Hierarchical Optimal Force-Position Control of a Turning Process

Machining process control technologies are currently not well integrated into machine tool controllers and, thus, servomechanism dynamics are often ignored when designing and implementing process controllers. In this brief, a hierarchical controller is developed that simultaneously regulates the servomechanism motions and cutting forces in a turning operation. The force process and servomechanism system are separated into high and low levels, respectively, in the hierarchy. The high-level goal is to maintain a constant cutting force to maximize productivity while not violating a spindle power constraint. This goal is systematically propagated to the lower level and combined with the low-level goal to track the reference position. Since the only control signal (i.e., motor voltage) resides at the lower level, a single controller is designed at the bottom level that simultaneously meets both the high- and low-level goals. Simulations are conducted that validate the developed methodology. The results illustrate that the controller can simultaneously achieve the low-level position tracking goal and the high-level force-tracking goal

Hierarchical Optimal Control of a Turning Process - Linearization Approach

Machining process control technologies are currently not well integrated into machine tool controllers and, thus, servomechanism dynamics are often ignored when designing and implementing process controllers. In this paper, a hierarchical controller is developed that simultaneously regulates the servomechanism positions and cutting forces in a lathing operation. The force process and servomechanism system are separated into high and low levels, respectively, in the hierarchy. The high level goal is to maintain a constant cutting force to maximize productivity while not violating a spindle power constraint. This goal is systematically propagated to the lower level and combined with the low level goal to track the reference position. Since there are only control signals at the lower level, in this case the motor voltages, a single controller is designed at the bottom level that will meet both the high level and low level goals. Simulations are conducted to validate the developed methodology

Sustained release of anticancer agent phytic acid from its chitosan-coated magnetic nanoparticles for drug-delivery system

Chitosan (CS) iron oxide magnetic nanoparticles (MNPs) were coated with phytic acid (PTA) to form phytic acid-chitosan-iron oxide nanocomposite (PTA-CS-MNP). The obtained nanocomposite and nanocarrier were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, vibrating sample magnetometry, transmission electron microscopy, and thermogravimetric and differential thermogravimetric analyses. Fourier transform infrared spectra and thermal analysis of MNPs and PTA-CS-MNP nanocomposite confirmed the binding of CS on the surface of MNPs and the loading of PTA in the PTA-CS-MNP nanocomposite. The coating process enhanced the thermal stability of the anticancer nanocomposite obtained. X-ray diffraction results showed that the MNPs and PTA-CS-MNP nanocomposite are pure magnetite. Drug loading was estimated using ultraviolet-visible spectroscopy and showing a 12.9% in the designed nanocomposite. Magnetization curves demonstrated that the synthesized MNPs and nanocomposite were superparamagnetic with saturation magnetizations of 53.25 emu/g and 42.15 emu/g, respectively. The release study showed that around 86% and 93% of PTA from PTA-CS-MNP nanocomposite could be released within 127 and 56 hours by a phosphate buffer solution at pH 7.4 and 4.8, respectively, in a sustained manner and governed by pseudo-second order kinetic model. The cytotoxicity of the compounds on HT-29 colon cancer cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The HT-29 cell line was more sensitive against PTA-CS-MNP nanocomposite than PTA alone. No cytotoxic effect was observed on normal cells (3T3 fibroblast cells). This result indicates that PTA-CS-MNP nanocomposite can inhibit the proliferation of colon cancer cells without causing any harm to normal cell

Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health.

Many essential biological processes including cell regulation and signalling are mediated through the assembly of protein complexes. Changes to protein-protein interaction (PPI) interfaces can affect the formation of multiprotein complexes, and consequently lead to disruptions in interconnected networks of PPIs within and between cells, further leading to phenotypic changes as functional interactions are created or disrupted. Mutations altering PPIs have been linked to the development of genetic diseases including cancer and rare Mendelian diseases, and to the development of drug resistance. The importance of these protein mutations has led to the development of many resources for understanding and predicting their effects. We propose that a better understanding of how these mutations affect the structure, function, and formation of multiprotein complexes provides novel opportunities for tackling them, including the development of small-molecule drugs targeted specifically to mutated PPIs.H.J. is currently funded by an Astex Pharmaceuticals Sustaining Innovation Postdoctoral Fellowship hosted at the Wellcome Trust Sanger Institute. M.A.T was supported by scholarships from Promega Corporation, as well as the College of Agricultural and Life Sciences and the Department of Biochemistry at the University of Wisconsin-Madison, USA. B.O.M was supported by the Bill and Melinda Gates Foundation. D.B.A is the recipient of a C. J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476) and is funded by the Wellcome Trust and Jack Brockhoff Foundation (JBF 4186, 2016). T.L.B. receives funding from the University of Cambridge and The Wellcome Trust for facilities and support

SDM: a server for predicting effects of mutations on protein stability

Here, we report a webserver for the improved SDM, used for predicting the effects of mutations on protein stability. As a pioneering knowledge-based approach, SDM has been highlighted as the most appropriate method to use in combination with many other approaches. We have updated the environment-specific amino-acid substitution tables based on the current expanded PDB (a 5-fold increase in information), and introduced new residue-conformation and interaction parameters, including packing density and residue depth. The updated server has been extensively tested using a benchmark containing 2690 point mutations from 132 different protein structures. The revised method correlates well against the hypothetical reverse mutations, better than comparable methods built using machine-learning approaches, highlighting the strength of our knowledge-based approach for identifying stabilising mutations. Given a PDB file (a Protein Data Bank file format containing the 3D coordinates of the protein atoms), and a point mutation, the server calculates the stability difference score between the wildtype and mutant protein. The server is available at http://structure.bioc.cam.ac.uk/sdm2Gates HIT-TB and the EU MM4TB [Project ID: 260872 to A.P.P. and T.L.B.]; Bill & Melinda Gates Foundation [RG60453 to B.O.M.]; Jack Brockhoff Foundation [JBF 4186, 2016 to D.B.A.]; C.J. Martin Research Fellowship from the National Health and Medical Research Council of Australia [APP1072476]; Wellcome Trust Programme Grant [093167/Z/10/Z to D.B.A., T.L.B.]; Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) [MR/M026302/1]. Funding for open access charge: Bill & Melinda Gates Foundation [RG60453] Gates HIT-TB; Wellcome Trust Programme Grant [093167/Z/10/Z]; Newton Fund RCUK-CONFAP Grant awarded by the Medical Research Council (MRC) [MR/M026302/1

Google matrix of business process management

Development of efficient business process models and determination of their characteristic properties are subject of intense interdisciplinary research. Here, we consider a business process model as a directed graph. Its nodes correspond to the units identified by the modeler and the link direction indicates the causal dependencies between units. It is of primary interest to obtain the stationary flow on such a directed graph, which corresponds to the steady-state of a firm during the business process. Following the ideas developed recently for the World Wide Web, we construct the Google matrix for our business process model and analyze its spectral properties. The importance of nodes is characterized by Page-Rank and recently proposed CheiRank and 2DRank, respectively. The results show that this two-dimensional ranking gives a significant information about the influence and communication properties of business model units. We argue that the Google matrix method, described here, provides a new efficient tool helping companies to make their decisions on how to evolve in the exceedingly dynamic global market.Comment: submitted to European Journal of Physics

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity

BACKGROUND: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported. METHODS: To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein. RESULTS:Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3' replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5'-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol. CONCLUSION: These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages

Human CD79b⁺ neutrophils in the blood are associated with early-stage melanoma.

PurposeDue to their abundance in the blood, low RNA content, and short lifespan, neutrophils have been classically considered to be one homogenous pool. However, recent work has found that mature neutrophils and neutrophil progenitors are composed of unique subsets exhibiting context-dependent functions. In this study, we ask if neutrophil heterogeneity is associated with melanoma incidence and/or disease stage.Experimental designUsing mass cytometry, we profiled melanoma patient blood for unique cell surface markers among neutrophils. Markers were tested for their predictiveness using flow cytometry data and random forest machine learning.ResultsWe identified CD79b+ neutrophils (CD3-CD56-CD19-Siglec8-CD203c-CD86LoCD66b+CD79b+) that are normally restricted to the bone marrow in healthy humans but appear in the blood of subjects with early-stage melanoma. Further, we found CD79b+ neutrophils present in tumors of subjects with head and neck cancer. AI-mediated machine learning analysis of neutrophils from subjects with melanoma confirmed that CD79b expression among peripheral blood neutrophils is highly important in identifying melanoma incidence. We noted that CD79b+ neutrophils possessed a neutrophilic appearance but have transcriptional and surface-marker phenotypes reminiscent of B cells. Compared to remaining blood neutrophils, CD79b+ neutrophils are primed for NETosis, express higher levels of antigen presentation-related proteins, and have an increased capacity for phagocytosis.ConclusionOur work suggests that CD79b+ neutrophils are associated with early-stage melanoma