Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val ...substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.
Ayurveda is a centuries old traditional medicine practiced in India even today. There are certain safe medicinal plants with well-established medicinal properties both in clinical practice as well as ...in modern scientific publications. Guduchi or Tinospora cordifolia (Willd.) Miers (Menispermaceae), is one such medicinal plant that has well known anti-inflammatory, immune-modulatory and other safe therapeutic applications including hepato-protection, because of which it was recommended by the Ministry of AYUSH, Government of India to be used in COVID-19 care. Therefore, Aabha Nagral's article “Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic-a Case Series,” published in 2021, was unanticipated. The article recounted histologically documented clinical cases of six patients who developed drug-induced autoimmune-like hepatitis after reported consumption of Guduchi or Guduchi containing formulations during the COVID-19 pandemic. Since the Ayurveda practitioners vouch by the safety of T. cordifolia (TC), it was felt that the story needed to be further scrutinized.
This article reviews the botanical entities, the substitutes and adulterants of species used as Guduchi, their pharmacological and toxicological properties. While the authentic botanical entity of Guduchi is TC, Tinospora sinensis and Tinospora crispa are also commonly traded in the Indian subcontinent as Guduchi or Giloy. Among these species, T. crispa is known to induce heapto-toxicity. In Nagral's article, there were variations in the reported six cases in terms of patient history and TC/TC product consumption. More importantly, the botanical authenticity of the consumed products was not investigated.
A review of published literature indicates that it is unlikely that the authentic TC could have induced autoimmune-like hepatitis of the patients. It is probable that a wrong species was self-administered by the patients. It is worth following up with the cases (patients), to investigate details of the products, so that other consumers do not suffer. Nagral's article however does highlight the serious issue of adulteration in herbal markets and the need for establishing a robust pharmacovigilant system in India.
MRI systems with proprietary hardware must use pulse programming, which is less expensive. Pulse programming consoles use Digital Signal Processor, Complex Programming Logic Device, and ...microcontrollers, which are typically restricted to particular architectures. General–purpose, extremely affordable electronics board featuring these architectures are now capable enough to be directly implemented in MRI consoles. Here we present the architectural details of various consoles with novel designs and their limitations. Finally, we propose a console design which was created utilising widely accessible Arduino Boards to connect to Pulseq-GPI implementations at a reduced cost of $225
In this study, we aimed to synthesize and characterize a nickel(II) complex-modified graphene oxide (Ni-GO) nanocomposite with enhanced photocatalytic and antimicrobial properties. The nanocomposite ...was prepared through a modified Hummer’s method, followed by an adsorption technique using the precursor complex Ni(bipy)3Cl2·5H2O, which was preferentially adsorbed onto the graphene oxide (GO) surface. The surface interaction between the nickel complex ions and GO was characterized using various analytical techniques, including FTIR, XRD, SEM-EDX, DRS, and XPS analyses. Photoluminescence analysis demonstrated the fluorescence property of the prepared composite. The DRS spectra indicated that the adsorption of composite particles extended to the visible region, making it excitable by visible light. The photocatalytic activity of the Ni-GO nanocomposite was tested by studying the degradation of an organic model pollutant, Rhodamine B dye, under real sunlight irradiation. The introduction of the Ni(II) complex onto the GO surface matrix intensified the photocatalytic property, making it more efficient under direct sunlight exposure. Comparisons with pristine graphite and GO revealed that Ni-GO exhibited enhanced photocatalytic potential. Additionally, we have evaluated the antimicrobial property of the Ni(II) complex-modified GO against Klebsiella pneumoniae. The results demonstrated that both the Ni(II) precursor complex and Ni-GO nanocomposite possessed an excellent antimicrobial efficacy, suggesting their potential use in antimicrobial applications. The synthesis and characterization of the Ni(II) complex-modified GO nanocomposite presented in this study showed promising results for both ameliorative photocatalytic and antimicrobial activities. These findings indicated the potential utility of Ni-GO as an efficient photocatalyst and antimicrobial agent, surpassing the performance of pristine graphite and GO. This research opens up new avenues for the development of advanced nanocomposites with diverse applications in environmental remediation and biomedical fields.
Display omitted
Natural alkaloid, tryptanthrin (indolo2,1-bquinazoline-6,12-dione) and its analogues are found to exhibit potent anti-tubercular activity against MDR-TB. A novel class of ...indolo2,1-bquinazolinones have been synthesized to evaluate their anti-mycobacterial activity. Enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis is one of the key enzymes and has been validated as an effective anti-microbial target. In silico molecular docking study demonstrates that the synthesized compounds exhibit high affinity for the M. tuberculosis drug target InhA. Phaitanthrin is a natural product, which belongs to a family of tryptanthrin and exhibits structural similarity except at position 6. Phaitanthrin derivatives are prepared by modifying the keto functionality of tryptanthrin. These phaitanthrin congeners are found to display promising anti-tubercular activity.
The emergence of drug resistance along with a declining pipeline of clinically useful antibiotics has made it vital to develop more effective antimicrobial therapeutics, particularly against ...difficult-to-treat Gram-negative pathogens (GNPs). Many antibacterial agents, including glycopeptide antibiotics such as vancomycin, are inherently inactive toward GNPs because of their inability to cross the outer membrane of these pathogens. Here, we demonstrate, for the first time, lipophilic cationic (permanent positive charge) vancomycin analogues were able to permeabilize the outer membrane of GNPs and overcome the inherent resistance of GNPs toward glycopeptides. Unlike vancomycin, these analogues were shown to have a high activity against a variety of multidrug-resistant clinical isolates such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the murine model of carbapenem-resistant A. baumannii infection, the optimized compound showed potent activity with no observed toxicity. The notable activity of these compounds is attributed to the incorporation of new membrane disruption mechanisms (cytoplasmic membrane depolarization along with outer and inner (cytoplasmic) membrane permeabilization) into vancomycin. Therefore, our results indicate the potential of the present vancomycin analogues to be used against drug-resistant GNPs, thus strengthening the antibiotic arsenal for combating Gram-negative bacterial infections.
Sixteen hour fermentation of the white flesh raw guava Lucknow 49 cultivar using Lactobacillus plantarum NCIM 2912 was taken up for enhancing the antioxidant potential. The fermented guava product ...with high antioxidant potential, total phenolic content and short and medium chain fatty acids can be used as functional food.
•Fermentation of Raw Guava fruit extract by L. plantarum NCIM 2912.•16 hour shake flask fermentation process optimized.•Increase in antioxidant activity, total phenolics, short and medium chain fatty acids.•Fermented product miscible in water and amorphous powder upon lyophilization.
PbO-CaF2-P2O5 glasses containing small concentrations of CuO from 0 to 0.6 mol% were prepared. A number of studies viz., dielectric studies (constant ', loss tan delta, ac conductivity sigmaac over a ...range of frequency and temperature), infrared, optical absorption ESR and photoluminescence spectra of these glasses, have been carried out. The variations observed in all these properties with the concentration of copper ions have been analyzed in the light of different oxidation states and environment of copper ions in the glass network.
One of the measures for the successful take of a skin graft is the prevention of friction, especially in cases of pressure ulcers in patients with head injury leading to altered sensorium. With ...existing measures such as the use of a pressure-relieving bed, frequent change of position, etc graft loss is common. Some additional measures are required. This study highlights the role of a donut-shaped ring dressing to protect the skin graft from friction.
PDF
