Crystal structure of the A domain from the a subunit of integrin CR3 (CD11 b/CD18)

AbstractWe have determined the high resolution crystal structure of the A domain from the a chain of integrin CR3. The domain adopts a classic α/β “Rossmann” fold and contains an unusual Mg2+ coordination site at its surface. One of the coordinating ligands is the glutamate side chain from another A domain molecule. We suggest that this site represents a general metal ion-dependent adhesion site (MIDAS) for binding protein ligands. We further propose that the subunits of integrins contain a MIDAS motif within a modified A domain. Our crystal structure will allow reliable models to be built for other members of the A domain superfamily and should facilitate development of novel adhesion modulatory drugs

Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran

SummaryTLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The β sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS

Toll-Like Receptor 4 Decoy, TOY, Attenuates Gram-Negative Bacterial Sepsis

Lipopolysaccharide (LPS), the Gram-negative bacterial outer membrane glycolipid, induces sepsis through its interaction with myeloid differentiation protein-2 (MD-2) and Toll-like receptor 4 (TLR4). To block interaction between LPS/MD-2 complex and TLR4, we designed and generated soluble fusion proteins capable of binding MD-2, dubbed TLR4 decoy receptor (TOY) using ‘the Hybrid leucine-rich repeats (LRR) technique’. TOY contains the MD-2 binding ectodomain of TLR4, the LRR motif of hagfish variable lymphocyte receptor (VLR), and the Fc domain of IgG1 to make it soluble, productive, and functional. TOY exhibited strong binding to MD-2, but not to the extracellular matrix (ECM), resulting in a favorable pharmacokinetic profile in vivo. TOY significantly extended the lifespan, when administered in either preventive or therapeutic manners, in both the LPS- and cecal ligation/puncture-induced sepsis models in mice. TOY markedly attenuated LPS-triggered NF-κB activation, secretion of proinflammatory cytokines, and thrombus formation in multiple organs. Taken together, the targeting strategy for sequestration of LPS/MD-2 complex using the decoy receptor TOY is effective in treating LPS- and bacteria-induced sepsis; furthermore, the strategy used in TOY development can be applied to the generation of other novel decoy receptor proteins

Relations between Average Distance, Heterogeneity and Network Synchronizability

By using the random interchanging algorithm, we investigate the relations between average distance, standard deviation of degree distribution and synchronizability of complex networks. We find that both increasing the average distance and magnifying the degree deviation will make the network synchronize harder. Only the combination of short average distance and small standard deviation of degree distribution that ensures strong synchronizability. Some previous studies assert that the maximal betweenness is a right quantity to estimate network synchronizability: the larger the maximal betweenness, the poorer the network synchronizability. Here we address an interesting case, which strongly suggests that the single quantity, maximal betweenness, may not give a comprehensive description of network synchronizability.Comment: 14 pages, and 7 figures (to be published in Physica A

Serum Neopterin Concentration and Impaired Glucose Metabolism: Relationship With β-Cell Function and Insulin Resistance

Aim: The purpose of this study was to measure the serum neopterin according to glucose metabolism and to evaluate neopterin as a predictor of type 2 diabetes (T2D) in a hospital-based cohort.Methods: A 75-g oral glucose tolerance test (OGTT) was performed by people who visited the outpatient clinic in Seoul National University Bundang Hospital for suspected abnormal glucose tolerance or a strong family history of T2D. Neopterin was measured using an enzyme-link immunosorbent assay with baseline samples from the OGTT.Results: Neopterin was measured in 184 participants. Indices related to glucose metabolism, such as the HOMA-IR, disposition index, etc. were calculated based on the results of the OGTT. The classifications for the 184 participants were: 24 (13%) had NGT, 89 (48.4%) prediabetes, and 60 (38.6%) T2D. Neopterin increased with deterioration of glucose metabolism (0.55 ± 0.25 vs. 0.58 ± 0.27 vs. 0.67 ± 0.27 ng/ml, p = 0.041; NGT, prediabetes, and T2D, respectively). Neopterin also correlated with fasting plasma glucose, 30-min and 120-min glucose of OGTT and HbA1c (r = 0.251, 0.259, 0.184, and 0.270, all p < 0.05). The HOMA-IR and disposition index correlated with neopterin (r = 0.291 and −0.170, respectively, both p < 0.05). When combined with C-peptide level, neopterin was as powerful as HOMA-IR in predicting future T2D.Conclusion: Serum neopterin appears to be related to impaired insulin secretion and insulin resistance in the development of T2D. Further investigation of the relationship between neopterin and glucose metabolism would be helpful to understand the pathophysiology for the development of T2D

Assembly strategies for polyethylene-degrading microbial consortia based on the combination of omics tools and the “Plastisphere”

Numerous microorganisms and other invertebrates that are able to degrade polyethylene (PE) have been reported. However, studies on PE biodegradation are still limited due to its extreme stability and the lack of explicit insights into the mechanisms and efficient enzymes involved in its metabolism by microorganisms. In this review, current studies of PE biodegradation, including the fundamental stages, important microorganisms and enzymes, and functional microbial consortia, were examined. Considering the bottlenecks in the construction of PE-degrading consortia, a combination of top-down and bottom-up approaches is proposed to identify the mechanisms and metabolites of PE degradation, related enzymes, and efficient synthetic microbial consortia. In addition, the exploration of the plastisphere based on omics tools is proposed as a future principal research direction for the construction of synthetic microbial consortia for PE degradation. Combining chemical and biological upcycling processes for PE waste could be widely applied in various fields to promote a sustainable environment

Risk of all-cause and cause-specific mortality associated with immune-mediated inflammatory diseases in Korea

ObjectiveImmune-mediated inflammatory disease (IMID) is associated with an increased risk of mortality. It is unclear whether the higher mortality is attributable to the IMIDs themselves or to the higher prevalence of comorbidities in IMIDs. We aimed to investigate whether IMIDs per se confer a higher risk of mortality.MethodsFrom the Korean National Health Insurance Service-National Sample Cohort database, this population-based cohort study included 25,736 patients newly diagnosed with IMIDs between January 2007 and December 2017, and 128,680 individuals without IMIDs who were matched for age, sex, income, hypertension, type 2 diabetes, dyslipidemia, and the Charlson comorbidity index. All individuals were retrospectively observed through December 31, 2019. The outcomes included all-cause and cause-specific mortalities. Adjustments for age, sex, and comorbidities were performed using multivariable Cox proportional hazard regression analyses, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the outcomes were estimated.ResultsThe adjusted risk of all-cause mortality was significantly lower in patients with IMIDs than that in those without (aHR, 0.890; 95% CI, 0.841–0.942). Regarding cause-specific mortality, cancer-specific (aHR, 0.788; 95% CI, 0.712–0.872) and cardiovascular disease-specific (aHR, 0.798; 95% CI, 0.701–0.908) mortalities were the two causes of death that showed significantly lower risks in patients with IMIDs. A similar trend was observed when organ based IMIDs were analyzed separately (i.e., gut, joint, and skin IMIDs).ConclusionAfter adjusting for comorbidities, IMIDs were associated with a lower risk of all-cause mortality compared to those without IMIDs. This was attributable to the lower risks of cancer-and cardiovascular disease-specific mortalities

Insights into salt tolerance from the genome of Thellungiella salsuginea

Thellungiella salsuginea, a close relative of Arabidopsis, represents an extremophile model for abiotic stress tolerance studies. We present the draft sequence of the T. salsuginea genome, assembled based on ∼134-fold coverage to seven chromosomes with a coding capacity of at least 28,457 genes. This genome provides resources and evidence about the nature of defense mechanisms constituting the genetic basis underlying plant abiotic stress tolerance. Comparative genomics and experimental analyses identified genes related to cation transport, abscisic acid signaling, and wax production prominent in T. salsuginea as possible contributors to its success in stressful environments

Identification of Direct Target Genes Using Joint Sequence and Expression Likelihood with Application to DAF-16

A major challenge in the post-genome era is to reconstruct regulatory networks from the biological knowledge accumulated up to date. The development of tools for identifying direct target genes of transcription factors (TFs) is critical to this endeavor. Given a set of microarray experiments, a probabilistic model called TRANSMODIS has been developed which can infer the direct targets of a TF by integrating sequence motif, gene expression and ChIP-chip data. The performance of TRANSMODIS was first validated on a set of transcription factor perturbation experiments (TFPEs) involving Pho4p, a well studied TF in Saccharomyces cerevisiae. TRANSMODIS removed elements of arbitrariness in manual target gene selection process and produced results that concur with one's intuition. TRANSMODIS was further validated on a genome-wide scale by comparing it with two other methods in Saccharomyces cerevisiae. The usefulness of TRANSMODIS was then demonstrated by applying it to the identification of direct targets of DAF-16, a critical TF regulating ageing in Caenorhabditis elegans. We found that 189 genes were tightly regulated by DAF-16. In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification. TRANSMODIS is computationally efficient and robust, making it a useful probabilistic framework for finding immediate targets