The rockefeller university

Background Frontal fibrosing alopecia (FFA) is a scarring alopecia with unclear pathogenesis and a progressive course. The disease has a major impact on patients' quality of life and there is a lack of effective treatment to halt disease progression. Methods We profiled lesional and nonlesional scalp biopsies collected in 2017 from patients with FFA (n= 12) compared with scalp biopsies from patients with alopecia areata (AA) (n= 8) and controls (n= 8) to evaluate gene and protein expression, including the primary outcome (CXCL9). We determined significant differences between biomarkers using a two-sided Student'st-test adjustingP-values by false discovery rate. Results Significant increases were seen in CD8+ cytotoxic T cells, CD11c+ dendritic cells, CD103+ and CD69+ tissue-resident memory T cells in FFA and AA vs. control scalp (P< 0 center dot 05), with corresponding significantly upregulated granzyme B mRNA, particularly in FFA (P< 0 center dot 01). In AA, cellular infiltrates were primarily concentrated at the bulb, while in FFA these were mainly localized at the bulge. FFA demonstrated significant upregulation of T helper 1/intereferon (IFN) (IFN-gamma, CXCL9/CXCL10), the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway (STAT1, JAK3) and fibrosis-related products (vimentin, fibronectin;P< 0 center dot 05), with no concomitant downregulation of hair keratins and the T-regulatory marker, forkhead box P3, which were decreased in AA. The stem cell markers CD200 and K15 demonstrated significantly reduced expression only in FFA (P< 0 center dot 05). Conclusions These data suggest that follicular damage and loss of stem cells in FFA may be mediated through immune attack in the bulge region, with secondary fibrosis and reduced but still detectable stem cells. JAK/STAT-targeting treatments may be able to prevent permanent follicular destruction and fibrosis in early disease stages. What is already known about this topic? Frontal fibrosing alopecia (FFA) has a rising prevalence and currently lacks effective therapeutic options. While FFA is considered to have pathomechanisms similar to lichen planopilaris, underlying immune polarization in FFA is largely unknown, hindering development of targeted treatments. What does this study add? FFA lesional and even nonlesional scalp showed robust immune activation, with CD8+ cytotoxic T cells juxtaposed to follicular stem cells, increased interferon-gamma production and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling, and concomitant upregulation of many fibrosis markers. Unlike alopecia areata, FFA is characterized by active production of hair keratins and increased regulatory T cells. Our results suggest that Tc1 T cells may mediate follicular damage and subsequent fibrosis in FFA. What is the translational message? FAA may result from T helper 1/JAK-STAT-mediated follicular damage and concomitant fibrosis. Early therapeutic targeting of this pathway may have the potential to prevent disease progression.

Obstructive sleep apnea (OSA), a chronic sleep disorder characterized by repetitive reduction or cessation of airflow during sleep, is widely prevalent and is associated with adverse neurocognitive sequelae including increased risk of Alzheimer's disease (AD). In humans, OSA is more common in elderly males. OSA is characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), and recent epidemiological studies point to CIH as the best predictor of neurocognitive sequelae associated with OSA. The sex- and age- specific effects of OSA-associated CIH on specific cell populations such as gamma-aminobutyric acid (GABA)-ergic neurons in the hippo campus and the medial prefrontal cortex (mPFC), regions important for cognitive function, remain largely unknown. The present study examined the effect of 35 days of either moderate (10% oxygen) or severe (5% oxygen) CIH on GABAergic neurons in the mPFC and hippocampus of young and aged male and female mice as well as post-accelerated ovarian failure (AOF) female mice. In the mPFC and hippocampus, the number of GABA-labeled neurons increased in aged and young severe CIH males compared to controls but not in young moderate CIH males. This change was not representative of the individual GABAergic cell subpopulations, as the number of parvalbumin-labeled neurons decreased while the number of somatostatin-labeled neurons increased in the hippocampus of severe CIH young males only. In all female groups, the number of GABA-labeled cells was not different between CIH and controls. However, in the mPFC, CIH increased the number of parvalbumin-labeled neurons in young females and the number of somatostatin-labeled cells in AOF females but decreased the number of somatostatin-labeled cells in aged females. In the hippocampus, CIH decreased the number of somatostatin-labeled neurons in young females. CIH decreased the density of vesicular GABA transporter in the mPFC of AOF females only. These findings suggest sex-specific changes in GABAergic neurons in the hippo campus and mPFC with males showing an increase of this cell population as compared to their female counterparts following CIH. Age at exposure and severity of CIH also differentially affect the GABAergic cell population in mice.

Type II CRISPR-Cas systems provide immunity against phages and plasmids that infect bacteria through the insertion of a short sequence from the invader's genome, known as the 'spacer', into the CRISPR locus. Spacers are transcribed into guide RNAs that direct the Cas9 nuclease to its target on the invader. In liquid cultures, most bacteria acquire a single spacer. Multiple spacer integration is a rare event which significance for immunity is poorly understood. Here, we found that when phage infections occur on solid media, a high proportion of the surviving colonies display complex morphologies that contain cells with multiple spacers. This is the result of the viral-host co-evolution, in which the immunity provided by the initial acquired spacer is easily overcome by escaper phages. Our results reveal the versatility of CRISPR-Cas immunity, which can respond with both single or multiple spacer acquisition schemes to solve challenges presented by different environments.

We covalently attached human immunodeficiency virus type 1 (HIV-1) Env SOSIP trimers to iron oxide nanoparticles (IO-NPs) to create a particulate immunogen for neutralizing antibody (NAb) induction. The attached trimers, similar to 20 per particle, retained native-like antigenicity, judged by reactivity with NAbs and non-NAbs. Bivalent (BG505 and B41) trimer IO-NPs were made, as were IO-NPs displaying B41 trimers carrying a PADRE T-cell helper epitope (TCHE). We immunized mice with B41 soluble or IO-NP trimers after PADRE peptide priming. After two immunizations, IO-NP presentation and the TCHE tag independently and substantially increased anti-trimer antibody responses, but titer differences waned after two further doses. Notable and unexpected findings were that autologous NAbs to the N289 glycan hole epitope were consistently induced in mice given soluble but not IO-NP trimers. Various recombinant mannose binding lectins (MBLs) and MBLs in sera of both murine and human origin bound to soluble and IO-NP trimers. MBL binding occluded the autologous NAb epitope on the B41 IO-NP trimers, which may contribute to its poor immunogenicity. The exposure of a subset of broadly active NAb epitopes was also impaired by MBL binding, which could have substantial implications for the utility of trimer-bearing nanoparticles in general and perhaps also for soluble Env proteins. IMPORTANCE Recombinant trimeric SOSIP proteins are vaccine components intended to induce neutralizing antibodies (NAbs) that prevent cells from infection by human immunodeficiency virus type 1 (HIV-1). A way to increase the strength of antibody responses to these proteins is to present them on the surface of nanoparticles (NPs). We chemically attached about 20 SOSIP trimers to NPs made of iron oxide (IO). The resulting IO-NP trimers had appropriate properties when we studied them in the laboratory but, unexpectedly, were less able to induce NAbs than non-attached trimers when used to immunize mice. We found that mannose binding lectins, proteins naturally present in the serum of mice and other animals, bound strongly to the soluble and IO-NP trimers, blocking access to antibody epitopes in a way that may impede the development of NAb responses. These findings should influence how trimer-bearing NPs of various designs are made and used.

Vision not only detects and recognizes objects, but performs rich inferences about the underlying scene structure that causes the patterns of light we see. Inverting generative models, or "analysis-by-synthesis", presents a possible solution, but its mechanistic implementations have typically been too slow for online perception, and their mapping to neural circuits remains unclear. Here we present a neurally plausible efficient inverse graphics model and test it in the domain of face recognition. The model is based on a deep neural network that learns to invert a three-dimensional face graphics program in a single fast feedforward pass. It explains human behavior qualitatively and quantitatively, including the classic "hollow face" illusion, and it maps directly onto a specialized face-processing circuit in the primate brain. The model fits both behavioral and neural data better than state-of-the-art computer vision models, and suggests an interpretable reverse-engineering account of how the brain transforms images into percepts.

How do early embryos allocate the resources stored in the sperm and egg? Recently, we established isothermal calorimetry to measure heat dissipation by living zebra-fish embryos and to estimate the energetics of specific developmental events. During the reductive cleavage divisions, the rate of heat dissipation increases from similar to 60 nJ.s(-1) at the two-cell stage to similar to 90 nJ.s(-1) at the 1024-cell stage. Here we ask which cellular process(es) drive this increasing energetic cost. We present evidence that the cost is due to the increase in the total surface area of all the cells of the embryo. First, embryo volume stays constant during the cleavage stage, indicating that the increase is not due to growth. Second, the heat increase is blocked by nocodazole, which inhibits DNA replication, mitosis, and cell division; this suggests some aspect of cell proliferation contributes to these costs. Third, the heat increases in proportion to the total cell surface area rather than total cell number. Fourth, the heat increase falls within the range of the estimated costs of maintaining and assembling plasma membranes and associated proteins. Thus, the increase in total plasma membrane associated with cell proliferation is likely to contribute appreciably to the total energy budget of the embryo.

Highly proliferative cells have classically been thought to rely on anaerobic glycolysis for fuel. Weisel et al. show that germinal center B cells break this rule, as they primarily utilize fatty acid oxidation to meet their metabolic demands.

Bacterial and archaeal CRISPR-Cas systems provide RNA-guided immunity against genetic invaders such as bacteriophages and plasmids. Upon target RNA recognition, type III CRISPR-Cas systems produce cyclic-oligoadenylate second messengers that activate downstream effectors, including Csm6 ribonucleases, via their CARF domains. Here, we show that Enteroccocus italicus Csm6 (EiCsm6) degrades its cognate cyclic hexa-AMP (cA6) activator, and report the crystal structure of EiCsm6 bound to a cA6 mimic. Our structural, biochemical, and in vivo functional assays reveal how cA6 recognition by the CARF domain activates the Csm6 HEPN domains for collateral RNA degradation, and how CARF domain-mediated cA6 cleavage provides an intrinsic off-switch to limit Csm6 activity in the absence of ring nucleases. These mechanisms facilitate rapid invader clearance and ensure termination of CRISPR interference to limit self-toxicity.

Dear Editor, We have read with interest the paper by Fritzell et al. which suggests the association of bacteria, especially the anaerobic bacterium Cutibacterium acnes (previously Propionibacterium acnes), with pain-generating degenerated discs is likely to reflect contamination arising from the skin. We find this view surprising given that the recent studies of Capoor et al. [1] and Ohrt-Nissen et al. [2] directly visualized C. acnes as a biofilm within surgically removed intervertebral disc tissue. Such observations are practically impossible to explain by contamination as this would require the contaminant to form a biofilm deep within a retrieved nucleus tissue fragment during the brief time between removal and freezing. Against this background, we would like to highlight a series of potential methodological limitations within the Fritzell et al. study that could impact on their final results and conclusions regarding the association of C. acnes with degenerated discs.