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Glioblastoma (GBM) is the highest grade of glioma for which no effective therapy is currently available. Despite extensive research in diagnosis and therapy, there has been no significant improvement in GBM outcomes, with a median overall survival continuing at a dismal 15–18 months. In recent times, glioblastoma stem cells (GSCs) have been identified as crucial drivers of treatment resistance and tumor recurrence, and GBM therapies targeting GSCs are expected to improve patient outcomes. We used a multistep in silico screening strategy to identify repurposed candidate drugs against selected therapeutic molecular targets in GBM with potential to concomitantly target GSCs. Common differentially expressed genes (DEGs) were identified through analysis of multiple GBM and GSC datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). For identification of target genes, we selected the genes with most significant effect on overall patient survival. The relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples was also validated and their cancer dependency scores were assessed. Drugs targeting these genes and their corresponding proteins were identified from LINCS database using Connectivity Map (CMap) portal and by in silico molecular docking against each individual target using FDA-approved drug library from the DrugBank database, respectively. The molecules thus obtained were further evaluated for their ability to cross blood brain barrier (BBB) and their likelihood of resulting in drug resistance by acting as p-glycoprotein (p-Gp) substrates. The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal. We identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes. [ABSTRACT FROM AUTHOR]

Background: During the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms. Methods: The levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT–qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits. Results: In vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence. [ABSTRACT FROM AUTHOR]

Understanding the short‐term responses of mesophyll conductance (gm) and stomatal conductance (gsc) to environmental changes remains a challenging yet central aspect of plant physiology. This review synthesises our current knowledge of these short‐term responses, which underpin CO2 diffusion within leaves. Recent methodological advances in measuring gm using online isotopic discrimination and chlorophyll fluorescence have improved our confidence in detecting short‐term gm responses, but results need to be carefully evaluated. Environmental factors like vapour pressure deficit and CO2 concentration indirectly impact gm through gsc changes, highlighting some of the complex interactions between the two parameters. Evidence suggests that short‐term responses of gm are not, or at least not fully, mechanistically linked to changes in gsc, cautioning against using gsc as a reliable proxy for gm. The overarching challenge lies in unravelling the mechanistic basis of short‐term gm responses, which will contribute to the development of accurate models bridging laboratory insights with broader ecological implications. Addressing these gaps in understanding is crucial for refining predictions of gm behaviour under changing environmental conditions. Summary statement: This review synthesises our current knowledge of short‐term responses of mesophyll conductance (gm) to changes in environmental conditions. Recent advances in measurement techniques for the detection of short‐term gm responses are described and points of caution are highlighted, such as the impact of vapour pressure deficit or when using stomatal conductance (gsc) as a proxy for gm. [ABSTRACT FROM AUTHOR]

Abstract Background During the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms. Methods The levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT–qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits. Results In vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence.

Glioblastoma is a highly aggressive and complex pathology that has garnered significant interest among researchers and clinicians due to its high mortality rates. This research article provides a systematic analysis of key aspects related to glioblastoma, offering comprehensive insights into its underlying complexities. The text explores the epidemiological patterns, etiological factors, and genetic and molecular foundations underlying the development of GBM. It also examines the interplay between the immune system and the tumor, identifying specific immune markers with potential diagnostic value. The article describes the complex processes involved in tumor growth, including its interaction with surrounding tissues, the development of the tumor microenvironment, and the role of stem cells. It also provides an analysis of current treatment options and the challenges they face, particularly in relation to tumor resistance. The article concludes with a thorough examination of the changing landscape of diagnostic and therapeutic approaches. It highlights notable recent research findings and provides insight into potential advancements that could shape the future of medical interventions for glioblastoma. [ABSTRACT FROM AUTHOR]

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 Associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.

Grouted Sleeve Connections (GSC) play an important role in assembly of structural members for precast concrete structures. With many experimental work and parametric study have been done on the tension load-slip behavior of GSC, the mechanical behavior for the tension load-slip responses of GSC should also be studied and explained. The failure modes for GSC in tensile tests with different material properties are firstly analyzed here by investigations on 326 GSC specimens. To study the mechanism of the failure modes, a partial-interaction numerical model is introduced to simulate the load-slip responses of GSC with provided bond-slip characteristics. The different boundary conditions for long and short embedment lengths are described respectively. More than 400 data points in load-slip responses are collected from tensile tests of GSC. The verification between theoretical results with test results shows good agreement. Hence, with the partial-interaction numerical model, the corresponding GSC load-slip responses could be obtained by given material and dimensional properties. Furthermore, parametric study shows that load-slip responses of GSC in tensile behavior change with embedment lengths of reinforcing bars. The CT scan results also show that embedment lengths for reinforcement are suggested to be longer than the designed size by considering the original defects of the sleeves and the eccentricity of reinforcement in construction.

Land surface temperature (LST) is a fundamental variable of environmental monitoring and surface equilibrium. Although the HJ-1B infrared scanner (IRS) has accumulated many observations, further application of HJ-1B/IRS is limited by the lack of LST products. This study refined the ERA5 atmospheric profile database, instead of the widely used traditional TIGR atmospheric profile database, and simulated the coefficients of the generalized single-channel (GSCs) algorithms to improve LST retrieval. GSCs can be divided into the GSCw and GSCwT algorithms, depending on whether the input is atmospheric water vapor content (WVC) or in situ near-surface air temperature and WVC. Land surface emissivity (LSE) was obtained from the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) Global Emissivity Dataset (GED) and vegetation/snow cover products. Then, the retrieved LSTs were evaluated using the LSTs from the RTE algorithm, TIGRw/TIGRwT profiles, and in situ near-surface air temperature from the HiWATER experiment in China from 2012 to 2014. The bias (root mean square error (RMSE)) values are displayed as ERA5wT < RTE < ERA5w < TIGRwT < TIGRw. The accuracy of ERA5wT, with a bias (RMSE) of 0.02 K (2.30 K), is higher than that of RTE, with a bias (RMSE) of 0.74 K (2.47 K). The accuracy of RTE is preferable to that of ERA5w, with a bias (RMSE) of 0.89 K (2.48 K), followed by TIGRwT, with a bias (RMSE) of −1.18 K (2.50 K), and then, TIGRw, with a bias (RMSE) of 1.60 K (2.77 K). In summary, the accuracy of LST obtained by GSC from the refined ERA5 atmospheric profiles is higher than that obtained from the TIGR profiles. The accuracy of LST obtained by GSCwT is greater than that obtained by GSCw. The accuracy of LST obtained using in situ near-surface air temperature is higher than that obtained using ERA5 air temperature. The accuracy of LSEASTER is slightly better than that of LSEMOD21. The aforementioned conclusions can provide scientific support to generate HJ-1B/IRS LST products. [ABSTRACT FROM AUTHOR]

This paper presents a comparative study between the conventional PI (Proportional Integral) and backstepping controllers applied to the DFIG (Doubly Fed Induction Generator) used in WECS (Wind Energy Conversion System). These two different control strategies proposed in this work are developed to control the active and reactive power of the DFIG on the one hand, and to maintain the DC-link voltage constant for the inverting function on the other hand. This is ensured by generating control signals for two power electronic converters, RSC (Rotor Side Converter) and GSC (Grid Side Converter). In order to optimise the power production in the WT (Wind Turbine), an MPPT (Maximum Power Point Tracking) algorithm is applied along with each control technique. To simulate the effectiveness of the proposed controllers, MATLAB/Simulink Software is used, and the obtained results are analysed and discussed to compare PI and backstepping controllers in terms of robustness against wind speed variations and tracking performance in dynamic and steady states.

One presenilin gene (PSEN) is expressed in the sea urchin embryo, in the vegetal pole of the gastrula and then mainly in cilia cells located around the digestive system of the pluteus, as we recently have reported. PSEN expression must be accurately regulated for correct execution of these two steps of development. While investigating PSEN expression changes in embryos after expansion of endoderm with LiCl or of ectoderm with Zn2+ by whole-mount in situ hybridization (WISH) and quantitative PCR (qPCR), we detected natural antisense transcription of PSEN. We then found that Endo16 and Wnt5, markers of endo-mesoderm, and of Hnf6 and Gsc, markers of ectoderm, are also sense and antisense transcribed. We discuss that general gene expression could depend on both sense and antisense transcription. This mechanism, together with the PSEN gene, should be included in gene regulatory networks (GRNs) that theorize diverse processes in this species. We suggest that it would also be relevant to investigate natural antisense transcription of PSEN in the field of Alzheimer's disease (AD) where the role of human PSEN1 and PSEN2 is well known. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most lethal cancers, having a poor prognosis and a median survival of only about 15 months with standard treatment (surgery, radiation, and chemotherapy), which has not been significantly extended in decades. GBM demonstrates remarkable cellular heterogeneity, with glioblastoma stem-like cells (GSCs) at the apex. GSCs are a subpopulation of GBM cells that possess the ability to self-renew, differentiate, initiate tumor formation, and manipulate the tumor microenvironment (TME). GSCs are no longer considered a static population of cells with specific markers but are quite flexible phenotypically and in driving tumor heterogeneity and therapeutic resistance. In light of these features, they are a critical target for successful GBM therapy. Oncolytic viruses, in particular oncolytic herpes simplex viruses (oHSVs), have many attributes for therapy and are promising agents to target GSCs. oHSVs are genetically-engineered to selectively replicate in and kill cancer cells, including GSCs, but not normal cells. Moreover, oHSV can induce anti-tumor immune responses and synergize with other therapies, such as chemotherapy, DNA repair inhibitors, and immune checkpoint inhibitors, to potentiate treatment effects and reduce GSC populations that are partly responsible for chemo- and radio-resistance. Herein, we present an overview of GSCs, activity of different oHSVs, clinical trial results, and combination strategies to enhance efficacy, including therapeutic arming of oHSV. Throughout, the therapeutic focus will be on GSCs and studies specifically targeting these cells. Recent clinical trials and approval of oHSV G47Δ in Japan for patients with recurrent glioma demonstrate the efficacy and promise of oHSV therapy. [ABSTRACT FROM AUTHOR]

Recent studies have shown that mitochondrial morphology can modulate organelle function and greatly affect stem cell behavior, thus affecting tissue homeostasis. As such, we previously showed that the accumulation of fragmented mitochondria in aged Drosophila ovarian germline stem cells (GSCs) contributes to age‐dependent GSC loss. However, standard immunofluorescence methods to examine mitochondrial morphology yield images with insufficient resolution for rigorous analysis, while 3‐dimensional electron microscopy examination of mitochondrial morphology is labor intensive and allows only limited sampling of mitochondria. To overcome these issues, we utilized the expansion microscopy technique to expand GSC samples by 4‐fold in combination with mitochondrial immunofluorescence labeling. Here, we present a simple, inexpensive method for nanoscale optical imaging of mitochondria in the germline. This protocol may be beneficial for studies that require visualization of mitochondria or other fine subcellular structures in the Drosophila ovary.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, which remains difficult to cure. The very high recurrence rate has been partly attributed to the presence of GBM stem-like cells (GSCs) within the tumors, which have been associated with elevated chemokine receptor 4 (CXCR4) expression. CXCR4 is frequently overexpressed in cancer tissues, including GBM, and usually correlates with a poor prognosis. We have created a CXCR4-retargeted oncolytic herpesvirus (oHSV) by insertion of an anti-human CXCR4 nanobody in glycoprotein D of an attenuated HSV-1 (ΔICP34.5, ΔICP6, and ΔICP47), thereby describing a proof of principle for the use of nanobodies to target oHSVs toward specific cellular entities. Moreover, this virus has been armed with a transgene expressing a soluble form of TRAIL to trigger apoptosis. In vitro, this oHSV infects U87MG CXCR4+ and patient-derived GSCs in a CXCR4-dependent manner and, when armed, triggers apoptosis. In a U87MG CXCR4+ orthotopic xenograft mouse model, this oHSV slows down tumor growth and significantly improves mice survival. Customizing oHSVs with diverse nanobodies for targeting multiple proteins appears as an interesting approach for tackling the heterogeneity of GBM, especially GSCs. Altogether, our study must be considered as a proof of principle and a first step toward personalized GBM virotherapies to complement current treatments.

Glioblastoma (GBM) is the most common primary brain malignancy in adults with a dismal prognosis. Despite advances in genomic analysis and surgical technique and the development of targeted therapeutics, most treatment options are ineffective and mainly palliative. Autophagy is a form of cellular self-digestion with the goal of recycling intracellular components to maintain cell metabolism. Here, we describe some recent findings that suggest GBM tumors are more sensitive to the excessive overactivation of autophagy leading to autophagy-dependent cell death. GBM cancer stem cells (GSCs) are a subset of the GBM tumor population that play critical roles in tumor formation and progression, metastasis, and relapse, and they are inherently resistant to most therapeutic strategies. Evidence suggests that GSCs are able to adapt to a tumor microenvironment of hypoxia, acidosis, and lack of nutrients. These findings have suggested that autophagy may promote and maintain the stem-like state of GSCs as well as their resistance to cancer treatment. However, autophagy is a double-edged sword and may have anti-tumor properties under certain conditions. The role of the STAT3 transcription factor in autophagy is also described. These findings provide the basis for future research aimed at targeting the autophagy-dependent pathway to overcome the inherent therapeutic resistance of GBM in general and to specifically target the highly therapy-resistant GSC population through autophagy regulation. [ABSTRACT FROM AUTHOR]

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Glioblastoma (GBM) continues to be the most devastating primary brain malignancy. Despite significant advancements in understanding basic GBM biology and enormous efforts in developing new therapeutic approaches, the prognosis for most GBM patients remains poor with a median survival time of 15 months. Recently, the interplay between the SOX (SRY-related HMG-box) genes and lncRNAs (long non-coding RNAs) has become the focus of GBM research. Both classes of molecules have an aberrant expression in GBM and play essential roles in tumor initiation, progression, therapy resistance, and recurrence. In GBM, SOX and lncRNAs crosstalk through numerous functional axes, some of which are part of the complex transcriptional and epigenetic regulatory mechanisms. This review provides a systematic summary of current literature data on the complex interplay between SOX genes and lncRNAs and represents an effort to underscore the effects of SOX/lncRNA crosstalk on the malignant properties of GBM cells. Furthermore, we highlight the significance of this crosstalk in searching for new biomarkers and therapeutic approaches in GBM treatment. [ABSTRACT FROM AUTHOR]

The reciprocal inhibition between two signaling centers, the Spemann organizer (dorsal mesoderm) and ventral region (mesoderm and ectoderm), collectively regulate the overall development of vertebrate embryos. Each center expresses key homeobox transcription factors (TFs) that directly control target gene transcription. Goosecoid (Gsc) is an organizer (dorsal mesoderm)-specific TF known to induce dorsal fate and inhibit ventral/ectodermal specification. Ventx1.1 (downstream of Bmp signaling) induces the epidermal lineage and inhibits dorsal organizer-specific genes from the ventral region. Chordin (Chrd) is an organizer-specific secreted Bmp antagonist whose expression is primarily activated by Gsc. Alternatively, chrd expression is repressed by Bmp/Ventx1.1 in the ventral/epidermal region. However, the regulatory mechanisms underlying the transcription mediated by Gsc and Ventx1.1 remain elusive. Here, we found that the chrd promoter contained two cis-acting response elements that responded negatively to Ventx1.1 and positively to Gsc. In the ventral/ectodermal region, Ventx1.1 was directly bound to the Ventx1.1 response element (VRE) and inhibited chrd transcription. In the organizer region, Gsc was bound to the Gsc response elements (GRE) to activate chrd transcription. The Gsc-mediated positive response on the chrd promoter completely depended on another adjacent Wnt response cis-acting element (WRE), which was the TCF7 (also known as Tcf1) binding element. Site-directed mutagenesis of VRE, GRE, or WRE completely abolished the repressive or activator activity of Ventx1.1 and Gsc, respectively. The ChIP-PCR results confirmed the direct binding of Ventx1.1 and Gsc/Tcf7 to VRE and GRE/WRE, respectively. These results demonstrated that chrd expression is oppositely modulated by homeobox TFs, Ventx1.1, and Gsc/Tcf7 during the embryonic patterning of Xenopus gastrula. [ABSTRACT FROM AUTHOR]

The stability of a class of neural networks (NNs) with time-varying delay is explored in this work. The characteristics of integral inequalities are considered, and the general stability condition (GSC) of delayed NNs avoiding high-order delay is given in the form of quadratic functions. For the GSC of NNs, under the number of decision variables remains unchanged, the information of time-delay and its derivatives are further excavated by delay-partitioning approach. Meanwhile, the free-moving points are established in each subintervals divided, and the traditional static constraints are transformed into dynamic constraints, which relaxes the feasibility space. Based on these methods, the improved stability criteria are given. Finally, two examples are provided to illustrate the meliority of the method under the same number of decision variables. [ABSTRACT FROM AUTHOR]

Abstract Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults exhibiting infiltration into surrounding tissues, recurrence, and resistance to therapy. GBM infiltration is accomplished by many deregulated factors such as cell adhesion molecules (CAMs), which are membrane proteins that participate in cell-cell and cell-ECM interactions to regulate survival, proliferation, migration, and stemness. Methods A comprehensive bioinformatics analysis of CAMs (n = 518) in multiple available datasets revealed genetic and epigenetic alterations among CAMs in GBM. Univariate Cox regression analysis using TCGA dataset identified 127 CAMs to be significantly correlated with survival. The poor prognostic indicator PTGFRN was chosen to study its role in glioma. Silencing of PTGFRN in glioma cell lines was achieved by the stable expression of short hairpin RNA (shRNA) against the PTGFRN gene. PTGFRN was silenced and performed cell growth, migration, invasion, cell cycle, and apoptosis assays. Neurosphere and limiting dilution assays were also performed after silencing of PTGFRN in GSCs. Results Among the differentially regulated CAMs (n = 181, 34.9%), major proportion of them were found to be regulated by miRNAs (n = 95, 49.7%) followed by DNA methylation (n = 32, 16.7%), and gene copy number variation (n = 12, 6.2%). We found that PTGFRN to be upregulated in GBM tumor samples and cell lines with a significant poor prognostic correlation with patient survival. Silencing PTGFRN diminished cell growth, colony formation, anchorage-independent growth, migration, and invasion and led to cell cycle arrest and induction of apoptosis. At the mechanistic level, silencing of PTGFRN reduced pro-proliferative and promigratory signaling pathways such as ERK, AKT, and mTOR. PTGFRN upregulation was found to be due to the loss of its promoter methylation and downregulation of miR-137 in GBM. PTGFRN was also found to be higher in glioma stem-like cells (GSCs) than the matched differentiated glioma cells (DGCs) and is required for GSC growth and survival. Silencing of PTGFRN in GSCs reduced transcript levels of reprogramming factors (Olig2, Pou3f2, Sall2, and Sox2). Conclusion In this study, we provide a comprehensive overview of the differential regulation of CAMs and the probable causes for their deregulation in GBM. We also establish an oncogenic role of PTGFRN and its regulation by miR-137 in GBM, thus signifying it as a potential therapeutic target.

Glioblastoma (GBM) is one of the most lethal cancers, having a poor prognosis and a median survival of only about 15 months with standard treatment (surgery, radiation, and chemotherapy), which has not been significantly extended in decades. GBM demonstrates remarkable cellular heterogeneity, with glioblastoma stem-like cells (GSCs) at the apex. GSCs are a subpopulation of GBM cells that possess the ability to self-renew, differentiate, initiate tumor formation, and manipulate the tumor microenvironment (TME). GSCs are no longer considered a static population of cells with specific markers but are quite flexible phenotypically and in driving tumor heterogeneity and therapeutic resistance. In light of these features, they are a critical target for successful GBM therapy. Oncolytic viruses, in particular oncolytic herpes simplex viruses (oHSVs), have many attributes for therapy and are promising agents to target GSCs. oHSVs are genetically-engineered to selectively replicate in and kill cancer cells, including GSCs, but not normal cells. Moreover, oHSV can induce anti-tumor immune responses and synergize with other therapies, such as chemotherapy, DNA repair inhibitors, and immune checkpoint inhibitors, to potentiate treatment effects and reduce GSC populations that are partly responsible for chemo- and radio-resistance. Herein, we present an overview of GSCs, activity of different oHSVs, clinical trial results, and combination strategies to enhance efficacy, including therapeutic arming of oHSV. Throughout, the therapeutic focus will be on GSCs and studies specifically targeting these cells. Recent clinical trials and approval of oHSV G47Δ in Japan for patients with recurrent glioma demonstrate the efficacy and promise of oHSV therapy.

This paper presents a comparative study between the conventional PI (Proportional Integral) and backstepping controllers applied to the DFIG (Doubly Fed Induction Generator) used in WECS (Wind Energy Conversion System). These two different control strategies proposed in this work are developed to control the active and reactive power of the DFIG on the one hand, and to maintain the DC-link voltage constant for the inverting function on the other hand. This is ensured by generating control signals for two power electronic converters, RSC (Rotor Side Converter) and GSC (Grid Side Converter). In order to optimise the power production in the WT (Wind Turbine), an MPPT (Maximum Power Point Tracking) algorithm is applied along with each control technique. To simulate the effectiveness of the proposed controllers, MATLAB/Simulink Software is used, and the obtained results are analysed and discussed to compare PI and backstepping controllers in terms of robustness against wind speed variations and tracking performance in dynamic and steady states. [ABSTRACT FROM AUTHOR]

Recent studies have shown that mitochondrial morphology can modulate organelle function and greatly affect stem cell behavior, thus affecting tissue homeostasis. As such, we previously showed that the accumulation of fragmented mitochondria in aged Drosophila ovarian germline stem cells (GSCs) contributes to age‐dependent GSC loss. However, standard immunofluorescence methods to examine mitochondrial morphology yield images with insufficient resolution for rigorous analysis, while 3‐dimensional electron microscopy examination of mitochondrial morphology is labor intensive and allows only limited sampling of mitochondria. To overcome these issues, we utilized the expansion microscopy technique to expand GSC samples by 4‐fold in combination with mitochondrial immunofluorescence labeling. Here, we present a simple, inexpensive method for nanoscale optical imaging of mitochondria in the germline. This protocol may be beneficial for studies that require visualization of mitochondria or other fine subcellular structures in the Drosophila ovary. [ABSTRACT FROM AUTHOR]

Land surface temperature (LST) is a fundamental variable of environmental monitoring and surface equilibrium. Although the HJ-1B infrared scanner (IRS) has accumulated many observations, further application of HJ-1B/IRS is limited by the lack of LST products. This study refined the ERA5 atmospheric profile database, instead of the widely used traditional TIGR atmospheric profile database, and simulated the coefficients of the generalized single-channel (GSCs) algorithms to improve LST retrieval. GSCs can be divided into the GSCw and GSCwT algorithms, depending on whether the input is atmospheric water vapor content (WVC) or in situ near-surface air temperature and WVC. Land surface emissivity (LSE) was obtained from the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) Global Emissivity Dataset (GED) and vegetation/snow cover products. Then, the retrieved LSTs were evaluated using the LSTs from the RTE algorithm, TIGRw/TIGRwT profiles, and in situ near-surface air temperature from the HiWATER experiment in China from 2012 to 2014. The bias (root mean square error (RMSE)) values are displayed as ERA5wT < RTE < ERA5w < TIGRwT < TIGRw. The accuracy of ERA5wT, with a bias (RMSE) of 0.02 K (2.30 K), is higher than that of RTE, with a bias (RMSE) of 0.74 K (2.47 K). The accuracy of RTE is preferable to that of ERA5w, with a bias (RMSE) of 0.89 K (2.48 K), followed by TIGRwT, with a bias (RMSE) of −1.18 K (2.50 K), and then, TIGRw, with a bias (RMSE) of 1.60 K (2.77 K). In summary, the accuracy of LST obtained by GSC from the refined ERA5 atmospheric profiles is higher than that obtained from the TIGR profiles. The accuracy of LST obtained by GSCwT is greater than that obtained by GSCw. The accuracy of LST obtained using in situ near-surface air temperature is higher than that obtained using ERA5 air temperature. The accuracy of LSEASTER is slightly better than that of LSEMOD21. The aforementioned conclusions can provide scientific support to generate HJ-1B/IRS LST products.

The article presents the design and development of invasive weed optimization (IWO) for the sensor less speed control of doubly fed induction generator (DFIG) under balanced and unbalanced conditions. A healthy condition represents the balanced condition while unbalancing condition is characterized by unhealthy conditions like three-phase fault, single line to ground fault, the line-to-line fault, and double line to ground fault. The DFIG is driven by wind and integrated with the grid. The advantages associated with IWO technique are a simple mathematical approach and less data computation. Normally, DFIG consists of two back-to-back converters namely grid side converter (GSC) and rotor side converter (RSC). The GSC is an uncontrolled converter while the RSC is a controlled converter. The existing methods have poor performance parameters like settling time, peak overshoot for balanced conditions, and poor power quality parameters like total harmonic distortion (THD) for unbalanced conditions. An IWO technique has been applied to overcome such limitations. The effectiveness of the sensor less speed control is also analyzed with other techniques like Adaptive Neuro-Fuzzy Interference System (AN-FIS) & artificial neural network (ANN). The design of ANN is based on the feed-forward method using back propagation delay and the design of ANFIS is based on adaptive control and state space control strategy. It is observed that performance parameters like peak overshoot and settling time for the sensor less speed of DFIG are found to be more profound with IWO in comparison to ANFIS, ANN, and other existing techniques for balanced conditions. Similarly in the unbalanced condition, faulty current approaches are quite closer to their healthy state with the IWO method in comparison to other methods. In addition to this, minimum distortion (%THD) for the grid current under unbalanced conditions is also attained with IWO in comparison to ANFIS, ANN, and other existing techniques. Such application of IWO makes the system highly efficient and robust.

Background: Data on Afirma's genomic sequencing classifier (GSC) performance in atypia of undetermined significance (AUS) subcategories is limited. This study investigated GSC performance in AUS nodules with architectural atypia (AUS‐A), cytological atypia (AUS‐C), architectural and cytological atypia (AUS‐AC), and predominantly Hürthle cells (AUS‐HC). Methods: This study retrieved consecutive thyroid nodules having a recurrent cytologic diagnosis of AUS with qualifiers and a concurrent GSC diagnostic result. All nodules were followed by either surgical intervention or clinical and/or ultrasound monitoring (≥6 months). GSC benign call rate (BCR), rate of histology‐proven malignancy, and diagnostic parameters of GSC were calculated for individual AUS subcategories. Statistical analysis was performed using the Fisher exact test. Results: A total of 135 AUS nodules fulfilled inclusion criteria, including 79 AUS‐A, 9 AUS‐C, 29 AUS‐AC, and 18 AUS‐HC. BCR was 72.2%, 66.7%, 44.8%, and 77.8% in AUS‐A, AUS‐C, AUS‐AC, and AUS‐HC, respectively. AUS‐A showed a greater BCR than AUS‐AC (p <.05). All GSC‐benign nodules were considered benign on clinical or surgical follow‐up. Among GSC‐suspicious nodules, histology‐proven malignancies represented 4.5% of AUS‐A, 0% of AUS‐C, 56.3% of AUS‐AC, and 25.0% of AUS‐HC cases. AUS‐AC demonstrated a higher malignant rate compared with AUS‐A (p <.05). GSC offers 100% NPV and a wide range (5%–56%) of PPV across all AUS subcategories. AUS‐AC demonstrated a greater PPV compared with AUS‐A (p <.05). Conclusion: BCR of GSC and malignant rates associated with suspicious GSC may differ in various AUS subcategories. GSC‐suspicious nodules with both architectural and cytologic atypia are more likely to be malignant. These findings may improve clinical triage and/or management of patients with AUS thyroid nodules. Benign call rate of Afirma genomic sequencing classifier (GSC) testing may differ among atypia of undetermined significance subcategories. GSC‐suspicious nodules with both architectural and cytologic atypia are more likely to be malignant. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) patients exhibit high mortality and recurrence rates despite multimodal therapy. Small nucleolar RNA host genes (SNHGs) are a group of long noncoding RNAs that perform a wide range of biological functions. We aimed to reveal the role of SNHGs in GBM subtypes, cell infiltration into the tumor microenvironment (TME), and stemness characteristics. SNHG interaction patterns were determined based on 25 SNHGs and systematically correlated with GBM subtypes, TME and stemness characteristics. The SNHG interaction score (SNHGscore) model was generated to quantify SNHG interaction patterns. The high SNHGscore group was characterized by a poor prognosis, the mesenchymal (MES) subtype, the infiltration of suppressive immune cells and a differentiated phenotype. Further analysis indicated that high SNHGscore was associated with a weaker response to anti-PD-1/L1 immunotherapy. Tumor cells with high SNHG scores were more sensitive to drugs targeting the EGFR and ERK-MAPK signaling pathways. Finally, we assessed SNHG interaction patterns in multiple cancers to verify their universality. This is a novel and comprehensive study that provides targeted therapeutic strategies based on SNHG interactions. Our work highlights the crosstalk and potential clinical utility of SNHG interactions in cancer therapy. [ABSTRACT FROM AUTHOR]

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR ( p 53 I nactivating T RIM28 A ssociated R NA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR , in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28 -dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR , which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target., Competing Interests: SJ, MM, SM, BG, KP, LK, NJ, AC, VS, CK No competing interests declared, KS Reviewing editor, eLife, (© 2023, Jana et al.)

Rationale: Glioma stem cells (GSCs) have emerged as pivotal drivers of tumor malignancy, sustained by various microenvironmental factors, including immune molecules and hypoxia. In our previous study, we elucidated the significant role of transforming growth factor beta-induced protein (TGFBI), a protein secreted by M2-like tumor-associated macrophages, in promoting the malignant behavior of glioblastoma (GBM) under normoxic conditions. Building upon these findings, the objective of this study was to comprehensively explore the crucial role and underlying mechanisms of autocrine TGFBI in GSCs under hypoxic conditions. Methods: We quantified TGFBI expression in glioma specimens and datasets. In vitro and in vivo assays were employed to investigate the effects of TGFBI on sustaining self-renewal and tumorigenesis of GSCs under hypoxia. RNA-seq and LC-MS/MS were conducted to explore TGFBI signaling mechanisms. Results: TGFBI is preferentially expressed in GSCs under hypoxic conditions. Targeting TGFBI impair GSCs self-renewal and tumorigenesis. Mechanistically, TGFBI was upregulated by HIF1α in GSCs and predominantly activates the AKT-c-MYC signaling pathway in GSCs by stabilizing the EphA2 protein through preventing its degradation. Conclusion: TGFBI plays a crucial role in maintaining the stem cell properties of GSCs in the hypoxic microenvironment. Targeting the TGFBI/EphA2 axis emerges as a promising and innovative strategy for GBM treatment, with the potential to improve the clinical outcomes of patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The current prognosis for glioblastoma is dismal. Treatment-resistant glioblastoma stem cells (GSCs) and the failure of most drugs to reach therapeutic levels within the tumor remain formidable obstacles to successful treatment. Chalcones are aromatic ketones demonstrated to reduce malignant properties in cancers including glioblastoma. Nanomedicines can increase drug accumulation and tumor cell death. Carbon-dots are promising nanocarriers that can be easily functionalized with tumor-targeting ligands and anti-cancer drugs. Therefore, we synthesized a series of 4′-amino chalcones with the rationale that the amino group would serve as a "handle" to facilitate covalent attachment to carbon-dots and tested their cytotoxicity toward GSCs. We generated 31 chalcones (22 4′-amino and 9 4′ derivatives) including 5 novel chalcones, and found that 13 had an IC50 below 10 µM in all GSC lines. After confirming that the 4-amino group was not part of the active pharmacophore, chalcones were attached to transferrin-conjugated carbon-dots. These conjugates were significantly more cytotoxic than the free chalcones, with the C-dot-transferrin-2,5, dimethoxy chalcone conjugate inducing up to 100-fold more GSC death. Several of the tested chalcones represent promising lead compounds for the development of novel anti-GSC drugs. Furthermore, designing amino chalcones for carbon-dot mediated drug delivery is a rational and effective methodology. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults exhibiting infiltration into surrounding tissues, recurrence, and resistance to therapy. GBM infiltration is accomplished by many deregulated factors such as cell adhesion molecules (CAMs), which are membrane proteins that participate in cell-cell and cell-ECM interactions to regulate survival, proliferation, migration, and stemness. Methods: A comprehensive bioinformatics analysis of CAMs (n = 518) in multiple available datasets revealed genetic and epigenetic alterations among CAMs in GBM. Univariate Cox regression analysis using TCGA dataset identified 127 CAMs to be significantly correlated with survival. The poor prognostic indicator PTGFRN was chosen to study its role in glioma. Silencing of PTGFRN in glioma cell lines was achieved by the stable expression of short hairpin RNA (shRNA) against the PTGFRN gene. PTGFRN was silenced and performed cell growth, migration, invasion, cell cycle, and apoptosis assays. Neurosphere and limiting dilution assays were also performed after silencing of PTGFRN in GSCs. Results: Among the differentially regulated CAMs (n = 181, 34.9%), major proportion of them were found to be regulated by miRNAs (n = 95, 49.7%) followed by DNA methylation (n = 32, 16.7%), and gene copy number variation (n = 12, 6.2%). We found that PTGFRN to be upregulated in GBM tumor samples and cell lines with a significant poor prognostic correlation with patient survival. Silencing PTGFRN diminished cell growth, colony formation, anchorage-independent growth, migration, and invasion and led to cell cycle arrest and induction of apoptosis. At the mechanistic level, silencing of PTGFRN reduced pro-proliferative and promigratory signaling pathways such as ERK, AKT, and mTOR. PTGFRN upregulation was found to be due to the loss of its promoter methylation and downregulation of miR-137 in GBM. PTGFRN was also found to be higher in glioma stem-like cells (GSCs) than the matched differentiated glioma cells (DGCs) and is required for GSC growth and survival. Silencing of PTGFRN in GSCs reduced transcript levels of reprogramming factors (Olig2, Pou3f2, Sall2, and Sox2). Conclusion: In this study, we provide a comprehensive overview of the differential regulation of CAMs and the probable causes for their deregulation in GBM. We also establish an oncogenic role of PTGFRN and its regulation by miR-137 in GBM, thus signifying it as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary brain malignancy in adults with a dismal prognosis. Despite advances in genomic analysis and surgical technique and the development of targeted therapeutics, most treatment options are ineffective and mainly palliative. Autophagy is a form of cellular self-digestion with the goal of recycling intracellular components to maintain cell metabolism. Here, we describe some recent findings that suggest GBM tumors are more sensitive to the excessive overactivation of autophagy leading to autophagy-dependent cell death. GBM cancer stem cells (GSCs) are a subset of the GBM tumor population that play critical roles in tumor formation and progression, metastasis, and relapse, and they are inherently resistant to most therapeutic strategies. Evidence suggests that GSCs are able to adapt to a tumor microenvironment of hypoxia, acidosis, and lack of nutrients. These findings have suggested that autophagy may promote and maintain the stem-like state of GSCs as well as their resistance to cancer treatment. However, autophagy is a double-edged sword and may have anti-tumor properties under certain conditions. The role of the STAT3 transcription factor in autophagy is also described. These findings provide the basis for future research aimed at targeting the autophagy-dependent pathway to overcome the inherent therapeutic resistance of GBM in general and to specifically target the highly therapy-resistant GSC population through autophagy regulation.

Glioblastoma (GBM) continues to be the most devastating primary brain malignancy. Despite significant advancements in understanding basic GBM biology and enormous efforts in developing new therapeutic approaches, the prognosis for most GBM patients remains poor with a median survival time of 15 months. Recently, the interplay between the SOX (SRY-related HMG-box) genes and lncRNAs (long non-coding RNAs) has become the focus of GBM research. Both classes of molecules have an aberrant expression in GBM and play essential roles in tumor initiation, progression, therapy resistance, and recurrence. In GBM, SOX and lncRNAs crosstalk through numerous functional axes, some of which are part of the complex transcriptional and epigenetic regulatory mechanisms. This review provides a systematic summary of current literature data on the complex interplay between SOX genes and lncRNAs and represents an effort to underscore the effects of SOX/lncRNA crosstalk on the malignant properties of GBM cells. Furthermore, we highlight the significance of this crosstalk in searching for new biomarkers and therapeutic approaches in GBM treatment.

The reciprocal inhibition between two signaling centers, the Spemann organizer (dorsal mesoderm) and ventral region (mesoderm and ectoderm), collectively regulate the overall development of vertebrate embryos. Each center expresses key homeobox transcription factors (TFs) that directly control target gene transcription. Goosecoid (Gsc) is an organizer (dorsal mesoderm)-specific TF known to induce dorsal fate and inhibit ventral/ectodermal specification. Ventx1.1 (downstream of Bmp signaling) induces the epidermal lineage and inhibits dorsal organizer-specific genes from the ventral region. Chordin (Chrd) is an organizer-specific secreted Bmp antagonist whose expression is primarily activated by Gsc. Alternatively, chrd expression is repressed by Bmp/Ventx1.1 in the ventral/epidermal region. However, the regulatory mechanisms underlying the transcription mediated by Gsc and Ventx1.1 remain elusive. Here, we found that the chrd promoter contained two cis-acting response elements that responded negatively to Ventx1.1 and positively to Gsc. In the ventral/ectodermal region, Ventx1.1 was directly bound to the Ventx1.1 response element (VRE) and inhibited chrd transcription. In the organizer region, Gsc was bound to the Gsc response elements (GRE) to activate chrd transcription. The Gsc-mediated positive response on the chrd promoter completely depended on another adjacent Wnt response cis-acting element (WRE), which was the TCF7 (also known as Tcf1) binding element. Site-directed mutagenesis of VRE, GRE, or WRE completely abolished the repressive or activator activity of Ventx1.1 and Gsc, respectively. The ChIP-PCR results confirmed the direct binding of Ventx1.1 and Gsc/Tcf7 to VRE and GRE/WRE, respectively. These results demonstrated that chrd expression is oppositely modulated by homeobox TFs, Ventx1.1, and Gsc/Tcf7 during the embryonic patterning of Xenopus gastrula.

Background Analysis of cytologically indeterminate thyroid nodules with Afirma Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) can reduce surgical rate and increase malignancy rate of surgically resected indeterminate nodules. Methods Retrospective cohort analysis of all adults with cytologically indeterminate thyroid nodules from January 2013 through December 2019. We compared surgical and malignancy rates of those without molecular testing to those with GEC or GSC, analyzed test performance between GEC and GSC, and identified variables associated with molecular testing. Results 468 indeterminate thyroid nodules were included. No molecular testing was performed in 273, 71 had GEC, and 124 had GSC testing. Surgical rate was 68% in the group without molecular testing, 59% in GEC, and 40% in GSC. Malignancy rate was 20% with no molecular testing, 22% in GEC, and 39% in GSC (P = 0.022). GEC benign call rate (BCR) was 46%; sensitivity, 100%; specificity, 61%; and positive predictive value (PPV), 28%. GSC BCR was 60%; sensitivity, 94%; specificity, 76%; and PPV, 41%. Those with no molecular testing had larger nodule size, preoperative growth of nodules, and constrictive symptoms and those who underwent surgery in the no molecular testing group had higher body mass index, constrictive symptoms, higher Thyroid Imaging Reporting and Data System and Bethesda classifications. Type of provider was also associated with the decision to undergo surgery. Conclusion Implementation of GEC showed no effect on surgical or malignancy rate, but GSC resulted in significantly lower surgical and higher malignancy rates. This study provides insight into the factors that affect the real-world use of these molecular markers preoperatively in indeterminate thyroid nodules. [ABSTRACT FROM AUTHOR]

The stem cell niche, a regulatory microenvironment, houses and regulates stem cells for maintenance of tissues throughout an organism’s lifespan. While it is known that stem cell function declines with age, the role of niche cells in this decline is not completely understood. Drosophila exhibits a short lifespan with well-characterized ovarian germline stem cells (GSCs) and niche compartments, providing a good model with which to study stem cell biology. However, no inducible tools for temporal and spatial control of gene expression in the GSC-niche unit have been previously developed for aging studies. The current UAS-GAL4 systems are not ideal for aging studies because fly physiological aging may be affected by the temperature shifts used to manipulate GAL4 activity. Additionally, the actual needs of the aged niche may be masked by continuously driven gene expression. Since GeneSwitch GAL4 is conveniently activated by the steroid RU486 (mifepristone), we conducted an enhancer-trap screen to isolate GeneSwitch GAL4 lines with expression in the GSC-niche unit. We identified six lines with expression in germarial somatic cells, and two lines (#2305 and #2261) with expression in niche cap cells, the major constituent of the GSC niche. The use of lines #2305 or #2261 to overexpress Drosophila insulin-like peptide 2, which maintains GSC lifespan, in aged niche cap cells significantly delayed age-dependent GSC loss. These results support the notion that insulin signaling is beneficial for maintaining aged stem cells and also validate the utility of our GeneSwitch GAL4 lines for studying stem cell aging.

Under unbalanced grid condition, in a Doubly-Fed Induction Generator (DFIG), voltage, current, and flux of the stator become asymmetric. Therefore, active-reactive power and torque will be oscillating. In DFIG controlling Rotor Side Converter (RSC) aims to eliminate power and torque oscillations. However, simultaneous elimination of the power and torque oscillations is not possible. Also, Grid Side Converter (GSC) aims to regulate DC-Link voltage. In this paper, in order to regulate DC-Link voltage, an Extended State Observer (ESO) based on a Generalized ProportionalIntegral (GPI) controller, is employed. In this controlling method, DC-Link voltage is controlled without measuring the GSC current, and due to using the GPI controller, the improved dynamic response is resistant against voltage changes, and the settling time is reduced. To improve the transient stability and Low Voltage Fault Ride Through (LVRT) capability of DFIG, Statistic Fault Current Limiter (S-FCL) and Magnetic Energy Storage Fault Current Limiter (MES-FCL) are proposed in this paper. The proposed FCL does not only limit the fault current but also fasten voltage recovery. The simulations are implemented by MATLAB software in the synchronous positive and negative sequence reference (d-q). [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs’ stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs.

Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs' stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs. [ABSTRACT FROM AUTHOR]

This paper describes a voltage control scheme of a doubly fed induction generator (DFIG) wind turbine that can inject more reactive power to the grid during a fault so as to support the grid voltage. To achieve this, the coordinated control scheme using both rotor side converter (RSC) and grid side converters (GSC) controllers of the DFIG are employed simultaneously. The RSC and GSC controllers employ PI controller to operate smoothly. In the voltage control mode, the RSC and GSC are operated. During a fault, both RSC and GSC are used simultaneously to supply the reactive power into the grid (main line) depending on voltage dip condition to support the grid voltage. The proposed system is implemented for single DFIG wind turbine using MATLAB simulation software. The results illustrate that the control strategy injects the reactive power to support the voltage stability during a fault rapidly. Also, the braking system is designed to protect the wind turbine system from over speed. For this purpose, the braking resistors are being used. [ABSTRACT FROM AUTHOR]

Background: Diffuse midline gliomas (DMG) are pediatric tumors with negligible 2-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease, all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients. Current clues as to what causes tumor infiltration circle mainly around the tumor microenvironment, but there are currently no known determinants to predict the degree of invasiveness., Methods: In this study, we use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model interindividual invasion and elucidate the cellular supporting mechanisms., Results: We show that GSC models in 3D mirror the invasive behavior of the parental tumors, thus proving the ability of DMG to infiltrate as an autonomous characteristic of tumor cells. Furthermore, we distinguished 2 modes of migration, mesenchymal and ameboid-like, and associated the ameboid-like modality with GSCs derived from the most invasive tumors. Using transcriptomics of both organoids and primary tumors, we further characterized the invasive ameboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability driven by crucial over-expression of bone morphogenetic pathway 7 (BMP7). Finally, we deciphered MEK, ERK, and Rho/ROCK kinases activated downstream of the BMP7 stimulation as actionable targets controlling tumor cell motility., Conclusions: Our findings identify 2 new therapeutic avenues. First, patient-derived GSCs represent a predictive tool for patient stratification in order to adapt irradiation strategies. Second, autocrine and short-range BMP7-related signaling becomes a druggable target to prevent DMG spread and metastasis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Adult stem cells maintain tissue homeostasis. This unique capability largely depends on the stem cell niche, a specialized microenvironment, which preserves stem cell identity through physical contacts and secreted factors. In many cancers, latent tumor cell niches are thought to house stem cells and aid tumor initiation. However, in developing tissue and cancer it is unclear how the niche is established. The well-characterized germline stem cells (GSCs) and niches in the Drosophila melanogaster ovary provide an excellent model to address this fundamental issue. As such, we conducted a small-scale RNAi screen of 560 individually expressed UAS-RNAi lines with targets implicated in female fertility. RNAi was expressed in the soma of larval gonads, and screening for reduced egg production and abnormal ovarian morphology was performed in adults. Twenty candidates that affect ovarian development were identified and subsequently knocked down in the soma only during niche formation. Feminization factors (Transformer, Sex lethal, and Virilizer), a histone methyltransferase (Enhancer of Zeste), a transcriptional machinery component (Enhancer of yellow 1), a chromatin remodeling complex member (Enhancer of yellow 3) and a chromosome passenger complex constituent (Incenp) were identified as potentially functioning in the control of niche size. The identification of these molecules highlights specific molecular events that are critical for niche formation and will provide a basis for future studies to fully understand the mechanisms of GSC recruitment and maintenance.

Changes in mitochondrial dynamics (fusion and fission) are known to occur during stem cell differentiation; however, the role of this phenomenon in tissue aging remains unclear. Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging‐related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator, Dynamin‐related protein (Drp1), are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition. Overall, our results show that mitochondrial dynamics are altered during physiological aging, affecting stem cell homeostasis via coordinated changes in stemness signaling, niche contact, and cellular metabolism. Such effects may also be highly relevant to other stem cell types and aging‐induced tissue degeneration. [ABSTRACT FROM AUTHOR]