Epigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer's disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of ...DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.
Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic ...heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
We present final natural-system optical (ugriBV) and near-infrared (YJH) photometry of 134 supernovae (SNe) with probable white dwarf progenitors that were observed in 2004-2009 as part of the first ...stage of the Carnegie Supernova Project (CSP-I). The sample consists of 123 Type Ia SNe, 5 Type Iax SNe, 2 super-Chandrasekhar SN candidates, 2 Type Ia SNe interacting with circumstellar matter, and 2 SN 2006bt-like events. The redshifts of the objects range from to 0.0835; the median redshift is 0.0241. For 120 (90%) of these SNe, near-infrared photometry was obtained. Average optical extinction coefficients and color terms are derived and demonstrated to be stable during the five CSP-I observing campaigns. Measurements of the CSP-I near-infrared bandpasses are also described, and near-infrared color terms are estimated through synthetic photometry of stellar atmosphere models. Optical and near-infrared magnitudes of local sequences of tertiary standard stars for each supernova are given, and a new calibration of Y-band magnitudes of the Persson et al. standards in the CSP-I natural system is presented.
Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to ...joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.
Background:
Few population-based descriptive studies on the incidence of anterior cruciate ligament (ACL) reconstruction and concomitant pathology exist.
Hypothesis:
Incidence of ACL reconstruction ...has increased from 2002 to 2014.
Study Design:
Descriptive clinical epidemiology study.
Level of Evidence:
Level 3.
Methods:
The Truven Health Analytics MarketScan Commercial Claims and Encounters database, which contains insurance enrollment and health care utilization data for approximately 158 million privately insured individuals younger than 65 years, was used to obtain records of ACL reconstructions performed between 2002 and 2014 and any concomitant pathology using Current Procedures Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) codes. The denominator population was defined as the total number of person-years (PYs) for all individuals in the database. Annual rates were computed overall and stratified by age, sex, and concomitant procedure.
Results:
There were 283,810 ACL reconstructions and 385,384,623 PYs from 2002 to 2014. The overall rate of ACL reconstruction increased 22%, from 61.4 per 100,000 PYs in 2002 to 74.6 per 100,000 PYs in 2014. Rates of isolated ACL reconstruction were relatively stable over the study period. However, among children and adolescents, rates of both isolated ACL reconstruction and ACL reconstruction with concomitant meniscal surgery increased substantially. Adolescents aged 13 to 17 years had the highest absolute rates of ACL reconstruction, and their rates increased dramatically over the 13-year study period (isolated, +37%; ACL + meniscal repair, +107%; ACL + meniscectomy, +63%). Rates of isolated ACL reconstruction were similar for males and females (26.1 vs 25.6 per 100,000 PYs, respectively, in 2014), but males had higher rates of ACL reconstruction with concomitant meniscal surgery than females.
Conclusion:
Incidence rates of isolated ACL reconstruction and rates of concomitant meniscal surgery have increased, particularly among children and adolescents.
Clinical Relevance:
A renewed focus on adoption of injury prevention programs is needed to mitigate these trends. In addition, more research is needed on long-term patient outcomes and postoperative health care utilization after ACL reconstruction, with a focus on understanding the sex-based disparity in concomitant meniscal surgery.
The origin of trees and forests in the Mid Devonian (393–383 Ma) was a turning point in Earth history, marking permanent changes to terrestrial ecology, geochemical cycles, atmospheric CO2 levels, ...and climate. However, how all these factors interrelate remains largely unknown. From a fossil soil (palaeosol) in the Catskill region near Cairo NY, USA, we report evidence of the oldest forest (mid Givetian) yet identified worldwide. Similar to the famous site at Gilboa, NY, we find treefern-like Eospermatopteris (Cladoxylopsida). However, the environment at Cairo appears to have been periodically drier. Along with a single enigmatic root system potentially belonging to a very early rhizomorphic lycopsid, we see spectacularly extensive root systems here assigned to the lignophyte group containing the genus Archaeopteris. This group appears pivotal to the subsequent evolutionary history of forests due to possession of multiple advanced features and likely relationship to subsequently dominant seed plants. Here we show that Archaeopteris had a highly advanced root system essentially comparable to modern seed plants. This suggests a unique ecological role for the group involving greatly expanded energy and resource utilization, with consequent influence on global processes much greater than expected from tree size or rooting depth alone.
•The earliest fossil forest to date is recovered from the Devonian of New York•Three types of trees are identified from fossil soil evidence in plan view•Early lignophyte relatives of seed plants have surprisingly modern root systems•Advanced energetics in this group suggests a unique role in changing Earth history
Using data from a Middle Devonian fossil soil, Stein et al. report root systems from the earliest intact forest to date, including cladoxylopsids, possibly stigmarians and Archaeopteris. Striking seed plant-like features of the latter indicate a special role for this clade in the profound changes in Earth global systems that took place at that time.
Type III secretion systems (T3SSs) are protein transport nanomachines that are found in Gram-negative bacterial pathogens and symbionts. Resembling molecular syringes, T3SSs form channels that cross ...the bacterial envelope and the host cell membrane, which enable bacteria to inject numerous effector proteins into the host cell cytoplasm and establish trans-kingdom interactions with diverse hosts. Recent advances in cryo-electron microscopy and integrative imaging have provided unprecedented views of the architecture and structure of T3SSs. Furthermore, genetic and molecular analyses have elucidated the functions of many effectors and key regulators of T3SS assembly and secretion hierarchy, which is the sequential order by which the protein substrates are secreted. As essential virulence factors, T3SSs are attractive targets for vaccines and therapeutics. This Review summarizes our current knowledge of the structure and function of this important protein secretion machinery. A greater understanding of T3SSs should aid mechanism-based drug design and facilitate their manipulation for biotechnological applications.
Abstract
Context
Metformin is the first-line drug for treating diabetes but has a high failure rate.
Objective
To identify demographic and clinical factors available in the electronic health record ...(EHR) that predict metformin failure.
Methods
A cohort of patients with at least 1 abnormal diabetes screening test that initiated metformin was identified at 3 sites (Arizona, Mississippi, and Minnesota). We identified 22 047 metformin initiators (48% female, mean age of 57 ± 14 years) including 2141 African Americans, 440 Asians, 962 Other/Multiracial, 1539 Hispanics, and 16 764 non-Hispanic White people. We defined metformin failure as either the lack of a target glycated hemoglobin (HbA1c) (<7%) within 18 months of index or the start of dual therapy. We used tree-based extreme gradient boosting (XGBoost) models to assess overall risk prediction performance and relative contribution of individual factors when using EHR data for risk of metformin failure.
Results
In this large diverse population, we observed a high rate of metformin failure (43%). The XGBoost model that included baseline HbA1c, age, sex, and race/ethnicity corresponded to high discrimination performance (C-index of 0.731; 95% CI 0.722, 0.740) for risk of metformin failure. Baseline HbA1c corresponded to the largest feature performance with higher levels associated with metformin failure. The addition of other clinical factors improved model performance (0.745; 95% CI 0.737, 0.754, P < .0001).
Conclusion
Baseline HbA1c was the strongest predictor of metformin failure and additional factors substantially improved performance suggesting that routinely available clinical data could be used to identify patients at high risk of metformin failure who might benefit from closer monitoring and earlier treatment intensification.
Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A "cytokine hypothesis" of depression is supported by the observation that depressed ...individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, "sequenced treatment alternatives to relieve depression" (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.
Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients ...if the nodules are reliably diagnosed as benign without surgery.
To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules.
Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules.
A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3).
The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules.
Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%.
In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.
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