Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phosholipase C gamma 1 and protein kinase C pathways

This work was supported by the German Research Foundation DFG (SFB 850/B6) and by the Fritz-Thyssen foundation (Az.10.14.2.150) to C.-W.F and the Medical Research Council (MR/L010402/1) to D.P.K

Host-Pathogen Interaction in Leishmaniasis: Immune Response and Vaccination Strategies

Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. Leishmaniasis is a zoonotic and vector-borne infectious disease that is caused by the genus Leishmania belonging to the trypanosomatid family. The protozoan parasite has a digenetic life cycle involving a mammalian host and an insect vector. Leishmaniasisis is a worldwide public health problem falling under the neglected tropical disease category, with over 90 endemic countries, and approximately 1 million new cases and 20,000 deaths annually. Leishmania infection can progress toward the development of species–specific pathologic disorders, ranging in severity from self-healing cutaneous lesions to disseminating muco-cutaneous and fatal visceral manifestations. The severity and the outcome of leishmaniasis is determined by the parasite’s antigenic epitope characteristics, the vector physiology, and most importantly, the immune response and immune status of the host. This review examines the nature of host–pathogen interaction in leishmaniasis, innate and adaptive immune responses, and various strategies that have been employed for vaccine development.Funding: This research received no external funding

A review on development and application of plant-based bioflocculants and grafted bioflocculants

Flocculation is extensively employed for clarification through sedimentation. Application of eco-friendly plant-based bioflocculants in wastewater treatment has attracted significant attention lately with high removal capability in terms of solids, turbidity, color, and dye. However, moderate flocculating property and short shelf life restrict their development. To enhance the flocculating ability, natural polysaccharides derived from plants are chemically modified by inclusion of synthetic, nonbiodegradable monomers (e.g., acrylamide) onto their backbone to produce grafted bioflocculants. This review is aimed to provide an overview of the development and flocculating efficiencies of plant-based bioflocculants and grafted bioflocculants for the first time. Furthermore, the processing methods, flocculation mechanism, and the current challenges are discussed. All the reported studies about plant-derived bioflocculants are conducted under lab-scale conditions in wastewater treatment. Hence, the possibility to apply natural bioflocculants in food and beverage, mineral, paper and pulp, and oleo-chemical and biodiesel industries is discussed and evaluated

Nepali migrant workers and the need for pre-departure training on mental health: a qualitative study

Every year around 1,000 Nepali migrant workers die abroad. Every one in three females and one in ten males commit suicide, reflecting a high mental health risk among Nepali migrant workers. This study aims to identify triggers of mental ill-health among Nepali migrant workers and their perception on need of mental health components in the pre-departure orientation programme. We conducted five focus group discussions (FGD) and seven in-depth interviews with Nepali migrant workers and eight semi-structured interviews with stakeholders working for migrants. Participants were invited at Kathmandu’s international airport on return from abroad, at hotels or bus stations near the airport, through organisations working for migrants, and participants’ network. All FGD and interviews were conducted in Kathmandu and audio recorded, transcribed and translated into English. Data were analyzed thematically. High expectations from families back home, an unfair treatment at work, poor arrangements of accommodation, loneliness and poor social life abroad were frequently reported factors for poor mental health. Access to mental health services abroad by Nepali migrant was also poor. We found little on mental health in the pre-departure orientation. We need to improve our knowledge of mental health risks to provide better, more focused and more up-to-date pre-departure training to new migrant workers leaving Nepal

Hydrophobicity modulated antibacterial small molecule eradicates biofilm with potent efficacy against skin-infections

The role of molecular arrangement of hydrophobic and hydrophilic groups for designing membrane-active molecules remains largely ambiguous. To explore this aspect, herein we report a series of membrane-active small molecules by varying the spatial distribution of hydrophobic groups. The two terminal amino groups of linear triamines such as diethylene triamine, bis(trimethylene)triamine and bis(hexamethylene)triamine were conjugated with cationic amino acids bearing variable side chain hydrophobicity (such as diaminobutyric acid, ornithine and lysine). The hydrophobicity was also modulated through conjugation of different long chain fatty acids with the central secondary amino group of the triamine. Molecules with constant backbone hydrophobicity displayed an enhanced antibacterial activity and decreased hemolytic activity upon increasing the side chain hydrophobicity of amino acids. On the other hand, increased hydrophobicity in the backbone introduced a slight hemolytic activity but a higher increment in antibacterial activity resulting in better selective antibacterial compounds. The optimized lead compound derived from structure-activity-relationship (SAR) studies was the dodecanoyl analogue of lysine series of compounds consisting of bis(hexamethylene)triamine as the backbone. This compound was active against various Gram-positive and Gram-negative bacteria at a low concentration (MIC ranged between 3.1-6.3 µg/mL) and displayed low toxicity towards mammalian cells (HC50 = 890 µg/mL and EC50 against HEK = 85 µg/mL). Additionally, it was able to kill metabolically inactive bacterial cells and eradicate preformed biofilms of MRSA. This compound showed excellent activity in a mouse model of skin-infection with reduction of ~4 log MRSA burden at 40 mg/kg dose without any sign of skin-toxicity even at 200 mg/kg. More importantly, it revealed potent efficacy in an ex-vivo model of human skin-infection (with reduction of 85% MRSA burden at 50 μg/mL), which indicates great potential of the compound as an antibacterial agent to treat skin-infections

DMA, a Bisbenzimidazole, Offers Radioprotection by Promoting NFκB Transactivation through NIK/IKK in Human Glioma Cells

BACKGROUND: Ionizing radiation (IR) exposure often occurs for human beings through occupational, medical, environmental, accidental and/or other sources. Thus, the role of radioprotector is essential to overcome the complex series of overlapping responses to radiation induced DNA damage. METHODS AND RESULTS: Treatment of human glioma U87 cells with DMA (5- {4-methylpiperazin-1-yl}-2-[2'-(3, 4-dimethoxyphenyl)-5'-benzimidazolyl] in the presence or absence of radiation uncovered differential regulation of an array of genes and proteins using microarray and 2D PAGE techniques. Pathway construction followed by relative quantitation of gene expression of the identified proteins and their interacting partners led to the identification of MAP3K14 (NFκB inducing kinase, NIK) as the candidate gene affected in response to DMA. Subsequently, over expression and knock down of NIK suggested that DMA affects NFκB inducing kinase mediated phosphorylation of IKKα and IKKβ both alone and in the presence of ionizing radiation (IR). The TNF-α induced NFκB dependent luciferase reporter assay demonstrated 1.65, 2.26 and 3.62 fold increase in NFκB activation at 10, 25 and 50 µM DMA concentrations respectively, compared to control cells. This activation was further increased by 5.8 fold in drug + radiation (50 µM +8.5 Gy) treated cells in comparison to control. We observed 51% radioprotection in control siRNA transfected cells that attenuated to 15% in siRNA NIK treated U87 cells, irradiated in presence of DMA at 24 h. CONCLUSIONS: Our studies show that NIK/IKK mediated NFκB activation is more intensified in cells over expressing NIK and treated with DMA, alone or in combination with ionizing radiation, indicating that DMA promotes NIK mediated NFκB signaling. This subsequently leads to the radioprotective effect exhibited by DMA

Characterization of a Nonclassical Class I MHC Gene in a Reptile, the Galápagos Marine Iguana (Amblyrhynchus cristatus)

Squamates are a diverse order of vertebrates, representing more than 7,000 species. Yet, descriptions of full-length major histocompatibility complex (MHC) genes in this group are nearly absent from the literature, while the number of MHC studies continues to rise in other vertebrate taxa. The lack of basic information about MHC organization in squamates inhibits investigation into the relationship between MHC polymorphism and disease, and leaves a large taxonomic gap in our understanding of amniote MHC evolution. Here, we use both cDNA and genomic sequence data to characterize a class I MHC gene (Amcr-UA) from the Galápagos marine iguana, a member of the squamate subfamily Iguaninae. Amcr-UA appears to be functional since it is expressed in the blood and contains many of the conserved peptide-binding residues that are found in classical class I genes of other vertebrates. In addition, comparison of Amcr-UA to homologous sequences from other iguanine species shows that the antigen-binding portion of this gene is under purifying selection, rather than balancing selection, and therefore may have a conserved function. A striking feature of Amcr-UA is that both the cDNA and genomic sequences lack the transmembrane and cytoplasmic domains that are necessary to anchor the class I receptor molecule into the cell membrane, suggesting that the product of this gene is secreted and consequently not involved in classical class I antigen-presentation. The truncated and conserved character of Amcr-UA lead us to define it as a nonclassical gene that is related to the few available squamate class I sequences. However, phylogenetic analysis placed Amcr-UA in a basal position relative to other published classical MHC genes from squamates, suggesting that this gene diverged near the beginning of squamate diversification

Sensing and Integration of Erk and PI3K Signals by Myc

The transcription factor Myc plays a central role in regulating cell-fate decisions, including proliferation, growth, and apoptosis. To maintain a normal cell physiology, it is critical that the control of Myc dynamics is precisely orchestrated. Recent studies suggest that such control of Myc can be achieved at the post-translational level via protein stability modulation. Myc is regulated by two Ras effector pathways: the extracellular signal-regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K) pathways. To gain quantitative insight into Myc dynamics, we have developed a mathematical model to analyze post-translational regulation of Myc via sequential phosphorylation by Erk and PI3K. Our results suggest that Myc integrates Erk and PI3K signals to result in various cellular responses by differential stability control of Myc protein isoforms. Such signal integration confers a flexible dynamic range for the system output, governed by stability change. In addition, signal integration may require saturation of the input signals, leading to sensitive signal integration to the temporal features of the input signals, insensitive response to their amplitudes, and resistance to input fluctuations. We further propose that these characteristics of the protein stability control module in Myc may be commonly utilized in various cell types and classes of proteins

Charged Lepton Flavour Violating Radiative Decays ℓi→ℓj+γ\ell_i \to \ell_j + \gamma in See-Saw Models with A4A_4 Symmetry

The charged lepton flavour violating (LFV) radiative decays, $\mu\to e+\gamma$, $\tau\to \mu+\gamma$ and $\tau\to e +\gamma$ are investigated in a class of supersymmetric $A_4$ models with three heavy right-handed (RH) Majorana neutrinos, in which the lepton (neutrino) mixing is predicted to leading order (LO) to be tri-bimaximal. The light neutrino masses are generated via the type I see-saw mechanism. The analysis is done within the framework of the minimal supergravity (mSUGRA) scenario, which provides flavour universal boundary conditions at the scale of grand unification $M_X \approx 2 \times 10^{16}$ GeV. Detailed predictions for the rates of the three LFV decays are obtained in two explicit realisations of the $A_4$ models due to Altarelli and Feruglio and Altarelli and Meloni, respectively.Comment: Results unchanged, minor improvements made; version accepted for publication in JHE