TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown

Beyond the personal–anonymous divide: agency relations in powers of attorney in France in the eighteenth and nineteenth centuries

Powers of attorney are often interpreted as evidence of trust among the parties involved. We build a novel dataset of notarized powers of attorney, capturing a wide variety of agency relationships in four large French commercial cities in the eighteenth and nineteenth centuries, to test hypotheses on the relational basis of economic relationships. We find little support for the idea of a radical shift from personal to anonymous relationships during our period. Our results point to more nuanced transformations. The preference for proxies in the same occupation as the principal somewhat declined, while professional proxies emerged and principals used relational chains, especially involving notaries, to find proxies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151849/1/ehr12784_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151849/2/ehr12784.pd

Genetic Deletion of Laminin Isoforms β2 and γ3 Induces a Reduction in Kir4.1 and Aquaporin-4 Expression and Function in the Retina

Glial cells such as retinal Müller glial cells are involved in potassium ion and water homeostasis of the neural tissue. In these cells, inwardly rectifying potassium (Kir) channels and aquaporin-4 water channels play an important role in the process of spatial potassium buffering and water drainage. Moreover, Kir4.1 channels are involved in the maintenance of the negative Müller cell membrane potential. The subcellular distribution of Kir4.1 and aquaporin-4 channels appears to be maintained by interactions with extracellular and intracellular molecules. Laminins in the extracellular matrix, dystroglycan in the membrane, and dystrophins in the cytomatrix form a complex mediating the polarized expression of Kir4.1 and aquaporin-4 in Müller cells.The aim of the present study was to test the function of the β2 and γ3 containing laminins in murine Müller cells. We used knockout mice with genetic deletion of both β2 and γ3 laminin genes to assay the effects on Kir4.1 and aquaporin-4. We studied protein and mRNA expression by immunohistochemistry, Western Blot, and quantitative RT-PCR, respectively, and membrane currents of isolated cells by patch-clamp experiments. We found a down-regulation of mRNA and protein of Kir4.1 as well as of aquaporin-4 protein in laminin knockout mice. Moreover, Müller cells from laminin β2 and γ3 knockout mice had reduced Kir-mediated inward currents and their membrane potentials were more positive than those in age-matched wild-type mice.These findings demonstrate a strong impact of laminin β2 and γ3 subunits on the expression and function of both aquaporin-4 and Kir4.1, two important membrane proteins in Müller cells

Mathematical and connectionist models of human memory : a comparison

Recent convolution-based models of human memory (e.g. Lewandowsky & Murdock, 1989), have accounted for a wide range of data. However such models require the relevant mathematical operations to be provided to the network. Connectionist models, in contrast, have generally addressed different data, and not all architectures are appropriate for modelling single-trial learning. Furthermore, they tend to exhibit catastrophic interference in multiple list learning. In this paper we compare the ability of convolution-based models and DARNET (Developmental Associative Recall NET work), to account for human memory data. DARNET is a connectionist approach to human memory in which the system gradually learns to associate vectors, in one trial, into a memory trace vector. Either of the vectors can then be retrieved. It is shown that the new associative mechanism can be used to account for a wide range of relevant experimental data as successfully as can convolution-based models with the same higher-level architectures. Limitations of the models are also addressed

Modelling human memory : connectionism and convolution

The mathematical operation of convolution is used as an associative mechanism by several recent influential models of human memory. Convolution can be used to associate two vectors (representing items to be remembered) into a memory trace vector in one operation. An approximation to either of the input vectors can then be retrieved, using the other vector as a probe. Recent convolution-based memory models have accounted for a wide range of data. Connectionist models may have greater potential for providing developmental accounts, but the architectures that have been most widely used to account for developmental phenomena cannot perform one-trial learning and this has limited their use as models of human memory. We show that a connectionist-like architecture can learn, using a gradient-descent algorithm, to perform single-trial learning in a similar manner to convolution. The solution that the network finds leads to less variable retrieval than does convolution. Furthermore, the network can learn to carry out the convolution operation itself. This provides a link between connectionist and convolution approaches, and a basis for models with many of the attractions of both connectionist and convolution approaches

Expression of Dp71 in Müller glial cells: a comparison with utrophin- and dystrophin-associated proteins.

International audienceThe abnormal retinal electrophysiology observed in patients with Duchenne muscular dystrophy (DMD) has been attributed to an altered expression of C-terminal products of the dystrophin gene. It has been shown that Dp260 is expressed by photoreceptor cells, whereas Dp71 is present in glial cells. The present study was intended to identify all known members of the dystrophin superfamily and their associated proteins expressed in Müller glial cells (MGC)

Expression of Dp71 in Müller glial cells: a comparison with utrophin- and dystrophin-associated proteins.

International audienceThe abnormal retinal electrophysiology observed in patients with Duchenne muscular dystrophy (DMD) has been attributed to an altered expression of C-terminal products of the dystrophin gene. It has been shown that Dp260 is expressed by photoreceptor cells, whereas Dp71 is present in glial cells. The present study was intended to identify all known members of the dystrophin superfamily and their associated proteins expressed in Müller glial cells (MGC)

Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation

Background: The cerebro-oculo-facio-skeletal syndrome (COFS syndrome) is an autosomal recessive disorder which was initially described in a specific aboriginal population from Manitoba. In recent years, COFS syndrome has been linked in this original population to a defective DNA repair pathway and to a homozygous mutation in the major gene underlying Cockayne syndrome (CSB). However, most reports of suspected COFS syndrome outside this population have not been confirmed at the molecular level, leading to considerable heterogeneity within the syndrome and confusing overlaps between COFS syndrome and other eye and brain disorders. Objective: To refine the delineation of the syndrome on genetically proven COFS cases. Methods: We report the exhaustive clinical, cellular and molecular data of three unrelated COFS patients with mutations in the CSB gene. Results: All three patients present the cardinal features of COFS syndrome including extreme microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. They also exhibit a predominantly postnatal growth failure, a severe psychomotor retardation, with axial hypotonia and peripheral hypertonia and neonatal feeding difficulties. Fibroblasts from the patients show the same DNA repair defect which can be complemented by transfection of the CSB wild-type cDNA. Five new mutations in the CSB gene have been identified in these patients. Conclusions: Our data indicate that COFS syndrome represents the most severe end of the Cockayne spectrum. New diagnostic criteria for COFS syndrome are proposed, based on our findings and on the few genetically proven COFS cases from the literature