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Background In the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes. Methods Patients 1–18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (< 50 × 10 9 /L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation. Discussion ICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation. Trial registration Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434 . Registered on 11 December 2015

We report structural characterization of proteases mined in silico from solid tannery waste (STW) metagenome. The physico-chemical analysis revealed the molecular weight of selected query proteases in the range of 34–43 kDa except 52.46 kDa for Cp-6. Secondary structure analysis suggested the dominance of α-helices (26–51 %) followed by β-sheets (13–34 %). Conserved regions in the selected proteases were identified using multiple sequence alignment. Diversity analysis of the proteases was performed by aligning with their best hits and already characterized proteases of similar families. The 3D structures of 19 selected amino acid sequences were deduced using homology modeling and evaluated following Ramachandran plots (R-plots), stability of the 3D conformation, and overall quality factor (G factor). The R-plots of all structures had 96.4–98.9 % residues in the favoured region, whereas 0-0.8 % lied in the outlier region. Fifteen modeled protein structures passed the quality assessment criteria and were subsequently used for molecular docking. All models showed two domains except Cp-6, which had an extra domain. Ligand binding sites and active sites were identified using sequence and structural homologs of the respective protease molecules. Serine, lysine, and serine of different conserved motifs were specified as the active site residues in carboxypeptidases, whereas serine, aspartate, and histidine were specific to aminopeptidases Ap-1, Ap-2, and Ap-4. Further, Ap-8 and Ap-9 required Mn2+ for enzyme activity along with histidine and glutamate in their active sites. These 3D structures were used for molecular docking with their specific peptide ligands to obtain stable docked conformations. Successfully docked complexes indicated the catalytic activity of these enzymes in hydrolyzing the peptide ligand. The structural and functional insights gained from our study may help in the identification of novel industrially important proteases after validation through experimental studies.

Background Despite the widespread use of histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs), purified native HRP2 antigen is not standardly used in research applications or assessment of RDTs used in the field. Methods This report describes the purification of native HRP2 (nHRP2) from the HB3 Plasmodium falciparum culture strain. As this culture strain lacks pfhrp3 from its genome , it is an excellent source of HRP2 protein only and does not produce the closely-related HRP3. The nHRP2 protein was isolated from culture supernatant, infected red blood cells (iRBCs), and whole parasite lysate using nickel-metal chelate chromatography. Biochemical characterization of nHRP2 from HB3 culture was conducted by SDS-PAGE and western blotting, and nHRP2 was assayed by RDT, ELISA, and bead-based immunoassay. Results Purified nHRP2 was identified by SDS-PAGE and western blot as a − 60 kDa protein that bound anti-HRP-2 monoclonal antibodies. Mouse anti-HRP2 monoclonal antibody was found to produce high optical density readings between dilutions of 1:100 and 1:3,200 by ELISA with assay signal observed up to a 1:200,000 dilution. nHRP2 yield from HB3 culture by bead-based immunoassay revealed that both culture supernatant and iRBC lysate were practical sources of large quantities of this antigen, producing a total yield of 292.4 µg of nHRP2 from two pooled culture preparations. Assessment of nHRP2 recognition by RDTs revealed that Carestart Pf HRP2 and HRP2/pLDH RDTs detected purified nHRP2 when applied at concentrations between 20.6 and 2060 ng/mL, performing within a log-fold dilution of commercially-available recombinant HRP2. The band intensity observed for the nHRP2 dilutions was equivalent to that observed for P. falciparum culture strain dilutions of 3D7 and US06 F Nigeria XII between 12.5 and 1000 parasites/µL. Conclusions Purified nHRP2 could be a valuable reagent for laboratory applications as well as assessment of new and existing RDTs prior to their use in clinical settings. These results establish that it is possible to extract microgram quantities of the native HRP2 antigen from HB3 culture and that this purified protein is well recognized by existing monoclonal antibody lines and RDTs. Graphical Abstract

Purpose A systematic and repeatable process – Isolate and SEAL – can enable strategists to identify such potentially game-changing operational actions that will support significant business model innovations. Design/methodology/approach The end-to-end Isolate and SEAL process can be demonstrated using a historical review of the emergent strategy that produced the highly successful business model of Southwest Airlines. Findings Instead of trying to decide “what to do” to create an operational advantage, businesses attempting to innovate should first identify the core objective that operationalizes the winning profit logic. Practical implications Southwest fortuitously discovered its innovative profit logic when … Kelleher’ had to exhort his team to figure out how to deliver a four-plane schedule with three planes. Originality/value The potenrially game-changing two-step process: 10; Step 1 – Isolate: split the value chain’s elements into its component parts. 10; Step 2 – SEAL: Reconstruct the value chain using the four actions that effectively deliver the core objectives (Shift in space and time, Eliminate, Alter/Add, Leverage). 10;

Purpose This case study of the strategy of the U.S. grocery chain, ALDI, shows how businesses can use a systematic process to develop and iteratively refine the core strategy powering their business model.” Design/methodology/approach The case describes how ALDI, the upstart entrant established a foothold, a strategy stumble by Walmart, the market leader, provided the newcomer with an attractive opportunity to expand its competitive reach into more upscale neighborhoods. Findings Aldi is continuing to build a business model that allowes it to price its products at an order of magnitude below other grocers and also develop a reputation for private label quality that has ultimately enabled it to challenge leading discount grocers. Social implications Some analysts expect a significant number of supermarket war casualties–more grocery store bankruptcies and liquidations over the next few years. Originality/value ALDI has begun a campaign to offer its customers more value at even lower prices. Other foreign entrants sense their moment has arrived to leap into the fray now that giant Walmart finally seems open to attack. Amazon is experimenting with grocery selling. Recent chain store news headlines tell the breaking story: “Supermarket Wars!”

Abstract Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by memory loss, cognitive deterioration, and neuropsychiatric symptoms. Various drug targets implicated in AD are amyloid beta peptides, cholinesterase enzymes, and anti-amylogenic protein. Medicinal plants derived phytochemical constituents provide a vast pool of diverse compounds as a source of novel drugs. In view of this, the Caesalpinia bonducella seed extract and its active phytoconstituents were used to study the disease-modifying effects in Alzheimer’s disease. The present study successfully demonstrated the therapeutic potential of various phytochemicals as it binds to multiple drug targets, resulting in inhibition of acetylcholinesterase (AChE) enzyme, butyrylcholinesterase (BuChE), BACE-1 enzyme, and anti-amylogenic protein as indicated by docking analysis. In conclusion, phytochemicals identified can be used as a suitable lead to developing a molecule that might have multi-targeted directed ligand (MTDL) potential and disease amelioration effects in Alzheimer’s disease.

The current paper describes the design of a fourth-order compact narrow-band hairpin-line bandpass filter centered at 2.5 GHz and enhanced stopband suppression ~38 dB required for wireless local area network (IEEE802.11b). The size reduction of 24% has been achieved for a conventional hairpin-line filter with a second-order inward folding of the open-end arms with an improvement in the skirt characteristics. However, the folding mechanism has been overshadowed by the presence of spurious harmonics with an attenuation level of <10 dB. Subsequently, L-shaped spurlines with optimum dimensions have been incorporated in the coupled arms of the folded hairpin-line cells. Three fourth-order filters have been designed with the incorporation of spurlines in different coupling regions, fabricated, and tested experimentally. Accordingly, an extended stopband with a rejection level of 38 dB up to 4.48f0 and a size reduction of 18% over the conventional hairpin-line filter has been achieved.

In this paper we theoretically and empirically investigate the idea that firms diversify in part to utilize productive resources which are surplus to current operations Knowledge of these resources allows us to make predictions about the direction of a firm's expansion. In particular, we suggest that excess physical resources, most knowledge-based resources, and external financial resources are associated with more related diversification, while internal financial resources are associated with more unrelated diversification.

Parkinson’s disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50 mg/kg, orally for 13 weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3β through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD. Graphical abstract

In this article, a novel method of fault detection in nonuniformly excited linear antenna array has been reported. This method uses an evolutionary algorithm-based technique to generate approximate radiation pattern in tune with reference faulty pattern for a nonuniformly excited linear antenna array. Based on the approximation, a binary sequence-based method of exact fault detection has been developed. In order to illustrate the effectiveness of the method, 12- and 20-element Dolph Tschebyscheff linear antenna array with amplitude fault has been considered. Superiority of the proposed method has been demonstrated through comparative study.