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Dephosphorylation of pSer51 of the α subunit of translation initiation factor 2 (eIF2αP ) terminates signaling in the integrated stress response (ISR). A trimeric mammalian holophosphatase comprised of a protein phosphatase 1 (PP1) catalytic subunit, the conserved C-terminally located ~70 amino acid core of a substrate-specific regulatory subunit (PPP1R15A/GADD34 or PPP1R15B/CReP) and G-actin (an essential cofactor) efficiently dephosphorylate eIF2αP in vitro. Unlike their viral or invertebrate counterparts, with whom they share the conserved 70 residue core, the mammalian PPP1R15s are large proteins of more than 600 residues. Genetic and cellular observations point to a functional role for regions outside the conserved core of mammalian PPP1R15A in dephosphorylating its natural substrate, the eIF2 trimer. We have combined deep learning technology, all-atom molecular dynamics simulations, X-ray crystallography, and biochemistry to uncover binding of the γ subunit of eIF2 to a short helical peptide repeated four times in the functionally important N terminus of human PPP1R15A that extends past its conserved core. Binding entails insertion of Phe and Trp residues that project from one face of an α-helix formed by the conserved repeats of PPP1R15A into a hydrophobic groove exposed on the surface of eIF2γ in the eIF2 trimer. Replacing these conserved Phe and Trp residues with Ala compromises PPP1R15A function in cells and in vitro. These findings suggest mechanisms by which contacts between a distant subunit of eIF2 and elements of PPP1R15A distant to the holophosphatase active site contribute to dephosphorylation of eIF2αP by the core PPP1R15 holophosphatase and to efficient termination of the ISR in mammals. [ABSTRACT FROM AUTHOR]

This article proposes a discrete‐time design for the robust control technique of uncertainty and disturbance estimator (UDE), with studies on applications to real‐world systems. Despite the ease of implementation of discrete‐time strategies, almost all prior work on UDE is for designing continuous‐time control laws, with no general, complete research for discrete‐time design. To design an appropriate discrete‐time control law, a novel digital filter similar to the original analog filter for disturbance estimation is designed, a discrete‐time error‐based control law is derived, and a detailed stability analysis is provided. However, most real‐world, physical systems are nonlinear and continuous‐time in nature. Thus, the techniques of sampling and digital‐analog (D/A) conversion are used, enabling the control of linear, time‐invariant as well as a class of nonlinear, continuous‐time systems using discrete‐time UDE. The considered nonlinear system is for the phenomenon of wing‐rock motion. Simulations are performed for the proposed techniques, and results indicate highly accurate stabilization and tracking performance, with excellent disturbance rejection. In particular, it is seen that the proposed control law is less sensitive to initial values of the error when compared to the original continuous‐time UDE law. [ABSTRACT FROM AUTHOR]

Recent research has shown that the prevalence of stroke incidents and the number of survivors in developing countries surpass those from developed countries. This study aimed to enumerate the prevalence of post-stroke psychiatric and cognitive symptoms among stroke survivors from West and South Asia and Africa through a systematic review and meta-analysis. Data from each country was systematically acquired from five major databases (PsycINFO, Web of Science, Scopus, PubMed/Medline, and Google Scholar (for any missing articles and grey literature)). Meta-analytic techniques were then used to estimate the prevalence of various post-stoke psychiatric and cognitive symptoms. A total of 36 articles were accrued from 11 countries, of which 25 were evaluated as part of the meta-analysis. The pooled prevalence of post-stroke depression as per the Hospital Anxiety and Depression Scale (HADS), Hamilton Depression Rating Scale, Patient Health Questionnaire, Schedules for Clinical Assessment in Neuropsychiatry (SCAN), Geriatric Depression Scale, and the Montgomery–Asberg Depression Rating Scale ranged from 28.00 to 50.24%. Pooled prevalence of post-stroke anxiety based on the HADS and SCAN was 44.19% and 10.96%, respectively. The pooled prevalence of post-stroke cognitive impairment as per the Mini-Mental Status Examination was 16.76%. This present review has suggested that both psychiatric and cognitive symptoms are common among stroke survivors. Concerted efforts are needed to institute robust studies using culturally sensitive measures to contemplate mechanisms that address the unmet needs of this vulnerable population. [ABSTRACT FROM AUTHOR]