Molecular Structure,Stereochemistry and Interactions of Steffimycin B,and DNA Binding Anthracycline Antibiotic

Abstract

The crystal and molecular structure of anthracycline antibiotic steffimycin B(C₂₉H₃₂₀O₁₃) has been determined by X-ray diffraction and the stereochemistry revealed. The orthorhombic crystals belong to space group P2₁2₁2₁, with the dimensions; a = 8.253 (2), b = 8.198 (2), c = 40.850 (8) Å and Z = 4. Intensity data were collected for 2518 independent reflections. The structure was solved by direct methods and refined to an R value of 0.066 for 1410 reflections. The configuration in ring A is TR,8S,9S. Ring A adopts half chair conformation, while the sugar ring has the regular chair conformation. The molecule most probably binds to double helical DNA through intercalation and hydrogen bonding.     

SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies

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NMR assignment of actin depolymerizing and dynamics regulatory protein from Leishmania donovani

Leishmania donovani cofilin displays low sequence similarity to other mammalian cofilins and also possesses characteristic activity of its own. Determination of its solution structure would facilitate understanding of the molecular mechanism of actin dynamics regulation in this disease causing pathogen.     

Selective Targeting to Glioma with Nucleic Acid Aptamers

Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (K_d, 21.56 ± 4.60 nM and K_d, 21.11 ± 3.30 nM respectively) to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non-cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP) followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC) staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV) compared to the non-cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non-cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma.     

Involvement of adenylate cyclase/cAMP/CREB and SOX9/MITF in melanogenesis to prevent vitiligo

Molecular and Cellular Biochemistry - Vitiligo is autoimmune, acquired, idiopathic, chronic, and progressive de/hypopigmentary cutaneous condition that targets the cell-producing pigment called...     

Grey-box modeling and hypothesis testing of functional near-infrared spectroscopy-based cerebrovascular reactivity to anodal high-definition tDCS in healthy humans

Transcranial direct current stimulation (tDCS) has been shown to evoke hemodynamics response; however, the mechanisms have not been investigated systematically using systems biology approaches. Our study presents a grey-box linear model that was developed from a physiologically detailed multi-compartmental neurovascular unit model consisting of the vascular smooth muscle, perivascular space, synaptic space, and astrocyte glial cell. Then, model linearization was performed on the physiologically detailed nonlinear model to find appropriate complexity (Akaike information criterion) to fit functional near-infrared spectroscopy (fNIRS) based measure of blood volume changes, called cerebrovascular reactivity (CVR), to high-definition (HD) tDCS. The grey-box linear model was applied on the fNIRS-based CVR during the first 150 seconds of anodal HD-tDCS in eleven healthy humans. The grey-box linear models for each of the four nested pathways starting from tDCS scalp current density that perturbed synaptic potassium released from active neurons for Pathway 1, astrocytic transmembrane current for Pathway 2, perivascular potassium concentration for Pathway 3, and voltage-gated ion channel current on the smooth muscle cell for Pathway 4 were fitted to the total hemoglobin concentration (tHb) changes from optodes in the vicinity of 4x1 HD-tDCS electrodes as well as on the contralateral sensorimotor cortex. We found that the tDCS perturbation Pathway 3 presented the least mean square error (MSE, median <2.5%) and the lowest Akaike information criterion (AIC, median -1.726) from the individual grey-box linear model fitting at the targeted-region. Then, minimal realization transfer function with reduced-order approximations of the grey-box model pathways was fitted to the ensemble average tHb time series. Again, Pathway 3 with nine poles and two zeros (all free parameters), provided the best Goodness of Fit of 0.0078 for Chi-Square difference test of nested pathways. Therefore, our study provided a systems biology approach to investigate the initial transient hemodynamic response to tDCS based on fNIRS tHb data. Future studies need to investigate the steady-state responses, including steady-state oscillations found to be driven by calcium dynamics, where transcranial alternating current stimulation may provide frequency-dependent physiological entrainment for system identification. We postulate that such a mechanistic understanding from system identification of the hemodynamics response to transcranial electrical stimulation can facilitate adequate delivery of the current density to the neurovascular tissue under simultaneous portable imaging in various cerebrovascular diseases.     

Chemical oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its in vivo metabolism in rat brain and liver

We investigated in vivo the metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the brain and liver of rats 45 min after the systemic administration of 50 mg/kg of the neurotoxin. The metabolites present in brain and liver extracts were identified through multiple analytical methods by comparison to authentic compounds obtained from a number of chemical oxidations of MPTP. Our results indicate the presence of approximately 15% unreacted MPTP and relatively large amounts of both 1-methyl-4-phenylpyridinium (MPP+) and a mixture of three nonpolar lactams: 1-methyl-4-phenyl-5,6-dihydro-2(1H)-pyridinone, 1-methyl-4-phenyl-2(1H)-pyridinone, and a previously unreported metabolite 1-methyl-4-phenyl-2-piperidinone. Whereas MPP+ was more prevalent in the brain than in the liver, the lactam metabolites were more predominant in the liver. The amounts of the N-oxide and N-demethylated metabolites of MPTP were minimal.