Accurate Proteome-wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ

Protein quantification without isotopic labels has been a long-standing interest in the proteomics field. However, accurate and robust proteome-wide quantification with label-free approaches remains a challenge. We developed a new intensity determination and normalization procedure called MaxLFQ that is fully compatible with any peptide or protein separation prior to LC-MS analysis. Protein abundance profiles are assembled using the maximum possible information from MS signals, given that the presence of quantifiable peptides varies from sample to sample. For a benchmark dataset with two proteomes mixed at known ratios, we accurately detected the mixing ratio over the entire protein expression range, with greater precision for abundant proteins. The significance of individual label-free quantifications was obtained via a t test approach. For a second benchmark dataset, we accurately quantify fold changes over several orders of magnitude, a task that is challenging with label-based methods. MaxLFQ is a generic label-free quantification technology that is readily applicable to many biological questions; it is compatible with standard statistical analysis workflows, and it has been validated in many and diverse biological projects. Our algorithms can handle very large experiments of 500+ samples in a manageable computing time. It is implemented in the freely available MaxQuant computational proteomics platform and works completely seamlessly at the click of a button

Resonance properties and microstructure of ultracompliant metallic nanoelectromechanical systems resonators synthesized from Al-32 at. % Mo amorphous-nanocrystalline metallic composites

This study details the resonance properties of 20 nm thick nanoelectromechanical system scale cantilevers fabricated from a metallic Al-32 at. %Mo nanocomposite. The advantage of the Al-32 at. %Mo alloy is that its strength and near-atomic surface smoothness enable fabrication of single-anchored metallic cantilevers with extreme length-to-thickness ratios, as high as 400:1. This yields uniquely compliant structures with exquisite force sensitivity. For example, an 8 ??m long, 20 nm thick Al-32 at. %Mo device has a spring constant of K280 ??Nm. We show through transmission electron microscope analysis and continuum modeling that the relevant damping mechanisms are related to the device microstructure.open3

CHILES VI:HI and H alpha observations for z <0.1 galaxies; probing HI spin alignment with filaments in the cosmic web

We present neutral hydrogen (HI) and ionized hydrogen (H${\alpha}$) observations of ten galaxies out to a redshift of 0.1. The HI observations are from the first epoch (178 hours) of the COSMOS HI Large Extragalactic Survey (CHILES). Our sample is HI biased and consists of ten late-type galaxies with HI masses that range from $1.8\times10^{7}$ M$_{\odot}$ to $1.1\times10^{10}$ M$_{\odot}$. We find that although the majority of galaxies show irregularities in the morphology and kinematics, they generally follow the scaling relations found in larger samples. We find that the HI and H${\alpha}$ velocities reach the flat part of the rotation curve. We identify the large-scale structure in the nearby CHILES volume using DisPerSE with the spectroscopic catalog from SDSS. We explore the gaseous properties of the galaxies as a function of location in the cosmic web. We also compare the angular momentum vector (spin) of the galaxies to the orientation of the nearest cosmic web filament. Our results show that galaxy spins tend to be aligned with cosmic web filaments and show a hint of a transition mass associated with the spin angle alignment.Comment: 24 pages, 25 figures, 6 tables, accepted for publication in MNRA

Reconstruction of ancient microbial genomes from the human gut

Loss of gut microbial diversity1–6 in industrial populations is associated with chronic diseases7, underscoring the importance of studying our ancestral gut microbiome. However, relatively little is known about the composition of pre-industrial gut microbiomes. Here we performed a large-scale de novo assembly of microbial genomes from palaeofaeces. From eight authenticated human palaeofaeces samples (1,000–2,000 years old) with well-preserved DNA from southwestern USA and Mexico, we reconstructed 498 medium- and high-quality microbial genomes. Among the 181 genomes with the strongest evidence of being ancient and of human gut origin, 39% represent previously undescribed species-level genome bins. Tip dating suggests an approximate diversification timeline for the key human symbiont Methanobrevibacter smithii. In comparison to 789 present-day human gut microbiome samples from eight countries, the palaeofaeces samples are more similar to non-industrialized than industrialized human gut microbiomes. Functional profiling of the palaeofaeces samples reveals a markedly lower abundance of antibiotic-resistance and mucin-degrading genes, as well as enrichment of mobile genetic elements relative to industrial gut microbiomes. This study facilitates the discovery and characterization of previously undescribed gut microorganisms from ancient microbiomes and the investigation of the evolutionary history of the human gut microbiota through genome reconstruction from palaeofaeces.Ethics Overview of samples Reference-based taxonomic composition De novo genome reconstruction Methanobrevibacter smithii tip dating Functional genomic analysis Discussion Online content Method

Workgroup report: Public health strategies for reducing aflatoxin exposure in developing countries

10.1289/ehp.9302Environmental Health Perspectives114121898-190

Prevalence and risk factors for mesh erosion after laparoscopic-assisted sacrocolpopexy

The purpose of this study is to identify risk factors for mesh erosion in women undergoing minimally invasive sacrocolpopexy (MISC). We hypothesize that erosion is higher in subjects undergoing concomitant hysterectomy. This is a retrospective cohort study of women who underwent MISC between November 2004 and January 2009. Demographics, operative techniques, and outcomes were abstracted from medical records. Multivariable regression identified odds of erosion. Of 188 MISC procedures 19(10%) had erosions. Erosion was higher in those with total vaginal hysterectomy (TVH) compared to both post-hysterectomy (23% vs. 5%, p = 0.003) and supracervical hysterectomy (SCH) (23% vs. 5%, p = 0.109) groups. In multivariable regression, the odds of erosion for TVH was 5.67 (95% CI: 1.88–17.10) compared to post-hysterectomy. Smoking, the use of collagen-coated mesh, transvaginal dissection, and mesh attachment transvaginally were no longer significant in the multivariable regression model. Based on this study, surgeons should consider supracervical hysterectomy over total vaginal hysterectomy as the procedure of choice in association with MISC unless removal of the cervix is otherwise indicated

Soil surface temperatures reveal moderation of the urban heat island effect by trees and shrubs

Urban areas are major contributors to air pollution and climate change, causing impacts on human health that are amplified by the microclimatological effects of buildings and grey infrastructure through the urban heat island (UHI) effect. Urban greenspaces may be important in reducing surface temperature extremes, but their effects have not been investigated at a city-wide scale. Across a midsized UK city we buried temperature loggers at the surface of greenspace soils at 100 sites, stratified by proximity to city centre, vegetation cover and land-use. Mean daily soil surface temperature over 11 months increased by 0.6 °C over the 5 km from the city outskirts to the centre. Trees and shrubs in non-domestic greenspace reduced mean maximum daily soil surface temperatures in the summer by 5.7 °C compared to herbaceous vegetation, but tended to maintain slightly higher temperatures in winter. Trees in domestic gardens, which tend to be smaller, were less effective at reducing summer soil surface temperatures. Our findings reveal that the UHI effects soil temperatures at a city-wide scale, and that in their moderating urban soil surface temperature extremes, trees and shrubs may help to reduce the adverse impacts of urbanization on microclimate, soil processes and human health

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers\u27 tissue of origin

Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade – results of an explorative CGH meta-analysis

All available comparative genomic hybridisation (CGH) analyses (n=31, until 12/2003) of human hepatocellular carcinomas (HCCs; n=785) and premalignant dysplastic nodules (DNs; n=30) were compiled and correlated with clinical and histological parameters. The most prominent amplifications of genomic material were present in 1q (57.1%), 8q (46.6%), 6p (22.3%), and 17q (22.2%), while losses were most prevalent in 8p (38%), 16q (35.9%), 4q (34.3%), 17p (32.1%), and 13q (26.2%). Deletions of 4q, 16q, 13q, and 8p positively correlated with hepatitis B virus aetiology, while losses of 8p were more frequently found in hepatitis C virus-negative cases. In poorly differentiated HCCs, 13q and 4q were significantly under-represented. Moreover, gains of 1q were positively correlated with the occurrence of all other high-frequency alterations in HCCs. In DNs, amplifications were most frequently present in 1q and 8q, while deletions occurred in 8p, 17p, 5p, 13q, 14q, and 16q. In conclusion, aetiology and dedifferentiation correlate with specific genomic alterations in human HCCs. Gains of 1q appear to be rather early events that may predispose to further chromosomal abnormalities. Thus, explorative CGH meta-analysis generates novel and testable hypotheses regarding the cause and functional significance of genomic alterations in human HCCs