Signalling, desensitization and resensitization of neuromedin U receptors

The neuropeptides neuromedin U (NmU) and neuromedin S (NmS) show a high degree of conservation across species, primarily at the amidated C-terminus. NmU in particular is widely distributed in both the central nervous system and periphery and is involved in a plethora of physiological and pathological events. NmU and NmS mediate their actions via two family A, G protein-coupled receptors, NMU1 and NMU2, which share ~50% homology. The present study confirmed receptor coupling to Gαq/11, leading to increases in intracellular [Ca2+] and activation of extracellular signal-regulated protein kinase (ERK), as well as coupling to Gαi/o, leading to pertussis toxin-sensitive inhibition of adenylyl cyclase activity. This study also confirmed that different NmU analogues bind pseudo-irreversibly to recombinantly expressed NMUs and has shown receptor-dependent internalization of a fluorescently-tagged version of NmU. C-terminal eGFP-tagged NMUs showed co-internalization of ligand and receptor within ~2.5 min of ligand exposure. Cell-surface, receptor-bound ligand could be removed by a rapid (20 s), pH 2.0 washing without detrimental effect on signal transduction or cell viability, allowing examination of desensitization and resensitization in the absence of cell-surface, ligand-bound receptors. Desensitization of NMU2-mediated Ca2+ responses (that was independent of continued ligand binding) occurred within minutes of exposure to human (h) NmU-25. Acute exposure (5 min) to a maximum concentration of hNmU-25 followed by recovery in the absence (pH 2.0 wash) or the presence (pH 7.4 wash) of cell-surface, receptor-bound hNmU-25 showed that the continued presence of ligand markedly delayed receptor resensitization. Receptor internalization via a dynamin-dependent pathway was crucial for resensitization of NMU1 and NMU2. Further, resensitization was dependent on endosomal acidification, recycling and endothelin-converting enzyme-1 (ECE-1) activity, but not de novo protein synthesis. This suggests that processing of hNmU-25 by ECE-1 in acidified endosomes is critical for resensitization. Inhibition of ECE-1 also prolonged NMU-mediated ERK activation, suggesting G protein-independent signalling by a ligand-receptor dependent complex within endosomes. Although no significant differences were demonstrated in potency and signalling between the NMU subtypes or their ligands, resensitization (and potentially therefore G protein-dependent/independent signalling) was influenced by both the ligand (nature and length of the N-terminus) and the receptor (NMU1 versus NMU2).EThOS - Electronic Theses Online ServiceGBUnited Kingdo

An Enhanced Distributed Voltage Regulation Scheme for Radial Feeder in Islanded Microgrid

Even the simplest version of the distribution networks face challenges such as maintaining load voltage and system frequency stability and at the same time minimizing the circulating reactive power in grid-forming nodes. As the consumers at the far end of the radial distribution network face serious voltage fluctuations and deviations once the load varies. Therefore, this paper presents an enhanced distributed control strategy to restore the load voltage magnitude and to realize power-sharing proportionally in islanded microgrids. This proposed study considers the voltage regulation at the load node as opposed to the inverter terminal. At the same time, a supervisory control layer is put on to observe and correct the load voltage and system frequency deviations. This presented method is aimed at replacing paralleled inverter control methods hitherto used. Stability analysis using system-wide methodical small-signal models, the MATLAB/Simulink, and experimental results obtained with conventional and proposed control schemes verify the effectiveness of the proposed methodology

Augmenting the Stability of Automatic Voltage Regulators through Sophisticated Fractional-Order Controllers

The transition from traditional to renewable energy sources is a critical issue in current energy-generation systems, which aims to address climate change and the increased demand for energy. This shift, however, imposes additional burdens on control systems to maintain power system stability and quality within predefined limits. Addressing these challenges, this paper proposes an innovative Modified Hybrid Fractional-Order (MHFO) automatic voltage regulator (AVR) equipped with a fractional-order tilt integral and proportional derivative with a filter plus a second-order derivative with a filter FOTI-PDND2N2 controller. This advanced controller combines the benefits of a (FOTI) controller, known for enhancing dynamic performance and steady-state response, with a (PDND2N2) controller to improve system robustness and adaptability. The proposed MHFO controller stands out with its nine tunable parameters, providing more extensive control options than the conventional three-parameter PID controller and the five-parameter FOPID controller. Furthermore, a recent optimization approach using a growth optimizer (GO) has been formulated and applied to optimally adjust the MHFO controller’s parameters simultaneously. The performance of the proposed AVR based on the MHFO-GO controller is scrutinized by contrasting it with various established and developed optimization algorithms. The comparative study shows that the AVR based on the MHFO-GO controller surpasses other AVR controllers from the stability, robustness, and dynamic response speed points of view

An Accurate Model for Bifacial Photovoltaic Panels

Recently, there has been increasing concerns over bifacial PV (BPV) modules over the conventional monofacial PV (MPV) modules owing to their potential to add extra electrical energy from their rear-side irradiance. However, adding the rear-side irradiance to the front-side irradiance results in the increased nonlinearity of the BPV modules compared to MPV modules. Such nonlinearity makes the conventional methods unable to accurately extract the BPV module parameters. In this context, the precise determination of the BPV module parameters is a crucial issue for establishing energy yield estimations and for the proper planning of BPV installations as well. This paper proposes a new model for the BPV modules based on the MPV modeling, in which a new parameter is added to the MPV model to adjust the value of the model series resistance in order to provide a generic model for BPV modules in both monofacial and bifacial operating regions. Moreover, a new determination method for optimizing BPV model parameters using the recently developed enhanced version of the success-history-based adaptive differential evolution (SHADE) algorithm with linear population size reduction, known as the LSHADE method, is applied. The determination process of the model parameters is adapted using a two-stage optimization scheme to model the full operating range of BPV modules. The accuracy of the obtained parameters using the proposed model is compared with the conventional single-diode and double-diode models of the BPV. The obtained results using the proposed model of the BPV module show the performance superiority and accuracy of the LSHADE method over the existing methods in the literature. Furthermore, the LSHADE method provides the successful and accurate extraction of the global optimized parameters to model MPV and BPV modules. Therefore, the proposed method can provide an accurate model for the whole operating range of BPV that would be beneficial for further studies of their economic and technical feasibility for wide installation plans

Gold-containing compound BDG-I inhibits the growth of A549 lung cancer cells through the deregulation of miRNA expression

Gold complex bis(diethyldithiocarbamato-gold(I)) bis(diphenylphosphino) methane (BDG-I) is cytotoxic toward different cancer cell lines. We compared the cytotoxic effect of BDG-I with that of cisplatin in the A549 lung cancer cell line. Additionally, we investigated the molecular mechanism underlying the toxic effect of BDG-I toward the A549 cell line and the identification of cancer-related miRNAs likely to be involved in killing the lung cancer cells. Further, X-ray crystallographic data of the compound were acquired. Using microarray, global miRNA expression profiling in BDG-I-treated A549 cells revealed 64 upregulated and 86 downregulated miRNAs, which targeted 4689 and 2498 genes, respectively. Biological network connectivity of the miRNAs was significantly higher for the upregulated miRNAs than for the downregulated miRNAs. Two of the 10 most upregulated miRNAs (hsa-mir-20a-5p and hsa-mir-15b-5p) were associated with lung cancer. AmiGo2 server and Panther pathway analyses indicated significant enrichment in transcription regulation of miRNA target genes that promote intrinsic kinase-mediated signaling, TGF-?, and GnRH signaling pathways, as well as oxidative stress responses. BDG-I crystal structure X-ray diffraction studies revealed gold?gold intramolecular interaction [Au?Au = 3.1198 (3) �] for a single independent molecule, reported to be responsible for its activity against cancer. Our present study sheds light on the development of novel gold complex with favorable anti-cancer therapeutic functionality.The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through the Research Project No. R5-16-02-14 .Scopu

Supplementary Material for: Hypomagnesemia in Hemodialysis Patients: Role of Proton Pump Inhibitors

<b><i>Background:</i></b> Recent observations have associated hypomagnesemia with increased risk of cardiovascular morbidity and mortality in hemodialysis patients. <b><i>Methods:</i></b> We did a 3-month chart review of 62 chronic hemodialysis patients at a single US hospital. All were dialyzed using a dialysate [Mg] of 0.75-1.0 mEq/l. Patients were divided into two groups: hypomagnesemic (mean predialysis plasma [Mg] <1.5 mEq/l) and non-hypomagnesemic (mean predialysis plasma [Mg] ≥1.5 mEq/l). <b><i>Results:</i></b> All patients were male; mean age was 64.3 ± 8.7 years and the majority (73%) diabetic. 24 patients (39%) had hypomagnesemia and 38 (61%) were not hypomagnesemic. There were no significant differences between the two groups in age, diabetes status, blood pressure, duration of dialysis, plasma calcium, phosphorus, albumin, intact parathyroid hormone (PTH), dialysis adequacy (Kt/V), or dietary protein intake (as estimated by normalized protein catabolic rate, nPCR). However, use of proton pump inhibitors (PPIs) was significantly associated with hypomagnesemia (plasma [Mg] 1.48 ± 0.16 mEq/l in the PPI group vs. 1.65 ± 0.26 mEq/l in the non-PPI group, p = 0.007). Adjustment for age, diabetes status, duration of dialysis, plasma albumin, Kt/V, nPCR, and diuretic use did not affect the association between PPI use and hypomagnesemia. <b><i>Conclusions:</i></b> Use of PPIs in patients dialyzed using a dialysate [Mg] of 0.75-1.0 mEq/l is associated with hypomagnesemia. We suggest monitoring plasma [Mg] in patients taking PPIs, with discontinuation of the medication if possible and/or adjustment of dialysate [Mg] to normalize plasma [Mg]

Gold-containing compound BDG-I inhibits the growth of A549 lung cancer cells through the deregulation of miRNA expression

Gold complex bis(diethyldithiocarbamato-gold(I)) bis(diphenylphosphino) methane (BDG-I) is cytotoxic toward different cancer cell lines. We compared the cytotoxic effect of BDG-I with that of cisplatin in the A549 lung cancer cell line. Additionally, we investigated the molecular mechanism underlying the toxic effect of BDG-I toward the A549 cell line and the identification of cancer-related miRNAs likely to be involved in killing the lung cancer cells. Further, X-ray crystallographic data of the compound were acquired. Using microarray, global miRNA expression profiling in BDG-I-treated A549 cells revealed 64 upregulated and 86 downregulated miRNAs, which targeted 4689 and 2498 genes, respectively. Biological network connectivity of the miRNAs was significantly higher for the upregulated miRNAs than for the downregulated miRNAs. Two of the 10 most upregulated miRNAs (hsa-mir-20a-5p and hsa-mir-15b-5p) were associated with lung cancer. AmiGo2 server and Panther pathway analyses indicated significant enrichment in transcription regulation of miRNA target genes that promote intrinsic kinase-mediated signaling, TGF-β, and GnRH signaling pathways, as well as oxidative stress responses. BDG-I crystal structure X-ray diffraction studies revealed gold–gold intramolecular interaction [Au…Au = 3.1198 (3) Å] for a single independent molecule, reported to be responsible for its activity against cancer. Our present study sheds light on the development of novel gold complex with favorable anti-cancer therapeutic functionality. Keywords: Lung cancer, Chrysotherapeutic agents, Gold, miRN

Dysregulation of Ki-67 Expression in T Cells of Children with Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral abnormalities such as impairments in social function and deficits in communication. The etiology of autism is unknown in most cases, but many studies have pointed towards the immune system as a causative agent in autism. Specific studies implicated lymphocytes, natural killer (NK) cells, monocytes, cytokines, and specific transcription factors in the development of ASD. The protein Ki-67 is n expressed in the proliferating cells and is used as a tool in several disorders. Ki-67 plays a crucial role in many neurological diseases. However, Ki-67 role in ASD is not fully understood. In this study, we investigated the possible role of Ki-67 expression in autistic children. We compared Ki-67 production in CD3+, CD4+, CD8+, CXCR4+, CXCR7+, CD45R+, HLA-DR+, GATA3+, Helios+, and FOXP3+ peripheral blood mononuclear cells (PBMCs) in autistic children to typically developing (TD) controls using immunofluorescence staining. We also determined Ki-67 mRNA levels in PBMCs using RT–PCR. The results revealed that autistic children had significantly increased numbers of CD3+Ki-67+, CD4+Ki-67+, CD8+Ki-67+, CXCR4+Ki-67+, CXCR7+Ki-67+, CD45R+Ki-67+, HLA-DR+Ki-67+, CXCR4+GATA3+, GATA3+Ki-67+ cells and decreased Helios+Ki-67+ and FOXP3+Ki-67+ cells compared with TD controls. In addition, the autistic children showed upregulation of Ki-67 mRNA levels compared with TD controls. Further studies need to be carried out to assess the exact role of Ki-67 and its therapeutic potential in ASD

5-Aminoisoquinolinone, a PARP-1 Inhibitor, Ameliorates Immune Abnormalities through Upregulation of Anti-Inflammatory and Downregulation of Inflammatory Parameters in T Cells of BTBR Mouse Model of Autism

Autism spectrum disorder (ASD) covers a range of neurodevelopmental disorders involving impairments in communication and repetitive and stereotyped patterns of behavior and reciprocal social interaction. 5-Aminoisoquinolinone (5-AIQ), a PARP-1 inhibitor, has neuroprotective and anti-inflammatory effects. We investigated the influence of 5-AIQ-treatment in BTBR T+ Itpr3tf/J (BTBR) mice as an autism model and used flow cytometry to assess the effect of 5-AIQ on FOXP3, Helios, GATA3, IL-9, IL-10 and IL-17A production by CXCR6+ and CD4+ T cells in the spleen. We also confirmed the effect of 5-AIQ treatment on expression of FOXP3, Helios, GATA3, IL-17A, IL-10, and IL-9 mRNA and protein expression levels in the brain tissue by quantitative PCR and western blotting. Our results demonstrated that 5-AIQ-treated BTBR mice had significantly increased numbers of CXCR6+FOXP3+, CXCR6+IL-10+, and CXCR6+Helios+ cells and decreased numbers of CD4+GATA3+, CD4+IL-9+, and CD4+IL-17A+ cells as compared with those in untreated BTBR mice. Our results further demonstrated that treatment with 5-AIQ in BTBR mice increased expression for FOXP3, IL-10, and Helios, and decreased expression for GATA3, IL-17A, and IL-9 mRNA. Our findings support the hypotheses that 5-AIQ has promising novel therapeutic effects on neuroimmune dysfunction in autism and is associated with modulation of Treg and Th17 cells

Dysregulation of Ki-67 Expression in T Cells of Children with Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral abnormalities such as impairments in social function and deficits in communication. The etiology of autism is unknown in most cases, but many studies have pointed towards the immune system as a causative agent in autism. Specific studies implicated lymphocytes, natural killer (NK) cells, monocytes, cytokines, and specific transcription factors in the development of ASD. The protein Ki-67 is n expressed in the proliferating cells and is used as a tool in several disorders. Ki-67 plays a crucial role in many neurological diseases. However, Ki-67 role in ASD is not fully understood. In this study, we investigated the possible role of Ki-67 expression in autistic children. We compared Ki-67 production in CD3+, CD4+, CD8+, CXCR4+, CXCR7+, CD45R+, HLA-DR+, GATA3+, Helios+, and FOXP3+ peripheral blood mononuclear cells (PBMCs) in autistic children to typically developing (TD) controls using immunofluorescence staining. We also determined Ki-67 mRNA levels in PBMCs using RT–PCR. The results revealed that autistic children had significantly increased numbers of CD3+Ki-67+, CD4+Ki-67+, CD8+Ki-67+, CXCR4+Ki-67+, CXCR7+Ki-67+, CD45R+Ki-67+, HLA-DR+Ki-67+, CXCR4+GATA3+, GATA3+Ki-67+ cells and decreased Helios+Ki-67+ and FOXP3+Ki-67+ cells compared with TD controls. In addition, the autistic children showed upregulation of Ki-67 mRNA levels compared with TD controls. Further studies need to be carried out to assess the exact role of Ki-67 and its therapeutic potential in ASD