Over the past decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics ...can play in addressing unmet medical needs and how this class of compounds can be an excellent complement or even preferable alternative to small molecule and biological therapeutics. In this Perspective, we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technological advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery. An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been critical to the discovery, design, and subsequent development of novel therapeutics.
Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of ...enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: ...height,waist,weight,waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.
Contamination of drinking water by per- and polyfluoroalkyl substances (PFASs) emitted from manufacturing plants, fire-fighting foams, and urban waste streams has received considerable attention due ...to concerns over toxicity and environmental persistence; however, PFASs in ambient air remain poorly understood, especially in the United States (US). We measured PFAS concentrations in ambient fine particulate matter (PM
2.5
) at 5 locations across North Carolina over a 1 year period in 2019. Thirty-four PFASs, including perfluoroalkyl carboxylic, perfluoroalkane sulfonic, perfluoroalkyl ether carboxylic and sulfonic acids were analyzed by UHPLC/ESI-MS/MS. Quarterly averaged concentrations ranged from <0.004-14.1 pg m
−3
. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) ranged from <0.18 to 14.1 pg m
−3
, comparable to previous PM
2.5
measurements from Canada and Europe (<0.02-3.5 pg m
−3
). Concentrations above 1 pg m
−3
were observed in July-September at Charlotte (14.1 pg m
−3
, PFOA), Wilmington (4.75 pg m
−3
, PFOS), and Research Triangle Park (1.37 pg m
−3
, PFOS). Notably, PM
2.5
has a short atmospheric lifetime (<2 weeks), and thus, the presence of PFOS in these samples raises questions about their sources, since PFOS production was phased out in the US ∼20 years ago. This is the first US study to provide insights into ambient PFAS concentrations in PM
2.5
.
Quarterly PFOS concentrations (pg m
−3
) in ambient PM
2.5
in North Carolina, US. Highest concentrations were measured during July-September.
The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( ...www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.
Archaeological evidence suggests that dogs were introduced to the islands of Oceania via Island Southeast Asia around 3,300 years ago, and reached the eastern islands of Polynesia by the fourteenth ...century AD. This dispersal is intimately tied to human expansion, but the involvement of dogs in Pacific migrations is not well understood. Our analyses of seven new complete ancient mitogenomes and five partial mtDNA sequences from archaeological dog specimens from Mainland and Island Southeast Asia and the Pacific suggests at least three dog dispersal events into the region, in addition to the introduction of dingoes to Australia. We see an early introduction of dogs to Island Southeast Asia, which does not appear to extend into the islands of Oceania. A shared haplogroup identified between Iron Age Taiwanese dogs, terminal-Lapita and post-Lapita dogs suggests that at least one dog lineage was introduced to Near Oceania by or as the result of interactions with Austronesian language speakers associated with the Lapita Cultural Complex. We did not find any evidence that these dogs were successfully transported beyond New Guinea. Finally, we identify a widespread dog clade found across the Pacific, including the islands of Polynesia, which likely suggests a post-Lapita dog introduction from southern Island Southeast Asia.
Deep Impact: Excavating Comet Tempel 1 A'Hearn, M. F; Belton, M. J. S; Delamere, W. A ...
Science (American Association for the Advancement of Science),
10/2005, Volume:
310, Issue:
5746
Journal Article
Peer reviewed
Deep Impact collided with comet Tempel 1, excavating a crater controlled by gravity. The comet's outer layer is composed of 1- to 100-micrometer fine particles with negligible strength (<65 pascals). ...Local gravitational field and average nucleus density (600 kilograms per cubic meter) are estimated from ejecta fallback. Initial ejecta were hot (>1000 kelvins). A large increase in organic material occurred during and after the event, with smaller changes in carbon dioxide relative to water. On approach, the spacecraft observed frequent natural outbursts, a mean radius of 3.0 ± 0.1 kilometers, smooth and rough terrain, scarps, and impact craters. A thermal map indicates a surface in equilibrium with sunlight.
Droplet growth in warm turbulent clouds Devenish, B. J.; Bartello, P.; Brenguier, J.-L. ...
Quarterly journal of the Royal Meteorological Society,
July 2012 Part B, Volume:
138, Issue:
667
Journal Article
Soil nitrogen mineralisation (N
), the conversion of organic into inorganic N, is important for productivity and nutrient cycling. The balance between mineralisation and immobilisation (net N
) ...varies with soil properties and climate. However, because most global-scale assessments of net N
are laboratory-based, its regulation under field-conditions and implications for real-world soil functioning remain uncertain. Here, we explore the drivers of realised (field) and potential (laboratory) soil net N
across 30 grasslands worldwide. We find that realised N
is largely explained by temperature of the wettest quarter, microbial biomass, clay content and bulk density. Potential N
only weakly correlates with realised N
, but contributes to explain realised net N
when combined with soil and climatic variables. We provide novel insights of global realised soil net N
and show that potential soil net N
data available in the literature could be parameterised with soil and climate data to better predict realised N
.
The UKIDSS Galactic Plane Survey Lucas, P. W.; Hoare, M. G.; Longmore, A. ...
Monthly notices of the Royal Astronomical Society,
11/2008, Volume:
391, Issue:
1
Journal Article
Peer reviewed
Open access
The UKIDSS Galactic Plane Survey (GPS) is one of the five near-infrared Public Legacy Surveys that are being undertaken by the UKIDSS consortium, using the Wide Field Camera on the United Kingdom ...Infrared Telescope. It is surveying 1868 deg2 of the northern and equatorial Galactic plane at Galactic latitudes −5° < b < 5° in the J, H and K filters and a ∼200-deg2 area of the Taurus–Auriga–Perseus molecular cloud complex in these three filters and the 2.12 μm (1–0) H2 filter. It will provide data on ∼2 × 109 sources. Here we describe the properties of the data set and provide a user's guide for its exploitation. We also present brief Demonstration Science results from DR2 and from the Science Verification programme. These results illustrate how GPS data will frequently be combined with data taken in other wavebands to produce scientific results. The Demonstration Science comprises six studies. (1) A GPS-Spitzer-GLIMPSE cross-match for the star formation region G28.983−0.603 to identify YSOs. This increases the number of YSOs identified by a factor of 10 compared to GLIMPSE alone. (2) A wide-field study of the M17 nebula, in which an extinction map of the field is presented and the effect of source confusion on luminosity functions in different subregions is noted. (3) H2 emission in the ρ Ophiuchi dark cloud. All the molecular jets are traced back to a single active clump containing only a few protostars, which suggests that the duration of strong jet activity and associated rapid accretion in low-mass protostars is brief. (4) X-ray sources in the nuclear bulge. The GPS data distinguishes local main-sequence counterparts with soft X-ray spectra from nuclear bulge giant counterparts with hard X-ray spectra. (5) External galaxies in the zone of avoidance. The galaxies are clearly distinguished from stars in fields at longitudes l > 90°. (6) IPHAS-GPS optical–infrared spectrophotometric typing. The (i′−J) versus (J−H) diagram is used to distinguish A–F type dwarfs, G dwarfs, K dwarfs and red clump giants in a field with high reddening.
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