Identification and prioritization of performance for trade decisions indicators: an application of Value Focused Thinking and Analytic Network Process

Abstract The development of a Performance Measurement System (PMS) in an organization is essential in order to adequately monitor operations and enable correct and timely decision-making. However, many organizations implement PMSs and are not successful, mainly because they neglect the design phase, which informs what has to be measured. Designing a PMS is a complex decision problem that involves multiple stakeholders. The objective of this research is to identify and prioritize the commercial performance indicators most valued by the stakeholders in this area in a company in the metal-mechanical segment. The research was divided into two stages, the first being a PO Soft (constructivist) approach: Value Focused Thinking - VFT, to identify performance indicators; and, in the second stage, the application of the PO Hard (Rationalist) Multicriteria Decision Support Method: Analytic Network Process - ANP, for modeling and prioritizing these. As a result, 30 performance indicators were identified, the most important ones being: percentage of target achievement, sales to new customers and percentage of growth for each customer. The results found proved to be capable of assisting the definition of strategy and business management in addition to the identification of indicators not monitored by the organization

Structural insights into Escherichia coli phosphopantothenoylcysteine synthetase by native ion mobility-mass spectrometry.

CoaBC, part of the vital coenzyme A biosynthetic pathway in bacteria, has recently been validated as a promising antimicrobial target. In this work, we employed native ion mobility-mass spectrometry to gain structural insights into the phosphopantothenoylcysteine synthetase domain of E. coli CoaBC. Moreover, native mass spectrometry was validated as a screening tool to identify novel inhibitors of this enzyme, highlighting the utility and versatility of this technique both for structural biology and for drug discovery

Increased bursting glutamatergic neurotransmission in an auditory forebrain area of the zebra finch (Taenopygia guttata) induced by auditory stimulation

The caudomedial nidopallium (NCM) is a telencephalic area involved in auditory processing and memorization in songbirds, but the synaptic mechanisms associated with auditory processing in NCM are largely unknown. To identify potential changes in synaptic transmission induced by auditory stimulation in NCM, we used a slice preparation for path-clamp recordings of synaptic currents in the NCM of adult zebra finches (Taenopygia guttata) sacrificed after sound isolation followed by exposure to conspecific song or silence. Although post-synaptic GABAergic and glutamatergic currents in the NCM of control and song-exposed birds did not present any differences regarding their frequency, amplitude and duration after song exposure, we observed a higher probability of generation of bursting glutamatergic currents after blockade of GABAergic transmission in song-exposed birds as compared to controls. Both song-exposed males and females presented an increase in the probability of the expression of bursting glutamatergic currents, however bursting was more commonly seen in males where they appeared even without blocking GABAergic transmission. Our data show that song exposure changes the excitability of the glutamatergic neuronal network, increasing the probability of the generation of bursts of glutamatergic currents, but does not affect basic parameters of glutamatergic and GABAergic synaptic currents.Fundacao de Pesquisa do Estado de Sao PauloFundacao de Pesquisa do Estado de Sao Paulo [03/0419-0]National Institute of HealthFogarty International Collaborative Research AwardNational Institute of Health-Fogarty International Collaborative Research Award [TW006955]Coordenacao de Aperfeicoamento de Pessoal de Nivel SuperiorCoordenacao de Aperfeicoamento de Pessoal de Nivel Superio

Control of phasic firing by a background leak current in avian forebrain auditory neurons

Central neurons express a variety of neuronal types and ion channels that promote firing heterogeneity among their distinct neuronal populations. Action potential (AP) phasic firing, produced by low-threshold voltage activated potassium currents (VAKCs), is commonly observed in mammalian brainstem neurons involved in the processing of temporal properties of the acoustic information. The avian caudomedial nidopallium (NCM) is an auditory area analogous to portions of the mammalian auditory cortex that is involved in the perceptual discrimination and memorization of birdsong and shows complex responses to auditory stimuli We performed in vitro whole-cell patch-clamp recordings in brain slices from adult zebra finches (Taeniopygia guttata) and observed that half of NCM neurons fire APs phasically in response to membrane depolarizations, while the rest fire transiently or tonically. Phasic neurons fired APs faster and with more temporal precision than tonic and transient neurons. These neurons had similar membrane resting potentials, but phasic neurons had lower membrane input resistance and time constant. Surprisingly phasic neurons did not express low-threshold VAKCs, which curtailed firing in phasic mammalian brainstem neurons, having similar VAKCs than the other NCM neurons. The phasic firing was determined not by VAKCs, but by the potassium background leak conductances, which was more prominently expressed in phasic neurons, a result corroborated by pharmacological, dynamic-clamp and modeling experiments. These results reveal a new role for leak currents in generating firing diversity in central neurons

Inhibitory network interactions shape the auditory processing of natural communication signals in the songbird auditory forebrain

The role of GABA in the central processing of complex auditory signals is not fully understood. We have studied the involvement of GABA(A)-mediated inhibition in the processing of birdsong, a learned vocal communication signal requiring intact hearing for its development and maintenance. We focused on caudomedial nidopallium (NCM), an area analogous to parts of the mammalian auditory cortex with selective responses to birdsong. We present evidence that GABA(A)-mediated inhibition plays a pronounced role in NCM`s auditory processing of birdsong. Using immunocytochemistry, we show that approximately half of NCM`s neurons are GABAergic. Whole cell patch-clamp recordings in a slice preparation demonstrate that, at rest, spontaneously active GABAergic synapses inhibit excitatory inputs onto NCM neurons via GABA(A) receptors. Multi-electrode electrophysiological recordings in awake birds show that local blockade of GABA(A)-mediated inhibition in NCM markedly affects the temporal pattern of song-evoked responses in NCM without modifications in frequency tuning. Surprisingly, this blockade increases the phasic and largely suppresses the tonic response component, reflecting dynamic relationships of inhibitory networks that could include disinhibition. Thus processing of learned natural communication sounds in songbirds, and possibly other vocal learners, may depend on complex interactions of inhibitory networks

Structural insights into Escherichia coli phosphopantothenoylcysteine synthetase by native ion mobility-mass spectrometry

CoaBC, part of the vital coenzyme A biosynthetic pathway in bacteria, has recently been validated as a promising antimicrobial target. In this work, we employed native ion mobility–mass spectrometry to gain structural insights into the phosphopantothenoylcysteine synthetase domain of E. coli CoaBC. Moreover, native mass spectrometry was validated as a screening tool to identify novel inhibitors of this enzyme, highlighting the utility and versatility of this technique both for structural biology and for drug discovery.D.S.H.C. acknowledges the support of the Croucher Foundation and the Cambridge Commonwealth, European and International Trust for receipt of a Croucher Cambridge International Scholarship. J.H. was financially supported by the Swiss National Science Foundation (SNSF Early PostDoc. Mobility fellowship, P2ZHP2_164947) and the EU H2020 Framework Programme (H2020-MSCA-IF-2017, ID: 789607) M.V.B.D., C.D., C.S., R.K. and V.M. would like to thank the Bill and Melinda Gates Foundation for funding (SHORTEN-TB OPP1158806). C.S. would also like to thank the National Health and Medical Research Council (Australia) for a NHMRC Overseas Biomedical Fellowship (1016357)

Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action

Selective Aurora A‑TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents

Publication status: PublishedAurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein–protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action