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The article describes five incidents related to human nature and philosophy. These incidents are: A man who is really a dog does not do well, is slow and clumsy though extremely good natured. There is also a dog who is really a man and is tormented by his inability to handle things and to express himself and thus cannot be good natured but is sly and furtive and ashamed of himself. He is hated by everyone and kicked into the corner of the room. The great Grandmothers were forgotten by everyone for a very long time. It was too late, their gnarled hands had grown into the wood of their cane handles, their lips had cleaved together into one membrane, their eyeballs had hardened and were immovably focused out or the chestnut grove where the children were flashing to and fro. Only old Agnes had a little life left in her. A man has been making deliveries in the garment district for years now every morning he takes the same garments on a moving rack through the streets to a shop and every evening takes them back again to the warehouse This happens because there is a dispute between the shop and the warehouse which cannot be settled.

The short story "Flaubert and Point of View," by Lydia Davis is presented.

The short story "Staying at the Pharmacist's," by Lydia Davis is presented.

The molecular mechanisms required for inositol 1,4,5trisphosphate receptor (InsP3R) targeting to specialized endoplasmic reticulum membrane domains are unknown. We report here a direct, high affinity interaction between InsP3R and ankyrin-B and demonstrate that this association is critical for InsP3R post-translational stability and localization in cultures of neonatal cardiomyocytes. Recombinant ankyrin-B membrane-binding domain directly interacts with purified cerebellar InsP3R (Kd = 2 nM). 220-kDa ankyrin-B co-immunoprecipitates with InsP3R in tissue extracts from brain, heart, and lung. Alanine-scanning mutagenesis of the ankyrin-B ANK (ankyrin repeat) repeat β-hairpin loop tips revealed that consecutive ANK repeat β-hairpin loop tips (repeats 22-24) are required for InsP3R interaction, thus providing the first detailed evidence of how ankyrin polypeptides associate with membrane proteins. Pulse-chase biosynthesis experiments demonstrate that reduction or loss of ankyrin-B in ankyrin-B (+/-) or ankyrin-B (-/-) neonatal cardiomyocytes leads to ∼3-fold reduction in half-life of newly synthesized InsP3R. Furthermore, interactions with ankyrin-B are required for InsP3R stability as abnormal InsP3R phenotypes, including mis-localization, and reduced halflife in ankyrin-B (+/-) cardiomyocytes can be rescued by green fluorescent protein (GFP)-220-kDa ankyrin-B but not by GFP-220-kDa ankyrin-B mutants, which do not associate with InsP3R. These new results provide the first physiological evidence of a molecular partner required for early post-translational stability of InsP3R. [ABSTRACT FROM AUTHOR]

Ankyrins are a family of adapter proteins required for localization of membrane proteins to diverse specialized membrane domains including axon initial segments, specialized sites at the transverse tubule/sarcoplasmic reticulum in cardiomyocytes, and lateral membrane domains of epithelial cells. Little is currently known regarding the molecular basis for specific roles of different ankyrin isoforms. In this study, we systematically generated alanine mutants of clusters of charged residues in the spectrin-binding domains of both ankyrin-B and -G. The corresponding mutants were evaluated for activity in either restoration of abnormal localization of the inositol trisphosphate receptor in the sarcoplasmic reticulum in mutant mouse car- diomyocytes deficient in ankyrin-B or in prevention of loss of lateral membrane in human bronchial epithelial cells depleted of ankyrin-G by small interfering RNA. Interestingly, ankyrin-B and -G share two homologous sites that result in loss of function in both systems, suggesting that common molecular interactions underlie diverse roles of these isoforms. Ankyrins G and B also exhibit differences; mutations affecting spectrin binding had no effect on ankyrin-B function but did abolish activity of ankyrin-G in restoring lateral membrane biogenesis. Depletion of β2-spectrin by small interfering RNA phenocopied depletion of ankyrin-G and resulted in a failure to form new lateral membrane in interphase and mitotic cells. These results demonstrate that ankyrin-G and β2-spectrin are functional partners in biogenesis of the lateral membrane of epithelial cells. [ABSTRACT FROM AUTHOR]

The product encoded by the X-linked inhibitor of apoptosis (XIAP) gene is a multi-functional protein which not only controls caspase-dependent cell death, but also participates in inflammatory signalling, copper homeostasis, response to hypoxia and control of cell migration. Deregulation of XIAP, either by elevated expression or inherited genetic deletion, is associated with several human disease states. Reconciling XIAP-dependent signalling pathways with its role in disease progression is essential to understand how XIAP promotes the progression of human pathologies. In this study we have created a panel of genetically modified XIAP-null cell lines using TALENs and CRISPR/Cas9 to investigate the functional outcome of XIAP deletion. Surprisingly, in our genetically modified cells XIAP deletion had no effect on programmed cell death, but instead the primary phenotype we observed was a profound increase in cell migration rates. Furthermore, we found that XIAP-dependent suppression of cell migration was dependent on XIAPdependent control of C-RAF levels, a protein kinase which controls cell signalling pathways that regulate the cytoskeleton. These results suggest that XIAP is not necessary for control of the apoptotic signalling cascade, however it does have a critical role in controlling cell migration and motility that cannot be compensated for in XIAP-knockout cells., (© 2022. The Author(s).)

Background: The communication skills of older adults living in care homes is an underexplored topic. Ageing can lead to reduced communication ability and activity; and in the care home environment there may also be fewer communication opportunities. This situation is likely to negatively impact well-being. Previous reviews have found evidence of the effectiveness of behavioural interventions in increasing well-being, but no systematic review to date has focused specifically on the evidence base for group language and communication interventions in this population., Aims: To identify and evaluate the evidence for behavioural interventions with older adults, delivered in groups in care homes, that specifically included a language or communication activity. To explore the impact of such intervention on the specific domains of language, communication and social interaction. To determine whether behavioural mechanisms of action can be identified., Methods & Procedures: Embase, Medline, Ovid Nursing database, Psych info and CINAHL complete were searched and produced 158 records for screening, of which 22 remained for review. In order to identify and evaluate the quality of the evidence base presented the following research questions were posed: What research has been conducted in this area? What is the methodological quality of the studies identified? How complete is the intervention reporting? How was change measured in the domains of language, communication and social interaction? Is there evidence of efficacy, indicated by statistically significant improvement, in these domains? How did the interventions work? Synthesis tools employed included the PEDro-P Scale, the TIDieR checklist and the ITAX., Main Contribution: A total of 22 studies met the criteria for review. One study used solely language or communication interventions, but the remaining 21 studies used behavioural interventions which incorporated language and communication activities to varying degrees. Studies fell into four broad intervention types: reminiscence or life review; cognitive stimulation; narrative or storytelling; and multi-modality group communication. The majority of studies were of fair methodological quality, with a moderate level of detail provided in treatment reporting. Statistically significant improvement was reported by authors in all four intervention types and across language, communication and social domains. Social interaction, social support and behavioural skills were the most consistent mechanisms of action in the reviewed behavioural interventions., Conclusions & Implications: Despite limitations in the evidence base, there are important positive signs for the beneficial effects of supporting language and communication in care homes. Blinding of assessors, and the accuracy and accessibility of statistical reporting are important areas to address in order to improve the quality of the evidence base., What This Paper Adds: Ageing can lead to reduced communication ability and activity, and in the care home setting there may also be fewer communication opportunities. This situation is likely to negatively impact well-being. Previous reviews have found evidence of the effectiveness of behavioural interventions in increasing well-being. The communication skills of older adults living in care homes is an underexplored topic. No systematic review to date has focused specifically on the evidence base for group language and communication interventions in this population. This review reveals important positive signs for the beneficial effects of supporting language and communication in care homes. Social interaction, social support, and behavioural skills were the most consistent mechanisms of action in the reviewed behavioural interventions., (© 2021 Royal College of Speech and Language Therapists.)

Spectrins are tetrameric actin-cross-linking proteins that form an elastic network, termed the membrane skeleton, on the cytoplasmic surface of cellular membranes. At the plasma membrane, the membrane skeleton provides essential support, preventing loss of membrane material to environmental shear stresses. The skeleton also controls the location, abundance, and activity of membrane proteins that are critical to cell and tissue function. The ability of the skeleton to modulate membrane stability and function requires adaptor proteins that bind the skeleton to membranes. The principal adaptors are the ankyrin proteins, which bind to the beta-subunit of spectrin and to the cytoplasmic domains of numerous integral membrane proteins. Here, we present the crystal structure of the ankyrin-binding domain of human beta2-spectrin at 1.95 A resolution together with mutagenesis data identifying the binding surface for ankyrins on beta2-spectrin.