BackgroundThe interrogation of proteomes (“proteomics”) in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine.Methodology/Principal FindingsWe present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (∼100 fM–1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states.Conclusions/SignificanceWe describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.

On 11 March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic 1. The strategies based on non-pharmaceutical interventions that were used to contain the outbreak in China appear to be effective 2 , but quantitative research is still needed to assess the efficacy of non-pharmaceutical interventions and their timings 3. Here, using epidemiological data on COVID-19 and anonymized data on human movement 4,5 , we develop a modelling framework that uses daily travel networks to simulate different outbreak and intervention scenarios across China. We estimate that there were a total of 114,325 cases of COVID-19 (interquartile range 76,776-164,576) in mainland China as of 29 February 2020. Without non-pharmaceutical interventions, we predict that the number of cases would have been 67-fold higher (interquartile range 44-94-fold) by 29 February 2020, and we find that the effectiveness of different interventions varied. We estimate that early detection and isolation of cases prevented more infections than did travel restrictions and contact reductions, but that a combination of non-pharmaceutical interventions achieved the strongest and most rapid effect. According to our model, the lifting of travel restrictions from 17 February 2020 does not lead to an increase in cases across China if social distancing interventions can be maintained, even at a limited level of an on average 25% reduction in contact between individuals that continues until late April. These findings improve our understanding of the effects of non-pharmaceutical interventions on COVID-19, and will inform response efforts across the world.

We performed a genome-wide association study (GWAS) of systemic lupus erythematosus (SLE) in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina Human610-Quad BeadChips and replicating 78 SNPs in two additional cohorts (3,152 cases and 7,050 controls). We identified nine new susceptibility loci (ETS1, IKZF1, RASGRP3, SLC15A4, TNIP1, 7q11.23, 10q11.22, 11q23.3 and 16p11.2; 1.77 x 10(-25) < or = P(combined) < or = 2.77 x 10(-8)) and confirmed seven previously reported loci (BLK, IRF5, STAT4, TNFAIP3, TNFSF4, 6q21 and 22q11.21; 5.17 x 10(-42) < or = P(combined) < or = 5.18 x 10(-12)). Comparison with previous GWAS findings highlighted the genetic heterogeneity of SLE susceptibility between Chinese Han and European populations. This study not only advances our understanding of the genetic basis of SLE but also highlights the value of performing GWAS in diverse ancestral populations.

About 8,000 years ago in the Fertile Crescent, a spontaneous hybridization of the wild diploid grass Aegilops tauschii (2n 5 14; DD) with the cultivated tetraploid wheat Triticum turgidum (2n 5 4x 5 28; AABB) resulted in hexaploid wheat (T. aestivum; 2n 5 6x 5 42; AABBDD) 1,2 . Wheat has since become a primary staple crop worldwide as a result of its enhanced adaptability to a wide range of climates and improved grain quality for the production of baker's flour 2 . Here we describe sequencing the Ae. tauschii genome and obtaining a roughly 90-fold depth of short reads from libraries with various insert sizes, to gain a better understanding of this genetically complex plant. The assembled scaffolds represented 83.4% of the genome, of which 65.9% comprised transposable elements. We generated comprehensive RNA-Seq data and used it to identify 43,150 protein-coding genes, of which 30,697 (71.1%) were uniquely anchored to chromosomes with an integrated high-density genetic map. Whole-genome analysis revealed gene family expansion in Ae. tauschii of agronomically relevant gene families that were associated with disease resistance, abiotic stress tolerance and grain quality. This draft genome sequence provides insight into the environmental adaptation of bread wheat and can aid in defining the large and complicated genomes of wheat species.We selected Ae. tauschii accession AL8/78 for genome sequencing because it has been extensively characterized genetically (Supplementary Information). Using a whole genome shotgun strategy, we generated 398 Gb of high-quality reads from 45 libraries with insert sizes ranging from 200 bp to 20 kb (Supplementary Information). A hierarchical, iterative assembly of short reads employing the parallelized sequence assembler SOAPdenovo 3 achieved contigs with an N50 length (minimum length of contigs representing 50% of the assembly) of 4,512 bp (Table 1). Paired-end information combined with an additional 18.4 Gb of Roche/454 long-read sequences was used sequentially to generate 4.23-Gb scaffolds (83.4% were non-gapped contiguous sequences) with an N50 length of 57.6 kb (Supplementary Information). The assembly represented 97% of the 4.36-Gb genome as estimated by K-mer analysis (Supplementary Information). We also obtained 13,185 Ae. tauschii expressed sequence tag (EST) sequences using Sanger sequencing, of which 11,998 (91%) could be mapped to the scaffolds with more than 90% coverage (Supplementary Information).To aid in gene identification, we performed RNA-Seq (53.2 Gb for a 117-Mb transcriptome assembly) on 23 libraries representing eight tissues including pistil, root, seed, spike, stamen, stem, leaf and sheath (Supplementary Information). Using both evidence-based and de novo gene predictions, we identified 34,498 high-confidence protein-coding loci. FGENESH 4 and GeneID models were supported by a 60% overlap with either our ESTs and RNA-Seq reads, or with homologous proteins. More than 76% of the gene models had a significant match (E value # 10 25; alignment length $ 60%) in the ...

BACKGROUND The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS We observed a significant association (P<1.00×10 −10) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P = 5.10×10 −5) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

Some conjugated polymers have luminescence properties that are potentially useful for applications such as light-emitting diodes, whose performance is ultimately limited by the maximum quantum efficiency theoretically attainable for electroluminescence, ,. If the lowest-energy excited states are strongly bound excitons (electron-hole pairs in singlet or triplet spin states), this theoretical upper limit is only 25% of the corresponding quantum efficiency for photoluminescence: an electron in the π-band and a hole (or missing electron) in the π-band can form a triplet with spin multiplicity of three, or a singlet with spin multiplicity of one, but only the singlet will decay radiatively. But if the electron-hole binding energy is sufficiently weak, the ratio of the maximum quantum efficiencies for electroluminescence and photoluminescence can theoretically approach unity. Here we report a value of ∼50% for the ratio of these efficiencies (electroluminescence:photoluminescence) in polymer light-emitting diodes, attained by blending electron transport materials with the conjugated polymer to improve the injection of electrons. This value significantly exceeds the theoretical limit for strongly bound singlet and triplet excitons, assuming they comprise the lowest-energy excited states. Our results imply that the exciton binding energy is weak, or that singlet bound states are formed with higher probability than triplets.

Jasmonates play a number of diverse roles in plant defense and development. CORONATINE INSENSITIVE1 (COI1), an F-box protein essential for all the jasmonate responses, interacts with multiple proteins to form the SCF COI1 E3 ubiquitin ligase complex and recruits jasmonate ZIM-domain (JAZ) proteins for degradation by the 26S proteasome. To determine which protein directly binds to jasmonoyl-isoleucine (JA-Ile)/coronatine (COR) and serves as a receptor for jasmonate, we built a high-quality structural model of COI1 and performed molecular modeling of COI1-jasmonate interactions. Our results imply that COI1 has the structural traits for binding JA-Ile or COR. The direct binding of these molecules with COI1 was further examined using a combination of molecular and biochemical approaches. First, we used the immobilized jasmonate approach to show that the COI1 protein in crude leaf extracts can bind to the jasmonate moiety of JA-Ile. Second, we employed surface plasmon resonance technology with purified COI1 and JAZ1 protein to reveal the interaction among COI1, JA-Ile, and JAZ1. Finally, we used the photoaffinity labeling technology to show the direct binding of COR with purified insect-expressed COI1. Taken together, these results demonstrate that COI1 directly binds to JA-Ile and COR and serves as a receptor for jasmonate.

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