PIM kinase-responsive microsecond-lifetime photoluminescent probes based on selenium-containing heteroaromatic tricycle

Microsecond-lifetime binding-responsive organic photoluminescent probes for PIM kinases were developed based on selenium-comprising heteroaromatic tricycle.</p

Benzoselenadiazole-based responsive long-lifetime photoluminescent probes for protein kinases

Benzoselenadiazole-containing inhibitors of protein kinases were constructed and their capability to emit phosphorescence in the kinase-bound state was established. Labelling of the inhibitors with a red fluorescent dye led to sensitive responsive photoluminescent probes for protein kinase CK2 that emitted red light with a long (microsecond-scale) decay time upon excitation of the probes with a pulse of near-UV light

Microbiome Analysis of the Rhizosphere from Wilt Infected Pomegranate Reveals Complex Adaptations in Fusarium—A Preliminary Study

Wilt disease affecting pomegranate crops results in rapid soil-nutrient depletion, reduced or complete loss in yield, and crop destruction. There are limited studies on the phytopathogen Fusarium oxysporum prevalence and associated genomic information with respect to Fusarium wilt in pomegranate. In this study, soil samples from the rhizosphere of different pomegranate plants showing early stage symptoms of wilt infection to an advanced stage were collected from an orchard situated in Karnataka, India. A whole metagenome sequencing approach was employed to gain insights into the adaptations of the causative pathogen F. oxysporum. Physicochemical results showed a drop in the pH levels, N, Fe, and Mn, and increase in electrical conductivity, B, Zn, Cl, Cu was observed in the early and intermediate stage samples. Comparative abundance analysis of the experimental samples ESI and ISI revealed an abundance of Proteobacteria phyla Achromobacter sp. 2789STDY5608625, Achromobacter sp. K91, and Achromobacter aegrifaciens and Eukaryota namely Aspergillus arachidicola, Aspergillus candidus, and Aspergillus campestris. Functional pathway predictions implied carbohydrate binding to be significant (p &lt; 0.05) among the three experimental samples. Microbiological examination and whole microbiome analysis confirmed the prevalence of F. oxysporum in the soil samples. Variant analysis of F. oxysporum revealed multiple mutations in the 3IPD gene with high impact effects. 3-Isopropylmalate dehydratase and carbohydrate-active enzymes could be good targets for the development of antifungals that could aid in biocontrol of F. oxysporum. The present study demonstrates the capabilities of the whole metagenome sequencing approach for rapid identification of potential key players of wilt disease pathogenesis wherein the symptomatology is complex

Unexpected CK2 beta-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2

Protein kinase CK2, a heterotetrameric holoenzyme composed of two catalytic chains (CK2 alpha) attached to a homodimer of regulatory subunits (CK2 beta), is a target for drug development for cancer therapy. Here, we describe the tetraiodobenzimidazole derivative ARC-3140, a bisubstrate inhibitor addressing the ATP site and the substrate-binding site of CK2 with extraordinary affinity (K-i = 84 pM). In a crystal structure of ARC-3140 in complex with CK2 alpha, three copies of the inhibitor are visible, one of them at the CK2 beta interface of CK2 alpha. Subsequent interaction studies based on microscale thermophoresis and fluorescence anisotropy changes revealed a significant impact of ARC-3140 and of its tetrabromo equivalent ARC-1502 on the CK2 alpha/CK2 beta interaction. A structural inspection revealed that ARC-3140, unlike CK2 beta antagonists described so far, interferes with both sub-interfaces of the bipartite CK2 alpha/CK2 beta interaction. Thus, ARC-3140 is a lead for the further development of highly effective compounds perturbating the quaternary structure of the CK2 alpha(2)beta(2) holoenzyme

Crystal structure-guided design of bisubstrate inhibitors and photoluminescent probes for protein kinases of the PIM family

We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg)6 fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. The new inhibitors were derivatized with biotin or fluorescent dye Cy5 and then applied for the detection of PIM kinases in biochemical solutions and in complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of active recombinant PIM-2). Fluorescent probes were efficiently taken up by U2OS cells and showed a high extent of co-localization with PIM-1 fused with a fluorescent protein. Overall, the developed inhibitors and derivatives represent versatile chemical tools for studying PIM function in cellular systems in normal and disease physiology

All India Difficult Airway Association 2016 guidelines for the management of unanticipated difficult tracheal intubation in obstetrics

The various physiological changes in pregnancy make the parturient vulnerable for early and rapid desaturation. Severe hypoxaemia during intubation can potentially compromise two lives (mother and foetus). Thus tracheal intubation in the pregnant patient poses unique challenges, and necessitates meticulous planning, ready availability of equipment and expertise to ensure maternal and foetal safety. The All India Difficult Airway Association (AIDAA) proposes a stepwise plan for the safe management of the airway in obstetric patients. These guidelines have been developed based on available evidence; wherever robust evidence was lacking, recommendations were arrived at by consensus opinion of airway experts, incorporating the responses to a questionnaire sent to members of the AIDAA and the Indian Society of Anaesthesiologists (ISA). Modified rapid sequence induction using gentle intermittent positive pressure ventilation with pressure limited to ≤20 cm H 2 O is acceptable. Partial or complete release of cricoid pressure is recommended when face mask ventilation, placement of supraglottic airway device (SAD) or tracheal intubation prove difficult. One should call for early expert assistance. Maternal SpO 2 should be maintained ≥95%. Apnoeic oxygenation with nasal insufflation of 15 L/min oxygen during apnoea should be performed in all patients. If tracheal intubation fails, a second- generation SAD should be inserted. The decision to continue anaesthesia and surgery via the SAD, or perform fibreoptic-guided intubation via the SAD or wake up the patient depends on the urgency of surgery, foeto-maternal status and availability of resources and expertise. Emergency cricothyroidotomy must be performed if complete ventilation failure occurs