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Addresses the problem of scheduling a set of N final products on M machines in a job shop environment that involve both machining and assembly operations. Minimization of production flow time; Development of a mathematical model to obtain optimal solutions.

Introduction: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent., Methods: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology., Results: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm 3 ) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm 3 ) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %)., Conclusion: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN., Competing Interests: Declaration of competing interest Dr. Deanna Kelly serves on an advisory board for Alkermes, Teva, and Janssen. Dr. Richard Adebayo has served on the advisory boards of Janssen and a consultant for Invega product. Dr. Raymond Loves serves as a consultant for the Maryland Department of Health and the SMI Advisor, American Psychiatric Association. Dr. Sophie Lanzkron has served as an advisor for Bluebird bio, Novo Nordisk, Pfizer, Novartis and Magenta. She has research funding from Imana, Novartis, GBT, Takeda, CSL-Behring, HRSA, PCORI, MD CHRC. Dr. Robert Buchanan has served on the advisory board for Acadia, Merck and Neurocranial, is a consultant for Boehringer-Ingelheim, and is on DSMB for Merck, Negron, and Roche. All other authors have no conflicts to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Transient receptor potential canonical type 6 (TRPC6) is a non-voltage-gated channel that principally conducts calcium. Elevated channel activation contributes to fibrosis, hypertrophy, and proteinuria, often coupled to stimulation of nuclear factor of activated T-cells (NFAT). TRPC6 is post-translationally regulated, but a role for O-linked β-N-acetyl glucosamine (O-GlcNAcylation) as elevated by diabetes, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated at Ser14, Thr70, and Thr221 in the N-terminus ankryn-4 (AR4) and linker (LH1) domains. Mutagenesis to alanine reveals T221 as a critical controller of resting TRPC6 conductance, and associated NFAT activity and pro-hypertrophic signaling. T→A mutations at sites homologous in closely related TRPC3 and TRPC7 also increases their activity. Molecular modeling predicts interactions between Thr221- O -GlcNAc and Ser199, Glu200, and Glu246, and combined alanine substitutions of the latter similarly elevates resting NFAT activity. Thus, O-GlcNAcylated T221 and interactions with coordinating residues is required for normal TRPC6 channel conductance and NFAT activation., Competing Interests: D.A.K. receives grant support from Boehringer Ingelheim pursuing the use of a selective TRPC6 antagonist for treatment of Duchenne Muscular Dystrophy., (© 2023 The Authors.)

Tuberous sclerosis complex-2 (TSC2) negatively regulates mammalian target of rapamycin complex 1 (mTORC1), and its activity is reduced by protein kinase B (Akt) and extracellular response kinase (ERK1/2) phosphorylation to activate mTORC1. Serine 1364 (human) on TSC2 bidirectionally modifies mTORC1 activation by pathological growth factors or hemodynamic stress but has no impact on resting activity. We now show this modification biases to ERK1/2 but not Akt-dependent TSC2-mTORC1 activation. Endothelin-1-stimulated mTORC1 requires ERK1/2 activation and is bidirectionally modified by phospho-mimetic (S1364E) or phospho-silenced (S1364A) mutations. However, mTORC1 activation by Akt-dependent stimuli (insulin or PDGF) is unaltered by S1364 modification. Thrombin stimulates both pathways, yet only the ERK1/2 component is modulated by S1364. S1364 also has negligible impact on mTORC1 regulation by energy or nutrient status. In vivo, diet-induced obesity, diabetes, and fatty liver couple to Akt activation and are also unaltered by TSC2 S1364 mutations. This contrasts to prior reports showing a marked impact of both on pathological pressure-stress. Thus, S1364 provides ERK1/2-selective mTORC1 control and a genetic means to modify pathological versus physiological mTOR stimuli., (© 2022 Dunkerly-Eyring et al.)

In the title compound, C22H26O2, the aromatic rings are inclined to one another by 8.39 (9)° and the mol-ecule has an E conformation about the C=C bond. In the crystal, mol-ecules stack head-to-tail along the b-axis direction. They are linked by very weak C-H⋯O contacts, forming C(4) chains along [100]. Two chains are linked by a pair of very weak C-H⋯O contacts, enclosing inversion-dimeric R 2 (2)(8) ring motifs. There are also C-H⋯π inter-actions present, which link the double-stranded chains, forming a two-dimensional network.