The DNA molecules that can be extracted from archaeological and palaeontological remains are often degraded and massively contaminated with environmental microbial material. This reduces the efficacy ...of shotgun approaches for sequencing ancient genomes, despite the decreasing sequencing costs of high‐throughput sequencing (HTS). Improving the recovery of endogenous molecules from the DNA extraction and purification steps could, thus, help advance the characterization of ancient genomes. Here, we apply the three most commonly used DNA extraction methods to five ancient bone samples spanning a ~30 thousand year temporal range and originating from a diversity of environments, from South America to Alaska. We show that methods based on the purification of DNA fragments using silica columns are more advantageous than in solution methods and increase not only the total amount of DNA molecules retrieved but also the relative importance of endogenous DNA fragments and their molecular diversity. Therefore, these methods provide a cost‐effective solution for downstream applications, including DNA sequencing on HTS platforms.
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colorectal area that demonstrates a dramatically increasing incidence worldwide. This study provides novel insights into the ...capacity of the exogenous β-hydroxybutyrate and ketogenic diet (KD) consumption to alleviate dextran sodium sulfate (DSS)-induced UC in rats. Remarkably, both interventions attenuated disease activity and colon weight-to-length ratio, and improved macro and microstructures of the damaged colon. Importantly, both β-hydroxybutyrate and KD curbed the DSS-induced aberrant NLRP3 inflammasome activation as observed in mRNA and protein expression analysis. Additionally, inhibition of the NLRP3/NGSDMD-mediated pyroptosis was detected in response to both regimens. In parallel, these modalities attenuated caspase-1 and its associated consequences of IL-1β and IL-18 overproduction. They also mitigated apoptosis as indicated by the inactivation of caspase-3. The anti-inflammatory effects of BHB and KD were confirmed by the reported decline in the levels of inflammatory markers including MPO, NFκB, IL-6, and TNF-α. Moreover, these interventions exhibited antioxidative properties by reducing ROS production and improving antioxidative enzymes. Their effectiveness in mitigating UC was also evident in the renovation of normal intestinal epithelial barrier function, as shown by correcting the discrepancies in the levels of tight junction proteins ZO-1, OCLN, and CLDN5. Furthermore, their effects on the intestinal microbiota homeostasis were investigated. In terms of autophagy, exogenous β-hydroxybutyrate upregulated BECN-1 and downregulated p62, which may account for its superiority over KD in attenuating colonic damage. In conclusion, this study provides experimental evidence supporting the potential therapeutic use of β-hydroxybutyrate or β-hydroxybutyrate-boosting regimens in UC.
This paper demonstrates an intruder detection system using a strain-based optical fiber Bragg grating (FBG), machine learning (ML), and adaptive thresholding to classify the intruder as no intruder, ...intruder, or wind at low levels of signal-to-noise ratio. We demonstrate the intruder detection system using a portion of a real fence manufactured and installed around one of the engineering college's gardens at King Saud University. The experimental results show that adaptive thresholding can help improve the performance of machine learning classifiers, such as linear discriminant analysis (LDA) or logistic regression algorithms in identifying an intruder's existence at low optical signal-to-noise ratio (OSNR) scenarios. The proposed method can achieve an average accuracy of 99.17% when the OSNR level is <0.5 dB.
Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by uncontrolled joint inflammation and damage to bone and cartilage. Previous studies have shown that chemokine receptors have ...important roles in RA development, and that blocking these receptors effectively inhibits RA progression. Our study was undertaken to investigate the role of AMG487, a selective CXCR3 antagonist, in DBA/1J mice bearing collagen-induced arthritis (CIA). Following induction of CIA, animals were treated with 5 mg/kg AMG487 intraperitoneally every 48 h, starting from day 21 until day 41 and evaluated for clinical score, and histological hallmarks of arthritic inflammation. We further investigated the effect of AMG487 on Th1 (T-bet), Th17 (IL-17A, RORγt, STAT3), Th22 (IL-22), and T regulatory (Treg; Foxp3 and IL-10) cells in splenic CXCR3+ and CD4+ T cells using flow cytometry. We also assessed the effect of AMG487 on T-bet, RORγt, IL-17A, IL-22, Foxp3, and IL-10 at both mRNA and protein levels using RT-PCR and Western blot analyses of knee samples. The severity of clinical scores, and histological inflammatory damage decreased significantly in AMG487-treated compared with CIA control mice. Moreover, the percentage of Th1, Th17, and Th22 cells decreased significantly and that of Treg cells increased in AMG487-treated mice. We further observed that AMG487-treatment downregulated T-bet, IL-17A, RORγt, and IL-22, whereas it upregulated Foxp3 and IL-10 mRNA and protein levels. This study demonstrates the antiarthritic effects of AMG487 in CIA animal model and supports the development of CXCR3 antagonists as a novel strategy for the treatment of inflammatory and arthritic conditions.
•We investigated the possible anti-arthritic effects of the CXCR3 antagonist AMG487.•Arthritis was induced with collagen intradermal injection into DBA/1 J mice.•AMG487 retarded arthritis development and progression.•AMG487 inhibited Th17/RORγt and STAT3 signaling pathways.•AMG487 regulated Th1/Treg-related transcription factors.
This article presents the performance evaluation of the frame-angle-based (FAB) direct torque controller (DTC) for <inline-formula><tex-math notation="LaTeX">3\phi</tex-math></inline-formula> ...induction motor drives (IMDs), which are fed by <inline-formula><tex-math notation="LaTeX">3\phi</tex-math></inline-formula> six-pulse wavelet-modulated (WM) dc-ac power electronic converters (PECs). The tested DTC is designed to adjust the <inline-formula><tex-math notation="LaTeX">d^{e}\text{- and }q^{e}</tex-math></inline-formula>-axis components of the voltages (<inline-formula><tex-math notation="LaTeX">v^{e}_{ds}</tex-math></inline-formula> and <inline-formula><tex-math notation="LaTeX">v^{e}_{qs}</tex-math></inline-formula>) applied to a <inline-formula><tex-math notation="LaTeX">3\phi</tex-math></inline-formula> IMD. The adjustments in <inline-formula><tex-math notation="LaTeX">v^{e}_{ds}</tex-math></inline-formula> and <inline-formula><tex-math notation="LaTeX">v^{e}_{qs}</tex-math></inline-formula> are created in response to changes in the load torque, command torque, drive speed, and/or system parameters. Desired adjustments in <inline-formula><tex-math notation="LaTeX">v^{e}_{ds}</tex-math></inline-formula> and <inline-formula><tex-math notation="LaTeX">v^{e}_{qs}</tex-math></inline-formula> are set by regulating the angle <inline-formula><tex-math notation="LaTeX">\vartheta</tex-math></inline-formula> of the frame created by <inline-formula><tex-math notation="LaTeX">v^{e}_{ds}</tex-math></inline-formula> and <inline-formula><tex-math notation="LaTeX">v^{e}_{qs}</tex-math></inline-formula>. This frame produces reference modulating signals that are required to generate WM switching pulses for operating the <inline-formula><tex-math notation="LaTeX">3\phi</tex-math></inline-formula> dc-ac PEC in the IMD. The complete IMD system, incorporating the FAB-DTC, is implemented for a 10-hp IMD system for performance evaluation. Tests of the FAB-DTC for the 10-hp IMD are conducted for various changes in the load torque, command torque, drive speed, and system parameters. Simulation and experimental test results demonstrate fast, accurate, reliable, and dynamic responses with minor sensitivity to variations in system parameters.
In this research, two novel series of dibenzob,fazepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric ...features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).
Highlights
Two novel series of dibenzob,fazepines were designed and synthesised based on the rigidification principle in drug design.
The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.
5e was the most active anti-topo II congener (IC
50
= 6.36 ± 0.36 µM).
5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC
50
= 13.05 ± 0.62 µM).
In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm
3
compared to doxorubicin treatment.
This article presents a performance comparison of the solid, low impedance, high impedance, frequency-selective, and isolated grounding systems. A grounding system (for any power system component) is ...designed as an impedance (<inline-formula><tex-math notation="LaTeX">\bar{Z}_{G}</tex-math></inline-formula>) that connects the neutral point to the ground. The impedance <inline-formula><tex-math notation="LaTeX">\bar{Z}_{G}</tex-math></inline-formula> is constructed using a combination of <inline-formula><tex-math notation="LaTeX">R</tex-math></inline-formula>, <inline-formula><tex-math notation="LaTeX">L</tex-math></inline-formula>, and <inline-formula><tex-math notation="LaTeX">C</tex-math></inline-formula> elements. The values and combination type (series or parallel) of <inline-formula><tex-math notation="LaTeX">R</tex-math></inline-formula>, <inline-formula><tex-math notation="LaTeX">L</tex-math></inline-formula>, and <inline-formula><tex-math notation="LaTeX">C</tex-math></inline-formula> determine the possible influence of <inline-formula><tex-math notation="LaTeX">\bar{Z}_{G}</tex-math></inline-formula> on ground currents and potentials. Each grounding system is related to a system voltages level, a specific combination of <inline-formula><tex-math notation="LaTeX">R</tex-math></inline-formula>, <inline-formula><tex-math notation="LaTeX">L</tex-math></inline-formula>, and <inline-formula><tex-math notation="LaTeX">C</tex-math></inline-formula>, and a range of <inline-formula><tex-math notation="LaTeX">R</tex-math></inline-formula>, <inline-formula><tex-math notation="LaTeX">L</tex-math></inline-formula>, and <inline-formula><tex-math notation="LaTeX">C</tex-math></inline-formula> values. The solid, low impedance, high impedance, frequency-selective, and isolated grounding systems are designed for a <inline-formula><tex-math notation="LaTeX">3\phi</tex-math></inline-formula> transformer and a <inline-formula><tex-math notation="LaTeX">3\phi</tex-math></inline-formula> synchronous generator in order to compare their influences on ground currents and potentials during ground faults. The transformer and generator are tested for line-to-ground and double line-to-ground faults with all designed grounding systems. Test results show that some grounding systems can reduce ground currents only, while others can reduce ground potentials only. Such capabilities can be used to fulfill certain system and operation requirements (e.g., service continuity, ground capacity, etc.).
•DCs and CNS have increased activation of NF-κB in EAE mice.•DCs and CNS have decreased Nrf2 signaling in EAE mice.•Nutraceutical compound AKBA attenuates NF-κB in brain/periphery of EAE mice.•AKBA ...activates Nrf2 signaling in brain and periphery of EAE mice.•AKBA ameliorates clinical symptoms in EAE mice.
Multiple sclerosis (MS) is characterized by chronic autoimmune inflammation of central nervous system (CNS), i.e. brain and spinal cord. Autoimmune inflammation of the CNS and periphery causes demyelination of axons ultimately leading to clinical symptoms such as gait imbalance, lack of coordination and paraplegia. Innate immune cells such as dendritic cells and neutrophils play a critical role in the initiation and progression of MS through upregulation of oxidants. Two prominent pathways that play important role in regulation of oxidant-antioxidant balance are nuclear factor-erythroid factor 2-related factor 2(Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Nrf2-mediated upregulation of antioxidants counteracts NF-κB-mediated oxidant generation. Therefore, this study evaluated the effects of nutraceutical drug, acetyl-11-keto-β-boswellic acid (AKBA) in relapsing remitting model of experimental autoimmune encephelomyelitis (EAE). Efficacy of AKBA was explored on clinical symptoms, Nrf2, hemeoxygenase-1 (HO-1), NF-κB, inducible nitric oxide synthase (iNOS) in CNS and periphery of SJL/J mice. Our results show that expression of p-NF-κB and iNOS is elevated, whereas expression of Nrf2 and HO-1 is decreased in CD11c + DCs and CNS, which is linked with appearance of clinical symptoms in immunized SJL/J mice. Treatment of immunized SJL/J mice with AKBA causes improvement of clinical symptoms and downregulation of inflammatory markers in CD11c + DCs (p-NF-κB, iNOS, and nitrotyrosine), and CNS (p-NF-κB, iNOS, nitrotyrosine,lipid peroxides, and total antioxidant capacity). Treatment of immunized SJL/J mice with AKBA also causes rectification of Nrf2 signaling in CD11c + DCs, and CNS. These results propose AKBA ameliorates EAE disease progression through rectification of Nrf2 signaling and attenuation of NF-κB pathway in RR model of EAE. Therefore, nutraceutical compound, AKBA may be therapeutically useful in RRMS.
Proteoglycans are a major component of extracellular matrix and contribute to normal embryonic and postnatal development by ensuring tissue stability and signaling functions. We studied five patients ...with recessive joint dislocations and congenital heart defects, including bicuspid aortic valve (BAV) and aortic root dilatation. We identified linkage to chromosome 11 and detected a mutation (c.830G>A, p.Arg277Gln) in B3GAT3, the gene coding for glucuronosyltransferase-I (GlcAT-I). The enzyme catalyzes an initial step in the synthesis of glycosaminoglycan side chains of proteoglycans. Patients' cells as well as recombinant mutant protein showed reduced glucuronyltransferase activity. Patient fibroblasts demonstrated decreased levels of dermatan sulfate, chondroitin sulfate, and heparan sulfate proteoglycans, indicating that the defect in linker synthesis affected all three lines of O-glycanated proteoglycans. Further studies demonstrated that GlcAT-I resides in the cis and cis-medial Golgi apparatus and is expressed in the affected tissues, i.e., heart, aorta, and bone. The study shows that reduced GlcAT-I activity impairs skeletal as well as heart development and results in variable combinations of heart malformations, including mitral valve prolapse, ventricular septal defect, and bicuspid aortic valve. The described family constitutes a syndrome characterized by heart defects and joint dislocations resulting from altered initiation of proteoglycan synthesis (Larsen-like syndrome, B3GAT3 type).
Norovirus (HNoV) is a leading cause of gastroenteritis globally, and there are currently no treatment options or vaccines available to combat it. RNA-dependent RNA polymerase (RdRp), one of the viral ...proteins that direct viral replication, is a feasible target for therapeutic development. Despite the discovery of a small number of HNoV RdRp inhibitors, the majority of them have been found to possess a little effect on viral replication, owing to low cell penetrability and drug-likeness. Therefore, antiviral agents that target RdRp are in high demand. For this purpose, we used in silico screening of a library of 473 natural compounds targeting the RdRp active site. The top two compounds, ZINC66112069 and ZINC69481850, were chosen based on their binding energy (BE), physicochemical and drug-likeness properties, and molecular interactions. ZINC66112069 and ZINC69481850 interacted with key residues of RdRp with BEs of -9.7, and -9.4 kcal/mol, respectively, while the positive control had a BE of -9.0 kcal/mol with RdRp. In addition, hits interacted with key residues of RdRp and shared several residues with the PPNDS, the positive control. Furthermore, the docked complexes showed good stability during the molecular dynamic simulation of 100 ns. ZINC66112069 and ZINC69481850 could be proven as potential inhibitors of the HNoV RdRp in future antiviral medication development investigations.
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