scholarly journals Replacement of S14 protein in ribosomes of zinc-starved mycobacteria reduces spectinamide sensitivity

2020 ◽  
Author(s):  
Yunlong Li ◽  
Ravi K. Koripella ◽  
Manjuli R. Sharma ◽  
Richard E. Lee ◽  
Rajendra K. Agrawal ◽  
...  
Keyword(s):  
Mycobacterium Smegmatis ◽  
Ribosomal Proteins ◽  
Chronic Phase ◽  
Binding Pocket ◽  
Drug Candidates ◽  
Contact Points ◽  
Zinc Depletion ◽  
Effective Drugs ◽  
The Impact ◽  
Mycobacterial Protein

Zinc is an essential micronutrient for mycobacteria and its depletion induces multiple adaptive changes in cellular physiology, the most remarkable of which are remodeling and hibernation of ribosomes. Ribosome remodeling, induced upon relatively moderate depletion of zinc, involves replacement of multiple ribosomal proteins containing the zinc-binding CXXC motif (called C+ r-proteins) by their motif-free C- paralogs. Acute zinc depletion induces binding of mycobacterial protein Y (Mpy) to the 70S C- ribosome, thereby stabilizing the ribosome in an inactive state that is also resistant to kanamycin and streptomycin. Because the Mpy binding region on the ribosome is proximal to the binding pocket of spectinamides (Spa), the preclinical drug candidates for tuberculosis, we addressed the impact of remodeling and hibernation of ribosomes on Spa sensitivity. We report here that while Mpy binding has no significant effect on Spa sensitivity to the ribosome, replacement of S14c+ with its C- counterpart reduces the binding affinity of the drug by ∼2-fold, causing increased Spa tolerance in Mycobacterium smegmatis and Mycobacterium tuberculosis cells harboring the C- ribosome. The altered interaction between Spa and ribosomes likely results from new contact points for D67 and R83 residues of S14c- with U1138 and C1184 of 16S rRNA helix 34, respectively. Given that M. tuberculosis induces ribosome remodeling during progression from acute to chronic phase of a lung infection, our findings highlight new considerations in the development of Spa as effective drugs against TB.

scholarly journals Zinc depletion induces ribosome hibernation in mycobacteria

2018 ◽  
Vol 115 (32) ◽  
pp. 8191-8196 ◽  
Author(s):  
Yunlong Li ◽  
Manjuli R. Sharma ◽  
Ravi K. Koripella ◽  
Yong Yang ◽  
Prem S. Kaushal ◽  
...  
Keyword(s):  
Mycobacterium Smegmatis ◽  
Ribosomal Proteins ◽  
Specific Protein ◽  
Zinc Homeostasis ◽  
Aminoglycoside Resistance ◽  
Zinc Depletion ◽  
Binding Pockets ◽  
Mouse Model Of Infection ◽  
Decoding Region ◽  
Mycobacterial Protein

Bacteria respond to zinc starvation by replacing ribosomal proteins that have the zinc-binding CXXC motif (C+) with their zinc-free (C−) paralogues. Consequences of this process beyond zinc homeostasis are unknown. Here, we show that the C− ribosome in Mycobacterium smegmatis is the exclusive target of a bacterial protein Y homolog, referred to as mycobacterial-specific protein Y (MPY), which binds to the decoding region of the 30S subunit, thereby inactivating the ribosome. MPY binding is dependent on another mycobacterial protein, MPY recruitment factor (MRF), which is induced on zinc depletion, and interacts with C− ribosomes. MPY binding confers structural stability to C− ribosomes, promoting survival of growth-arrested cells under zinc-limiting conditions. Binding of MPY also has direct influence on the dynamics of aminoglycoside-binding pockets of the C− ribosome to inhibit binding of these antibiotics. Together, our data suggest that zinc limitation leads to ribosome hibernation and aminoglycoside resistance in mycobacteria. Furthermore, our observation of the expression of the proteins of C− ribosomes in Mycobacterium tuberculosis in a mouse model of infection suggests that ribosome hibernation could be relevant in our understanding of persistence and drug tolerance of the pathogen encountered during chemotherapy of TB.

scholarly journals Interphotoreceptor coupling: an evolutionary perspective

2021 ◽  
Author(s):  
Lorenzo Cangiano ◽  
Sabrina Asteriti
Keyword(s):  
Visual Information ◽  
Signal To Noise Ratio ◽  
Electrical Coupling ◽  
Physiological Role ◽  
Cellular Processes ◽  
Contact Points ◽  
Highly Sensitive ◽  
The Many ◽  
The Impact

AbstractIn the vertebrate retina, signals generated by cones of different spectral preference and by highly sensitive rod photoreceptors interact at various levels to extract salient visual information. The first opportunity for such interaction is offered by electrical coupling of the photoreceptors themselves, which is mediated by gap junctions located at the contact points of specialised cellular processes: synaptic terminals, telodendria and radial fins. Here, we examine the evolutionary pressures for and against interphotoreceptor coupling, which are likely to have shaped how coupling is deployed in different species. The impact of coupling on signal to noise ratio, spatial acuity, contrast sensitivity, absolute and increment threshold, retinal signal flow and colour discrimination is discussed while emphasising available data from a variety of vertebrate models spanning from lampreys to primates. We highlight the many gaps in our knowledge, persisting discrepancies in the literature, as well as some major unanswered questions on the actual extent and physiological role of cone-cone, rod-cone and rod-rod communication. Lastly, we point toward limited but intriguing evidence suggestive of the ancestral form of coupling among ciliary photoreceptors.

Analysis of the breakage rate function for selected process parameters in quartzite milling

2012 ◽  
Vol 33 (1) ◽  
pp. 117-129 ◽  
Author(s):  
Tomasz Olejnik
Keyword(s):  
Process Parameters ◽  
Rate Function ◽  
Variable Number ◽  
Specific Rate ◽  
Gardner Equation ◽  
Contact Points ◽  
Batch System ◽  
Grinding Media ◽  
Breakage Rate ◽  
The Impact

Analysis of the breakage rate function for selected process parameters in quartzite milling The paper presents the results of studies on quartzite milling in a ball mill. The milling was conducted in a batch system, for diversified compositions of balls. The milling product was subjected to granulometrical, morphological and strength analyses. On the basis of the developed Reid's theory and using the Austin-Gardner equation, a form of the function circumscribing the specific rate of comminution of selected size fractions was determined. The values of the breakage rate function bi, j for the mill's apparatus conditions were determined. The impact was investigated for a variable number of grinding media contact points on the values of specific rate S and the values of the breakage rate function bi, j. Furthermore, the values of coefficients occurring in the equations circumscribing the specific rate of milling S and breakage parameter bi, j were determined.

Abstract 83: Modulation of Macrophage Function via Metabolism by Trypanosoma cruzi

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sue-Jie Koo ◽  
Nisha J Garg
Keyword(s):  
Trypanosoma Cruzi ◽  
Chronic Phase ◽  
Etiologic Agent ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Transcription Control ◽  
Metabolic Gene Expression ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Impact

Chagas heart disease is an inflammatory cardiomyopathy which presents with mononuclear infiltrates in the interstitium and myocardial fibrosis in the chronic phase. Incomplete clearance by macrophages of the etiologic agent, Trypanosoma cruzi , is a significant cause of chronic disease development in approximately 30% of those serologically positive for the blood-borne parasite. The differential metabolic status, anaerobic glycolysis and mitochondria-dependent oxidative phosphorylation, are respectively associated with pro-inflammatory (M1) and anti-inflammatory (M2) functional activation of macrophages. Reactive oxygen species (ROS) have been shown to be an intracellular signal for glycolysis while peroxisome proliferator-activated receptors (PPARs) that enhance fatty acid oxidation provide transcription control of macrophage functional state. In our studies using diverse T. cruzi isolates, we showed that SylvioX10 (virulent), but not TCC (non-virulent), isolates are able to differentially control extracellular and intracellular ROS levels in macrophages. We found in macrophages infected with SylvioX10, the nuclear expression of PPAR-α was increased by 18 hours post-infection, and mitochondrial metabolic activity was similar to that of not-infected and M2 controls; which indicates anti-inflammatory function of macrophages, and therefore prohibiting T. cruzi clearance. In our ongoing studies, we are examining the impact of PPAR-α inhibitors in modulating the metabolic gene expression profile, functional phenotype and parasite survival in macrophages. Our data will provide the first indication that host macrophages have deficient pro-inflammatory capacity due to sub-optimal glucose oxidation, and enhancing the metabolism that supports T. cruzi clearance will provide a valuable basis for a strategy to arrest Chagas disease progression.

Exploration of Umbelliferone Based Derivatives as Potent MAO Inhibitors: Dry vs. Wet Lab Evaluation

2019 ◽  
Vol 18 (21) ◽  
pp. 1857-1871 ◽  
Author(s):  
Priyanka Dhiman ◽  
Neelam Malik ◽  
Anurag Khatkar
Keyword(s):  
Active Site ◽  
Docking Simulation ◽  
Selectivity Index ◽  
Drug Candidates ◽  
Ic50 Value ◽  
Spectrophotometric Titrations ◽  
Wet Lab ◽  
Inhibitory Potential ◽  
Anxiety Depression ◽  
The Impact

Background: Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson’s disease. Objective: We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. Method: A series of different umbelliferone derivatives was designed and synthesized, and the derivatives were screened for hMAO-A and hMAO-B inhibition. Moreover, the mechanistic insight for enzyme- compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. Results: Compound 5 with bromo 5-bromo-isatin exhibited a remarkable hMAO-A inhibitory potential (7.473±0.035 µM and the selectivity index of 0.14) revealing the impact of hybrid coumarin and 5- bromo-2-oxoindolin-3-yl ring with hydrazine linker on the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32±0.044µM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2-oxo-2H-chromen ring led the important binding infractions within the hMAO active site. Conclusion: Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants.

scholarly journals Dynamics of language reorganization after left temporo-parietal and frontal stroke

Brain ◽  
2020 ◽  
Vol 143 (3) ◽  
pp. 844-861 ◽  
Author(s):  
Anika Stockert ◽  
Max Wawrzyniak ◽  
Julian Klingbeil ◽  
Katrin Wrede ◽  
Dorothee Kümmerer ◽  
...  
Keyword(s):  
Functional Mri ◽  
Chronic Phase ◽  
Global Network ◽  
Lesion Location ◽  
Post Stroke ◽  
Language Functions ◽  
Language Recovery ◽  
Patient Groups ◽  
The Impact ◽  
General Networks

Abstract The loss and recovery of language functions are still incompletely understood. This longitudinal functional MRI study investigated the neural mechanisms underlying language recovery in patients with post-stroke aphasia putting particular emphasis on the impact of lesion site. To identify patterns of language-related activation, an auditory functional MRI sentence comprehension paradigm was administered to patients with circumscribed lesions of either left frontal (n = 17) or temporo-parietal (n = 17) cortex. Patients were examined repeatedly during the acute (≤1 week, t1), subacute (1–2 weeks, t2) and chronic phase (>6 months, t3) post-stroke; healthy age-matched control subjects (n = 17) were tested once. The separation into two patient groups with circumscribed lesions allowed for a direct comparison of the contributions of distinct lesion-dependent network components to language reorganization between both groups. We hypothesized that activation of left hemisphere spared and perilesional cortex as well as lesion-homologue cortex in the right hemisphere varies between patient groups and across time. In addition, we expected that domain-general networks serving cognitive control independently contribute to language recovery. First, we found a global network disturbance in the acute phase that is characterized by reduced functional MRI language activation including areas distant to the lesion (i.e. diaschisis) and subsequent subacute network reactivation (i.e. resolution of diaschisis). These phenomena were driven by temporo-parietal lesions. Second, we identified a lesion-independent sequential activation pattern with increased activity of perilesional cortex and bilateral domain-general networks in the subacute phase followed by reorganization of left temporal language areas in the chronic phase. Third, we observed involvement of lesion-homologue cortex only in patients with frontal but not temporo-parietal lesions. Fourth, irrespective of lesion location, language reorganization predominantly occurred in pre-existing networks showing comparable activation in healthy controls. Finally, we detected different relationships of performance and activation in language and domain-general networks demonstrating the functional relevance for language recovery. Our findings highlight that the dynamics of language reorganization clearly depend on lesion location and hence open new perspectives for neurobiologically motivated strategies of language rehabilitation, such as individually-tailored targeted application of neuro-stimulation.

scholarly journals Prognostic significance of cellular vascular endothelial growth factor (VEGF) expression in the course of chronic myeloid leukaemia

2009 ◽  
Vol 137 (7-8) ◽  
pp. 379-383 ◽  
Author(s):  
Ana Vidovic ◽  
Gradimir Jankovic ◽  
Dragica Tomin ◽  
Maja Perunicic-Jovanovic ◽  
Irena Djunic ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor ◽  
The Impact

Introduction. Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML), a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF) is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. Objective. The aim of this study was the follow-up of VEGF expression during the course of CML. Methods. We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years). At the commencement of the study, 29 patients were in chronic phase (CP), 25 in an accelerated phase (AP), and 31 in the blast crisis (BC). The temporal expression (percentage positivity per 1000 analysed cells) VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts) and clinical parameters (organomegaly, duration of CP, AP, and BC) of disease progression. Results. The expression of VEGF protein was most pronounced in AP (ANOVA, p=0.033). The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011). High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042). Conclusion. Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.

scholarly journals Efflux-Mediated Resistance to New Oxazolidinones and Pleuromutilin Derivatives inEscherichia coliwith Class Specificities in the Resistance-Nodulation-Cell Division-Type Drug Transport Pathways

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Sabine Schuster ◽  
Martina Vavra ◽  
Winfried V. Kern
Keyword(s):  
Escherichia Coli ◽  
Cell Division ◽  
Drug Transport ◽  
Binding Pocket ◽  
Entrance Channel ◽  
Transport Pathways ◽  
Double Mutation ◽  
Content Type ◽  
Rnd Transporter ◽  
The Impact

ABSTRACTA major contribution of the resistance-nodulation-cell division (RND)-transporter AcrB to resistance to oxazolidinones and pleuromutilin derivatives inEscherichia coliwas confirmed. However, we discovered significant differences in efflux inhibitor activities, specificities of the homologous pump YhiV (MdtF), and the impact of AcrB pathway mutations. Particularly, entrance channel double-mutation I38F I671T and distal binding pocket mutation F615A revealed class-specific transport routes of oxazolidinones and pleuromutilin derivatives. The findings could contribute to the understanding of the RND-type multidrug transport pathways.

scholarly journals Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics

Amino Acids ◽  
2020 ◽  
Vol 52 (9) ◽  
pp. 1207-1226
Author(s):  
Yun Ding ◽  
Joey Paolo Ting ◽  
Jinsha Liu ◽  
Shams Al-Azzam ◽  
Priyanka Pandya ◽  
...  
Keyword(s):  
Amino Acids ◽  
Its Sequence ◽  
Peptide Therapeutics ◽  
Large Proteins ◽  
Drug Candidates ◽  
Ongoing Development ◽  
The Stability ◽  
Natural Amino Acids ◽  
The Impact ◽  
As Toxicity

Abstract With the development of modern chemistry and biology, non-proteinogenic amino acids (NPAAs) have become a powerful tool for developing peptide-based drug candidates. Drug-like properties of peptidic medicines, due to the smaller size and simpler structure compared to large proteins, can be changed fundamentally by introducing NPAAs in its sequence. While peptides composed of natural amino acids can be used as drug candidates, the majority have shown to be less stable in biological conditions. The impact of NPAA incorporation can be extremely beneficial in improving the stability, potency, permeability, and bioavailability of peptide-based therapies. Conversely, undesired effects such as toxicity or immunogenicity should also be considered. The impact of NPAAs in the development of peptide-based therapeutics is reviewed in this article. Further, numerous examples of peptides containing NPAAs are presented to highlight the ongoing development in peptide-based therapeutics.

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