Off-Label Biologic Regimens in Psoriasis: A Systematic Review of Efficacy and Safety of Dose Escalation, Reduction, and Interrupted Biologic Therapy

Objectives: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment

Deliberating Animal Values: a Pragmatic-Pluralistic Approach to Animal Ethics.

Debates in animal ethics are largely characterized by ethical monism, the search for a single, timeless, and essential trait in which the moral standing of animals can be grounded. In this paper, we argue that a monistic approach towards animal ethics hampers and oversimplifies the moral debate. The value pluralism present in our contemporary societies requires a more open and flexible approach to moral inquiry. This paper advocates the turn to a pragmatic, pluralistic approach to animal ethics. It contributes to the development of such an approach in two ways. It offers a pragmatist critique of ethical monism in animal ethics and presents the results of a qualitative study into the value diversity present in the different ways of thinking about animals in the Netherlands. Carefully arranged group discussions resulted in the reconstruction of four distinctive moral value frameworks that may serve as instruments in the future process of moral inquiry and deliberation in the reflection on animal use. © 2010 The Author(s)

How to make a sex chromosome

Sex chromosomes can evolve once recombination is halted between a homologous pair of chromosomes. Owing to detailed studies using key model systems, we have a nuanced understanding and a rich review literature of what happens to sex chromosomes once recombination is arrested. However, three broad questions remain unanswered. First, why do sex chromosomes stop recombining in the first place? Second, how is recombination halted? Finally, why does the spread of recombination suppression, and therefore the rate of sex chromosome divergence, vary so substantially across clades? In this review, we consider each of these three questions in turn to address fundamental questions in the field, summarize our current understanding, and highlight important areas for future work

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

Background: A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs). Results: We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an `autosomal Barr body' with less compacted chromatin and incomplete RNAP II exclusion. Conclusions: 3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi