Exploring Epigenetic Reprogramming During Central Nervous System Infection

Epigenetics involves the study of various modes of adaptable transcriptional regulation, contributing to cell identity, characteristics, and function. During central nervous system (CNS) infection, epigenetic mechanisms can exert pronounced control over the maturation and antimicrobial properties of nearly every immune cell type. Epigenetics is a relatively new field, with the first mention of these marks proposed only a half-century ago and a substantial body of immunological epigenetic research emerging only in the last few decades. Here, we review the best-characterized epigenetic marks and their functions as well as illustrate how various immune cell populations responding to CNS infection utilize these marks to organize their activation state and inflammatory processes. We also discuss the metabolic and clinical implications of epigenetic marks and the rapidly expanding set of tools available to researchers that are enabling elucidation of increasingly detailed genetic regulatory pathways. These considerations paint an intricate picture of inflammatory regulation, where epigenetic marks influence genetic, signaling, and environmental elements to orchestrate a tailored immunological response to the threat at hand, cementing epigenetics as an important player in immunity

A Proposal for the Use of a Fixed Low-Energy Selective Laser Trabeculoplasty for Open Angle Glaucoma

Selective laser trabeculoplasty (SLT) has been in routine clinical use for over 20 years with millions of patients successfully treated and a low rate of clinically significant complications. The procedure requires the clinician to manually position the laser beam on the trabecular meshwork using a gonioscopy lens and to titrate the SLT laser energy based on the amount of pigmentation in the angle, as well as the observation of small bubbles produced by the laser effect. We propose that SLT energy titration is unnecessary either to achieve intraocular pressure (IOP) reduction or to minimize potential side effects. Ample evidence to support our proposal includes multiple clinical reports demonstrating comparable levels of IOP reduction resulting from different laser energies, a large variety of energy and other laser parameters used in commercially available SLT lasers, and the nature of the laser-induced changes in the trabecular meshwork tissue with respect to energy. Despite these variations in laser parameters, SLT consistently reduces IOP with a low complication rate. We propose that using low fixed energy for all patients will effectively and safely lower patients' IOP while reducing the complexity of the SLT procedure, potentially making SLT accessible to more patients

A Proposal for the Use of a Fixed Low-Energy Selective Laser Trabeculoplasty for Open Angle Glaucoma

Selective laser trabeculoplasty (SLT) has been in routine clinical use for over 20 years with millions of patients successfully treated and a low rate of clinically significant complications. The procedure requires the clinician to manually position the laser beam on the trabecular meshwork using a gonioscopy lens and to titrate the SLT laser energy based on the amount of pigmentation in the angle, as well as the observation of small bubbles produced by the laser effect. We propose that SLT energy titration is unnecessary either to achieve intraocular pressure (IOP) reduction or to minimize potential side effects. Ample evidence to support our proposal includes multiple clinical reports demonstrating comparable levels of IOP reduction resulting from different laser energies, a large variety of energy and other laser parameters used in commercially available SLT lasers, and the nature of the laser-induced changes in the trabecular meshwork tissue with respect to energy. Despite these variations in laser parameters, SLT consistently reduces IOP with a low complication rate. We propose that using low fixed energy for all patients will effectively and safely lower patients\u27 IOP while reducing the complexity of the SLT procedure, potentially making SLT accessible to more patients

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Large-scale association analyses identify host factors influencing human gut microbiome composition

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P <5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) <P <5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis

Affectus Hispaniae en la historiografía del Alto Imperio

This paper analyses texts written by Greek and Latin High Empire historians dealing with Hispania. Some of the authors have a very positive view (Florus, Iustinus, Appian) while others are clearly negative (Veleius Paterculus, Valerius Maximus) though most of them show little interest, indifference or variety of opinions. When there is interest in the region or praise, it is because the author comes from Hispania or he is trying to please an emperor born in Hispania, but it could also be due to a universal conception of history revealing a critical attitude towards Roman imperialism, as in Appian. The praise found in Iustinus’s epitome should be attributed to the author of the epitome rather than to Pompeius Trogus. This can be taken as evidence for situating Iustinus’s life and work in the 2nd century A.D. Loathing of Hispania seems to have its origins in conservative, ‘optimate’ nationalist circles, who perceive the province as the ‘popular’ region that acclaimed and welcomed ‘seditious’ individuals such as Tiberius Gracchus and Sertorius.Se estudian en este trabajo los textos de historiadores del Alto Imperio, latinos y griegos, que tratan sobre Hispania. En algunos autores encontramos una visión muy positiva (Floro, Justino, Apiano) y en otros claramente negativa (Veleyo Patérculo, Valerio Máximo), aunque en la mayoría de los casos hay escasa atención, indiferencia o diversidad de opiniones. El interés por la región y los elogios pueden estar motivados por el origen hispánico del autor o su voluntad de agradar a algún emperador oriundo de Hispania, pero también por una concepción universal de la historia que denota en ocasiones una posición crítica con el imperialismo romano, como es el caso de Apiano. La alabanza que hallamos en el epítome de Justino creemos que debe atribuirse más al epitomador que a Pompeyo Trogo, lo que apoyaría una datación temprana de la vida y la obra de Justino (s. II d.C.). La aversión hacia Hispania parece haber surgido en medios conservadores, “optimates” nacionalistas, que ven la provincia como el territorio “popular”, que encumbró y acogió a “sediciosos” como Tiberio Graco y Sertorio

The TESS-Keck Survey II: An Ultra-Short Period Rocky Planet and its Siblings Transiting the Galactic Thick-Disk Star TOI-561

We report the discovery of TOI-561, a multi-planet system in the galactic thick disk that contains a rocky, ultra-short period planet (USP). This bright ($V=10.2$) star hosts three small transiting planets identified in photometry from the NASA TESS mission: TOI-561 b (TOI-561.02, P=0.44 days, $R_b = 1.45\pm0.11\,R_\oplus$), c (TOI-561.01, P=10.8 days, $R_c=2.90\pm0.13\,R_\oplus$), and d (TOI-561.03, P=16.3 days, $R_d=2.32\pm0.16\,R_\oplus$). The star is chemically ([Fe/H]$=-0.41\pm0.05$, [$\alpha$/H]$=+0.23\pm0.05$) and kinematically consistent with the galactic thick disk population, making TOI-561 one of the oldest ($10\pm3\,$Gyr) and most metal-poor planetary systems discovered yet. We dynamically confirm planets b and c with radial velocities from the W. M. Keck Observatory High Resolution Echelle Spectrometer. Planet b has a mass and density of $3.2\pm0.8\,M_\oplus$ and $5.5^{+2.0}_{-1.6}\,$g$\,$cm$^{-3}$, consistent with a rocky composition. Its lower-than-average density is consistent with an iron-poor composition, although an Earth-like iron-to-silicates ratio is not ruled out. Planet c is $7.0\pm2.3\,M_\oplus$ and $1.6\pm0.6\,$g$\,$cm$^{-3}$, consistent with an interior rocky core overlaid with a low-mass volatile envelope. Several attributes of the photometry for planet d (which we did not detect dynamically) complicate the analysis, but we vet the planet with high-contrast imaging, ground-based photometric follow-up and radial velocities. TOI-561 b is the first rocky world around a galactic thick-disk star confirmed with radial velocities and one of the best rocky planets for thermal emission studies.Comment: Accepted at The Astronomical Journal; 25 pages, 10 figure