The evolution of the SARS‐CoV‐2 new variants reported to be 70% more contagious than the earlier one is now spreading fast worldwide. There is an instant need to discover how the new variants ...interact with the host receptor (ACE2). Among the reported mutations in the Spike glycoprotein of the new variants, three are specific to the receptor‐binding domain (RBD) and required insightful scrutiny for new therapeutic options. These structural evolutions in the RBD domain may impart a critical role to the unique pathogenicity of the SARS‐CoV‐2 new variants. Herein, using structural and biophysical approaches, we explored that the specific mutations in the UK (N501Y), South African (K417N‐E484K‐N501Y), Brazilian (K417T‐E484K‐N501Y), and hypothetical (N501Y‐E484K) variants alter the binding affinity, create new inter‐protein contacts and changes the internal structural dynamics thereby increases the binding and eventually the infectivity. Our investigation highlighted that the South African (K417N‐E484K‐N501Y), Brazilian (K417T‐E484K‐N501Y) variants are more lethal than the UK variant (N501Y). The behavior of the wild type and N501Y is comparable. Free energy calculations further confirmed that increased binding of the spike RBD to the ACE2 is mainly due to the electrostatic contribution. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. The triple mutants (South African and Brazilian) may pose a serious threat to the efficacy of the already developed vaccine. Our analysis would help to understand the binding and structural dynamics of the new mutations in the RBD domain of the Spike protein and demand further investigation in in vitro and in vivo models to design potential therapeutics against the new variants.
This study precisely explored the mechanism of the interaction of the spike RBD with the host ACE2 and revealed the differences in the binding of the reference and new variants. The systematic investigation revealed that the South African and Brazilian variants are more lethal than the others due to inter‐protein contacts specifically the electrostatic while the N501Y is comparable with the wild type. We hypothesized that the residue at 501Y is continuously subjected to positive selection pressure. We further demonstrated the dynamic behavior is also changed with the protein evolution. Conclusively, this study provides strong basis for structure and rationale‐based drug designing against the new variant by exploring the noticeable differences.
We explored whether medical health workers had more psychosocial problems than nonmedical health workers during the COVID-19 outbreak.
An online survey was run from February 19 to March 6, 2020; a ...total of 2,182 Chinese subjects participated. Mental health variables were assessed via the Insomnia Severity Index (ISI), the Symptom Check List-revised (SCL-90-R), and the Patient Health Questionnaire-4 (PHQ-4), which included a 2-item anxiety scale and a 2-item depression scale (PHQ-2).
Compared with nonmedical health workers (n = 1,255), medical health workers (n = 927) had a higher prevalence of insomnia (38.4 vs. 30.5%, p < 0.01), anxiety (13.0 vs. 8.5%, p < 0.01), depression (12.2 vs. 9.5%; p< 0.04), somatization (1.6 vs. 0.4%; p < 0.01), and obsessive-compulsive symptoms (5.3 vs. 2.2%; p < 0.01). They also had higher total scores of ISI, GAD-2, PHQ-2, and SCL-90-R obsessive-compulsive symptoms (p ≤ 0.01). Among medical health workers, having organic disease was an independent factor for insomnia, anxiety, depression, somatization, and obsessive-compulsive symptoms (p < 0.05 or 0.01). Living in rural areas, being female, and being at risk of contact with COVID-19 patients were the most common risk factors for insomnia, anxiety, obsessive-compulsive symptoms, and depression (p < 0.01 or 0.05). Among nonmedical health workers, having organic disease was a risk factor for insomnia, depression, and obsessive-compulsive symptoms (p < 0.01 or 0.05).
During the COVID-19 outbreak, medical health workers had psychosocial problems and risk factors for developing them. They were in need of attention and recovery programs.
The evolution of new SARS‐CoV‐2 variants around the globe has made the COVID‐19 pandemic more worrisome, further pressuring the health care system and immunity. Novel variations that are unique to ...the receptor‐binding motif (RBM) of the receptor‐binding domain (RBD) spike glycoprotein, i. e. L452R‐E484Q, may play a different role in the B.1.617 (also known as G/452R.V3) variant's pathogenicity and better survival compared to the wild type. Therefore, a thorough analysis is needed to understand the impact of these mutations on binding with host receptor (RBD) and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to explore the impact of specific mutations (L452R‐E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2. Our analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic‐stability, residual flexibility and structural compactness. Moreover, the new variant had altered the bonding network and structural‐dynamics properties significantly. MM/GBSA technique was used, which further established the binding differences between the wild type and B.1.617 variant. In conclusion, this study provides a strong impetus to develop novel drugs against the new SARS‐CoV‐2 variants.
Structural and biomolecular simulation techniques were used in this study to explore the impact of specific mutations in the B.1.617 variant of SARS‐CoV‐2 on the binding of receptor‐binding domain (RBD) to the host receptor ACE2. The analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic stability, residual flexibility, and structural compactness.
Gram-negative bacteria use various secretion systems to deliver their secreted effectors. Among them, type IV secretion system exists widely in a variety of bacterial species, and secretes type IV ...secreted effectors (T4SEs), which play vital roles in host-pathogen interactions. However, experimental approaches to identify T4SEs are time- and resource-consuming. In the present study, we aim to develop an
stacked ensemble method to predict whether a protein is an effector of type IV secretion system or not based on its sequence information. The protein sequences were encoded by the feature of position specific scoring matrix (PSSM)-composition by summing rows that correspond to the same amino acid residues in PSSM profiles. Based on the PSSM-composition features, we develop a stacked ensemble model PredT4SE-Stack to predict T4SEs, which utilized an ensemble of base-classifiers implemented by various machine learning algorithms, such as support vector machine, gradient boosting machine, and extremely randomized trees, to generate outputs for the meta-classifier in the classification system. Our results demonstrated that the framework of PredT4SE-Stack was a feasible and effective way to accurately identify T4SEs based on protein sequence information. The datasets and source code of PredT4SE-Stack are freely available at http://xbioinfo.sjtu.edu.cn/PredT4SE_Stack/index.php.
Parkinson's disease (PD) arises as neurodegenerative disorder and characterized by progressive deterioration of motor functions due to forfeiture of dopamine-releasing neurons. During PD, neurons at ...stake loss their functionality that results into cognition impairment and forgetfulness, commonly called as dementia. Recently, nanoparticles (NPs) have been reported for easy drug delivery through blood-brain barrier (BBB) into the central nervous system (CNS) against the conventional drug delivery systems. However, present study attempted to elucidate the α-synuclein activity, a major factor casing PD, in presence of its inhibitor cerium oxide (CeO
) nanoparticle via computational biology approach. A computational analysis was also conducted for the α-synuclein activity with biocompatible metal NPs such as GOLD NPs and SPIONs to scrutinize the efficacy and degree of inhibition induced by the CeO
NP. The obtained results concluded that CeO
NP fit best in the active site of α-synuclein with good contacts and interaction, and potentially inhibited the PD against L-DOPA drug selected as positive control in the designed PD biochemical pathway. Hence, CeO
NP has been purposed as potential inhibitor of α-synuclein and can be employed as nano-drug against the PD.
Helicobacter Pylori is a known causal agent of gastric malignancies and peptic ulcers. The extremophile nature of this bacterium is protecting it from designing a potent drug against it. Therefore, ...the use of computational approaches to design antigenic, stable and safe vaccine against this pathogen could help to control the infections associated with it. Therefore, in this study, we used multiple immunoinformatics approaches along with other computational approaches to design a multi-epitopes subunit vaccine against H. Pylori. A total of 7 CTL and 12 HTL antigenic epitopes based on c-terminal cleavage and MHC binding scores were predicted from the four selected proteins (CagA, OipA, GroEL and cagA). The predicted epitopes were joined by AYY and GPGPG linkers. Β-defensins adjuvant was added to the N-terminus of the vaccine. For validation, immunogenicity, allergenicity and physiochemical analysis were conducted. The designed vaccine is likely antigenic in nature and produced robust and substantial interactions with Toll-like receptors (TLR-2, 4, 5, and 9). The vaccine developed was also subjected to an in silico cloning and immune response prediction model, which verified its efficiency of expression and the immune system provoking response. These analyses indicate that the suggested vaccine may produce particular immune responses against H. pylori, but laboratory validation is needed to verify the safety and immunogenicity status of the suggested vaccine design.
Aliphatic‐aromatic copolyesters offer a promising solution to mitigate plastic pollution, but high content of aliphatic units (>40 %) often suffer from diminished comprehensive performances. ...Poly(butylene oxalate‐co‐furandicarboxylate) (PBOF) copolyesters were synthesized by precisely controlling the oxalic acid content from 10 % to 60 %. Compared with commercial PBAT, the barrier properties of PBOF for H2O and O2 increased by more than 6 and 26 times, respectively. The introduction of the oxalic acid units allowed the water contact angle to be reduced from 82.5° to 62.9°. Superior hydrophilicity gave PBOF an excellent degradation performance within a 35‐day hydrolysis. Interestingly, PBO20F and PBO30F also displayed obvious decrease of molecular weight during hydrolysis, with elastic modulus >1 GPa and tensile strength between 35–54 MPa. PBOF achieved the highest hydrolysis rates among the reported PBF‐based copolyesters. The hydrolytic mechanism was further explored based on Fukui function analysis and density functional theory (DFT) calculation. Noncovalent analysis indicated that the water molecules formed hydrogen bonding interaction with adjacent ester groups and thus improved the reactivity of carbonyl carbon. PBOF not only meet the requirements of the high‐performance packaging market but can quickly degrade after the end of their usage cycles, providing a new choice for green and environmental protection.
Fully bio‐based PBOF copolyesters formed from oxalic acid, 2,5‐furandicarboxylic acid and butanediol are capable of realizing a circular carbon economy at the source. The theoretical evidence that the oxalic acid segment has the lowest hydrolysis energy barrier corresponds to the fastest hydrolysis rate, indicating that the oxalic acid segment confers excellent degradation ability as the active site of hydrolysis.
High-risk human papillomaviruses (hrHPVs) are the most prevalent viruses in human diseases including cervical cancers. Expression of E6 protein has already been reported in cervical cancer cases, ...excluding normal tissues. Continuous expression of E6 protein is making it ideal to develop therapeutic vaccines against hrHPVs infection and cervical cancer. Therefore, we carried out a meta-analysis of multiple hrHPVs to predict the most potential prophylactic peptide vaccines. In this study, immunoinformatics approach was employed to predict antigenic epitopes of hrHPVs E6 proteins restricted to 12 Human HLAs to aid the development of peptide vaccines against hrHPVs. Conformational B-cell and CTL epitopes were predicted for hrHPVs E6 proteins using ElliPro and NetCTL. The potential of the predicted peptides were tested and validated by using systems biology approach considering experimental concentration. We also investigated the binding interactions of the antigenic CTL epitopes by using docking. The stability of the resulting peptide-MHC I complexes was further studied by molecular dynamics simulations. The simulation results highlighted the regions from 46-62 and 65-76 that could be the first choice for the development of prophylactic peptide vaccines against hrHPVs. To overcome the worldwide distribution, the predicted epitopes restricted to different HLAs could cover most of the vaccination and would help to explore the possibility of these epitopes for adaptive immunotherapy against HPVs infections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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