mg L-1 6-furfurylaminopurine (KIN). The ethyl acetate extracts of cell suspension cultures analyzed by GC revealed that the maximum production of compounds The anti-inflammatory activity of these extracts exhibited significant inhibition of NO production. Furthermore, the phytochemical study of EtOAc and MeOH extracts of the biomass on day 20 led to the identification of 17 known compounds. The structures of compounds were assigned by analysis of 1D and 2D NMR data and the remainder by GC-MS. This is the first report of the production of the (-)-Artemesinol, (-)-Artemesinol glucoside, Encecalin and 3,5-diprenyl-acetophenone compounds by a cell suspension cultures of A. pichinchensis.

The consequences of Sickle Cell Disease (SCD), including ongoing hematopoietic stress and hemolysis, vascular damage and chronic therapies , such as blood transfusions and Hydroxyurea on hematopoietic stem and progenitor cell (HSPC) have not been characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients stratified by treatment and controls. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, and two to five-fold more CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a and by very high levels of expression of the CD49f antigen. These findings were present to varying degrees in all patients, whether or not they were naïve or on chronic therapy. HU treatment tended to normalizes many of these parameters. Chronic stress erythropoiesis, inflammation caused by SCD and hydroxyurea therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.

Perovskite based solar cells have achieved tremendous progress reaching record efficiency in the past 5 years. Numerous new processes and chemistry have been reported and contribute to the perovskite rapid progress. Continuous efficiency improvements are still necessary for perovskite solar cells, and an exploratory data analysis on devices performance over multiple studies could boost the technology development. Such analysis could identify patterns or provide insights that are not obvious in a single study. Here we present a high quality dataset containing only independently certified Pb-based perovskite solar cells summarizing their efficiency, relevant I-V metrics, manufacturing processes and materials used. Analysis over the dataset provides insights on how aperture size, perovskite deposition methods and materials used in each functional layer affect the final solar cell efficiency and I-V metrics. Future directions are also suggested for efficiency improvements.

Mammary neoplasm affects a population of intact and elderly female dogs and 50% are malignant. In order to study this disease, cell culture is as a promising preclinical model, creating the opportunity to deposit cell lines at a cell bank, allowing a great reproducibility of the assays and making the validation of the results more reliable. Another important aspect is the possibility to establish models for better understanding tumour characteristics, such as vasculogenic mimicry. Due the importance of cancer cell lines in preclinical models, this study aimed to establish and characterize primary cell lines from canine mammary gland tumours according to immunophenotype and tumorigenicity, and with its ability to form vasculogenic mimicry-like structures in vitro and in vivo. Cell cultures were evaluated for morphology, phenotype, vasculogenic mimicry and tumorigenicity abilities. We collected 17 primary mammary carcinoma and 3 metastasis and had a satisfactory result in 10 of them. All cell lines presented spindle shape or polygonal morphology and expressed concomitant pan-cytokeratin and cytokeratin 8/18. Four cell lines had vasculogenic mimicry ability in vitro and two of them showed in vivo tumorigenic potential and forming VM in the xenotransplant tumour. Cell characterization of those lines will help to create a database for more knowledge of mammary carcinomas in dogs, including studies of tumour behaviour and new therapeutic targets.

Hematopoietic stem cells (HSCs) are responsible for the production of blood cells throughout the human life span. Single HSCs can give rise to at least eight distinct blood cell lineages. Together, hematopoiesis, erythropoiesis and angiogenesis coordinate several biological processes, such as cellular interactions in development and proliferation, guided migration, lineage programming and reprogramming by transcription factors. Any dysregulation of these processes may result in hematological disorders and/or malignancies. Several studies of the molecular mechanisms governing HSC maintenance have demonstrated that protein regulation by the ubiquitin proteasomal pathway is crucial for normal HSC function. Recent studies have shown that the reversal of ubiquitination by deubiquitinating enzymes (DUBs) plays an equally important role in hematopoiesis; however, there is only limited additional information regarding the biological function of DUBs. In this review, we focus on recent discoveries that have led to a better understanding of the physiological roles of DUBs in hematopoiesis, erythropoiesis and angiogenesis. In addition, we discuss the DUBs associated with common hematological disorders and malignancies, which may potentially be therapeutic drug targets.

White adipose tissue (WAT) is distributed in several depots that have distinct metabolic and inflammatory functions. In our body there are subcutaneous (sWAT), visceral (vWAT) and bone marrow fat depots (BFAT). Obesity affects size, function and inflammatory state of WATs. This process can alter the stem cell niches present in these tissues and affect the functions of stem cells residing within. In particular, obesity may affect the activity of mesenchymal stromal cells (MSCs) present in WAT. MSCs are an heterogenous population containing stromal cells, progenitor cells, fibroblasts and stem cells that are able to differentiate in adipocytes, chondrocytes, osteocytes and other mesodermal derivatives. We performed a comparison of the effects of obesity on MSCs obtained from sWAT, vWAT and BFAT. Our study evidenced that obesity affected mainly the biological functions of MSCs obtained from bone marrow and vWAT with a decrease in proliferation rate, reduced percentage of cells in S phase and trigger of senescence. The onset of senescence was confirmed by expression of genes belonging to RB and P53 pathways. Our study evidenced that negative consequences of obesity on body physiology may be related also to impairment in the functions of stromal compartment present in the several adipose tissues. This finding provides new insights on the targets that should be considered for an effective treatment of obesity-related diseases.

Background: The central channel of the nuclear pore complex (NPC) plays an important role in the selective transport of proteins between the nucleus and cytoplasm. Previous studies have demonstrated that depletion of the Nup62 complex, constructing the nuclear pore channel in premeiotic Drosophila cells, resulted in absence of meiotic cells. We attempted understanding the mechanism underlying the cell cycle arrest before meiosis. Methods: We induced dsRNAs against the nucleoporin mRNAs using the Gal4/UAS system in Drosophila. Results: The cell cycle of the Nup62-depleted cells was arrested before meiosis without CDK1 activation. Ectopic over-expression of CycB, but not constitutively active CDK1, resulted in partial rescue from the arrest. CycB accumulated precociously in the nuclei of Nup62-depleted cells and cells depleted of exportin (encoded by emb). Protein complexes containing CycB, Emb, and Nup62 complex components were observed in premeiotic spermatocytes. CycB, which had precociously migrated into the nucleus, was associated with Emb, and the complex was transported back to the cytoplasm through the central channel, interacting with the Nup62 complex. Conclusion: We proposed that CycB is exported with Emb through the channel interacting with the Nup62 complex before initiation of meiosis. The nuclear export ensures production of active CycB-CDK1 in the cytoplasm.

Poor survival of human pluripotent stem cells (hPSCs) following freezing, thawing, or passaging hinders maintenance and differentiation in stem cell research. Rho-associated kinases (ROCKs) play a crucial role in hPSC survival. To date, a typical ROCK inhibitor, Y-27632, has been the primary agent used in hPSC research. Here, we report that another ROCK inhibitor, fasudil, can be used as an alternative. Fasudil increased hPSC growth due to survival rather than proliferation following thawing and passaging, similar to Y-27632. It did not affect pluripotency and genetic integrity including mitochondrial genome (mtDNA). Notably, the genes related to metabolism, mTORC1, and TP53 have mainly displayed a faster recovery pattern with ROCK inhibitors than control. Furthermore, fasudil was confirmed as useful for the single dissociation of hPSCs and for aggregation. It also increased retinal pigment epithelium (RPE) differentiation and the survival of neural crest cells during differentiation. These findings suggest that fasudil can replace Y-27632 for use in stem cell research.

Accurate channel estimation is of utmost importance for massive MIMO systems that allow providing significant improvements in spectral and energy efficiency. In this work, we investigate the spectral efficiency performance and present a channel estimator for multi-cell massive MIMO systems subjected to pilot-contamination. The proposed channel estimator performs well under moderate to aggressive pilot contamination scenarios without prior knowledge of the inter-cell large-scale channel coefficients and noise power. The estimator approximates the performance of a linear Minimum Mean Square Error (MMSE) as the number of antennas increases. Following, we derive a lower bound closed-form spectral efficiency of the Maximum Ratio Combining (MRC) detector in the proposed channel estimator. The simulation results highlight that the proposed estimator performance approaches the linear minimum mean square error (LMMSE) channel estimator asymptotically.

Accurate channel estimation is of utmost importance for massive MIMO systems to provide significant improvements in spectral and energy efficiency. In this work, we present a study on the distribution of a simple but yet effective and practical channel estimator for multi-cell massive MIMO systems suffering from pilot-contamination. The proposed channel estimator performs well under moderate to aggressive pilot contamination scenarios without previous knowledge of the inter-cell large-scale channel coefficients and noise power, asymptotically approximating the performance of the linear MMSE estimator as the number of antennas increases. We prove that the distribution of the proposed channel estimator can be accurately approximated by the circularly-symmetric complex normal distribution, when the number of antennas, M, deployed at the base station is greater than 10.

Carbon-based nanomaterials, such as carbon nanomaterials, play an important role in many promising nanomaterials in the field of biomedicine. Among them, carbon nanomaterials are a new kind of porous carbon nanomaterials with great application potential. Therefore, based on carbon nanomaterials, the interaction between biomaterials and cells and surface modification were analyzed. Studies have shown that the interaction between the surface of biological materials and cells is mainly the mutual molecular recognition between the surface receptors of cell membranes and the ligands on the surface of biomaterials. Therefore, biomimetic modification of the surface of biomaterials is used to enhance cell affinity and specific recognition. The carbon nanomaterial has a large specific surface area and pore volume, can provide high drug-loading capacity, has an adjustable pore structure and pores, can control the release of the drug molecules, and has a good application prospect in the field of drug delivery systems.

Brain cancer is the tenth leading cause of death in the U.S. Glioblastoma multiforme (GBM) is the most lethal primary malignant central nervous system tumor in adults. The present study employed samples from 1985-2014 to discover the difference in prognosis among glioblastoma subtypes after the evolution of treatment modalities over the past few years. The current study aims to find the differences between Glioblastoma multiforme (GBM) and giant cell glioblastoma (GCG) in terms of prognosis among adults and elderly patients in the U.S. This study is a historical cohort type of study and is conducted on adults and elderly individuals with GBM or GCG from the years 1985-2014 in the U.S. Data were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. The study exposure was GBM or GCG and the outcome was mortality. The potential confounders were age, sex, race, ethnicity, year of diagnosis, primary site, and surgery. A chi-square test was used for categorical data. A univariate analysis was used for variables having a p-value < 0.05. Potential confounders were selected and evaluated using multivariate logistic regression models to calculate the odds ratio with stepwise selection. The study sample was 25,117. The incidences of GBM and GCG were not similar in relation to age group. Also, Spanish-Hispanic ethnicity was independently protective of GBM and GCG as compared to Non-Spanish-Hispanic ethnicity patients with GBM have a higher mortality rate than do GCG patients. The mortality rate was higher among patients diagnosed before 2010. In conclusion, GCG was not statistically significant in association to reduced mortality. Non-Spanish-Hispanics with GBM or GCG had a higher mortality rate than did Spanish-Hispanics. Factors such as being female, being age >59, and having a year of diagnosis before 2010 were independently associated with increased mortality.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T-cells for targeted cancer therapy. CAR T-cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T-cell therapies were approved by the U. S Food and Drug Administration; one for the treatment of pediatric Acute Lymphoblastic Leukemia (ALL), the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T-cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B-cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin’s lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T-cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This Commentary summarizes the current state of knowledge on CAR T-cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.

The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats and neuronal excitability were evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males were associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII and choline acetyltransferase in the DG. Enhanced excitability in females were associated with increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs were associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors.