Infectious diseases account for a large proportion of global health emergencies and are rising more so owing to the paucity of effective vaccination and chemotherapeutic strategies. The severity is compounded by the development of antibiotic resistance among major pathogenic strains, capable of residing in the hostile host microenvironment by hijacking its signaling mechanisms and molecular circuitry. Among such processes, studies on epidermal growth factor receptor (EGFR) have revealed specific contributions of this classical oncogenic signaling axis during distinct infection conditions. Here, we review the current status of EGFR family members in the context of host-pathogen interactions and speculate the possible dimensions of exploration and manipulation of the EGFR pathway for host-directed therapeutic purposes.
Mycobacterium tuberculosis (Mtb)-driven lipid accumulation is intricately associated with the progression of tuberculosis (TB) disease. Although several studies elucidating the mechanisms for lipid droplet (LD) biosynthesis exist, we provide evidence for the significance of their regulated turnover via macroautophagy/autophagy during Mtb infection. We demonstrate that Mtb utilizes EGFR (epidermal growth factor receptor) signaling to induce the expression of the histone acetylation reader, BRD4 (bromodomain containing 4). The EGFR-BRD4 axis suppresses lipid-specific autophagy, and hence favors cellular lipid accumulation. Specifically, we found that pharmacological inhibition or knockdown of Egfr or Brd4 enhances autophagic flux and concomitantly decreases cellular LDs that is otherwise maintained at a significant level in chloroquine-treated or Atg5 knocked down autophagy-compromised host cells. In line with the enhanced lipophagy, we found that loss of EGFR or BRD4 function restricts mycobacterial burden that is rescued by external replenishment with oleic acid. We also report that the EGFR-BRD4 axis exerts additional effects by modulating pro-angiogenic gene expression and consequently aberrant angiogenesis during mycobacterial infection. This is important in the context of systemic Mtb dissemination as well as for the efficient delivery of anti-mycobacterial therapeutics to the Mtb-rich core of TB granuloma. Finally, utilizing an in vivo mouse model of TB, we show that pharmacological inhibition of EGFR and BRD4 compromises LD build-up via enhanced lipophagy and normalizes angiogenesis, thereby restricting Mtb burden and rescuing mice from severe TB-like pathology. These findings shed light on the novel roles of BRD4 during Mtb infection, and its possible implication in potentiating anti-TB responses.
Mycobacterium tuberculosis (Mtb)-driven lipid accumulation is intricately associated with the progression of tuberculosis (TB) disease. Although several studies elucidating the mechanisms for lipid droplet (LD) biosynthesis exist, we provide evidence for the significance of their regulated turnover via macroautophagy/autophagy during Mtb infection. We demonstrate that Mtb utilizes EGFR (epidermal growth factor receptor) signaling to induce the expression of the histone acetylation reader, BRD4 (bromodomain containing 4). The EGFR-BRD4 axis suppresses lipid-specific autophagy, and hence favors cellular lipid accumulation. Specifically, we found that pharmacological inhibition or knockdown of Egfr or Brd4 enhances autophagic flux and concomitantly decreases cellular LDs that is otherwise maintained at a significant level in chloroquine-treated or Atg5 knocked down autophagy-compromised host cells. In line with the enhanced lipophagy, we found that loss of EGFR or BRD4 function restricts mycobacterial burden that is rescued by external replenishment with oleic acid. We also report that the EGFR-BRD4 axis exerts additional effects by modulating pro-angiogenic gene expression and consequently aberrant angiogenesis during mycobacterial infection. This is important in the context of systemic Mtb dissemination as well as for the efficient delivery of anti-mycobacterial therapeutics to the Mtb-rich core of TB granuloma. Finally, utilizing an in vivo mouse model of TB, we show that pharmacological inhibition of EGFR and BRD4 compromises LD buildup via enhanced lipophagy and normalizes angiogenesis, thereby restricting Mtb burden and rescuing mice from severe TB-like pathology. These findings shed light on the novel roles of BRD4 during Mtb infection, and its possible implication in potentiating anti-TB responses. Abbreviations: ATG5: autophagy related 5; BRDs: bromodomain containing; COL18A1: collagen type XVIII alpha 1 chain; EGFR: epidermal growth factor receptor; EP300: E1A binding protein p300; KDR: kinase insert domain receptor; KLF5: Kruppel like factor 5; LDs: lipid droplets; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; Mtb: Mycobacterium tuberculosis; PECAM1: platelet and endothelial cell adhesion molecule 1; SQSTM1/p62: sequestosome 1; TB: tuberculosis; THBS1: thrombospondin 1; VEGF: vascular endothelial growth factor
The study emphasizes the local and regional level coastal vulnerability in the context of climate change induced present sea level rise using Sea level and tidal gauge data and advanced geo spatial technologies along the eastern coast of India.The coast is a potential hot spot zone were found the immediate effect of sea level rise.Presently climate change induced global warming and the melting of ice sheets and continental glaciers continually increase the sea level, which leads the natural hazards such as Tsunami, storm surges, thermal expansion of sea water and cyclones.The study was used SRTM global DEM with 90 m resolution to derive the coastal elevation, inundation risk zones along the eastern coast of India.The sea level rise scenario has been explained by using a 5 th order polynomial curve which also interpolates and extrapolate the gaps within the available data of four tidal gauge stations.The results show that northern portion (Ganga-Brahmaputra delta region) of the coast, mostly affected by the sea level rise (4.7 mm per year) where the Sundarban region is the most vulnerable region due to the lower elevation (ranges 0 to 20 m) and higher tidal influence.Also Visakhapatnam and Bhubaneswar have a higher rate of sea level rise respectively 0.73 and 0.43 which increase the erosional activity and probable inundation level.As this study reveals the level of vulnerability, it helps to develop mitigation and adaptation measures in those most vulnerable areas to sea level rise problems.The final results support and suggests planners and decision makers in the spatial identification for the future strategies.
A large proportion of the world is inflicted with health concerns arising from infectious diseases. Moreover, there is a widespread emergence of antibiotic resistance among major infectious agents, partially stemming from their continuous dialog with the host and their enormous capacity to remodel the latter towards a secure niche. Among the several infection-driven events, moderation of WNT signaling pathway has been identified to be strategically tuned during infections to govern host-pathogen interactions. Primarily known for its role in arbitrating early embryonic developmental events; aberrant activation of the WNT pathway has also been associated with immunological consequences during diverse patho-physiological conditions. Here, we review the different mechanisms by which components of WNT signaling pathway are exploited by discrete bacterial agents for their pathogenesis. Furthermore, recent advances on the cross-talk of WNT with other signaling pathways, the varied modes of WNT-mediated alteration of gene expression; and WNT-dependent post-transcriptional and post-translational regulation of the immune landscape during distinct bacterial infections would be highlighted.
In this paper, an unsupervised generative modeling method that generates synthetic images with the help of Deep Convolutional Generative Adversarial Networks (DCGANs). A method has been put forward that uses labelled Magnetic Resonance Imaging (MRI) dataset and then applies DCGAN on the limited amount of data, hence enlarging the dataset size as well as its diversity through the use of GAN. Further the synthetic images and training dataset are merged together and trained into a Convolutional Neural Network (CNN) and its different architectures for the classification of four different stages of Alzheimer's disease. The classification performance using CNN yielded an accuracy of 69%, ResNet50 yielded respectively. On increasing the number of epochs as well as the number of dataset images more accuracy can be obtained.
Mycobacterium tuberculosis (Mtb)-driven lipid accumulation is intricately associated with the progression of tuberculosis (TB) disease. Although several studies elucidating the mechanisms for lipid droplet (LD) biosynthesis exist, we provide evidence for the significance of their regulated turnover via macroautophagy/autophagy during Mtb infection. We demonstrate that Mtb utilizes EGFR (epidermal growth factor receptor) signaling to induce the expression of the histone acetylation reader, BRD4 (bromodomain containing 4). The EGFR-BRD4 axis suppresses lipid-specific autophagy, and hence favors cellular lipid accumulation. Specifically, we found that pharmacological inhibition or knockdown of Egfr or Brd4 enhances autophagic flux and concomitantly decreases cellular LDs that is otherwise maintained at a significant level in chloroquine-treated or Atg5 knocked down autophagy-compromised host cells. In line with the enhanced lipophagy, we found that loss of EGFR or BRD4 function restricts mycobacterial burden that is rescued by external replenishment with oleic acid. We also report that the EGFR-BRD4 axis exerts additional effects by modulating pro-angiogenic gene expression and consequently aberrant angiogenesis during mycobacterial infection. This is important in the context of systemic Mtb dissemination as well as for the efficient delivery of anti-mycobacterial therapeutics to the Mtb-rich core of TB granuloma. Finally, utilizing an in vivo mouse model of TB, we show that pharmacological inhibition of EGFR and BRD4 compromises LD buildup via enhanced lipophagy and normalizes angiogenesis, thereby restricting Mtb burden and rescuing mice from severe TB-like pathology. These findings shed light on the novel roles of BRD4 during Mtb infection, and its possible implication in potentiating anti-TB responses.Abbreviations: ATG5: autophagy related 5; BRDs: bromodomain containing; COL18A1: collagen type XVIII alpha 1 chain; EGFR: epidermal growth factor receptor; EP300: E1A binding protein p300; KDR: kinase insert domain receptor; KLF5: Kruppel like factor 5; LDs: lipid droplets; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; Mtb: Mycobacterium tuberculosis; PECAM1: platelet and endothelial cell adhesion molecule 1; SQSTM1/p62: sequestosome 1; TB: tuberculosis; THBS1: thrombospondin 1; VEGF: vascular endothelial growth factor
Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and SIRT6 (H3K9 deacetylase) orchestrate cholesterol build-up in in vitro and in vivo mouse models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while SIRT6 along with G9a represses the genes involved in cholesterol efflux. The accumulated cholesterol in Mtb infected macrophages promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and pharmacological inhibition in vivo; or utilization of BMDMs derived from Sirt6-/- mice or in vivo infection in haplo-insufficient Sirt6-/+ mice; hampered host cholesterol accumulation and restricted Mtb burden. These findings shed light on the novel roles of G9a and SIRT6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival.
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