Kmer-Node2Vec: a Fast and Efficient Method for Kmer Embedding from the Kmer Co-occurrence Graph, with Applications to DNA Sequences.

Learning low-dimensional continuous vector representation for short k-mers divided from long DNA sequences is key to DNA sequence modeling that can be utilized in many bioinformatics investigations, such as DNA sequence retrieval and classification. DNA2Vec is the most widely used method for DNA sequence embedding. However, it poorly scales to large data sets due to its extremely long training time in kmer embedding. In this paper, we propose a novel efficient graph-based kmer embedding method, named Kmer-Node2Vec, to tackle this concern. Our method converts the large DNA corpus into one kmer co-occurrence graph, and extracts kmer relation on the graph by random walks to learn fast and high-quality kmer embedding. Extensive experiments show that our method is faster than DNA2Vec by 29 times for training on a 4GB data set, and on par with DNA2Vec in terms of task-specific accuracy of sequence retrieval and classification.

The transmission pattern and clinical course of the first 417 patients with COVID-19 infection in Shenzhen, China.

OBJECTIVE: To explore the transmission patterns and clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first identified in Wuhan, China in December 2019 as clustered and non-clustered cases of coronavirus disease (COVID-19) emerged in Shenzhen, China. METHODS: This retrospective study included the patients that were confirmed by laboratory detection of SARS-CoV-2 in Shenzen between 19 January 2020 and 21 February 2020. Data on the epidemiological and clinical characteristics were analysed. The patients were divided into non-clustered and clustered groups. The time course, intervals between first and second COVID-19 cases and other transmission patterns were compared between the groups. RESULTS: The 417 patients were divided into clustered (n = 235) and non-clustered groups (n = 182). Compared with the non-clustered group, the clustered group had significantly more young (≤20 years) and old (>60 years) patients. The clustered group had significantly more severe cases (nine of 235; 3.83%) compared with the non-clustered group (three of 182; 1.65%). Patients with severe disease spent 4-5 more days of hospitalization than patients with moderate and mild disease. CONCLUSION: This retrospective study analysed the transmission patterns and clinical course of the first wave of COVID-19 infection in Shenzhen, China.

Efficient synthesis of novel colchicine-magnolol hybrids and evaluation of their inhibitory activity on key proteases of 2019-nCoV replication and acute lung injury.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV), is a life-threatening infectious condition. Acute lung injury is a common complication in patients with COVID-19. 3-chymotrypsin-like protease (3CLpro) of 2019-nCoV and neutrophil elastase are critical targets of COVID-19 and acute lung injury, respectively. Colchicine and magnolol are reported to exert inhibitory effects on inflammatory response, the severe comorbidity in both COVID-19 and acute lung injury. We thus designed and synthesized a series of novel colchicine-magnolol hybrids based on a two-step synthetic sequence. It was found that these novel hybrids provided unexpected inhibition on 3CLpro and neutrophil elastase, a bioactivity that colchicine and magnolol did not possess. These findings not only provide perquisites for further in vitro and in vivo investigation to confirm the therapeutic potentiality of novel colchicine-magnolol hybrids, but also suggest that the concurrent inhibition of 3CLpro and neutrophil elastase may enable novel colchicine-magnolol hybrids as effective multi-target drug compounds.

Saliva diagnostics: emerging techniques and biomarkers for salivaomics in cancer detection.

INTRODUCTION: The pursuit of easy-to-use, non-invasive and inexpensive diagnostics is an urgent task for clinicians and scientists. Saliva is an important component of body fluid with regular changes of contents under various pathophysiological conditions, and the biomarkers identified from saliva shows high application potentials and values in disease diagnostics. This review introduces the latest developments in saliva research, with an emphasis on the detection and application of salivary biomarkers in cancer detection. AREAS COVERED: Detection of disease-specific biomarkers in saliva samples by existing salivaomic methods can be used to diagnose various human pathological conditions and was introduced in details. This review also covers the saliva collection methods, the analytical techniques as well as the corresponding commercial products, with an aim to describe an holistic process for saliva-based diagnostics. EXPERT OPINION: Saliva, as a non-invasive and collectable body fluid, can reflect the pathophysiological changes of the human body to a certain extent. Identification of reliable saliva biomarkers can provide a convenient way for cancer detection in clinical applications.

Histidine-rich proteins in prokaryotes: metal homeostasis and environmental habitat-related occurrence.

Increasing amounts of histidine-rich proteins (HRPs) have been found in microorganisms. We systematically analyzed the proteomes of 675 prokaryotes including 52 archaea and 623 bacteria for histidine-rich motifs (HRMs). We show that HRPs are widespread in prokaryotic proteomes, with the majority being involved in metal homeostasis. HRPs are frequently found in the proteomes of certain orders of rhizobia and pathogenic Gram-negative bacteria, but are essentially absent in obligate intracellular pathogenic species. The occurrence of HRPs in the proteomes of prokaryotes is related to their habitats. We further revealed a class of globally histidine-rich bacterial proteins. This approach can readily be used to identify other single amino acid rich motifs (and proteins) in microbial proteomes to facilitate the exploration of their functions.

Solution structure of a novel α-conotoxin with a distinctive loop spacing pattern.

α-Pharmacological conotoxins are among the most selective ligands of nicotinic acetylcholine receptors with typical cysteine frameworks. They are characterized by the intercysteine loop and classified into various subfamilies, such as α3/5 and α4/7 conotoxins. A novel α-conotoxin, Pu14a (DCPPHPVPGMHKCVCLKTC), with a distinct loop spacing pattern between cysteines was reported recently. Pu14a belongs to the Cys framework 14 (-C-C-C-C) family containing four proline residues in the loop 1 region. Similar to another framework 14 conotoxin Lt14a (MCPPLCKPSCTNC-NH2), Pu14a has C1-C3/C2-C4 disulfide linkage, and can inhibit some subtypes of nicotinic acetylcholine receptors. In this study, the solution structure of Pu14a was investigated using 1H nuclear magnetic resonance spectroscopy to understand the structure-activity relationship of this conotoxin. 20 converged structures of this conopeptide, with RMSD value of 0.77 Å, were obtained based on distance constraints, dihedral angles and disulfide bond constraints. The three-dimensional structure of Pu14a showed remarkable difference from typical α-conotoxins because of a large intercysteine loop between C2 and C13, as well as a 3(10)-helix near the C-terminal. Furthermore, four proline residues in Pu14a adopted the trans conformation that may correlate with the large loop configuration and the biological activity of this conopeptide. The distinct structural characteristics of Pu14a will be very useful for studying the structure-activity relationship of α-conotoxins.

Molecular dynamics simulation of a carboxy murine neuroglobin mutated on the proximal side: heme displacement and concomitant rearrangement in loop regions.

Neuroglobin, a member of vertebrate globin family, is distributed primarily in the brain and retina. Considerable evidence has accumulated regarding its unique ligand-binding properties, neural-specific distribution, distinct expression regulation, and possible roles in processes such as neuron protection and enzymatic metabolism. Structurally, neuroglobin enjoys unique features, such as bis-histidyl coordination to heme iron in the absence of exogenous ligand, heme orientational heterogeneity, and a heme sliding mechanism accompanying ligand binding. In the present work, molecular dynamics (MD) simulations were employed to reveal functional and structural information in three carboxyl murine neuroglobin mutants with single point mutations F106Y, F106L and F106I, respectively. The MD simulation indicates a remarkable proximal effect on detectable displacement of heme and a larger tunnel in the protein matrix. In addition, the mutation at F106 confers on the CD region a very sensitive mobility in all three model structures. The dynamic features of neuroglobin demonstrate rearrangement of the inner space and highly active loop regions in solution. These imply that the conserved residue at the G5 site plays a key role in the physiological function of this unusual protein.

Solution structure of Hyp10Pro variant of conomarphin, a cysteine-free and D-amino-acid containing conopeptide.

Conotoxins are mainly disulfide-rich short peptides active on different ion channels, neurotransmitter receptors or transporters in nervous system, exhibiting highly diversified composition, structures and biological functions. Besides these kinds of conopeptides, some novel cysteine-free conopeptides have also been reported. Conomarphin, a cystine-free 15-residue conopeptide from Conus marmoreus, has been purified and classified into M-superfamily. In addition to its unique characteristic of a D-type phenylalanine at the third residue from the C-terminus, conomarphin has an unusual hydroxyproline residue at position 10. To make an effort to understand the role of hydroxyproline post-translational modification in conomarphin, (1)H NMR solution structure of Hyp10Pro variant of conomarphin was resolved and compared with the native conomarphin in the present work. The Hyp10Pro conomarphin has a type II-beta-turn near the C-terminus instead of a 3(10) helix in native conomarphin. The compact loop region in native conomarphin becomes more open when hydroxyproline is displaced by proline. This reveals that hydroxyproline residue is essential for the structure of conomarphin just like D-Phe13. The unusual post-translational modification of conomarphin implies a unique selectivity of hydroxylation in toxin sequence.

Purification and structural characterization of a D-amino acid-containing conopeptide, conomarphin, from Conus marmoreus.

Cone snails, a group of gastropod animals that inhabit tropical seas, are capable of producing a mixture of peptide neurotoxins, namely conotoxins, for defense and predation. Conotoxins are mainly disulfide-rich short peptides that act on different ion channels, neurotransmitter receptors, or transporters in the nervous system. They exhibit highly diverse compositions, structures, and biological functions. In this work, a novel Cys-free 15-residue conopeptide from Conus marmoreus was purified and designated as conomarphin. Conomarphin is unique because of its D-configuration Phe at the third residue from the C-terminus, which was identified using HPLC by comparing native conomarphin fragments and the corresponding synthetic peptides cleaved by different proteases. Surprisingly, the cDNA-encoded precursor of conomarphin was found to share the conserved signal peptide with other M-superfamily conotoxins, clearly indicating that conomarphin should belong to the M-superfamily, although conomarphin shares no homology with other six-Cys-containing M-superfamily conotoxins. Furthermore, NMR spectroscopy experiments established that conomarphin adopts a well-defined structure in solution, with a tight loop in the middle of the peptide and a short 3(10)-helix at the C-terminus. By contrast, no loop in L-Phe13-conomarphin was found, which suggests that D-Phe13 is essential for the structure of conomarphin. In conclusion, conomarphin may represent a new conotoxin family, whose biological activity remains to be identified.

Solution structure of an M-1 conotoxin with a novel disulfide linkage.

The M-superfamily of conotoxins has a typical Cys framework (-CC-C-C-CC-), and is one of the eight major superfamilies found in the venom of the cone snail. Depending on the number of residues located in the last Cys loop (between Cys4 and Cys5), the M-superfamily family can be divided into four branches, namely M-1, -2, -3 and -4. Recently, two M-1 branch conotoxins (mr3e and tx3a) have been reported to possess a new disulfide bond arrangement between Cys1 and Cys5, Cys2 and Cys4, and Cys3 and Cys6, which is different from those seen in the M-2 and M-4 branches. Here we report the 3D structure of mr3e determined by 2D (1)H NMR in aqueous solution. Twenty converged structures of this peptide were obtained on the basis of 190 distance constraints obtained from NOE connectivities, as well as six varphi dihedral angle, three hydrogen bond, and three disulfide bond constraints. The rmsd values about the averaged coordinates of the backbone atoms were 0.43 +/- 0.19 A. Although mr3e has the same Cys arrangement as M-2 and M-4 conotoxins, it adopts a distinctive backbone conformation with the overall molecule resembling a 'flying bird'. Thus, different disulfide linkages may be employed by conotoxins with the same Cys framework to result in a more diversified backbone scaffold.