The rockefeller university

Many cellular processes rely on precise and timely deformation of the

Background: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. Objective: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. Methods: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2: 1) using transcriptomic and immunohistochemistry analyses. Results: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 x 10(-5)) and 65.5% versus 13.9% at 12 weeks (P = 9.5 3 10(-19)), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including T(H)1/CXCL9, T(H)2/CCL18/CCL22, T(H)17/CCL20/DEFB4A, and T(H)22/IL22/S100A's, were restricted to the IL-22-high drug group (P <.05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. Conclusions: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.

Many bacteria and archaea have the unique ability to heritably alter their genomes by incorporating small fragments of foreign DNA, called spacers, into CRISPR loci. Once transcribed and processed into individual CRISPR RNAs, spacer sequences guide Cas effector nucleases to destroy complementary, invading nucleic acids. Collectively, these two processes are known as the CRISPR-Cas immune response. In this Progress article, we review recent studies that have advanced our understanding of the molecular mechanisms underlying spacer acquisition and that have revealed a fundamental link between the two phases of CRISPR immunity that ensures optimal immunity from newly acquired spacers. Finally, we highlight important open questions and discuss the potential basic and applied impact of spacer acquisition research.

In November 2017, a formal debate on the role of bacteria in the pathogenesis of hidradenitis suppurativa (HS) was held at the 2nd Symposium on Hidradenitis Suppurativa Advances (SHSA) in Detroit, Michigan. In this report, we present both sides of the argument as debated at the SHSA meeting and then discuss the potential role of bacteria as classic infectious pathogens versus an alternative pathogenic role as activators of dysregulated commensal bacterial-host interactions. Although there was consensus that bacteria play a role in pathogenesis and thus are pathogenic, there was a compelling discussion about whether bacteria in HS incite an infectious disease as we classically understand it or whether bacteria might play a different role in HS pathogenesis.

RNA-binding proteins (RBPs) control and coordinate each stage in the life cycle of RNAs. Although in vivo binding sites of RBPs can now be determined genome-wide, most studies typically focused on individual RBPs. Here, we examined a large compendium of 114 high-quality transcriptome-wide in vivo RBP-RNA cross-linking interaction datasets generated by the same protocol in the same cell line and representing 64 distinct RBPs. Comparative analysis of categories of target RNA binding preference, sequence preference, and transcript region specificity was performed, and identified potential posttranscriptional regulatory modules, i.e. specific combinations of RBPs that bind to specific sets of RNAs and targeted regions. These regulatory modules represented functionally related proteins and exhibited distinct differences in RNA metabolism, expression variance, as well as subcellular localization. This integrative investigation of experimental RBP-RNA interaction evidence and RBP regulatory function in a human cell line will be a valuable resource for understanding the complexity of post-transcriptional regulation.

Interest in the nonlinear properties of multi-mode optical waveguides has seen a recent resurgence on account of the large dimensionality afforded by the platform. The large volume of modes in these waveguides provides a new spatial degree of freedom for phase matching nonlinear optical processes. However, this spatial dimension is quantized, which narrows the conversion bandwidths of intermodal processes and constrains spectral and temporal tailoring of the light. Here we show that by engineering the relative group velocity within the spatial dimension, we can tailor the phase-matching bandwidth of intermodal parametric nonlinearities. We demonstrate group-velocity-tailored parametric nonlinear mixing between higher-order modes in a multi-mode fiber with gain bandwidths that are more than an order of magnitude larger than that previously thought possible for intermodal four-wave mixing. As evidence of the technological utility of this methodology, we seed this process to generate the first high-peak-power wavelength-tunable all-fiber quasi-CW laser in the Ti:sapphire wavelength regime. More generally, with the combination of intermodal interactions, which dramatically expand the phase-matching degrees of freedom for nonlinear optics, and intermodal group-velocity engineering, which enables tailoring of the bandwidth of such interactions, we showcase a platform for nonlinear optics that can be broadband while being wavelength agnostic. (C) 2018 Chinese Laser Press

Introduction: Obsessional thoughts and ritualized eating behaviors are characteristic of Anorexia Nervosa (AN), leading to the common suggestion that the illness shares neurobiology with obsessive-compulsive disorder (OCD). Resting-state functional connectivity MRI (rs-fcMRI) is a measure of functional neural architecture. This longitudinal study examined functional connectivity in AN within the limbic cortico-striato-thalamo-cortical (CSTC) loop, as well as in the salience network, the default mode network, and the executive control network (components of the triple network model of psychopathology). Methods: Resting-state functional connectivity MRI scans were collected in unmedicated female inpatients with AN (n = 25) and healthy controls (HC; n = 24). Individuals with AN were scanned before and after weight restoration and followed for one month after hospital discharge. HC were scanned twice over the same timeframe. Results: Using a seed-based correlation approach, individuals with AN had increased connectivity within the limbic CSTC loop when underweight, only. There was no significant association between limbic CSTC connectivity and obsessive-compulsive symptoms or prognosis. Exploratory analyses of functional network connectivity within the triple network model showed reduced connectivity between the salience network and left executive control network among AN relative to HC. These abnormalities persisted following weight restoration. Conclusions: The CSTC findings suggest that the neural underpinnings of obsessive-compulsive symptoms may differ from those of OCD. The inter-network abnormalities warrant examination in relation to illness-specific behaviors, namely abnormal eating behavior. This longitudinal study highlights the complexity of the neural underpinnings of AN.

Octonionic representation of O(9, 1) with special emphasis placed on the analytic properties of octonionic functions is investigated.