Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells’ biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironment, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The patients' reactions to radiation are varied, ranging from a complete response to even cancer progression during treatment. This concept illustrates how different levels of mitochondrial metabolism might contribute to this heterogeneity. Considering this notion can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.

Glioblastoma (GBM) still presents as one of the most aggressive tumors in the brain, which despite enormous research efforts remains incurable until today. As many theories evolve around the persistent recurrence of this malignancy the assumption of a small population of cells with a stem-like phenotype remains as a key driver of its infiltrative nature. In this article we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of Bone Morphogenic Protein 4 (BMP4), which induces GSC differentiation and hence reduces tumorigenicity. We therefore employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell based assays (MTT, limiting dilution and sphere formation assays), western blots, irradiation procedures and quantitative real-time PCR that depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1-expression might also serve as a marker protein to determine BMP4-susceptibility.

Abstract: The effect of collagen type 1 (Col I) oxidation on Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) remodeling is described as a model for acute oxidative stress. Morphologically, remodeling was presented by a mechanical rearrangement of adsorbed FITC-Col I and a trend for its organization in a fibril-like pattern - a process strongly abrogated in oxidized samples, but without visible changes in cell morphology. The cellular proteolytic activity was quantified in multiple samples utilizing fluorescence de-quenching (FRET effect). In the presence of ADMSCs a significant increase of native FITC-Col I fluorescence was observed, almost absent in the oxidized samples. Parallel studies in cell-free systems confirmed the enzymatic de-quenching of native FITC-Col I by Clostridial collagenase, again showing significant inhibition in oxidized samples. The structural changes in the oxidized Col I was further studied by Differential Scanning Calorimetry: an additional endotherm at 33.6°C along with the typical for native Col I at 40.5°C with sustained enthalpy (∆H) was observed in oxidized samples. Collectively, it has been evidenced that remodeling of Col I by ADMSCs is altered upon oxidation due to the intrinsic changes in the protein structure, thus presenting a novel mechanism for the control of stem cells' behavior toward collagen.

Background/Aim: Uterine leiomyoma, also known as fibroids, is the most common benign neoplasm of the female genital tract. Leiomyoma, including its subtypes, is the most common uterine tumor. The subtypes account for approximately 10% of leiomyomas. Intravenous leiomyomatosis, a uterine leiomyoma subtype, is an intravascular growth of benign smooth muscle cells, occasionally with pelvic or extrapelvic extension. Uterine leiomyosarcoma, a malignant tumor, tends to metastasize hematogenously, and distant metastasis to the lungs and liver is common. Therefore, this intravenous leiomyomatosis’ oncological features resemble those of the malignant tumor uterine leiomyosarcoma. Cancer stem cells migrate to distant organs via intravascular infiltration, leading to micrometastases. Materials and Methods: We examined the oncological properties of intravenous leiomyomatosis using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: CD44-positive mesenchymal tumor stem-like cells were detected in both intravenous leiomyomatosis and uterine leiomyosarcoma. The oncological nature of intravenous leiomyomatosis was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in intravenous leiomyomatosis, Cyclin E and Ki-67-positive cells were rare, and no pathological findings suspected to be malignant were observed. Conclusion: It is expected that establishing a treatment method targeting cancer stem cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis.

: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evi-dence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infil-trative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the ex-pression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show using in vitro limiting dilution assays, quantita-tive real-time PCR and ex vivo adult organotypic brain slice transplantation cultures that thera-peutic doses of calcitriol, the hormonally active form of vitamin D3, reduces stemness to varying extent in a panel of investigated GSC lines and effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to com-pletely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in fol-low-up studies.

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from ethyl acetate soluble fraction of Acacia auriculiformis stem bark. Column chromatography, gel filtration and NMR spectroscopy were used to purified and characterized betulin from the extract. Betulin which is a known inducer of apoptosis was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1epsilon (CK1epsilon), glycogen synthase kinase 3alpha/β (GSK-3alpha/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6) and vascular endothelial growth factor receptor 2 kinase (VEGFR2) and with activity in µM range. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to underline its putative use as anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway similarly to imatinib mesylate, a well-known inhibitor of ABL1 kinase. The interaction of betulin and ABL1 was studied by molecular docking showing an interaction of the inhibitor with the ATP binding pocket. Altogether, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and notably for treatment of leukemia.

Zebrafish is an excellent model for observing human genetic disorders. Hearing impairment is the most common genetic disorder including syndromic & non-syndromic hearing loss. Stem cell therapies are considered a new hope in case of hearing impairment. Stem cells are the master cells of the human body and having the capability to differentiate into any other form of cells in more than 200 types of cells (regeneration). This review article describes zebrafish as a biomedical model for stem cell research in hearing impairment, which revolutionized the biomedical arena to compete for the challenges.

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

The commercial popularity of Virtual Reality attracted educators’ interest and brought new opportunities to the educational landscape. At the same time, Learning Analytics emerged with the promise to revolutionise the traditional practices by introducing ways to systematically assess and improve the effectiveness of instruction. However, the collection of ‘big’ educational data is mostly associated with web-based platforms as they offer direct access to learners’ activities with minimal effort. On the antipode, the nature of VR limits the opportunities for such data collection. Hence, in the context of this work, we present a four-dimensional theoretical framework, that accounts the information that can be gathered from VR-supported instruction, and propose a set of structural elements which can be utilised for the development of a Learning Analytics prototype system. The outcomes of this work are expected to support practitioners to maximise the potential of their interventions and provide inspiration for new ones.

Along just over a century of research we moved from learning how to cultivate tissues in a dish to grasping the concepts for creating an entire brain in a vat. As we approach the divisive moment in which we can first detect signs of awareness in such artificially developed organoids, we need to lay foundation for what lays ahead. It is crucial that ethical, legal and moral implications of organoid research are clear and that boundaries are set to separate scientific progress from human life preservation. The largest obstacle may be the definition of consciousness itself, which has arguably been historically neglected by philosophy, psychology and neurosciences at large. One reason may be the difficulties posed by the underlying qualities of awareness, such as its subjective and heterogeneous nature. Another reason may lie on the possibly that consciousness is an overarching emergent property of our brain. For the time being, one can see brain organoids as philosophical zombies, physical analogues of the human brain which mimic sentient human reactions but lack experiential properties of sensation (a.k.a. qualia).

The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CA^H1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer.Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway’s two-layered and highly context-dependent regulation of cell growth versus stemness.

Cell-based therapies and tissue engineering applications require biocompatible substrates that support and regulate the growth, survival, and differentiation of specific cell types. Extensive research efforts in regenerative medicine are devoted to the development of tunable biomaterials which support various cell types including stem cells. In this research, the non-cytotoxic biopolymer polycaprolactone (PCL) was fabricated into 2D and 3D scaffolds with or without the low-pressure oxygen plasma treatment to enhance hydrophilicity. Cellular responses and biocompatibility were evaluated using a human Wharton’s jelly mesenchymal stem cell line (BCP-K1). The 2D PCL scaffolds enhanced initial cell attachment compared to the 3Ds indicated by a higher expression of focal adhesion kinase (FAK). Whilst, the 3D scaffolds promoted cell proliferation and migration as evidenced by higher cyclin A expression and filopodial protrusion, respectively. The 3D scaffolds potentially protected the cell entering to apoptosis/necrosis program and induced cell differentiation, evaluated by gene expression. Both 2D and 3D PCL appeared to have stronger effects on cell behavior than a control substrate (polystyrene). In summarize, the different configuration and surface properties of PCL scaffolds provide various options for modulation of stem cell behaviors, including attachment, proliferation, survival, and differentiation, when combined with specific growth factors and culture conditions.

Ovarian cancer is the most lethal gynecological malignancy. Poor overall survival, particularly for patients with high grade serous (HGS) ovarian cancer, are often attributed to late stage at diagnosis and relapse following chemotherapy. HGS ovarian cancer is a heterogenous disease in that few genes are consistently mutated between patients. Additionally, HGS ovarian cancer is characterized by high genomic instability. For these reasons personalized approaches may be necessary for effective treatment and cure. Understanding the molecular mechanisms that contribute to tumor metastasis and chemoresistance are essential to improve survival rates. One favored model for tumor metastasis and chemoresistance is the cancer stem cell (CSC) model. CSCs are cells with enhanced self-renewal properties that are enriched following chemotherapy. Elimination of this cell population is thought to be a mechanism to increase therapeutic response. Therefore, accurate identification of stem cell populations that are most clinically relevant is necessary. While many CSC identifiers (ALDH, OCT4, CD133, and side population) have been established, it is still not clear which population(s) will be most beneficial to targeted in patients. Therefore, there is a critical need to characterize CSCs with reliable markers and find their weaknesses that will make the CSCs amenable to therapy. Many signaling pathways are implicated for their roles in CSC initiation and maintenance. Therapeutically targeting pathways needed for CSC initiation or maintenance may be an effective way of treating HGS ovarian cancer patients. In conclusion, the prognosis for HGS ovarian cancer may be improved by combining CSC phenotyping with targeted therapies for pathways involved in CSC maintenance.

Recent evidence indicates that the risk of being diagnosed with cancer in a tissue is strongly correlated (0.80) with the number of stem cell divisions accumulated by the tissue. Since cell division can generate random mutations during DNA replication, this correlation has been used to propose that cancer is largely caused by the accumulation of unavoidable mutations in driver genes. However, no correlation between the number of gene mutations and cancer risk across tissues has been reported. Because many somatic mutations in cancers originate prior to tumor initiation and the number of cell divisions occurring during tumor growth is similar among tissues, here I use whole genome sequencing information from 22,086 cancer samples and incidence data from the largest cancer registry in each continent to study the relationship between the number of gene mutations and the risk of cancer across 33 tissue types. Results show a weak positive correlation (mean = 0.14) between these two parameters in each of the five cancer registries. The correlation became stronger (mean = 0.50) when gender-related cancers were excluded. Results also show that 1,003 samples from 29 cancer types have zero mutations in genes. These data suggest that cancer etiology can be better explained by the accumulation of stem cell divisions than by the accumulation of gene mutations. Possible mechanisms by which the accumulation of cell divisions in stem cells increases the risk of cancer are discussed.

Diamond-like carbon (DLC) layers are known for their high corrosion and wear resistance, low friction, and high biocompatibility. However, it is often necessary to dope DLC layers with additional chemical elements to strengthen their adhesion to the substrate. Ti-DLC layers (doped with 0.4, 2.1, 3.7, 6.6, 12.8 at.% of Ti) were prepared by dual pulsed laser deposition, and pure DLC, glass, and polystyrene (PS) were used as controls. In vitro cell-material interactions were investigated with an emphasis on cell adhesion, proliferation, and osteogenic differentiation. We observed slightly increasing roughness and contact angle and decreasing surface free energy on Ti-DLC layers with increasing Ti content. Three-week biological experiments were performed using adipose tissue-derived stem cells (ADSCs) and bone marrow mesenchymal stem cells (bmM-SCs) in vitro. The cell proliferation activity was similar or slightly higher on the Ti-doped materials than on glass and PS. Osteogenic cell differentiation on all materials was proved by collagen and osteocalcin production, ALP activity, and Ca deposition. The bmMSCs exhibited greater initial proliferation potential and an earlier onset of osteogenic differentiation than the ADSCs. The ADSCs showed a slightly higher formation of focal adhesions, higher metabolic activity, and Ca deposition with increasing Ti content.

Although the existing paradigm states that CMV reactivation is under control of cellular immune response, the role of humoral counterpart is underestimated. Anti-CMV positive woman after conditioning with Bu-Flu-ATG underwent stem cell transplantation from fully matched, seronegative sibling donor. In immunodeficient recipient fast and significant decrease of specific immune response was observed but reconstitution of marrow-derived B and NK cells was prior thymic origin T cells. The lowest CMV-IgG(89 U/ml) was observed just before CMV viremia. Noteworthy, the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was observed later, but in the first phase immune reconstitution of the PHA-induced IFNγ release was significantly lower than that CMV-induced. It corresponds with NK cells increase at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells by pentamer technique. Most of NK cells are CD16+, thus are stimulated by residual IgG. In immunocompetent donor the cellular and humoral immune response increases in parallel manner but symptoms of CMV mononucleosis were observed till the increase of specific IgG. Our observations shed light on a unique host-CMV interaction: indicate that significant decrease of CMV-IgG is a good predictor for CMV reactivation during secondary immunodeficiency.

Background: Pathological bone fracturing is an escalating problem driven by increasing aging and obesity. Bioceramics, particularly tricalcium-phosphate-based materials (TCP), are renowned for their exceptional biocompatibility, osteoconductivity, and ability to promote biomineralization. In the present study, we designed and characterized TCP porous granules doped with Strontium (Sr) and Copper (Cu). Sr2+ ions were selected as it plays a crucial role in early bone formation, osteogenesis and angiogenesis; Cu2+ ions possesses antibacterial properties. Materials: The synthesized CuSr TCP granules were characterized by X-Ray Diffraction. Cytotoxicity and cell proliferation analyses assays were performed through the Lactate dehydrogenase (LDH) activity and CCK-8 viability tests in rat bone marrow-derived mesenchymal stem cells (BM-MSCs). Hemolytic activity was carried out with human red blood cells (RBCs). Early and late osteogenesis was assessed with alkaline phosphatase (ALP) and Alizarin Red S activity in human osteoblast progenitor cells and rat BM-MSCs. The influence of Sr and Cu-substituted TCP on angiogenesis was investigated in human umbilical vein endothelial cells (HUVECs). Results: We have demonstrated that a media enriched with CuSr TCP in concentrations ranging from 0.1 mg/ml to 1 mg/ml was not cytotoxic and did not significantly affect cell proliferation rate motility. Moreover, a concentration of 0.5 mg/ml has shown a 2.5-fold increase in the migration potential of BM-MSCs. We also found that CuSr TCP-enriched media slightly increased early osteogenesis. We also found that Sr and Cu substitutions in TCP particles significantly enhanced the measured angiogenic parameters compared to control and unsubstituted TCP granules. Conclusion: Our results demonstrate that TCP porous granules doped with Sr and Cu are biocompatible, promote osteodifferentiation and angiogenesis, and could be recommended for further in vivo studies.

The modeling of psychiatric disorders poses significant challenges due to the complex nature of these conditions, which encompass a range of neuropsychiatric diseases such as autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), post-traumatic stress disorder (PTSD), anxiety and depression. The rising global prevalence of mental disorders and the urgency for more effective treatments have propelled the development of innovative in vitro models. This review presents a thorough examination of two-dimensional (2D) versus three-dimensional (3D) induced pluripotent stem cell (iPSC) models of neuropsychiatric diseases, offering insights into their respective capacities to mimic neurodevelopment and cellular phenotypes observed in these conditions. Our comparative analysis reveals that while traditional 2D cultures have been instrumental in elucidating disease pathways and high-throughput drug screening, they fall short in replicating the intricate cellular architecture and environment of the human brain. On the other hand, 3D organoid models, including brain organoids, better recapitulate the spatial organization, cell-type diversity, and functional connectivity of brain tissue, offering a more physiologically relevant context for studying disease mechanisms and testing therapeutic interventions. We assess the progress in modeling ASD, Schizophrenia, Bipolar Disorder, PTSD, and depression, highlighting the advanced understanding of disease etiology and potential treatment avenues offered by 3D iPSC technologies. Challenges remain, including the scalability, reproducibility, and maturation of organoids, but the potential for personalized medicine and the elucidation of disease ontogeny is unparalleled. The review concludes with a perspective on the future directions of psychiatric disease modeling, emphasizing the integration of 3D iPSC models with high-throughput technologies and computational approaches to enhance our understanding and treatment of these debilitating conditions.

X-ray absorption fine structure (XAFS) spectroscopy, temperature-programmed reduction (TPR) and temperature-programmed hydride decomposition (TPHD) were employed to elucidate the structures of a series of PdRe/Al2O3 bimetallic catalysts for selective hydrogenation of furfural. TPR evidenced low-temperature Re reduction in the bimetallic catalysts consistent with migration of [ReO4]- (perrhenate) species to hydrogen-covered Pd nanoparticles on highly hydroxylated  Al2O3. TPHD revealed strong suppression of β-PdHx formation in the reduced catalysts prepared by (i) co-impregnation and (ii) [HReO4] impregnation of reduced Pd/Al2O3 indicating formation of Pd-rich alloy nanoparticles; however, reduced catalysts prepared by (iii) [Pd(NH3)4]2+ impregnation of calcined Re/Al2O3 and subsequent re-calcination did not. Re LIII X-ray absorption edge shifts were used to determine average Re oxidation states after reduction at 400°C. XAFS spectroscopy and high-angle annular dark field (HAADF)-scanning transmission electron microscopy (STEM) revealed that a reduced 5 wt.% Re/Al2O3 catalyst contained small Re clusters and nanoparticles comprising Re atoms in low positive oxidation states (~1.5+) and incompletely reduced Re species (primarily Re4+). XAFS spectroscopy of the bimetallic catalysts evidenced Pd-Re bonding consistent with Pd-rich alloy formation. Pd and Re total first-shell coordination numbers suggest that either Re is segregated to the surface (and Pd to the core) of alloy nanoparticles and/or segregated Pd nanoparticles are larger than Re nanoparticles (or clusters). The Cowley short-range order parameters are strongly positive indicating a high degree of heterogeneity (clustering or segregation of metal atoms) in these bimetallic catalysts. Catalysts prepared using the Pd(NH3)4[ReO4]2 double complex salt (DCS) exhibit greater Pd-Re intermixing but remain heterogeneous on the atomic scale.

Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM), having an essential role in the regulation of hematopoietic stem cell (HSCs) differentiation and proliferation. Myelodysplastic syndromes (MDS) are a group of myeloid disorders impacting hematopoietic stem and progenitor cells (HSCPs) and characterised by BM failure, ineffective haematopoiesis, cytopenia, a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as cell cycle arrest and pro-tumorigenic roles including induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, immunomodulation function, and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators secreted by MSCs abnormally, including increased expressions of inflammatory factors and decreased expressions of hematopoietic factors, contributing to the development and progression of MDS. Therefore, MSCs can be targeted for the treatment of MDS and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.

Although fine dust can cause various disorders, including cardiovascular, neurological, renal, reproductive, motor, systemic, respiratory, and cancerous diseases, there are not enough research for an oral disease. In this study we used various methods, including quantitative PCR, flow cytometry, immunocytochemistry, ELISA, and Alizarin O staining, to reveal the preventive effects of hemp-derived biomaterials in periodontal cells against fine dust. In this study, the two biomaterials (MSE; mature hemp stem extract and IE; induced exosomes derived from gingival cells exposed to MSE) revealed three main biological functions against fine dust. First, two materials suppressed the levels of inflammatory genes and activated anti-inflammatory genes in gingival cells. Second, these materials activated differentiation to osteoblast, periodontal ligament cells (PDLCs) and pulp progenitor cells (PPCs) from periodontal ligament stem cells (PDLSCs). Third, IE and MSE activated upregulation of LL-37 and down-regulation of MCP-1 in gingival cells and PDLSCs, respectively. Consequently, MSE and IE showed potential as a functional biomaterial in various fields, including pharmaceuticals, cosmetics, and foods.

Fabrication of scaffolds via 3D printing is a promising approach for tissue engineering. In this study, we combined 3D printing with cryogenic crosslinking to create biocompatible gela-tin/oxidized alginate (Gel/OxAlg) scaffolds with large pore sizes, beneficial for bone tissue re-generation. To enhance the osteogenic effects and mechanical properties of these scaffolds, we evaluated the impact of hydroxyapatite (HAp) on the rheological characteristics of the 2.86% (1:1) Gel/OxAlg ink. We investigated the morphological and mechanical properties of scaffolds with low, 5% and high 10% HAp content, as well as the resulting bio and osteogenic effects. Scanning electron microscopy revealed a reduction in pore sizes from 160-180 µm (HAp-free) to 120-140 µm for both HAp-containing scaffolds. Increased stability and higher Young’s moduli were measured for 5% and 10% HAp (18 and 21 kPa, respectively) compared to 11 kPa for HAp-free constructs. Biological assessments with mesenchymal stem cells indicated excellent cytocompati-bility and osteogenic differentiation in all scaffolds, with high degree of mineralization in HAp-containing constructs. Scaffolds with 5% HAp exhibit improved mechanical characteristics and shape fidelity, demonstrate positive osteogenic impact, and enhance bone tissue formation. Increasing the HAp content to 10% did not show any advantages in osteogenesis, offering a minor increase in mechanical strength at the cost of significantly compromised shape fidelity.

Study of alterations in Osteoarthritis (OA) of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts. Plasma levels of GPCs and Notum were measured of 25 patients and 24 healthy subjects. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured during 21 days with culture me-dium and osteogenic medium. Protein and gene expression levels of GPCs and Notum were de-termined by ELISA and qPCR at 0, 7 ,14 and 21 days. GPC5 and Notum have been found de-creased in OA patients’ plasma. OA BM-MSCs showed downexpression of GPC6 and upregula-tion of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPC2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in OA. Furthermore, the protein levels of GPC2, GPC5 and Notum de-creased and GPC3 increased. Glypicans and Notum are altered in BM-MSCs and during osteo-genic differentiation from patients with OA. Furthermore, GPC5 and Notum can be proposed as new biomarkers of the pathology. The alterations found indicate that Notum could be a prom-ising therapeutic strategy for Osteoarthritis.

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encodes presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD, however it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA and kainate compared to isogenic control and healthy lines. The data shows that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

Mesenchymal stem cells (MSCs), whose main function is tissue repair, use collagen to restore the structural integrity of damaged tissue, maintaining its organization through concomitant remodelling. The non-enzymatic glycation of collagen is likely to compromise its communication with MSC, which indeed underlies various pathological conditions such as late complications of diabetes and aging. However, data on the effect of more early stages of collagen glycation on the MSC interaction are lacking. This study focused on the fate of in vitro glycated rat tail collagen (RTC) in contact with MSCs after its pre-exposure to glucose for 1 or 5 days. Using human adipose tissue-derived MSCs (ADMSCs), we showed that their interaction with glycated collagen is significantly altered, manifested morphologically by reduced cell spreading, less formation of focal adhesions, and weaker development of the actin cytoskeleton, further confirmed by ImageJ morphometric analysis. This suggests a poorer recognition of early glycated collagen by integrin receptors, possibly due to steric hindrance of their binding sites. These morphological events were also accompanied by greatly reduced fibril-like reorganization of adsorbed FITC-collagen (a sign of impaired remodeling), complemented by reduced sensitivity to proteases. The latter was confirmed in two ways: measuring directly FITC-collagen degradation by the attached cells and quantifying the proteolysis reduction upon exogenous addition of collagenase in a cell-free system. The mechanism of the observed effects is unclear, although differential scanning calorimetry confirmed the presence of weak structural changes in glycated collagen. All this led us to conclude that the reason for the morphological changes of ADMSCs is the impaired interaction with early-glycated collagen due to the hindrance of complementary sequences for integrins, which certainly also affects the mechanical remodeling of collagen. However, the impaired collagenolytic activity, together with the observed small changes in the thermal transition profile, undoubtedly indicate some internal changes in the structural organization of the collagen molecule occurring even at this early stage of glycation, which in turn contributes further to the impaired MSC remodeling activity.

Human arteries show structural and functional peculiarities according to the nutrient and oxygen needs of a specific vascular district. This architectural heterogeneity is reflected in the pathological setting of cardiovascular diseases (CVDs). Indeed, the responsiveness to cardiovascular risk factors, the morphological and molecular patterns are discriminating factors among CVDs affecting different vascular beds. Micro-RNAs (miRNAs) are endogenous regulators of gene expression and fine tuners of vascular cell differentiation, thus these non-coding RNAs can modulate the arterial heterogeneity. The identification of a miRNA signature artery-specific would be promising in the therapy of CVDs, especially in frail elderly patients. In the present review we will provide a concise description of the arterial tree heterogeneity on structural and cellular basis, mainly in the pathological context. Secondly, we will address the miRNA potential as crucial mediators of arterial heterogeneity focusing on abdominal aorta and femoral artery, with the final goal of strengthening the search of more targeted therapies in CVDs and stratification approaches in frail elderly patients.

This review centers on the pivotal role of the oncoprotein FOSL1, within the dimeric AP-1 transcription factor consisting of FOS-related elements. FOSL1 emerges as a key regulator governing invasion and metastatic dissemination, therefore making it a promising target for therapeutic intervention in cancer patients. The review provides a comprehensive survey of the regulatory mechanisms that exert influence over FOSL1. These encompass a spectrum of transcriptional and post-translational modifications. Notably, we unveiled the intricate involvement of diverse non-coding RNAs, specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the modulation of FOSL1 expression through targeted interactions with its mRNA transcripts. Furthermore, an exploration into the functional dimensions of FOSL1 unfolds, encompassing apoptosis, proliferation, and migration. This investigation is accompanied by a thorough examination of the elaborate signaling pathways that underpin these multifaced roles. Additionally, emphasis is placed on the role of FOSL1 in orchestrating the stimulation of various cytokines, including TGF-beta, and the initiation of IL-6 and VEGF production in tumor-associated macrophages (TAMs) that transverse into the tumor microenvironment. A distinct focus is dedicated to appraising the prognostic implications associated with FOSL1. Finally, insights emerge into the evolving roles of FOSL1 in the context of mechanisms governing resistance and dependency on targeted therapeutic modalities.

Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3-4 decades, but addition of targeted agents in recent years have led to improved survival in select subsets of patients as well as a better biologic understanding of the disease. One key paradigm of bench-to-bedside practice in the context of adult AML currently is the focus on leukemia stem cell (LSC)-targeted therapies. Here we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML, through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon.

Tumor heterogeneity is a major obstacle to achieving consistent outcomes in cancer therapy. We offer a novel perspective on tumor heterogeneity, informed by an advanced understanding of tumor evolution. We understand any cells, or any organism, will inherently respond with specific capacities when faced with adversity. Our concepts, which extend beyond canonical views, posit that tumor evolution is driven by cellular responses to survival challenges. The disease is driven by a rudimentary action taken by any organism when confronted with adversity - a cellular response to generate specific capacities to overcome the threat - the responses that utilize advantageous genetic mutations and other cellular contents to attain these capacities and further drive the disease. The disease is initiated by a cellular response to survival challenges and the ongoing development of hallmark cancer capabilities, as cells endeavor to obtain a competitive advantage, results in increased molecular disarray, observed as tumor heterogeneity. When the evolutionary drive for survival is impeded by therapeutic inhibition of critical genes, cell death occurs, a phenomenon termed oncogene addiction. Drawing from the same idea that cells responding to survival challenges, we recognize the increasing primitiveness of cancer during its progress stems from the innate cellular response to the demand for regeneration under sustained cellular damage. This necessitates a regression to a more primitive state purposed to renew progeny, unleashing a hitherto undiscerned cellular capacity. Taken together, the ideas explored herein pave the way for novel cancer therapies and the betterment of human health.

Management of Sclerotinia stem rot (SSR) disease in Brassica napus is heavily reliant on prophylactic fungicide applications at flowering, which often provides inconsistent control depending on timing of ascospore release in the field and environmental conditions. Understanding host response to Sclerotinia sclerotiorum infection is essential for sustainable disease management in the future. This study determined the host response of nine B. napus varieties to four aggressive S. sclerotiorum isolates across two years by measuring four disease variables; area under the disease progress stairs (AUDPS), seed production, sclerotia number and average sclerotia weight. Brassica napus varieties varied greatly in their response to the four measured variables, with varieties producing the highest AUDPS not the same varieties that had the lowest seed production, the highest numbers of sclerotia or heaviest sclerotia. Repeating the experiment over two years using the same varieties and isolates identified the impact of environment as the most influential factor on measured disease variables, highlighting the complexity of disease responses to diverse isolates and host genotypes under different environments. It was recommended that both long-term (such as inoculum production) and short-term (such as seed production) disease outcomes be combined with lesion length measurement (i.e. AUDPS) for future host screening studies.

Multicellular organisms organize themselves according to two principles; first, the equilibrium between the driving force of unstable state cells and apoptosis or senescence; and second, the mutual equilibrium between the functional requirements of different types of cells. For the first principle, we deduce that stem cells at different levels have their own growth limits, which are determined by two factors: the ability of the stem cells to enter an unstable state (specifically, the ability of cells to divide and differentiate); and the rate of cellular senescence, loss of function, and finally, apoptosis. The superposition of stem cell limits at different levels over each other can amplify small differences at the genetic level. Moreover, the growth limits of different organs are different, which lead to different individuals having completely different appearances. The second principle is that the sum of the specific output functions of an organ must be equal to the overall demand for the function to be provided by the organ. If negative entropy input can meet this equilibrium, defects in certain genes will cause these defective individuals to become larger or develop other morphology.

Studies on the cutting propagation of plants belonging to the genus Rhododendron are limited to R. mucronulatum and R. yedoense, which are mainly used as ornamental flowering trees, and additional studies on a greater variety of species are required. This study examined the characterisitics of cutting propagation according to treatment with growth regulators indole-3-butyric acid (IBA) and α-naphthaleneacetic acid (NAA) to generate basic data on the methods of reproducing R. micarnthum Turcz.. The number of roots (r=0.740**), length of root (r=0.844**), and number of leaves (r=0.649**) affected the rooting rate of R. micarnthum Turcz., and the number of roots (r=0.646**), length of roots (r=0.673**), number of leaves (r=0.738**), and chlorophyll content (r=0.710**) affected the survival rate. Further, the rooting and survival rates were highly correlated (r=0.794**). The growth characteristics of underground sections after growth regulator treatment were as follows: the number of formed roots was 7.0 and 7.2, and the length of roots was 6.2 cm and 5.3 cm in 150 mg·L-1 and 250 mg·L-1 NAA treatment groups, respectively. The rooting rate was 60% or above in the growth regulator treatment groups compared to that in the control group. Particularly, the rooting rates of 150 mg·L-1 and 250 mg·L-1 NAA treatment groups were 90% or above, and the latent period before rooting was shorter than other treatment groups at approximately 14 days, which was considered to be effective for root growth. The aboveground growth characteristics after propagating the cuttings showed that groups treated with 150 mg·L-1 and 250 mg·L-1 NAA showed a significantly higher plant length (5.2-5.8 cm), number of leaves (6.2 and 6.9), and leaf-length and leaf-width as compared to other treatment groups. Moreover, the survival rates of 150 mg·L-1 and 250 mg·L-1 NAA treatment groups were 80% or above, and the sound root growth manifested in the tendency of good aboveground growth. Additionally, IBA and NAA were highly correlated to the rooting and survival rates during cutting propagation of R. micarnthum Turcz.. The rooting and survival rates increased with the increase in growth regulator concentration. Particularly, NAA had a higher correlation to the rooting and survival rates than IBA (r=0.7316**, 0.7013**). Thus, R. micarnthum Turcz. could be propagated through cutting. Growth regulator treatment with 150 mg·L-1 and 250 mg·L-1 of NAA was effective for rooting and root growth of cutting, and these treatments were considered appropriate because the effects of aboveground growth were positive.

Additive manufacturing or 3D printing applying polycaprolactone-(PCL)-based medical devices represents an important branch of tissue engineering, where the sterilization method is a key process for further safe application in vitro and in vivo. In this study, the authors intend to access the most suitable gamma radiation conditions to sterilize PCL-based scaffolds in a preliminary biocompatibility assessment, envisioning future studies for airway obstruction conditions. Three radiation levels were considered, 25 kGy, 35 kGy and 45 kGy and evaluated as to their cyto- and biocompatibility. All three groups presented biocompatible properties, indicating an adequate sterility condition. As for the cytocompatibility analysis, devices sterilized by 35 kGy and 45 kGy showed better results, with the 45 kGy showing overall improved outcomes. This study allowed to select the most suitable sterilization condition for PCL-based scaffolds, aiming at immediate future assays, by applying 3D-customized printing techniques to specific airway obstruction lesions of the trachea.

Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that Aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a novel ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. Treatment of OCSCs with 974 significantly inhibited ALDH activity, expression of stemness genes, spheroid, and colony formation. In vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. Transcriptomic sequencing of cells treated with 974 revealed significant downregulation of genes related to stemness and chemoresistance as well as senescence and senescence associated secretory phenotype (SASP). We confirmed that 974 inhibited senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSCs survival and ALDH1A1 inhibition sup-presses chemotherapy induced senescence and stemness. Targeting ALDH1A1 using small molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to pre-vent ovarian cancer recurrence and has potential for clinical translation.

Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of perspective patients and stakeholders in health care. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. Methods: PubMed, Web of Science and the Cochrane library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the biology of stem cells. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. Conclusion: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution, and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-β) pathway and discuss how the dysregulation of the TGF-β pathway promotes oncogenic attributes in TNBC which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-β inhibition as a potent method to target mesenchymal (CD44⁺/CD24^-) and epithelial (ALDH^high) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-β as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-β, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-β inhibitors targeting based on clinical trials are summarized for further investigation which may lead to the development of novel therapies to improve TNBC patient prognosis.

In humankind’s endeavor to explore beyond our planet and travel further into space, we are now at the threshold of an era in which it is possible to move to and from low Earth orbit (LEO) with increasing ease and reduced cost. Through the International Space Station (ISS) U.S. National Laboratory, investigators from industry, academia, and government can easily access the unique LEO environment on the ISS to conduct research and development (R&D) activities in ways not possible on Earth. A key advantage of the LEO environment for life sciences research is the ability to conduct experiments in sustained microgravity conditions. The ability to conduct long-term research in microgravity enables opportunities for novel, fundamental studies in tissue engineering and regenerative medicine, including research on stem cell proliferation and differentiation, biofabrication, and disease modeling using microphysiological systems (MPS) that build on prior research using simulated microgravity conditions (Grimm, D., et al. 2018). Over the last decade, space-based research has demonstrated that microgravity informs our knowledge of fundamental biology and accelerates advancements in health care and medical technologies (International Space Station 2019). The benefits provided by conducting biomedical research in LEO may lead to breakthroughs not achievable on Earth. We are now at a transition point, in which nations are changing their approach to space-based R&D. The focus is shifting from government-funded fundamental science toward the expansion of privately funded R&D with terrestrial application and economic value that will drive a robust marketplace for innovation and manufacturing in LEO. Making this long-term transition requires public-private participation and near-term funding to support critical R&D to leverage the benefits of the LEO environment and de-risk space-based research. Studies conducted on the ISS over the past several years have indicated that one area with potential significant economic value and benefit to life on Earth is space-based biomanufacturing, or the use of biological and nonbiological materials to produce commercially relevant biomolecules and biomaterials for use in preclinical, clinical, and therapeutic applications. We must take advantage of the remaining lifetime of the ISS as a valuable LEO platform to demonstrate this economic value and Earth benefit. By facilitating access to the space station, the ISS National Lab is uniquely positioned to enable the R&D necessary to bridge the gap between the initial discovery phase of space-based biomedical research and the development of a sustainable, investment-worthy biomanufacturing market in LEO supported by future commercial platforms. Through a joint effort, the Center for the Advancement of Science in Space (CASIS), which manages the ISS National Lab, and the University of Pittsburgh’s McGowan Institute for Regenerative Medicine brought together thought leaders from around the U.S. for a Biomanufacturing in Space Symposium that consisted of a series of working sessions to review data from past space-based tissue engineering and regenerative medicine research, discuss relevant current space-based R&D in this area, and consider potential future markets to address the questions: What are the most promising opportunities to leverage the ISS to advance space-based biomanufacturing moving forward? What are the current gaps or barriers that, if overcome, could clear pathways toward private investment in LEO as a valued site for research, development, and production activity? And, most importantly: For which opportunities do the most compelling value propositions exist? The goal of the Biomanufacturing in Space Symposium was to help identify the specific areas in which government and industry investment would be most likely to stimulate advancements that overcome barriers. This would lead to a more investment-ready landscape for private interests to enter the market and fuel exponential growth. The symposium was meant to serve as the first step in developing a roadmap to a sustainable market for biomanufacturing in space. The symposium identified and prioritized multiple key R&D opportunities to advance space-based biomanufacturing. These opportunities fall in the areas of disease modeling, stem cells and stem-cell-derived products, and biofabrication. Additionally, symposium participants highlighted the critical need for additional data to help validate and de-risk these opportunities and concluded that approaches such as automation, artificial intelligence (AI), and machine learning will be needed to produce and capture the required data. Symposium participants also came to a consensus that public-private partnerships and funding will be needed to advance the opportunities toward a biomanufacturing marketplace in LEO. This paper will summarize the current state of the science and technology on the ISS and in the fields of tissue engineering and regenerative medicine; provide an overview of biomanufacturing R&D in space to date; review the goals of the Biomanufacturing in Space Symposium; highlight the key commercial opportunities and gaps identified during the symposium; provide information on potential market sizes; and briefly discuss the next steps in developing a roadmap to biomanufacturing in space.

The emergence of three-dimensional human organoids has opened the door for development of patient-derived cancer organoid (PDO) models, which closely recapitulate parental tumor tissue. Mainstays of preclinical cancer modeling include in vitro cell lines and patient-derived xenografts, but these models lack the cellular heterogeneity seen in human tumors. Moreover, xenograft establishment is resource- and time-intensive, rendering these models difficult to use to inform clinical trials and decisions. PDOs, however, can be created efficiently and retain tumor-specific properties such as cellular heterogeneity, cell-cell and cell-stromal interactions, tumor microenvironment, and therapeutic responsiveness. PDO models and drug screening protocols have been described for several solid tumors and, more recently, for gliomas. Since PDOs can be developed in clinically relevant timeframes and share many characteristics of parent tumors, they may enhance the ability to provide precision oncologic care for patients. This review explores the current literature on cancer organoids, highlighting the history of PDO development, organoid models of glioma, and potential clinical applications of PDOs.

There are many theories of carcinogenesis arguing against the orthodox mutation theory, debating on such as “epigenetic alteration” that is inheritable and yet, theoretically, reversible. Our integrated theory describes that any extracellular, intracellular, or intranuclear stressors, mutagenic or not, can initiate a lengthy tumorigenesis to engender a benign or malignant tumor, but the aberrations directly establishing cellular immortality and autonomy may be epigenetic or genetic alterations in the genomic DNA. A neoplasm is considered a semi-new organism with autonomy; it therefore should have genetic mutations to be “new”. We may be able to direct cancer cells towards differentiation as a remedy, because the extracellular milieu may control the phenotype of a cell and the tissue or organ made of the cell’s progenies, and the cytoplasm of a cell may override the nucleus in the phenotypic control. However, the nucleus retains the capacity to manifest itself if allowed by the microenvironment, which then allows the already reversed cells to revert back to tumor cells again. Neoplasms are malignant if they bear epigenetic or genetic anomalies in mutator genes defined as those whose alterations allow or accelerate alterations to occur in other genes, whereas neoplasms are benign if they bear epigenetic or genetic aberrations only in non-mutator genes. It is imperative to identify the immediate tumor-causing cellular alterations defined as those directly responsible for immortality and autonomy, and for treatment purposes to identify the extracellular and intracellular factors that control the phenotype of cancer cells.

Three-dimensional (3D) bioprinting promises to be essential in tissue engineering for solving the rising demand for organs and tissues. Some bioprinters are commercially available, but their impact on the field of TE is still limited due to their cost or difficulty to tune. Herein, we present a low-cost easy-to-build printhead for microextrusion-based bioprinting (MEBB) that can be installed in many desktop 3D printers to transform them into 3D bioprinters. We can extrude bioinks with precise control of print temperature between 2 - 60 ºC. We validated the versatility of the printhead, by assembling it in three low-cost open-source desktop 3D printers. Multiple units of the printhead can also be easily put together in a single printer carriage for building a multi-material 3D bioprinter. Print resolution was evaluated by creating representative calibration models at different temperatures using natural hydrogels such as gelatin and alginate, and synthetic ones like poloxamer. Using one of the three modified low-cost 3D printers, we successfully printed cell-laden lattice constructs with cell viabilities higher than 90% after 24h post printing. Controlling temperature and pressure according to the rheological properties of the bioinks was essential in achieving optimal printability and great cell viability. The cost per unit of our device, which can be used with syringes of different volume, is less expensive than any other commercially available product. These data demonstrate an affordable open-source printhead with the potential to become a reliable alternative to commercial bioprinters for any laboratory.

Stem cells are currently being used in many clinical trials for regenerative purposes. These are promising results for stem cells in the treatment of several diseases, including cancer. Nevertheless, there are still many variables which should be addressed before the application of stem cells for cancer treatment. One approach should be to establish well-characterized therapeutic stem cell banks to minimize the variation in results from different clinical trials and facilitate their effective use in basic and translational research.

Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

Liver cirrhosis leads to hepatic dysfunction and life-threatening conditions. Though clinical efficacy of autologous bone marrow-drived mesenchymal stem cells (BM-MSC) transplantation in alcoholic cirrhosis (AC) was demonstrated, the relevant mechanism has not been elucidated. We aimed to identify predictive factors and gene/pathways for responders after autologous BM-MSC transplantation. Fifty-five patients with biopsy-proven AC underwent autologous BM-MSC transplantation. The characteristics of responders who showed improvement in fibrosis score (≥ 1) after transplantation were compared with those of non-responders. BM-MSCs were analyzed with cDNA microarrays to identify genes and pathways that were differentially expressed in responder after transplantation. Thirty-three patients (66%) were responders. In the multivariate analysis, initial high Laennec score (p=0.007, odds ratio 3.73) and performance of BM-MSC transplantation (p=0.033, odds ratio 5.75) were predictive factors for responder. Three genes (olfactory receptor 2L8, microRNA4520-2, and chloride intracellular channel protein 3) were upregulated in responders and 11 metabolic pathways (inositol phosphate, ATP-binding cassette transporters, protein kinase signaling, extracellular matrix-receptor interaction, endocytosis, phagosome, hematopoietic cell lineage, adipocytokine, peroxisome proliferator-activated receptor, fat digestion/absorption, and insulin resistance) were upregulated in non-responders (p<0.05). BM-MSC transplantation is warranted treatment for AC patients with high Laennec score. Cell-based therapy utilizing response-relating genes or pathway can be treatment candidate.

Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase and established autopsy and biopsy as routine pathology services, in turn establishing morphological traits for tumors and establishing immortality and autonomy as indispensable criteria for neoplasms. A century ago medical doctors and biologists initiated “experimental cancer research” as the second phase, in which they, with help from chemists, established many chemical-induced animal models of carcinogenesis. In this phase, the two-hit theory and stepwise carcinogenesis of “initiation-promotion” or “initiation-promotion-progression” were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. For the last 40 years, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many peers had already collected the lesions from animals for analyses of “cancer” mechanisms before the lesions became autonomous. We herein review monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in all animal models. It is imperative to resume many forerunners’ work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

A new mathematical model is presented to study the effects of macrophages on the bone fracture healing process. The model consists of a system of nonlinear ordinary differential equations that represents the interactions among classically and alternatively activated macrophages, mesenchymal stem cells, osteoblasts, and pro- and anti-inflammatory cytokines. A qualitative analysis of the model is performed to determine the equilibria and their corresponding stability properties. Numerical simulations are also presented to support the theoretical results and to monitor the evolution of a broken bone for different types of fractures under various medical interventions. The model can be used to guide clinical experiments and to explore possible medical treatments that accelerate the bone fracture healing process either by surgical interventions or drug administrations.

Reactive oxygen species (ROS), which were originally classified as exclusively deleterious compounds, have gained increasing interest in the recent years given their action as bona fide signalling molecules. The main target of ROS action is the reversible oxidation of cysteines, leading to the formation of disulfide bonds, which modulate protein conformation and activity. ROS endowed with signalling properties are mainly produced by NADPH oxidases at the plasma membrane, but their action also involves a complex machinery of multiple redox-sensitive protein families that differs in their subcellular localization and their activity. Given that the levels and distribution of ROS are highly dynamic in part due to their limited stability, the development of various fluorescent ROS sensors, some of which are quantitative (ratiometric), represents a clear breakthrough in the field and have been adapted to both ex vivo and in vivo applications. The physiological implication of ROS signalling will be presented mainly in the frame of morphogenetics processes, embryogenesis, regeneration, and stem cell differentiation. Gain and loss of function as well as pharmacological strategies have demonstrated the wide but specific requirement of ROS signalling at multiple stages of these processes and its intricate relationship with other well-known signalling pathways.

Background: In spinal cord injury, radical treatment is still a persistent hope for patients and clinicians. Our study aimed to determine the different histological changes in central, cranial and caudal sites of compressed spinal cord as a result of neuroectodermal stem cells (NESCs) transplantation in rats. Material and methods: For extraction of NESCs, future brains were extracted from mice embryos (10-days old) and cultured. Eighty, male rats were divided randomly into control, sham (20 rats each); while 40 rats were subjected to compressed spinal cord injury (CSCI). Seven days after spinal cord injury, rats were subdivided into 2 groups (20 rats each); an untreated and treated with NESCs injected cranial and caudal to the site of the spinal cord injury. Rats were sacrificed 4 weeks after transplantations of NESCs and specimens from the spinal cord at the central, cranial and caudal to site of spinal cord injury were proceeded to be stained with haematoxylin & eosin, osmic acid and Immunohistochemistry of glial fibrillary acidic protein (GFAP). Results: Sections of CSCI revealed areas of hemorrhages, necrosis and cavitation limited by reactive astrocytosis, with upregulation of GFAP expression. Evidence of remyelination and mitigation of histopathological features, reactive astrocytosis in CSCI sections were more pronounced in cranial than in caudal region. Conclusions: NESCs transplantation ameliorated the pathological changes, promoted remyelination.

The enhancement of early diagnosis of lung cancer is mandatory to improve prognosis. We observed the increase cancer stem cells (CSC) and circulating tumor cells (CTC) in blood of mice on d3 after Lewis lung carcinoma (LLC) cell implantation before disease symptom. Besides we have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. We hypothesized that reprogramming of spleen CD8+ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8+ T-cells derived from the spleen of C57BL/6 mice (rsCD8+T-cells). The rsCD8+T-cells were able to migrate to lung and were more resistant after the exhaustion in vitro in comparison with naïve sCD8+T-cells. In the orthotopic LLC model, the rsCD8+T-cells therapy increased the amount of proliferating CD8+ and CD4+ T-cells in blood and lung from mice. The amount of CSC decreased in the blood and lung of mice treated with rsCD8+ T-cells. A morphological study revealed a decrease in the number of metastases in lung tissue. The antitumor effects of rsCD8+T-cells are based on the activation of the host immune response by increasing the populations of CD8+ and CD4+ T-cells and apoptosis of CSCs.

Inherited heart diseases (IHDs) are caused by genetic mutations that disrupt the physiological structure and function of the heart. Understanding the mechanisms behind these diseases is crucial for developing personalised interventions in cardiovascular medicine. Development of induced pluripotent stem cells, which can then be differentiated to any nucleated adult cell type, has enabled the creation of personalised single-cell and multicellular models, providing unprecedented insights into the pathophysiology of IHDs. This review provides a comprehensive overview of recent advancements in human iPSC models used to dissect the molecular and genetic underpinnings of common IHDs. We examine multicellular models and tissue engineering approaches, such as cardiac organoids, engineered heart tissue, and multicellular co-culture systems, which simulate complex intercellular interactions within heart tissue. Recent advancements in stem cell models offer a more physiologically relevant platform to study disease mechanisms, enabling researchers to observe cellular interactions, study disease progression, and identify therapeutic strategies. By leveraging these innovative models, we can gain deeper insights into the molecular and cellular mechanisms underlying IHDs, ultimately paving the way for more effective diagnostic and therapeutic strategies.

Open Educational Resources (OER), educational materials permit unrestricted use and adaption, have proven beneficial for cost savings and curriculum flexibility. However, OER are not frequently used in college courses. An OER initiative was designed to understand the factors contribute to increasing access to STEM course materials. This study employed a survey to investigate faculty awareness and usage of OER and explore support needed to increase the use of OER in STEM. Results indicated that one-sixth of the respondents were unaware of OER, and 53% had never used OER. The motivating factors for OER usage included cost-free licenses, day-one availability to students, and increased access. The support strategies for new OER creation included OER workshops, grants, and recognition for OER authoring. In conclusion, the current study fills a gap in the existing literature by documenting motivating factors for faculty to integrate OER into STEM for the first time.

Gamba grass (Andropogon gayanus Kunth) is a tussock-forming forage species adapted to acid soils of Brazilian savannas and cultivated for grazing pastures. Four decades since its releasing, Planaltina prevails as the most commercialized cultivar of the species, even though the new cultivar BRS Sarandi could be a better alternative for Gamba grass-based farms by presenting greater leaf:stem ratio. The objective of this study was to evaluate the average daily live weight gain (ADG) of Nellore bulls (Bos indicus) for two Gamba grass cultivars – Planaltina and Sarandi. The experiment was conducted in Planaltina, Federal District, Brazil, during 3 years, namely 2018, 2018-2019 and 2020. The experimental design was completely randomized block with two treatments and three replicates, each one continuously stocked at three stocking rates (SR) - 1.3, 2.6 and 4 young bulls/ha. Canopy height (CH), forage mass (FM), plant-part proportion (leaf, stem and dead material) and nutritive value were evaluated. In 2018, mean ADG for Sarandi pastures was greater (0.690 kg/bull/d) than Planaltina (0.490 kg/bull/d) (P=0.0839). In the subsequent year (2018-2019), there was no effect of cultivar (P = 0.4089), while in 2020 the ADG was again affected by cultivar (P=0.0412), confirming the advantage of Sarandi (0.790 kg/bull/d) over Planaltina (0.650 kg/bull/d). In 2018 and 2020, the percentage of stems for Sarandi was about 3-6 pp lesser than for Planaltina (P

Background: Since cytokine receptor like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. Methods: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno associated virus (AAV) or AAV containing CRLF1 was determined by morpholog-ical, histological and microCT analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were deter-mined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes us-ing real time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Results: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondro-genic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and Cardiotrophin like Cytokine (CLC) stimulated catabolic events via STAT3 activation. Conclusion: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Recently, interest in STEM education has grown among researchers and educators, also considering the skills required to address the challenges of the 21st century. Supporting learning in STEM subjects is an open challenge, especially during secondary education, which is reflected in the implementation of innovative pedagogical practices, including approaches focused on Game-Based Learning (GBL). This study analyzed the main issues addressed by research on game-based educational approaches applied to STEM teaching and learning in secondary school and their evolving trends. A text analysis of abstracts published in the past decade was conducted using T-lab software. The “Word Analysis” function was used for preliminary visual mapping; then the “Specificity Analysis” and “Thematic Analysis of Elementary Contexts” functions were applied to explore changes in research directions and to map the themes covered by the most recent studies. The results showed that the implementation of games in STEM disciplines is a promising area of inquiry. A shift in research directions also emerged, currently more focused on studying how GBL can foster engagement and the emotional component of learning. Adapting to rapidly changing technology and integrating essential skills such as coding and computational thinking are additional challenges that the research community is facing.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration-resistance is often developed during the course of treatment, though its influences require further understanding. This study explores the human microbiome for its implications in castration-resistance and metastasis in prostate cancer. RNA sequencing data was downloaded for bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These sequences were mapped to bacterial sequences to yield species-level abundance approximations. Numerous species were found to correlate to the expression of known markers of castration-resistance, including AR, PI3K, and AKT. Castration-resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for relation to these species. EGFR and SLC3A2 were widely downregulated with greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration-resistance and stemness in prostate cancer. By considering the microbiome’s importance in these factors, we may better understand the highly aggressive and highly invasive nature of prostate cancer, allowing for needed improvement in the treatment of this disease.

Cancer, a globally prevalent and often deadly disease, holds promise for improved treatment through the integration of innovative medical technologies and interdisciplinary collaborations. Despite advancements, current cancer therapies lack a specific focus on addressing recurrence and targeting cancer stem cells (CSCs), known contributors to relapse. In this study, we utilized three types of cancer cells and generated three types of CSCs derived from them to conduct proteomic analysis and identified shared cell surface biomarkers as potential targets for a comprehensive treatment strategy. The selected biomarkers underwent evaluation through shRNA treatment, revealing contrasting functions in cancer and CSCs. Knocking down the identified protein showed promising results in regulating epithelial-mesenchymal transition (EMT) and stemness via the ERK signaling pathway. This led to a reduction in resistance to anticancer agents, ultimately enhancing the overall anticancer effects. Additionally, the biomarker's significance in clinical patient outcomes was confirmed using bioinformatics. Our study suggests a novel cancer treatment strategy that addresses existing limitations in current anticancer therapies.

The purpose of the research was to obtain information about the necessity and efficiency of the application of localized irrigation to some qualitative indices of plum trees in the nursery, against the background of different fertilization treatments. The expected results to be obtained by applying differentiated rules of irrigation and fertilization will consist in obtaining a healthy, vigorous fruit tree planting material, increasing production in the nursery. With fruit trees in the nursery, as with all cultivated plants, the growth process depends to the greatest extent on the climate and soil conditions available to them. The use of fertilizers in tree culture becomes necessary to renew the reserve of nutrients consumed by plants or leached in depth, then to improve the physical condition, the chemical composition, and the overall state of fertilization of the soil. It is necessary to intervene every year, in several rounds, with fertilizations that ensure, on the one hand, the achievement of a certain level of production, and on the other hand, a certain level and ratio of nutritional elements by returning the amounts of elements easily accessible nutrients extracted with the harvest to be able to maintain, in this way, the fertility of the soil in accordance with the age of the plantation and the level of production. The two varieties of plum studied were Stanley and Cacanska Lepotica, two valuable varieties for the quality of the fruit. During the research, the fertilization treatments had the highest contribution (34.50 %) on the stem diameter, compared to irrigation (20.67 %) and respectively the variety (5.63 %), considering that the variety did not significantly influence the increase in diameter of the grafted trees.

Mammalian fertilization initiates the reprogramming of oocytes and sperm, leading to the formation of a totipotent zygote. The zygotic genome remains transcriptionally silent throughout this intricate process, undergoing the maternal-to-zygotic transition (MZT) and subsequent zygotic genome activation (ZGA). Histone modifications are pivotal in shaping cellular identity and gene expression in many mammals. Recent advances in chromatin analysis enable a detailed exploration of histone modifications during ZGA. This review delves into conserved and unique regulatory strategies, providing essential insights into the dynamic changes in histone modifications and their variants during ZGA in mammals. The objective is to explore recent advancements in leading mechanisms related to histone modifications governing this embryonic development phase in depth. These considerations will be useful for informing future therapeutic approaches that target epigenetic regulation in diverse biological contexts, ranging from regenerative medicine to cancer research. It will also contribute to the extensive areas of evolutionary and developmental biology and possibly lay the foundation for future research and discussion on this seminal topic.

Stroke remains one of the leading causes of death and disability worldwide. Current reperfusion treatments for ischaemic stroke are limited due to their narrow therapeutic window in rescuing ischaemic penumbra. Stem cell therapy offers a promising alternative. As a regenerative medicine, stem cells offer a wider range of treatment strategies, including long-term intervention for chronic patients, through the reparation and replacement of injured cells via mechanisms of differentiation and proliferation. The purpose of this review is to evaluate the therapeutic role of stem cells for ischaemic stroke. The paper discusses the pathology during acute, subacute, and chronic phases of cerebral ischaemic injury, highlights the mechanisms involved in mesenchymal, endothelial, haematopoietic, and neural stem cell-mediated cerebrovascular regeneration and evaluates the pre-clinical and clinical data concerning the safety and efficacy of stem cell-based treatments. Treatment of stroke patients with different type of stem cells appears to be safe and efficacious even at relatively higher concentrations irrespective of the route and timing of administration. Priming or preconditioning of cells prior to administration appears to help augment their therapeutic impact. However, larger patient cohorts and later phase trials are required to consolidate these findings.

Mammalian cells have evolved to function under Earth’s gravity, but how they respond to microgravity remains largely unknown. Neural stem cells (NSCs) are essential for the maintenance of central nervous system (CNS) functions during development and the regeneration of all CNS cell populations. Here, we examined the behavior of space (SPC)-flown NSCs as they readapted to Earth’s gravity. We found that most of these cells survived the space flight and self-renewed. Yet, some showed autophagy-like behaviors (ALB). To ascertain if the secretome from SPC-flown NSCs contained molecules inducing this behavior, we incubated naïve, non-starved NSCs in a medium containing SPC-NSCs secretome. We found a four-fold increase in the ALB rate. Proteomic analysis of the secretome revealed that the protein of highest content produced by SPC-NSCs was secreted protein acidic and rich in cysteine (SPARC), which triggers endoplasmic reticulum (ER) stress leading to lethal ALB. These results offer novel knowledge on the response of neural cells, particularly NSCs, subjected to space microgravity. Moreover, some secreted proteins have been identified as microgravity sensing, paving a new venue for future research aiming at targeting SPARC metabolism. Although we did not establish a direct relationship between ALB and SPARC as a potential marker, these results represent the first step in the identification of gravity sensing molecules as targets to be modulated and to design effective countermeasures to mitigate intracranial hypertension in astronauts using structure-based-protein design.

The cancer stem cell hypothesis suggests that neoplastic cells with stem characteristics hierarchically regulate tumor generation and its high cellular heterogeneity. These cells have been detected in all cancer types, and specific signaling pathways give the regulation of self-renewal and differentiation. In prostate cancer, androgen receptor signaling has been extensively studied, and in non-stem cells, it promotes cell proliferation and tumor progression, but in the cancer stem cell population, it negatively regulates processes such as self-renewal. However, in other types of cancer, such as breast and glioblastoma, the androgen receptor seems to favor the maintenance of cancer stem cells, suggesting that androgen signaling has different effects depending on the tumor context. This review discusses the role of androgen receptor in maintaining cancer stem cells by regulating proliferation, self-renewal, and differentiation, as well as the possible signaling pathways involved in these processes.

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

A FIB/STEM interfacial study was performed on a TBC/Ti₂AlC MAX phase system, oxidized in an aggressive burner rig test (Mach 0.3 at 1300°C for 500 h). The 7YSZ TBC, a-Al₂O₃ TGO, and MAXthal 211 Ti₂AlC base were variously characterized by TEM/STEM, EDS, SADP, and HRTEM. The YSZ was a mix of ‘clean’ featureless and ‘faulted’ high contrast grains. The latter exhibited ferro-elastic domains of high Y content tetragonal t'' variants. No martensite was observed. The TGO was essentially a duplex a-Al₂O₃ structure of inner columnar plus outer equiaxed grains. It maintained a perfectly intact, clean interface with the Ti₂AlC substrate. The Ti₂AlC substrate exhibited no interfacial Al-depletion zone, but rather numerous faults along the basal plane of the hexagonal structure. These are believed to offer a means of depleting Al by forming crystallographic, low-Al planar defects, proposed as Ti_2.5AlC_1.5. These characterizations support and augment prior optical, SEM, and XRD findings that demonstrated remarkable durability for the YSZ/Ti₂AlC MAX phase system in aggressive burner tests.

ECM provides various mechanical cues that are able to affect the self‑renewal and differentiation of mesenchymal stem cells (MSC). Little is known however how these ques work in a pathological environment, such as acute oxidative stress. To better understand the behavior of human adipose tissue-derived MSC (ADMSC) in such conditions here we provide morphological and quantitative evidence for significantly altered early steps of mechanotransduction when adhering to oxidized collagen (Col-Oxi). This affects both focal adhesion (FA) formation and YAP/TAZ signaling events. Representative morphological images show that ADMSCs spread better within 2 h of adhesion on native collagen (Col), while they tended to round up on Col-Oxi. It correlates also with the less development of the actin cytoskeleton and FA formation, confirmed quantitatively by morpho-metric analysis using ImageJ. As shown by immunofluorescence analysis, oxidation also affected the ratio of cytosolic to nuclear YAP/TAZ activity, concentrating in the nucleus for Col while remaining in the cytosol for Col-Oxi, suggesting abrogated signal transduction. Comparative AFM studies show that native collagen forms relatively coarse aggregates, much thinner with Col-Oxi, possibly reflecting its altered ability to aggregate. On the other hand, the corresponding Young's moduli were only slightly changed, so viscoelastic properties cannot explain the observed biological differences. However, the roughness of the protein layer decreases dramatically, from RRMS equal to 27.95 + 5.1 nm for Col to 5.51 + 0.8 nm for Col-Oxi (p<0.05), which dictates our conclusion that it is the most altered parameter in oxidation. Thus, it appears to be a predominantly topo-graphic response that affects the mechanotransduction of ADMSCs by oxidized collagen.

The European mink (Mustela lutreola) is one of Europe's most endangered species, and it is on the brink of extinction in the Iberian Peninsula. The species' precarious situation requires the application of new ex-situ conservation methodologies that complement the existing ex-situ and in-situ conservation measures. Here, we report for the first time the establishment of a biobank of European mink mesenchymal stem cells (emMSC) and oocytes from specimens found dead in the Iberian Peninsula, either free or in captivity. New emMSC lines were isolated from different tissues: bone marrow (emBM-MSC), oral mucosa (emOM-MSc), dermal skin (emDS-MSC), oviduct (emO-MSc), endometrium (emE-MSC), testicular (emT-MSC), and adipose tissue from two different adipose depots: subcutaneous (emSCA-MSC) and ovarian (emOA-MSC). All the eight emMSC lines showed plastic adhesion, detectable expression of characteristic markers of MSCs and, when cultured under osteogenic and adipogenic conditions, differentiation capacity to these lineages. Additionally, we were able to keep 227 Cumulus-oocyte complexes (COCs) in the biobank, 97 of which are grade I or II. The European mink MSC and oocyte biobank will allow for the conservation of the species' genetic variability, the application of assisted reproduction techniques, and the development of in vitro models for studying the molecular mechanisms of infectious diseases that threaten the species' precarious situation.

In patients with unilateral tinnitus with normal hearing, several studies have compared the ipsilateral and contralateral ears; however, few studies have investigated its relationship with the duration of tinnitus. We compared the auditory brainstem response and otoacoustic emission parameters between ipsilateral and contralateral ears in adults with unilateral tinnitus and normal hearing. This retrospective review included 84 patients with unilateral tinnitus and normal hearing who underwent auditory brainstem response and otoacoustic emission; they were categorized according to the duration of tinnitus. The latencies and amplitudes of waves I, III, and V, and V/I ratio of both ears in auditory brainstem response, and the results of distortion-product otoacoustic emission and transient evoked otoacoustic emission were examined. The auditory brainstem response parameters, distortion-product otoacoustic emission parameters, and transient evoked otoacoustic emission parameters between the ipsilateral and contralateral ears along the duration of tinnitus were analyzed. Moreover, the failure rates of both distortion-product otoacoustic emission and transient evoked otoacoustic emission between the ears along with the duration and the effects of the variables on the amplitude and latency of each wave were examined. Although there was little significant difference between the ipsilateral and contralateral ears, laterality seemed to have an effect on wave I latency in the multiple linear regression analysis. The distortion-product otoacoustic emission failure rate of the ipsilateral ear was higher than that of the contralateral ear in all patients. However, there was no remarkable difference between the ears in the distortion-product otoacoustic emission and transient evoked otoacoustic emission parameters throughout the duration. We found that outer hair cells and the distal portion of the cochlear nerve are possible pathologic lesions in tinnitus with normal hearing and cochlear synaptopathy could be suspected. Further studies, including those on inner hair cells and higher central cortex, are needed.

An infestation of parkinsonia (Parkinsonia aculeata) located on Alexandria Station, Northern Territory, Australia was successfully treated with a bioherbicide using stem implanted capsules. The bioherbicide containing three endemic endophytic fungi (Lasiodiplodia pseudotheobromae, Macrophomina phaseolina and Neoscytalidium novaehollan-diae) is the first Australian registered woody weed bioherbicide. The product was effectively administered to the plant stems using a mechanical device, resulting in subsequent development of a dieback event, which, after a period of establishment, has moved through the adjacent untreated plant population resulting in significant decline in infestation vigour and reduced recruitment. This is the first report of large-scale management of parkinsonia by this method.

The Steepest Descent (or Ascent) algorithm is one of the most widely used algorithms in Science, Technology, Engineering, and Mathematics (STEM). However, this powerful mathematical tool is neither taught nor even mentioned in K12 education. We study whether it is feasible for elementary school students to learn this algorithm, while also aligning with the standard school curriculum. We also look at whether it can be used to create enriching activities connected to children’s real-life experiences, thus enhancing the integration of STEM and fostering Computational Thinking. To address these questions, we conducted an empirical study in two phases. In the first phase, we tested the feasibility with teachers. In a face-to-face professional development work-shop with 457 mathematics teachers actively participating using an online platform, we found that after a 10-minute introduction they could successfully apply the algorithm and use it in a couple of models. They were also able to complete two complex and novel tasks: selecting models and adjusting the parameters of a model that uses the steepest descent algorithm. In a second phase, we tested the feasibility with 90 fourth graders from 3 low Socioeconomic Status (SES) schools. Using the same introduction and posing the same questions, we found that they were able to understand the algorithm and successfully complete the tasks on the online platform. Additionally, we found that close to 75% of the students completed the two complex modeling tasks and performed similarly to the teachers.

The Steepest Descent (or Ascent) algorithm is one of the most widely used algorithms in Science, Technology, Engineering, and Mathematics (STEM). However, this powerful mathematical tool is neither taught nor even mentioned in K12 education. We study whether it is feasible for elementary school students to learn this algorithm, while also aligning with the standard school curriculum. We also look at whether it can be used to create enriching activities connected to children’s real-life experiences, thus enhancing the integration of STEM and fostering Computational Thinking. To address these questions, we conducted an empirical study in two phases. In the first phase, we tested the feasibility with teachers. In a face-to-face professional development work-shop with 457 mathematics teachers actively participating using an online platform, we found that after a 10-minute introduction they could successfully apply the algorithm and use it in a couple of models. They were also able to complete two complex and novel tasks: selecting models and adjusting the parameters of a model that uses the steepest descent algorithm. In a second phase, we tested the feasibility with 90 fourth graders from 3 low Socioeconomic Status (SES) schools. Using the same introduction and posing the same questions, we found that they were able to understand the algorithm and successfully complete the tasks on the online platform. Additionally, we found that close to 75% of the students completed the two complex modeling tasks and performed similarly to the teachers.

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M):alginate (A) ratios. We selected hydrogels containing 4% (w/v) M and 2% (w/v) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various disease and also for drug screening.

The last two decades have witnessed a surge in investigations proposing stem cells as a promising strategy to treat stroke. Since growth factor release is considered as one of the most important aspects of cell-based therapy, stem cells over-expressing growth factors are hypothesized to yield higher levels of therapeutic efficiency. In pre-clinical studies of the last 15 years that were investigating the efficiency of stem cell therapy for stroke, a variety of stem cell types were genetically modified to over-express various factors. In this review we summarize the current knowledge on the therapeutic efficiency of stem cell-derived growth factors, encompassing techniques employed and time points to evaluate. In addition, we discuss several types of stem cells, including the recently developed model of epidermal neural crest stem cells, and genetically modified stem cells over-expressing specific factors, which could elevate the restorative potential of naive stem cells. The restorative potential is based on enhanced survival/differentiation potential of transplanted cells, apoptosis inhibition, infarct volume reduction, neovascularization or functional improvement. Since the majority of studies have focused on the short-term curative effects of genetically engineered stem cells, we emphasize the need to address their long-term impact.

Trophoblasts are the first cell-type to be specified during embryogenesis, and they are essential for placental morphogenesis and function. Trophoblast stem (TS) cells are the progenitor cells for all trophoblast lineages; control of TS cell differentiation into distinct trophoblast subtypes is not well understood. Mice lacking the transcription factor OVO-like 2 (OVOL2) fail to produce a functioning placenta, and die around embryonic day 10.5, suggesting that OVOL2 may be critical for trophoblast development. Therefore, our objective was to determine the role of OVOL2 in mouse TS cell fate. We found that OVOL2 was highly expressed in mouse placenta and differentiating TS cells. Placentas and TS cells lacking OVOL2 showed poor trophoblast differentiation potential, including increased expression of stem-state associated genes (Eomes, Esrrb, Id2) and decreased levels of differentiation-associated transcripts (Gcm1, Tpbpa, Prl3b1, Syna). Ectopic OVOL2 expression in TS cells elicited precocious differentiation. OVOL2 bound proximate to the gene encoding inhibitor of differentiation 2 (ID2), a dominant negative helix-loop-helix protein, and directly repressed its activity. Overexpression of ID2 was sufficient to reinforce the TS cell stem state. Our findings reveal a critical role of OVOL2 as a regulator of TS cell differentiation and placental development, in-part by coordinating repression of ID2.

The American Academy of Arts and Sciences suggested the definition of science literacy emphasize how crucial understanding the scientific process and the ability to evaluate conflicting scientific evidence is. The purpose of this article is to present an evidence-supported curriculum covering the fundamentals of logic, reasoning, and argumentation skills to address the emphasized basic knowledge, skills, and abilities required to be scientifically literate, which will prepare the public to understand and engage with science meaningfully. An analytic-synthetic approach toward understanding the notion of public is taken using a theoretical biomimetics framework that identifies naturally occurring objects or phenomena that descriptively captures the essence of a construct to facilitate creative problem-solving. In the present case, the problem being solved is how to reconcile what is meant by public, how it ought to be interpreted, the different levels of confidence in science that exist, and various understandings of science all with one another. The results demonstrate there is an inherent denotative-connotative inconsistency in the traditional notion of public that can be explicated through the concept of a fractal allowing for comprehension of the relationship between public confidence in, and understanding of, science.

Adipose-derived stem cells (ADSCs) were suggested for treating degenerative osteoarthritis, suppressing inflammatory responses, and repairing damaged soft tissues. Moreover, the ADSCs have the potential to undergo self-renewal and differentiate into bone, tendon, cartilage, and ligament. Recently, investigation of the self-renewal and differentiation of the ADSCs becomes an attractive area. In this work, a pneumatic microdevice has been developed to study the gene expression of the ADSCs after the stimulation of multi-axial tensile strain. The ADSCs were cultured on the microdevice and experienced multi-axial tensile strain during a 3-day culture course. Self-renewal and differentiation abilities were investigated by mRNA expressions of NANOG, SOX2, OCT4, SOX9, PPAR-γ, and RUNX2. The result showed that the genes related self-renewal were significantly up-regulated after the tensile stimulation. Higher proliferation ratio of the ADSCs was also shown by cell viability assay. The microdevice provides a promising platform for cell-based study under mechanical tensile stimulation.

Stem cells derived from dental tissues—dental stem cells—are flavored due to their easy acquisition. Among them, dental pulp stem cells (DPSCs) extracted from the dental pulp have many advantages such as high proliferation and highly purified population. Although their ability for neurogenic differentiation has been highlighted and neurogenic differentiation using electrospun nanofibers (NFs) has been performed, graphene-incorporated NFs have never been applied for DPSC neurogenic differentiation. Here reduced graphene oxide (RGO)-polycaprolactone (PCL) hybrid electrospun NFs were developed and applied for enhanced neurogenesis of DPSCs. First, RGO-PCL NFs were fabricated by electrospinning with incorporation of RGO and alignments, and their chemical and morphological characteristics were evaluated. Furthermore, in vitro NF properties such as influence on the cellular alignments and cell viability of DPSCs were also analyzed. The influences of NFs on DPSCs neurogenesis was also analyzed. The results confirmed that an appropriate concentration of RGO promoted better DPSC neurogenesis. Furthermore, the use of random NFs facilitated contiguous junctions of differentiated cells, whereas the use of aligned NFs facilitated aligned junction of differentiated cells along the direction of NF alignments. Our findings showed that RGO-PCL NFs can be a useful tool for DPSC neurogenesis, which will help regeneration in neurodegenerative and neurodefective diseases.

Mesenchymal stem cells (MSCs) have emerged as a promising treatment for inflammatory diseases. It is described that the immunomodulatory effect of MSCs takes place both by direct cell-to-cell contact and by means of soluble factors that leads to an increased accumulation of regulatory immune cells at the sites of inflammation. Similar efficacy of MSCs has been described regardless the route of administration used, the inflammation conditions and the MHC context. These observations arise the question as to whether the migration of the MSCs to the inflamed tissues is a pre-requisite to achieve their beneficial effect. To address this, we examined the biodistribution and the efficacy of intraperitoneal luciferase-expressing human expanded adipose derived stem cells (Luci-eASCs) in a mouse model of colitis. Luci-eASC-infused mice were stratified according to their response to the Luci-eASC treatment. According to the stratification criteria, there was a tendency to increase the bioluminescence signal in the intestine at the expense of a decrease in the bioluminescence signal in the liver in the `responder´ mice. These data thus suggest that the accumulation of the eASCs to the inflamed tissues is beneficial to achieve an optimal modulation of inflammation.

Current knowledge of the RNA world indicates two different genetic codes being present throughout the living world. In contrast to non-coding RNAs that are built of repetitive nucleotide syntax, the sequences that serve as templates for proteins share – as main characteristics – a non-repetitive syntax. The differences in their syntax structure is coherent with the difference of the functions they represent. Whereas non-coding RNAs build groups that serve as regulatory tools in nearly all genetic processes, the coding sections represent the evolutionarily successful function of the genetic information storage medium. The DNA genomes themselves are rather inactive, whereas the non-coding RNA domain is highly active, even as non-random genetic innovation operators. This indicates that repetitive syntax is the essential pre-requisite for RNA interactions to install variable RNA-group-identities, whereas the non-repetitive syntax serves as a stable conservation tool for successful selection processes out of RNA-groups cooperation and competition. The interaction opportunities of RNA loops with repetitive syntax are higher than with non-repetitive ones. Interestingly, these two genetic codes resemble the function of all natural languages, i.e., (a) everyday language use for organization and coordination of biotic group behavior, and (b) artificial (instrumental) language use for conservation of blueprints for complex protein-body constructions.

Placenta-derived mesenchymal stem cells (PD-MSCs) have been highlighted as therapeutic sources in several degenerative diseases. Recently, microRNAs (miRNAs) were mediated one of the therapeutic mechanisms of PD-MSCs in regenerative medicine. To enhance the therapeutic effects of PD-MSCs, we established functionally enhanced PD-MSCs with phosphatase of regenerating liver-1 overexpression (PRL-1(+)). However, the profile and functions of miRNAs induced by PRL-1(+) PD-MSCs in a rat model with hepatic failure prepared by bile duct ligation (BDL) remained unclear. Hence, the objectives of the present study were to analyze the expression of miRNAs and investigate their therapeutic mechanisms for hepatic regeneration via PRL-1(+) in a rat model with BDL. We selected candidate miRNAs based on microarray analysis. Under hypoxic conditions, compared with invaded naïve PD-MSCs, invaded PRL-1(+) PD-MSCs showed improved integrin-dependent migration ability through RHO family-targeted miRNA expression (e.g., hsa-miR-30a-5p, 340-5p, and 146a-3p). Moreover, rno-miR-30a-5p and 340-5p regulated engraftment into injured rat liver by transplanted PRL-1(+) PD-MSCs through the integrin family. Additionally, an increase in PDGFRA by suppressing rno-miR-27a-3p improved vascular structure in rat liver tissues after PRL-1(+) PD-MSCs transplantation. Furthermore, decreased rno-miR-122-5p was significantly correlated with increased proliferation of hepatocytes in liver tissues by PRL-1(+) PD-MSCs by activating IL-6 signaling pathway through the repression of rno-miR-21-5p. Taken together, these findings improve the understanding of therapeutic mechanisms based on miRNA-mediated stem cell therapy in liver diseases.

The use of chimeric antigen receptors (CAR-T cells) for the treatment of patients with malignant haematological diseases has become a well-established application, for conditions such as refractory or relapsed B cell acute lymphoblastic leukaemia (B-ALL), B cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR-T cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR-T cells with approval by different regulatory agencies around the globe. In the USA the Food and Drug Administration (FDA) has approved 6 commercial CAR-T cells that are widely distributed worldwide. At the time of this writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR-T cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all the current areas of treatments with CAR-T cells, we offer a brief summary of some of the most relevant aspects of the use of CAR-T cells for some of these conditions.

Background/Objectives: The increasing incidence and mortality rates of liver cancer have heightened the demand for the development of effective anticancer drugs with minimal side effects. In this study, the roles of exosomes derived from liver cancer stem cells (LCSCs) with PRELI (Protein of Relevant Evolutionary and Lymphoid Interest) modulation, and their miRNAs were investigated to explore the therapeutic for liver cancer. The purpose of this study is to identify a more effective and less toxic anticancer agent beyond the well-known Notch, p51, and Hippo signaling pathways, and to specifically propose the potential of PRELI-induced exosomes as an anticancer therapeutic candidate. Methods: Various techniques, such as miRNA profiling, flow cytometry, western blotting, and immunocytochemistry, were used to evaluate the effects of ex-osomes under PRELI up- and downregulation. Results: PRELI upregulation altered expression levels of miRNAs, including hsa-miR-378a-3p (involved in stem-like properties), hsa-miR-25-3p (contributing to cell proliferation), and hsa-miR-423-3p (driving invasiveness). Exosomes with downregulated PRELI inhibited AKT/mTORC1 signaling, while this signaling pathway was ac-tivated in LCSCs transfected with the candidate miRNAs. Under PRELI up-regulation, exosomes showed increased surface marker expression, promoting cancer progression. Conclusions: The modulation of PRELI in LCSCs affects miRNA expression significantly, revealing candidate miRNA targets for liver cancer treatment. Exosomes with PRELI down-regulation show potential as a novel therapeutic strategy.

Mesenchymal Stem Cells (MSCs) secretions, usually containing growth factors, cytokines, and chemokines, have improved wound healing via a paracrine mechanism. This makes them particularly valuable as potential cell therapeutics. Similarly, wound healing is mainly regulated via paracrine signaling of growth factors, cytokines, and chemokines. Chronic wound healing has prolonged inflammatory, proliferative, or remodeling phases, resulting in tissue fibrosis and non-healing ulcers. The growth factors, cytokines, and chemokines secreted by MSCs can be applied to wounds by transplanting cells or using the secretome/conditioned medium (CM) of MSCs, which contains these secreted bioactive molecules. For their success in increasing the wound healing rate, MSCs offer a promising option for treating chronic wounds. This review provides a concise summary of current knowledge of the biological properties of MSCs and describes the use of MSCs for wound healing. In particular, the scope of this review focuses on the role of MSCs in wound healing by increasing wound healing rate with the secretion of growth factors, cytokines, and chemokines. In addition, the function and type of MSCs also have been discussed.

Background: Knee osteoarthritis (OA) significantly affects quality of life and imposes economic burdens due to its prevalence and the disability it causes. The efficacy of current treatments is limited to alleviate the symptoms and not for regenerative purposes. This study aims to evaluate the efficacy and safety of combining hyaluronic acid (HA), human umbilical cord mesenchymal stem cells (hUC-MSCs), and synthetic human growth hormone (somatotropin) in the treatment of knee OA, assessing pain relief, functional improvement, and cartilage regeneration. Methods: A four-arm, double-blind randomized trial was conducted with 51 knees from 28 subjects, aged ≥ 50 with primary knee OA. Treatments involved are HA alone, HA with hUC-MSCs, HA with somatotropin, and a combination of all three. Efficacy was measured through the International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and visual analog score (VAS) along with MRI T2 mapping of cartilage were taken on pre-implantation, 6th and 12th month. Results: All treatment arms showed improvement in VAS and WOMAC scores over 12 months, suggesting some pain relief and functional improvement. However, MRI T2 mapping showed no significant cartilage regeneration across the groups. Conclusion: While combined use of HA, hUC-MSCs, and somatotropin improved symptoms of knee OA, it did not enhance cartilage regeneration significantly. The study highlights the potential of these combinations for symptom management but underscores the need for further research to optimize these therapies for regenerative outcomes.

Background: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with a rapidly increasing prevalence. Current therapeutic options primarily manage symptoms, not modifying the disease. Secretome-based therapies have emerged as a promising avenue for AD treatment in targeting multiple pathways and promoting neuroprotection and regeneration. This systematic review evaluated the preclinical and clinical evidences for secretome-based therapies in AD.Methods: A systematic search was conducted across Scopus, PubMed, ScienceDirect, and Cochrane Library. The SYRCLE risk of bias (RoB) tool was used for preclinical studies and Cochrane RoB 2.0 for clinical studies. We performed qualitative analysis of study results.Results: Included 21 in vivo studies and 2 clinical trials revealed promising outcomes of treatments involving secretomes, exosomes, and extracellular vesicles from different cell sources. The therapies could reduce amyloid plaque load, reactive gliosis, and enhance neuronal density. These findings suggested the treatments reveal mechanism of action in neuroprotection, neuroregeneration, and inflammation modulation, which are critical in AD pathology. Ongoing trials also supported the safety and efficacy of the treatment strategies. However, translational medical study faces several challenges regarding large-scale production, optimization of protocols, and understanding biomarkers. The heterogeneity in secretome-based therapies administration have complicated the comparison of study outcomes and the translation of preclinical findings into clinical settings. Deeper understanding of the secretome's mechanisms of action, optimal dosing, and delivery methods are needed to maximize therapeutic outcomes.Conclusion: Despite secretome-based therapies hold significant promise for AD treatment, addressing the identified gaps and limitations is crucial for advancing these therapies from preclinical research to clinical practice.

Epigenetic modifications play a significant role in determining the fate of AFSC in terms of differentiation into multiple lineages. There is a tight correlation among DNA methylation, histone modifications, and small noncoding RNAs during the epigenetic control of stem cells differentiation. The present study investigates the role of miRNAs in differentiation of AFSC and addresses how their unique signatures contribute to lineage-specific differentiation. miRNAs profile was assessed in AFSC after 4 weeks of endothelial and muscular differentiation. Our results showed a decreased expression of for 5 miRNAs (miR-125b-5p, hsa-miR-18a-5p, hsa-miR-137, hsa-miR-21-5p and hsa-let-7a-5p) and an increased expression for 12 miRNAs (miR-134-5p, miR-103a-3p, let-7i-5p, miR-214-3p, let-7c-5p, miR-129-5p, miR-210-3p, let-7d-5p, miR-375, miR-181-5p, miR-125a-5p, hsa-let-7e-5p) in EPC compared with undifferentiated AFSC. Smooth muscle differentiation of AFSC revealed significant changes in 9 miRNAs from total of 84 tested; 3 were downregulated (miR-18a-5p, miR-137, sa-miR-21-5p) and 6 were upregulated (miR-155-5p, miR-20a-5p, let-7i-5p, hsa-miR-134-5p, hsa-miR-214-3p, hsa-miR-375). miRNAs are molecular regulators of cell fate and differentiation, recent advances in molecular biology techniques revealed miRNA regulatory networks that can provide us information of endothelial and muscle cell biology in terms of homeostasis, growth, differentiation, and vascular function.

Heat shock factor 1 (HSF1) is a transcription factor crucial for regulating heat shock response (HSR), one of the significant cellular protective mechanisms. When cells are exposed to proteotoxic stress, HSF1 induces the expression of heat shock proteins (HSPs) to act as chaperones, correcting the protein-folding process and maintaining proteostasis. In addition to its role in HSR, HSF1 is overexpressed in multiple cancer cells, where its activation promotes malignancy and leads to poor prognosis. The mechanisms of HSF1-induced tumorigenesis are complex and involve diverse signaling pathways, dependent on cancer type. With its important roles in tumorigenesis and tumor progression, targeting HSF1 offers a novel cancer treatment strategy. In this article, we examine the basic function of HSF1 and its regulatory mechanisms, focus on the mechanisms involved in HSF1’s roles in different cancer types, and examine current HSF1 inhibitors as novel therapeutics to treat cancers.

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

Brain disorders pose a significant global healthcare challenge due to their complexity and profound impact on individuals and society. This review explores recent advancements in brain disease research, deepening our understanding and progress towards treatments. Technological innovations, like high-resolution imaging and optogenetics, play a pivotal role in illuminating cellular structures and dissecting neural circuits. Genetic analysis identifies dis-ease-associated genes and mutations, yet translating findings to clinical applications remains challenging. Epigenomics, transcriptomics, and proteomics provide molecular insights, un-covering disrupted pathways in conditions like Alzheimer's disease. Stem cell models elucidate developmental mechanisms, and immunotherapies, including CAR T cells, emerge as prom-ising strategies for brain cancers like glioblastoma. Genome editing tools, exemplified by CRISPR, enable precise modification of disease genes in models, deepening our understanding of pathogenesis. Multifaceted approaches integrating human studies, animal models, and bi-oinformatics propel the field forward. However, complexities persist, as disease specificity for cell types or brain regions remains an enigma, and genetic factors interact with environmental influences, highlighting disease intricacies. Ultimately, interdisciplinary efforts combining bi-ophysical and psychospiritual perspectives are essential to fully understand brain health and unlock transformative treatments for these debilitating disorders. A comprehensive under-standing of brain disorders is vital to improve the quality of life for millions and alleviate the global burden of neurological afflictions. Continued collaborative research will lead to an era of improved brain health worldwide.

PdRe/Al2O3 catalysts are highly selective for hydrogenation of furfural to furfuryl alcohol (FAL). Moreover, synergy between the metals can result in greater specific activity (higher turnover frequency, TOF) than exhibited by either metal alone. Bimetallic catalyst structure depends strongly on the metal precursors employed and their addition sequence to the support. In this work, PdRe/Al2O3 catalysts were prepared by: (i) co impregnation (CI) and sequential impregnation (SI) of  Al2O3 using HReO4 and Pd(NO3)2, (ii) SI using NH4ReO4 and [Pd(NH3)4(NO3)2], (iii) HReO4 addition to a reduced and passivated Pd/Al2O3 catalyst, and (iv) impregnation with the double complex salt (DCS), [Pd(NH3)4(ReO4)2]. Raman spectroscopy and temperature-programmed reduction (TPR) evidence larger supported PdO crystallites in catalysts prepared using Pd(NO3)2 than [Pd(NH3)4(NO3)2]. Surface [ReO4]- species detected by Raman exhibit TPR peak temperatures from ranging 85 to 260°C (versus 375°C for Re/Al2O3). After H2 reduction at 400°C, the catalysts were characterized by chemisorption, temperature-programmed hydride decomposition (TPHD), CO diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and scanning transmission electron microscopy (STEM) with energy-dispersive x-ray (EDX) spectroscopy. The CI catalyst containing supported Pd-Re alloy crystallites had a TOF similar to Pd/Al2O3 but higher (61%) FAL selectivity. In contrast, catalysts prepared by methods (ii-iv) containing supported Pd-Re nanoparticles exhibit higher TOFs and up to 78% FAL selectivity.

The cast defects strongly degrade the mechanical properties in cast alloys. The effect of Sn addition on Al-Si alloys was investigated by 3D computed tomography, SEM and TEM. Amorphous Sn oxides are found near the alumina film, cause more shrinkage pores, initiate cracks and deteriorate mechanical properties. This work suggests not adding Sn in various Al alloys used in cast state.

Purpose: Oxidative stress is responsible for over seventy five diseases and other harmful cytological challenges including cancer, type 2 diabetes mellitus, lipid peroxidation, distortion of cell membrane integrity, shortening of telomerase among others. Antioxidant potency of any plant is a very positive remedy to the debilitating effects of prooxidants and oxidants. The study was aimed at investigating the antioxidant potency of methanol extract of Pentaclethra macrophylla stem bark- in vitro and in vivo. Methods: Different phytochemicals were determined using standard methods. Nitric oxide, 1, 1-diphenyl-2- picrylhydrazyl (DPPH) radical scavenging activity, total antioxidant capacity and ferric reducing/anti-radical power were used to investigate the in vitro antioxidant activity. Catalase assay, superoxide dismutase, malondialdehyde and glutathione peroxidase were used to determine the in vivo antioxidant efficacy using six groups of five rats. Results: The result showed various quantities of phytochemicals, including antioxidant phytochemicals-flavonoids, tannins and total phenolics. The in vitro assay showed that 250 μg/ml of extract had the highest percentage inhibition of DPPH radical (93.93%). The 125 μg/ml had the highest scavenging activity of nitric oxide radical (49.47%) while 250μg/ml showed the least with 41.73%. Other methods showed various degrees of activity. The in vivo antioxidant showed that the principal mechanism of antioxidant activity is by modulating the iron-dependent catalase activity. Conclusion: Pentaclethra macrophylla has both in vitro and in vivo antioxidant activities and therefore is useful in ameliorating the debilitating effects of oxidants.

Spermatogonial stem cells (SSCs) are the only primitive spermatogonial cells in males that can naturally transmit genetic information to their offspring and replicate throughout their lives. Phospholipase D family member 6 (PLD6) has recently been found to be a surface marker for SSCs in mice and boars; however, it has not been validated in cattle. The results of RT-PCR and qRT-PCR found that the relative expression of PLD6 gene in the testicular tissues of 2-year-old Simmental calves was significantly higher than that of 6-month-old calves. Immunofluorescent staining further verified the expression of PLD6 protein in bovine spermatogenic cells like germ cell marker VASA. Based on multiple bioinformatic databases, PLD6 is a conservative protein which has high homology with mouse Q5SWZ9 protein. It is closely involved in the normal functioning of the reproductive system. Molecular dynamics simulation analyzed the binding of PLD6 as a phospholipase to cardiolipin (CL), and PLD6-CL complex showed high stability. The protein interaction network analysis showed that there is a significant relationship between PLD6 and piRNA binding protein. PLD6 acts as an endonuclease and participates in piRNA production. In addition, PLD6 in bovine and mouse testes has a similar expression pattern with the spermatogonium-related genes VASA and PIWIL2. In conclusion, these analyses imply that PLD6 has a relatively high expression in bovine testes and could be used as a biomarker for spermatogenic cells including SSCs.

Mixed lineage leukemia 1 (MLL1) introduces 1-, 2- and 3-methylation into histone H3K4 through the evolutionarily conserved set domain. In this study, bovine embryonic stem cells (bESCs, named bESCs-F7) were established from the in vitro fertilized (IVF) embryos by Wnt signaling inhibition, while its contribution to endoderm in vivo is limited. To improve the quality of bESCs, MM-102, an inhibitor of MLL1, was applied to the culture. The results showed that MLL1 inhibition along with GSK3 and MAP2K inhibition (3i) at the embryonic stage did not affect bESCs establishment and pluripotency. MLL1 inhibition improves the pluripotency and differentiation potentials of bESCs via up-regulation of stem cell signaling pathways such as PI3K-Akt and WNT. MLL1 inhibition decreases H3K4me1 modification at promoters in bESCs and altered the distribution of DNA methylation in bESCs. In summary, MLL1 inhibition enables bESCs to acquire better pluripotency, and its application may provide high quality pluripotent stem cells for domestic animals.

In the context of market relations in agriculture in the Kyzylorda region, in order to meet the needs of animal husbandry in complete feed, it is necessary to create a solid forage base. The successful solution to the tasks of increasing the number of livestock and increasing the productivity of animal husbandry in the ecological conditions of the Aral Sea region largely depends on the timely procurement of feed and the transfer of feed production to an industrial basis. It is possible to increase the production of high-quality feeds through the introduction of high-yielding varieties, the use of new resource-saving cultivation and harvesting technologies, the optimal organization of cultivation production processes, and increasing the efficiency of the use of technical means. Of all the harvested types of feeds, alfalfa has the best effect on increasing milks yield and meat gains. The green mass of alfalfa is well-eaten by all farm animals. For example, when feeding cattle, its utilization rate is 92.6%. In terms of protein richness, alfalfa hay surpasses many other feeds, so 100 kg of alfalfa hay contains 11.6 kg of digestible protein, 1.77 kg of calcium, 0.22 kg of phosphorus, and 4.5 g of carotene. In addition, in the conditions of rice crop rotation, according to its biological characteristics, alfalfa (Medicago sativa L.) is considered indispensable in agrotechnical and reclamation relations, especially in saline soils. The economic value of alfalfa lies in its wide ecological plasticity, the ability to grow back quickly after mowing, and high productivity.

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

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

Based on its large surface area and covering the whole human body, the skin body’s largest organ and its main function is protection. Injuries and wound healing involving the skin offer valuable lessons shared with and of relevance to other organ systems and the diseases that impact them. Arguably the most complex human body process, wound healing is a multifaceted process that involves multiple cells and the extracellular matrix (ECM), with each component playing a specific role in the different stages of the healing process. Importantly, studies indicate that cells with stem cell-like properties are present within many of the human tissues and play key roles in case of tissue and cellular injury. Cell-to-cell and cell-to-ECM interactions are salient in wound healing subsequent to an injury. Microenvironment related factors and the variations therein including hypoxia or the abundance of oxygen, the presence/absence of growth factors and cytokines add to the complexity of the wound healing process and impact cell function and result in compromised or enhanced wound healing. This expert review critically examines the advances in biochemical and analytical tools that are enable the analysis of numerous cells and molecules within the wound microenvironment, revealing great cellular heterogeneity as well as novel molecular targets of importance to enhance wound healing. In a broader angle, we emphasize the ways in which wound healing is significant in the search for perfect skin after injury and in many common complex human diseases including cancer. In all, wound healing is a centrepiece of integrative biology research and applications in medicine as well as dermatology as discussed in this review.

Porcine epidemic diarrhea virus (PEDV) causes severe enteric disease in pigs, particularly neonatal piglets. Attempts to develop a safe and effective vaccine have been unsuccessful. Ginseng stem-leaf saponins (GSLS), a promising oral adjuvant candidate, can improve intestinal immune responses in poultry and mice. However, the low stability limits the further use. Poly lactic-co-glycolic acid (PLGA), a biocompatible and biodegradable nanoparticle, have been widely used in biomedicine for stable and targeted drug delivery. In this study, we developed GSLS-PLGA nanoparticles (GSLS-NPs) and evaluated the mucosal adjuvant efficacy in vitro and in vivo. GSLS-NPs significantly enhanced antigen internalization and pro-inflammatory cytokine secretion by DC2.4 cells. Mice orally administered GSLS-NPs before intramuscular inoculation generated CD11b+CD8α- and CD11b-CD103+ dendritic cells in the spleen and draining mesenteric lymph nodes, respectively, which are the types mainly responsible for antigen presentation. Additionally, enhanced neutralizing and non-neutralizing antibody responses and expanded activities of specific effector and memory CD4+ and CD8+ T cells were also observed in mice immunized with PEDV vaccines plus GSLS-NPs compared to mice receiving the vaccines alone. Furthermore, GSLS-NPs showed a good safety profile and presented great advantages over GSLS aqueous solution. Collectively, our results highlight the potential of GSLS-NPs as a mucosal adjuvant and provide an attractive vaccination strategy for combatting PEDV. Further study is required to evaluate the efficacy of this mucosal adjuvant in swine.

Brain stem cells (neural stem cells or NSCs) and neurons of a chosen kind reprogramming is a potential technique for cell therapy. It is possible to reprogram non-neuronal cells, for example, by using a predetermined group of factors, nuclear transfer, and the induced transcriptional factors (TFs) expression in a related lineage of cells, and non-coding microRNAs (miRNAs). Researchers have additionally been attempting to improve reprogramming methods, whether it is by employing unique sets of biomolecules and particular TFs or by delivering relevant miRNA and Biomolecules. The technique of miRNA mediated is intriguing for its capability to quickly create a range of biologically desirable cell types for therapy from different lineages of cells. Current findings have made significant advancements towards changing the somatic cells to diverse particular neuronal subgroups with greater efficiency, using reprogramming of miRNA-mediated neural cells, despite the fact that the precise processes need to be discovered. To further understand how miRNAs might direct somatic cells to become neural, we need to look at the latest research on their function in neural reprogramming over the differentiated cells. Recent findings on the role of miRNAs in the initiation of cell reprogramming and the determination of the neuronal subtype's destiny are the primary focus of this comprehensive overview. Furthermore, we cover the far more latest results concerning certain miRNAs' activity in controlling different phases of neuronal differentiation, which contributes in comprehending the interaction network of miRNAs and their receptors.

Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. They arrest in the G0 phase and generate non-CSC progeny by self-renewing and pluripotency activity, resulting in tumor recurrence, metastasis, and chemoresistance. One CSC can stimulate tumor relapse and can re-grow a metastatic tumor. So, CSC is a promising target for eradicating tumors, and developing an anti-CSC method has become a top priority in cancer therapy. In recent years competing endogenous RNA (ceRNA) have emerged as an important class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. To overcome therapeutic resistance due to CSCs, we need to improve our existing understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed in order to discuss the role of ceRNAs in CSCs function. We reviewed the role of ceRNAs in acquiring CSCs characteristics in the form of different pathways including Rho GTPase/F-actin_ Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) (Hippo), Wnt/β-catenin pathway, transforming growth factor (TGF)-b–urothelial carcinoma-associated 1 (UCA1)–Slug pathway, etc. Finally, considering the comprehensive impacts of the ceRNA network on different pathways, a treatment strategy driving the ceRNA network might be effective. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.

The main aspects of material research: material synthesis, material structure, and material properties, are interrelated. Acquiring atomic structure information of electron beam sensitive materials by electron microscope, such as porous zeolites, organic-inorganic hybrid perovskites, metal-organic frameworks, is an important and challenging task. The difficulties in characterization of the structures will inevitably limit the optimization of their synthesis methods and further improve their performance. The emergence of integrated differential phase contrast scanning transmission electron microscopy (iDPC-STEM), a STEM characterization technique capable of obtaining images with high signal-to-noise ratio under lower doses, has made great breakthroughs in the atomic structure characterization of these materials. This article reviews the developments and applications of iDPC-STEM in electron beam sensitive materials, and provides an outlook on its capabilities and development.