Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation

T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17, and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17, and Tregs during a T-dependent response but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic α1 subunit of adenosine monophosphate-activated protein kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN–AMPK metabolic signaling nexus essential for selectively promoting Tfh responses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Are placebo-controlled trials still important for obsessive compulsive disorder?

Original article can be found at: http://www.sciencedirect.com/science/journal/02785846 Copyright Elsevier Inc. DOI: 10.1016/j.pnpbp.2005.11.012 [Full text of this article is not available in the UHRA]The use of placebos as reference agents in randomised controlled trials for psychiatric disorders has come under question for ethical reasons. Alternative methods for validating the efficacy of new treatments exist, but may not be as reliable as placebo. In this paper we examine arguments for and against the ongoing use of placebo agents in the development of new treatments for obsessive compulsive disorder in the context of evidence from randomised controlled trials.Peer reviewe

Intracellular ATP Influences Synaptic Plasticity in Area CA1 of Rat Hippocampus via Metabolism to Adenosine and Activity-Dependent Activation of Adenosine A(1) Receptors

The extent to which brain slices reflect the energetic status of the in vivo brain has been a subject of debate. We addressed this issue to investigate the recovery of energetic parameters and adenine nucleotides in rat hippocampal slices and the influence this has on synaptic transmission and plasticity.Weshow that, although adenine nucleotide levels recover appreciably within 10minof incubation, it takes 3 h for a full recovery of the energy charge (to >= 0.93) and that incubation of brain slices at 34°C results in a significantly higher ATP/AMP ratio and a threefold lower activity of AMP-activated protein kinase compared with slices incubated at room temperature. Supplementation of artificial CSF with D-ribose and adenine (Rib/Ade) increased the total adenine nucleotide pool of brain slices, which, when corrected for the influence of the dead cut edges, closely approached in vivo values. Rib/Ade did not affect basal synaptic transmission or paired-pulse facilitation but did inhibit long-term potentiation (LTP) induced by tetanic or weak theta-burst stimulation. This decrease in LTP was reversed by strong theta-burst stimulation or antagonizing the inhibitory adenosine A1 receptor suggesting that the elevated tissue ATP levels had resulted in greater activity-dependent adenosine release during LTP induction. This was confirmed by direct measurement of adenosine release with adenosine biosensors. These observations provide new insight into the recovery of adenine nucleotides after slice preparation, the sources of loss of such compounds in brain slices, the means by which to restore them, and the functional consequences of doing so

Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study

Background: In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary. Aim: To explore ‘real world’ treatment utilising longitudinal UK JSLE Cohort Study data. Methods: Data collected between 07/2009–05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice. Result: 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65–2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator. Conclusions: Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly

Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.

ObjectivesJuvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggest variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with "genetic" SLE vs remaining SLE patients.MethodsBased on a sequencing panel designed in 2018, target enrichment and next-generation sequencing was performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets.ResultsWe identified damaging gene variants in approximately 3.5% of jSLE patients. When compared with the remaining cohort, "genetic" SLE affected younger children, and more Black African/Caribbean patients. "Genetic" SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive 1st line treatment was chosen in "genetic" SLE patients, but more 2nd and 3rd-line agents were used. "Genetic" SLE associated with anti-dsDNA antibody positivity at diagnosis, and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit.ConclusionApproximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in "genetic" SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment, and target-directed treatment, thereby increasing efficacy and reducing toxicity

(Mis)communicating across boundaries - Interpersonal and intergroup considerations

The metaphor of boundary is ubiquitous and has guided much research on interpersonal and intergroup communication This article explores the metaphor by reviewing the literature on boundaries with a focus on miscommunication and problematic talk. In particular, the tensions around privacy and self-disclosure, and rules about family communication are good examples of communication and miscommunication across interpersonal boundaries. In the intergroup arena, the negotiation of boundaries implicates the sociostructural relations between, groups and the choices individuals make based on the identities that are salient to them in a given context. We argue that miscommunication can best be conceived of as an indicator of tension in negotiating boundaries as they emerge and change in interaction