ObjectiveSince December 2019, a newly identified coronavirus (severe acute respiratory syndrome coronavirus (SARS-CoV-2)) has caused outbreaks of pneumonia in Wuhan, China. SARS-CoV-2 enters host cells via cell receptor ACE II (ACE2) and the transmembrane serine protease 2 (TMPRSS2). In order to identify possible prime target cells of SARS-CoV-2 by comprehensive dissection of ACE2 and TMPRSS2 coexpression pattern in different cell types, five datasets with single-cell transcriptomes of lung, oesophagus, gastric mucosa, ileum and colon were analysed.DesignFive datasets were searched, separately integrated and analysed. Violin plot was used to show the distribution of differentially expressed genes for different clusters. The ACE2-expressing and TMPRRSS2-expressing cells were highlighted and dissected to characterise the composition and proportion.ResultsCell types in each dataset were identified by known markers. ACE2 and TMPRSS2 were not only coexpressed in lung AT2 cells and oesophageal upper epithelial and gland cells but also highly expressed in absorptive enterocytes from the ileum and colon. Additionally, among all the coexpressing cells in the normal digestive system and lung, the expression of ACE2 was relatively highly expressed in the ileum and colon.ConclusionThis study provides the evidence of the potential route of SARS-CoV-2 in the digestive system along with the respiratory tract based on single-cell transcriptomic analysis. This finding may have a significant impact on health policy setting regarding the prevention of SARS-CoV-2 infection. Our study also demonstrates a novel method to identify the prime cell types of a virus by the coexpression pattern analysis of single-cell sequencing data.
There is heterogeneity in the observed O2peak response to similar exercise training, and different exercise approaches produce variable degrees of exercise response (trainability). The aim of this study was to combine data from different laboratories to compare O2peak trainability between various volumes of interval training and Moderate Intensity Continuous Training (MICT). For interval training, volumes were classified by the duration of total interval time. High-volume High Intensity Interval Training (HIIT) included studies that had participants complete more than 15 min of high intensity efforts per session. Low-volume HIIT/Sprint Interval Training (SIT) included studies using less than 15 min of high intensity efforts per session. In total, 677 participants across 18 aerobic exercise training interventions from eight different universities in five countries were included in the analysis. Participants had completed 3 weeks or more of either high-volume HIIT (n = 299), low-volume HIIT/SIT (n = 116), or MICT (n = 262) and were predominately men (n = 495) with a mix of healthy, elderly and clinical populations. Each training intervention improved mean O2peak at the group level (P < 0.001). After adjusting for covariates, high-volume HIIT had a significantly greater (P < 0.05) absolute O2peak increase (0.29 L/min) compared to MICT (0.20 L/min) and low-volume HIIT/SIT (0.18 L/min). Adjusted relative O2peak increase was also significantly greater (P < 0.01) in high-volume HIIT (3.3 ml/kg/min) than MICT (2.4 ml/kg/min) and insignificantly greater (P = 0.09) than low-volume HIIT/SIT (2.5 mL/kg/min). Based on a high threshold for a likely response (technical error of measurement plus the minimal clinically important difference), high-volume HIIT had significantly more (P < 0.01) likely responders (31%) compared to low-volume HIIT/SIT (16%) and MICT (21%). Covariates such as age, sex, the individual study, population group, sessions per week, study duration and the average between pre and post O2peak explained only 17.3% of the variance in O2peak trainability. In conclusion, high-volume HIIT had more likely responders to improvements in O2peak compared to low-volume HIIT/SIT and MICT.
In the past decade, a concerted effort to successfully capture specific tertiary packing interactions produced specific three-dimensional structures for many de novo designed proteins that are validated by nuclear magnetic resonance and/or X-ray crystallographic techniques. However, the success rate of computational design remains low. In this review, we provide an overview of experimentally validated, de novo designed proteins and compare four available programs, RosettaDesign, EGAD, Liang-Grishin, and RosettaDesign-SR, by assessing designed sequences computationally. Computational assessment includes the recovery of native sequences, the calculation of sizes of hydrophobic patches and total solvent-accessible surface area, and the prediction of structural properties such as intrinsic disorder, secondary structures, and three-dimensional structures. This computational assessment, together with a recent community-wide experiment in assessing scoring functions for interface design, suggests that the next-generation protein-design scoring function will come from the right balance of complementary interaction terms. Such balance may be found when more negative experimental data become available as part of a training set.
MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, MlklD139V, that alters the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of MlklD139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).
Designing protein sequences that can fold into a given structure is a well-known inverse protein-folding problem. One important characteristic to attain for a protein design program is the ability to recover wild-type sequences given their native backbone structures. The highest average sequence identity accuracy achieved by current protein-design programs in this problem is around 30%, achieved by our previous system, SPIN. SPIN is a program that predicts sequences compatible with a provided structure using a neural network with fragment-based local and energy-based nonlocal profiles. Our new model, SPIN2, uses a deep neural network and additional structural features to improve on SPIN. SPIN2 achieves over 34% in sequence recovery in 10-fold cross-validation and independent tests, a 4% improvement over the previous version. The sequence profiles generated from SPIN2 are expected to be useful for improving existing fold recognition and protein design techniques. SPIN2 is available at http://sparks-lab.org.
Locating sequences compatible to a protein structural fold is the well-known inverse protein-folding problem. While significant progress has been made, the success rate of protein design remains low. As a result, a library of designed sequences or profile of sequences is currently employed for guiding experimental screening or directed evolution. Sequence profiles can be computationally predicted by iterative mutations of a random sequence to produce energy-optimized sequences, or by combining sequences of structurally similar fragments in a template library. The latter approach is computationally more efficient but yields less accurate profiles than the former because of lacking tertiary structural information. Here we present a method called SPIN that predicts Sequence Profiles by Integrated Neural network based on fragment-derived sequence profiles and structure-derived energy profiles. SPIN improves over the fragment-derived profile by 6.7% (from 23.6% to 30.3%) in sequence identity between predicted and wild-type sequences. The method also reduces the number of residues in low complex regions by 15.7% and has a significant better balance of hydrophilic and hydrophobic residues at protein surfaces. The accuracy of sequence profiles obtained is comparable to those generated from the protein design program RosettaDesign 3.5. This highly efficient method for predicting sequence profiles from structures will be useful as a single-body scoring term for improving scoring functions used in protein design and fold recognition. It also complements protein design programs in guiding experimental design of the sequence library for screening and directed evolution of designed sequences. The SPIN server is available at http://sparks-lab.org.
Objective HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype–disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA–B27 and HLA–DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. Methods Five hundred sixty‐eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. Results Associations were observed between the overall microbial composition and both the HLA–B27 genotype and the HLA–DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). Conclusion This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA‐B27 and HLA–DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.
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