Free energy landscape and thermodynamics properties of novel mutations in PncA of pyrazinamide resistance isolates of Mycobacterium tuberculosis.

Pyrazinamide (PZA) is one of the first-line antituberculosis therapy, active against non-replicating Mycobacterium tuberculosis (Mtb). The conversion of PZA into pyrazinoic acid (POA), the active form, required the activity of pncA gene product pyrazinamidase (PZase) activity. Mutations occurred in pncA are the primary cause behind the PZA resistance. However, the resistance mechanism is important to explore using high throughput computational approaches. Here we aimed to explore the mechanism of PZA resistance behind novel P62T, L120R, and V130M mutations in PZase using 200 ns molecular dynamics (MD) simulations. MD simulations were performed to observe the structural changes for these three mutants (MTs) compared to the wild types (WT). Root means square fluctuation, the radius of gyration, free energy landscape, root means square deviation, dynamic cross-correlation motion, and pocket volume were found in variation between WT and MTs, revealing the effects of P62T, L120R, and V130M. The free energy conformational landscape of MTs differs significantly from the WT system, lowering the binding of PZA. The geometric shape complementarity of the drug (PZA) and target protein (PZase) further confirmed that P62T, L120R, and V130M affect the protein structure. These effects on PZase may cause vulnerability to convert PZA into POA.Communicated by Ramaswamy H. Sarma.

Tracing down the Updates on Dengue Virus-Molecular Biology, Antivirals, and Vaccine Strategies.

BACKGROUND: Nearly half of the world is at risk of developing dengue infection. Dengue virus is the causative agent behind this public healthcare concern. Millions of dengue cases are reported every year, leading to thousands of deaths. The scientific community is working to develop effective therapeutic strategies in the form of vaccines and antiviral drugs against dengue. METHODS: In this review, a methodological approach has been used to gather data from the past five years to include the latest developments against the dengue virus. RESULTS: Different therapeutics and antiviral targets against the dengue virus are at different stages of development, but none have been approved by the FDA. Moreover, various vaccination strategies have also been discussed, including attenuated virus vaccines, recombinant subunit vaccines, viral vector vaccines, DNA vaccines, nanotechnology, and plant-based vaccines, which are used to develop effective vaccines for the dengue virus. Many dengue vaccines pass the initial phases of evaluation, but only two vaccines have been approved for public use. DENGVAXIA is the only FDA-approved vaccine against all four stereotypes of the dengue virus, but it is licensed for use only in individuals 6-16 years of age with laboratory-confirmed previous dengue infection and living in endemic countries. Takeda is the second vaccine approved for use in the European Union, the United Kingdom, Brazil, Argentina, Indonesia, and Thailand. It produced sustained antibody responses against all four serotypes of dengue virus, regardless of previous exposure and dosing schedule. Other dengue vaccine candidates at different stages of development are TV-003/005, TDENV PIV, V180, and some DNA vaccines. CONCLUSION: There is a need to put more effort into developing effective vaccines and therapeutics for dengue, as already approved vaccines and therapeutics have limitations. DENGVAXIA is approved for use in children and teenagers who are 6-16 years of age and have confirmed dengue infection, while Takeda is approved for use in certain countries, and it has withdrawn its application for FDA approval.

Room-Temperature Ferromagnetism in Mn-Doped ZnO Nanoparticles Synthesized by the Sol-Gel Method.

In the current work, pure ZnO and Mn-doped ZnO nanoparticles were synthesized by the sol-gel autocombustion method. Structural analysis and phase determination were done by X-ray diffraction, and a hexagonal wurtzite structure was exhibited with disparate microstructures for all samples. Mn2+ ions were well composed, as evidenced by the fluctuation of lattice parameters, dislocation density, and lattice strain. Crystallite size decreases from 38.42 to 27.54 nm by increasing the doping concentration. Field emission scanning electron microscopy results shows the combination of evenly distributed spherical-like and hexagon-like structures. Fourier transform infrared spectra revealed that when Mn content increased, the absorption bands red-shifted. The drop in the energy band gap from 3.25 eV for ZnO to 2.99 eV for Zn0.96Mn0.04O was predicted by ultraviolet-visible absorption spectra. This red shift in the energy band gap can be explained by the sp-d exchange interaction between the band electrons of ZnO and localized d electrons of Mn. A study of magnetic properties revealed the change of the diamagnetic attribute for pure ZnO to the room-temperature ferromagnetic attribute of doped samples. In the current study, room-temperature ferromagnetism was achieved for Mn-doped ZnO nanoparticles, which can serve as a desirable option for practical applications in the future.

Psychology in action: Social media communication, CSR, and consumer behavior management in banking.

In today's digitally interconnected world, social media emerges as a powerful tool, offering different opportunities for modern businesses. Not only do organizations use social media for marketing purposes, but they also endeavor to influence consumer psychology and behavior. Although prior studies indicate social media's efficacy in disseminating corporate social responsibility (CSR) communications, there remains a dearth of research addressing the impact of CSR-related messaging from banks on consumers' brand advocacy behavior (CBAB). Our study seeks to bridge this gap, exploring the CSR-CBAB relationship within the banking sector of an emerging economy. Additionally, we investigate the roles of consumers' emotions and values in mediating and moderating their CBAB, introducing two mediating factors, consumer happiness (HP) and admiration (BRAD), and moderating variable altruistic values (ATVL). Data collection involved an adapted questionnaire targeting banking consumers. The structural analysis revealed a positive correlation between a bank's CSR-related social media communications and CBAB. HP and BRAD were identified as mediators in this relationship, while ATVL emerged as a moderator. These findings hold significant theoretical and practical implications. For instance, our research highlights the indispensable role of social media in effectively conveying CSR-related information to banking consumers, subsequently enhancing their advocacy intentions.

Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein.

The emergence of recent SARS-CoV-2 has become a global health issue. This single-stranded positive-sense RNA virus is continuously spreading with increasing morbidities and mortalities. The proteome of this virus contains four structural and sixteen nonstructural proteins that ensure the replication of the virus in the host cell. However, the role of phosphoprotein (N) in RNA recognition, replicating, transcribing the viral genome, and modulating the host immune response is indispensable. Recently, the NMR structure of the N-terminal domain of the Nucleocapsid Phosphoprotein has been reported, but its precise structural mechanism of how the ssRNA interacts with it is not reported yet. Therefore, here, we have used an integrated computational pipeline to identify the key residues, which play an essential role in RNA recognition. We generated multiple variants by using an alanine scanning strategy and performed an extensive simulation for each system to signify the role of each interfacial residue. Our analyses suggest that residues T57A, H59A, S105A, R107A, F171A, and Y172A significantly affected the dynamics and binding of RNA. Furthermore, per-residue energy decomposition analysis suggests that residues T57, H59, S105 and R107 are the key hotspots for drug discovery. Thus, these residues may be useful as potential pharmacophores in drug designing.

Association of the CYP17-34T/C Polymorphism with Pancreatic Cancer Risk.

Pancreatic cancer is a leading cause of fatality worldwide. Several population studies have been conducted on genetic diagnosis of pancreatic cancer but the results from epidemiologic studies are very limited. CYP17A gene has a role in disease formation but its influence on pancreatic cancer is unclear. A polymorphism in the 5'UTR promoter region of CYP17A1-34T/C (A1/A2) has been associated with multiple cancers. The aim of the current study was to assess associations of this polymorphism and socio-demographic risk factors with pancreatic cancer. A total of 255 and 320 controls were enrolled in the study, and were genetically analyzed through PCR-RFLP. Statistical analysis was conducted with observed genotype frequencies and odds ratios (ORs) and 95% CIs were estimated using unconditional logistic regression. The impact of socio-demographic factors was accessed through Kaplen-Meir analysis. According to our results, the A2/A2 genotype was significantly associated with pancreatic cancer (OR=2.1, 95%CI = 1.3-3.5). Gender female (OR=2.6, 95%CI=1.8-3.7), age group 80s/80+ years (OR=2.2, 95% CI=1.2-4), smoking both former (OR=4.6, 95% CIs=2.5-8.8) and current (OR=3.6, 95% CI=2-6.7), and family history (OR=7.1; 95%CI = 4.6-11.4) were also found associated with increased risk. Current study suggests that along with established risk factors for pancreatic cancer CYP17A1-34T/C may play a role. However, on the basis of small sample size the argument cannot be fully endorsed and larger scale studies are recommended.