102 research outputs found
Solution structure of the second bromodomain of Brd2 and its specific interaction with acetylated histone tails
<p>Abstract</p> <p>Background</p> <p>Brd2 is a transcriptional regulator and belongs to BET family, a less characterized novel class of bromodomain-containing proteins. Brd2 contains two tandem bromodomains (BD1 and BD2, 46% sequence identity) in the N-terminus and a conserved motif named ET (extra C-terminal) domain at the C-terminus that is also present in some other bromodomain proteins. The two bromodomains have been shown to bind the acetylated histone H4 and to be responsible for mitotic retention on chromosomes, which is probably a distinctive feature of BET family proteins. Although the crystal structure of Brd2 BD1 is reported, no structure features have been characterized for Brd2 BD2 and its interaction with acetylated histones.</p> <p>Results</p> <p>Here we report the solution structure of human Brd2 BD2 determined by NMR. Although the overall fold resembles the bromodomains from other proteins, significant differences can be found in loop regions, especially in the ZA loop in which a two amino acids insertion is involved in an uncommon <it>π</it>-helix, termed <it>π</it>D. The helix <it>π</it>D forms a portion of the acetyl-lysine binding site, which could be a structural characteristic of Brd2 BD2 and other BET bromodomains. Unlike Brd2 BD1, BD2 is monomeric in solution. With NMR perturbation studies, we have mapped the H4-AcK12 peptide binding interface on Brd2 BD2 and shown that the binding was with low affinity (2.9 mM) and in fast exchange. Using NMR and mutational analysis, we identified several residues important for the Brd2 BD2-H4-AcK12 peptide interaction and probed the potential mechanism for the specific recognition of acetylated histone codes by Brd2 BD2.</p> <p>Conclusion</p> <p>Brd2 BD2 is monomeric in solution and dynamically interacts with H4-AcK12. The additional secondary elements in the long ZA loop may be a common characteristic of BET bromodomains. Surrounding the ligand-binding cavity, five aspartate residues form a negatively charged collar that serves as a secondary binding site for H4-AcK12. We suggest that Brd2 BD1 and BD2 may possess distinctive roles and cooperate to regulate Brd2 functions. The structure basis of Brd2 BD2 will help to further characterize the functions of Brd2 and its BET members.</p
ISSR Analysis on Genetic Diversity of Wild \u3ci\u3eAgrostis stolonifera\u3c/i\u3e L. Germplasm Resources
ISSR Analysis on Genetic Diversity of Wild \u3ci\u3eAgrostis stolonifera\u3c/i\u3e L. Germplasm Resources
Neural Multi-Objective Combinatorial Optimization with Diversity Enhancement
Most of existing neural methods for multi-objective combinatorial
optimization (MOCO) problems solely rely on decomposition, which often leads to
repetitive solutions for the respective subproblems, thus a limited Pareto set.
Beyond decomposition, we propose a novel neural heuristic with diversity
enhancement (NHDE) to produce more Pareto solutions from two perspectives. On
the one hand, to hinder duplicated solutions for different subproblems, we
propose an indicator-enhanced deep reinforcement learning method to guide the
model, and design a heterogeneous graph attention mechanism to capture the
relations between the instance graph and the Pareto front graph. On the other
hand, to excavate more solutions in the neighborhood of each subproblem, we
present a multiple Pareto optima strategy to sample and preserve desirable
solutions. Experimental results on classic MOCO problems show that our NHDE is
able to generate a Pareto front with higher diversity, thereby achieving
superior overall performance. Moreover, our NHDE is generic and can be applied
to different neural methods for MOCO.Comment: Accepted at NeurIPS 202
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Meta-analysis of 16S rRNA microbial data identified alterations of the gut microbiota in COVID-19 patients during the acute and recovery phases
Background
Dozens of studies have demonstrated gut dysbiosis in COVID-19 patients during the acute and recovery phases. However, a consensus on the specific COVID-19 associated bacteria is missing. In this study, we performed a meta-analysis to explore whether robust and reproducible alterations in the gut microbiota of COVID-19 patients exist across different populations.
Methods
A systematic review was conducted for studies published prior to May 2022 in electronic databases. After review, we included 16 studies that comparing the gut microbiota in COVID-19 patients to those of controls. The 16S rRNA sequence data of these studies were then re-analyzed using a standardized workflow and synthesized by meta-analysis.
Results
We found that gut bacterial diversity of COVID-19 patients in both the acute and recovery phases was consistently lower than non-COVID-19 individuals. Microbial differential abundance analysis showed depletion of anti-inflammatory butyrate-producing bacteria and enrichment of taxa with pro-inflammatory properties in COVID-19 patients during the acute phase compared to non-COVID-19 individuals. Analysis of microbial communities showed that the gut microbiota of COVID-19 recovered patients were still in unhealthy ecostates.
Conclusions
Our results provided a comprehensive synthesis to better understand gut microbial perturbations associated with COVID-19 and identified underlying biomarkers for microbiome-based diagnostics and therapeutics
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Highly potent multivalent VHH antibodies against Chikungunya isolated from an alpaca naïve phage display library
Background
Chikungunya virus (CHIKV) is a re-emerged mosquito-borne alphavirus that can cause musculoskeletal diseases, imposing a substantial threat to public health globally. High-affinity antibodies are need for diagnosis and treatment of CHIKV infections. As a potential diagnostic and therapeutic agent, the multivalent VHH antibodies is a promising tookit in nanomedicine. Here, we developed potent multivalent VHH antibodies from an alpaca naïve phage display library targeting the E2 glycoprotein of the CHIKV virus.
Results
In the present study, we generated 20 VHH antibodies using a naïve phage display library for binders to the CHIKV E2 glycoprotein. Of these, multivalent VHH antibodies Nb-2E8 and Nb-3C5 had specific high-affinity binding to E2 protein within the nanomolar range. The equilibrium dissociation constant (KD) was between 2.59–20.7 nM, which was 100-fold stronger than the monovalent antibodies’ affinity. Moreover, epitope mapping showed that Nb-2E8 and Nb-3C5 recognized different linear epitopes located on the E2 glycoprotein domain C and A, respectively. A facile protocol of sandwich ELISA was established using BiNb-2E8 as a capture antibody and HRP-conjugated BiNb-3C5 as a detection antibody. A good linear correlation was achieved between the OD450 value and the E2 protein concentration in the 5–1000 ng/mL range (r = 0.9864, P < 0.0001), indicating its potential for quantitative detection of the E2 protein.
Conclusions
Compared to monovalent antibodies, multivalent VHH antibodies Nb-2E8 and Nb-3C5 showed high affinity and are potential candidates for diagnostic applications to better detect CHIKV virions in sera.
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