RNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA 3D structure prediction. With agreement from crystallographers, the RNA structures are predicted by various ...groups before the publication of the crystal structures. We now report the prediction of 3D structures for six RNA sequences: four nucleolytic ribozymes and two riboswitches. Systematic protocols for comparing models and crystal structures are described and analyzed. In these six puzzles, we discuss (i) the comparison between the automated web servers and human experts; (ii) the prediction of coaxial stacking; (iii) the prediction of structural details and ligand binding; (iv) the development of novel prediction methods; and (v) the potential improvements to be made. We show that correct prediction of coaxial stacking and tertiary contacts is essential for the prediction of RNA architecture, while ligand binding modes can only be predicted with low resolution and simultaneous prediction of RNA structure with accurate ligand binding still remains out of reach. All the predicted models are available for the future development of force field parameters and the improvement of comparison and assessment tools.
Shared Decision Making (SDM) is an essential component of recovery oriented treatment for clients with severe and persistent mental illnesses. SDM has been found to be effective in improving outcome ...of treatment of non-psychiatric ailments, and studies of SDM in community mental health settings are limited. We designed and implemented a low tech SDM program in a non-academic community mental health center and evaluated the outcome on decisional certainty and satisfaction with services. The results suggest that SDM can be effectively integrated with evidence based psychiatric rehabilitation practices utilizing already existing resources.
Aim: The aim of the study was to compare chromogranin A (CgA) and stress levels before and after non-surgical periodontal therapy (NSPT). Materials and Methods: A sample of 40 patients in the age ...range 25-60 years were included in the study and were divided into gingivitis (10 subjects), chronic periodontitis (CP) (15 patients) and aggressive periodontitis (AgP) (15 patients). The patients were asked to complete two sets of stress questionnaires, plaque index, gingival index, probing depth and clinical attachment levels (CAL) were recorded. Salivary samples were taken at baseline and were repeated three months post NSPT. Results: CgA was detected in saliva samples of all the groups. A statistically significant correlation was established between levels of CgA and stress parameters, which was shown to be the highest in AgP (P < 0.001), followed by CP group (P < 0.005) at baseline. Following NSPT, an overall reduction was observed in the levels of CgA, which was correlated with the overall reduction in stress levels for AgP group (P < 0.005) followed by CP group (P < 0.037). Amongst the clinical parameters, CAL showed the strongest correlation with CgA both at baseline and after NSPT (P < 0.001). Conclusion: Stress was directly correlated to the levels of salivary CgA levels, which was the highest for aggressive periodontitis at baseline. NSPT showed a marked improvement in all the parameters. Levels of CgA and CAL showed a significant correlation in both the CP and AgP groups.
COVID-19 emergency use authorizations and approvals for vaccines were achieved in record time. However, there remains a need to develop additional safe, effective, easy-to-produce, and inexpensive ...prevention to reduce the risk of acquiring SARS-CoV-2 infection. This need is due to difficulties in vaccine manufacturing and distribution, vaccine hesitancy, and, critically, the increased prevalence of SARS-CoV-2 variants with greater contagiousness or reduced sensitivity to immunity. Antibodies from eggs of hens (immunoglobulin Y; IgY) that were administered the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were developed for use as nasal drops to capture the virus on the nasal mucosa. Although initially raised against the 2019 novel coronavirus index strain (2019-nCoV), these anti-SARS-CoV-2 RBD IgY surprisingly had indistinguishable enzyme-linked immunosorbent assay binding against variants of concern that have emerged, including Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529). This is different from sera of immunized or convalescent patients. Culture neutralization titers against available Alpha, Beta, and Delta were also indistinguishable from the index SARS-CoV-2 strain. Efforts to develop these IgY for clinical use demonstrated that the intranasal anti-SARS-CoV-2 RBD IgY preparation showed no binding (cross-reactivity) to a variety of human tissues and had an excellent safety profile in rats following 28-day intranasal delivery of the formulated IgY. A double-blind, randomized, placebo-controlled phase 1 study evaluating single-ascending and multiple doses of anti-SARS-CoV-2 RBD IgY administered intranasally for 14 days in 48 healthy adults also demonstrated an excellent safety and tolerability profile, and no evidence of systemic absorption. As these antiviral IgY have broad selectivity against many variants of concern, are fast to produce, and are a low-cost product, their use as prophylaxis to reduce SARS-CoV-2 viral transmission warrants further evaluation.
Clinical Trial Registration
https://www.clinicaltrials.gov/ct2/show/NCT04567810
, identifier NCT04567810.
Heartland and Bourbon viruses are pathogenic tick-borne viruses putatively transmitted by Amblyomma americanum, an abundant tick species in Missouri. To assess the prevalence of these viruses in ...ticks, we collected 2778 ticks from eight sampling sites at Tyson Research Center, an environmental field station within St. Louis County and close to the City of St. Louis, from May - July in 2019 and 2021. Ticks were pooled according to life stage and sex, grouped by year and sampling site to create 355 pools and screened by RT-qPCR for Bourbon and Heartland viruses. Overall, 14 (3.9%) and 27 (7.6%) of the pools were positive for Bourbon virus and Heartland virus respectively. In 2019, 11 and 23 pools were positive for Bourbon and Heartland viruses respectively. These positives pools were of males, females and nymphs. In 2021, there were 4 virus positive pools out of which 3 were positive for both viruses and were comprised of females and nymphs. Five out of the 8 sampling sites were positive for at least one virus. This included a site that was positive for both viruses in both years. Detection of these viruses in an area close to a relatively large metropolis presents a greater public health threat than previously thought.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively ...transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action in vivo is incompletely understood. Here, we demonstrate that 2B04, an antibody with an ultrapotent neutralizing activity (50% inhibitory concentration IC50 of 0.04 μg/ml), protects hamsters against SARS-CoV-2 in a prophylactic and therapeutic infection model. Protection is associated with reduced weight loss and viral loads in nasal turbinates and lungs after challenge. MAb 2B04 also blocked aerosol transmission of the virus to naive contacts. We next examined three additional MAbs (2C02, 2C03, and 2E06), recognizing distinct epitopes within the receptor binding domain of spike protein that possess either minimal (2C02 and 2E06, IC50 > 20 μg/ml) or weak (2C03, IC50 of 5 μg/ml) virus neutralization capacity in vitro. Only 2C03 protected Syrian hamsters from weight loss and reduced lung viral load after SARS-CoV-2 infection. Finally, we demonstrated that Fc-Fc receptor interactions were not required for protection when 2B04 and 2C03 were administered prophylactically. These findings inform the mechanism of protection and support the rational development of antibody-mediated protection against SARS-CoV-2 infections. IMPORTANCE The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has resulted in the loss of millions of lives. Safe and effective vaccines are considered the ultimate remedy for the global social and economic disruption caused by the pandemic. However, a thorough understanding of the immune correlates of protection against this virus is lacking. Here, we characterized four different monoclonal antibodies and evaluated their ability to prevent or treat SARS-CoV-2 infection in Syrian hamsters. These antibodies varied in their ability to neutralize the virus in vitro. Prophylactic administration of potent and weakly neutralizing antibodies protected against SARS-CoV-2 infection, and this effect was Fc receptor independent. The potent neutralizing antibody also had therapeutic efficacy and eliminated onward aerosol transmission. In contrast, minimally neutralizing antibodies provided no protection against infection with SARS-CoV-2 in Syrian hamsters. Combined, these studies highlight the significance of weakly neutralizing antibodies in the protection against SARS-CoV-2 infection and associated disease.
Aim: Periodontitis and diabetes mellitus share a bidirectional relationship. Resistin is an adipocytokine shown to be associated with type 2 diabetes mellitus. Hence, the present study aims to ...estimate the effect of non-surgical periodontal therapy (NSPT) on GCF resistin levels in healthy individuals with gingivitis and well controlled diabetics with periodontitis, and correlate the same with HbA1c levels of the diabetic subjects. Materials and Methods: The present study was a comparative interventional trial set in Department of Periodontics, the Oxford Dental College, Bangalore. Forty subjects participated in the study and were divided into two groups; group I (healthy individuals with gingivitis) and group II (diabetic individuals with mild to moderate periodontitis). Periodontal parameters were assessed and GCF was collected and analysed for resistin before and 3 months after NSPT. Statistical Analysis: All the analysis was done using SPSS version 18. A P value of < 0.05 was considered statistically significant. Results: A significant difference was observed in GCF resistin concentrations between the two groups at baseline, wherein group II had significantly higher values. Following NSPT, there was a significant reduction in GCF resistin concentrations in both the groups, however intergroup comparison showed no difference in the amount of reduction. When all samples were analysed together, no significant correlation could be found between resistin and the parameters assessed. Conclusion: Resistin levels are increased in diabetes related periodontitis. However, post treatment a similar response can be seen between healthy and well controlled diabetics. Hence, resistin can be used as an inflammatory biomarker for diabetes related periodontal disease.
The recent emergence of B.1.1.529, the Omicron variant
, has raised concerns of escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against ...B.1.1.529 is their activity in preclinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of several B.1.1.529 isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. Despite modelling data indicating that B.1.1.529 spike can bind more avidly to mouse ACE2 (refs.
), we observed less infection by B.1.1.529 in 129, C57BL/6, BALB/c and K18-hACE2 transgenic mice than by previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease and pathology with B.1.1.529 were also milder than with historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures. Although cell culture experiments have demonstrated a loss of potency of several anti-spike neutralizing antibodies ...against variant strains of SARS-CoV-2
, the in vivo importance of these results remains uncertain. Here we report the in vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which correspond to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with mutations at residue E484 of the spike protein, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016 combination therapy, both of which lost all protective activity, and the combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity. When administered after infection, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but not all-of the antibody products with Emergency Use Authorization should retain substantial efficacy against the prevailing variant strains of SARS-CoV-2.
Over the years, the Indian pharmaceutical sector has emerged as one of the world's prominent providers of affordable healthcare products. As per the Ministry of Chemicals and Fertilizers, the Indian ...pharmaceutical industry is the third largest producer in the world in terms of volume and the fourteenth in terms of value. During FY13, the total sales turnover of Indian pharmaceuticals products, which are largely generics, was about 1,200 billion. Indian pharmaceutical industry accounts for 9.3% of the global pharmaceutical production by volume and 1.5% of the global pharmaceutical production in terms of value. This industry has recorded a cumulative average growth rate of around 14% during the last 5 years. The study examines the Internal Determinants of export in Pharmaceutical industry.
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