111 research outputs found

    The compatibility of modern slaughter techniques with Halal slaughter:A review of the aspects of “modern” slaughter methods that divide scholarly opinion within the Muslim community

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    AbstractThe continuous expansion of the global halal meat market has attracted interest from governments, food business operators and the animal and meat science research fraternity. Despite this growing trend, and the enormous economic benefits associated with it, there is a lack of clarity regarding what is ‘authentic’ halal. Many Islamic jurists are reluctant to approve animal slaughter methods that were not practiced at the time of the Prophet of Islam, Mohammed. Others insist that since Islam holds animal welfare in high regard, any modern method of slaughter that is shown to improve animal welfare without compromising on the basic requirements of halal slaughter can be approved for halal production. This paper highlights the aspects of modern slaughter that continues to divide scholarly opinion among Islamic jurists. It also examines the arguments put forward by opponents and proponents regarding the acceptability of modern slaughter techniques for halal slaughter.</jats:p

    Oncogenic RET Kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans

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    To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation

    Concern for the ingroup and opposition to affirmative action.

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    The present experiments suggest that the desire to benefit the in-group drives dominant-group members&apos; policy preferences, independent of concern for out-groups&apos; outcomes. In Experiment 1, the effect of a manipulation of affirmative action procedures on policy support was mediated by how Whites expected the policy to affect fellow Whites, but not by the expected effect on minorities. In Experiments 2 and 3, when focused on losses for the White in-group, Whites&apos; racial identity was negatively related to support for affirmative action. However, when focused on gains for the Black out-group or when participants were told that Whites were not affected by the policy, racial identity did not predict attitudes toward the policy. In Experiments 2 and 3, perceived fairness mediated these effects

    Structure and Chemical Inhibition of the Ret Tyrosine Kinase Domain.

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    The RET proto-oncogene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of ligands. Loss-of-function mutations in RET are implicated in Hirschsprung disease, whereas activating mutations in RET are found in human cancers, including familial medullar thyroid carcinoma and multiple endocrine neoplasias 2A and 2B. We report here the biochemical characterization of the human RET tyrosine kinase domain and the structure determination of the non-phosphorylated and phosphorylated forms. Both structures adopt the same active kinase conformation competent to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status. In agreement with the structural data, enzyme kinetic data show that autophosphorylation produces only a modest increase in activity. Longer forms of RET containing the juxtamembrane domain and C-terminal tail exhibited similar kinetic behavior, implying that there is no cis-inhibitory mechanism within the RET intracellular domain. Our results suggest the existence of alternative inhibitory mechanisms, possibly in trans, for the autoregulation of RET kinase activity. We also present the structures of the RET tyrosine kinase domain bound to two inhibitors, the pyrazolopyrimidine PP1 and the clinically relevant 4-anilinoquinazoline ZD6474. These structures explain why certain multiple endocrine neoplasia 2-associated RET mutants found in patients are resistant to inhibition and form the basis for design of more effective inhibitors

    Structure of the MlaC-MlaD complex reveals molecular basis of periplasmic phospholipid transport

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    The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. It acts by removing ectopic lipids from the outer leaflet of the outer membrane and returning them to the inner membrane through three proteinaceous assemblies: the MlaA-OmpC complex, situated within the outer membrane; the periplasmic phospholipid shuttle protein, MlaC; and the inner membrane ABC transporter complex, MlaFEDB, proposed to be the founding member of a structurally distinct ABC superfamily. While the function of each component is well established, how phospholipids are exchanged between components remains unknown. This stands as a major roadblock in our understanding of the function of the pathway, and in particular, the role of ATPase activity of MlaFEDB is not clear. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD ÎČ6-ÎČ7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD

    Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

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    Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors
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