Fitting hierarchical Bayesian models to spatially correlated datasets using Markov chain Monte Carlo (MCMC) techniques is computationally expensive. Complicated covariance structures of the underlying spatial processes, together with high-dimensional parameter space, mean that the number of calculations required grows cubically with the number of spatial locations at each MCMC iteration. This necessitates the need for efficient model parameterizations that hasten the convergence and improve the mixing of the associated algorithms. We consider partially centred parameterizations (PCPs) which lie on a continuum between what are known as the centered (CP) and noncentered parameterizations (NCP). By introducing a weight matrix we remove the conditional posterior correlation between the fixed and the random effects, and hence construct a PCP which achieves immediate convergence for a three-stage model, based on multiple Gaussian processes with known covariance parameters. When the covariance parameters are unknown we dynamically update the parameterization within the sampler. The PCP outperforms both the CP and the NCP and leads to a fully automated algorithm which has been demonstrated in two simulation examples. The effectiveness of the spatially varying PCP is illustrated with a practical dataset of nitrogen dioxide concentration levels. Supplemental materials consisting of appendices, datasets, and computer code to reproduce the results are available online.
Wealth of structural data on theurapeutic targets in complex with monoclonal antibodies (mAbs) and advances in molecular modeling algorithms present exciting opportunities in the field of novel biologic design. Interleukin 23 (IL23), a well-known drug target for autoimmune diseases, in complex with mAb 7G10 offers prospect to design potent lead antibodies by traversing the complete epitope-paratope interface. Herein, key interactions aiding antibody-based neutralization in IL23-7G10 complex are resolute through PyMOL, LigPlo + , Antibody i-Patch, DiscoTope and FoldX. Six amino acids Ser31, Val33, Asn55, Lys59 in heavy chain and His34, Ser93 in light chain are subjected to in silico mutagenesis with residues Met, Trp, Ile, Leu and Arg. A set of 431 mutant macromolecules are outlined. Binding affinities of these molecules with IL23 are estimated through protein-protein docking by employing ZDOCK, ClusPro and RosettaDock. Subsequently, the macromolecules revealed comparable result with 7G10 are cross validated through binding free-energy calculations by applying Molecular Mechanics/Poisson Boltzman Surface Area method in CHARMM. Thirty nine designed theoretical antibodies showed improved outcome in all evaluations; from these, top 10 molecules showed at least nine unit better binding affinity compared to the known mAb. These molecules have the potential to act as lead antibodies. Subsequent molecular dynamics simulations too favored prospective of best ranked molecule to have therapeutic implications in autoimmune and inflammatory diseases. Abbreviations: IL23: interleukin 23; IL17: interleukin17; Ab: antibody; Ag: antigen; mAbs: monoclonal antibodies; STAT3: signal transducer and activator of transcription 3; STAT4: signal transducer and activator of transcription 4; PDB: protein databank; MM/PBSA: molecular mechanics Poisson-Boltzmann surface area; Ag-Ab: antigen- antibody complex; SPC/E: extended simple point charge; SD: steepest descents; PME: particle mesh ewald; dG: binding free energies; Fv: variable fragment.
The present study was undertaken with an aim to investigate the potential of targeting colonic mucosa following oral vaccine delivery to generate prophylactic humoral and mucosal immune response. In present study, response surface methodology (RSM) using the central composite design (CCD) was applied for optimization of process and composition to get uniform, stable reproducible eudragit nanoparticles suitable for targeting to colon. The optimized formulation had the composition of 173 μg HBsAg, 250 mg polymers concentration (4:1 combination of Eudragit S-100 and L-100) and 2% w/v Polyvinyl alcohol (PVA) along with adjuvant Monophosphoryl lipid A (MPLA). Mean particle size of optimized nanoparticles was found to be 730.4 nm, entrapment efficiency (58.38%) and polydispersity index of 0.185. Fluorescent spectroscopy, differential scanning calorimetry, and antigen integrity by SDS-PAGE established that antigen structure was preserved during and after formulation development. In-vitro release studies in different intestinal pH concluded antigen release at mild alkaline conditions. Real time fluorescence animal imaging confirmed the effective absorption and distribution of NPs at colon resulted in improved immune response. Present study concludes that Eudragit nanoparticles offers strong potential in colon targeting of vaccines through oral immunization.
There is a persisting global burden and considerable public health challenge by the plethora of ocular, genital and respiratory diseases caused by members of the Gram-negative bacteria of the genus Chlamydia. The major diseases are conjunctivitis and blinding trachoma, non-gonococcal urethritis, cervicitis, pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, and interstitial pneumonia. The failures in screening and other prevention programs led to the current medical opinion that an efficacious prophylactic vaccine is the best approach to protect humans from chlamydial infections. Unfortunately, there is no human Chlamydia vaccine despite successful veterinary vaccines. A major challenge has been the effective delivery of vaccine antigens to induce safe and effective immune effectors to confer long-term protective immunity. The dawn of the era of biodegradable polymeric nanoparticles and the adjuvanted derivatives may accelerate the realization of the dream of human vaccine in the foreseeable future.
Tephrosia apollinea is a legume species, native to southwest Asia and northeast Africa, rich in bioactive flavonoids (hydrophilic compounds). T. apollinea seeds were not considered previously as a potential source of lipophilic compounds such as: essential fatty acids, tocopherols, sterols, and squalene, hence, the present study were performed. The oil yield in T. apollinea seeds amounted to 11.8% dw. The T. apollinea seed oil was predominated by the polyunsaturated fatty acids - linoleic (26.8%) and α-linolenic (22.7%). High levels were recorded also for oleic (27.6%) and palmitic (14.9%) acids. Four tocopherols and one tocotrienol, with the domination of γ-tocopherol (98%) were identified in T. apollinea seed oil. The β-sitosterol (59%), Δ5-stigmasterol (21%) and campesterol (9%) were detected as main sterols in T. apollinea seed oil. The total content of tocochromanols, sterols, carotenoids and squalene in the T. apollinea seed oil was 256.7, 338.1, 12.5 and 1103.8 mg/100 g oil, respectively. T. apollinea seeds oil, due to the high concentration of lipophilic bioactive compounds can find a potential application in the food, cosmetic and pharmaceutical industry.
The Himalayan region with its complex geological features, steep slopes, rugged topography, and intense monsoonal rainfall create ideal conditions for landslides. The damage caused due to landslides is immense causing significant loss of life and property initiating a dire need to formulate strategies in minimizing its impact in areas affected by landslides. Several attempts have been presented by various researchers in order to establish rainfall intensity thresholds using various parameters of rainfall conditions. These methods provide deterministic thresholds, i.e., landslide or no landslide; such thresholds are not always suited for landslides. In this paper, rainfall thresholds have been evaluated using a statistical method which results in the probability of landslide occurrence for single or multiple rainfall parameters leading to slide initiation. The results are expressed in terms of probabilities by analyzing two different variants of Bayes theorem, i.e., 1D and 2D. Probabilistic thresholds were calculated for Kalimpong region of Darjeeling Himalayas using available rainfall and landslide data during the year 2010–2016. The probabilities calculated for landslide occurrence were found to be 0.37 for rainfall intensity greater than 10 mm/day. However, the probability for a combination of rainfall intensity of 30 mm/day with duration of 3 days was calculated to be 0.67. The results also depicted that landslides are related to rainfall event parameters especially with rainfall intensity.
Slow inactivation in voltage-gated sodium channels (Na V s) directly regulates the excitability of neurons, cardiac myocytes, and skeletal muscles. Although Na V slow inactivation appears to be conserved across phylogenies-from bacteria to humans-the structural basis for this mechanism remains unclear. Here, using site-directed labeling and EPR spectroscopic measurements of membrane-reconstituted prokaryotic Na V homologues, we characterize the conformational dynamics of the selectivity filter region in the conductive and slow-inactivated states to determine the molecular events underlying Na V gating. Our findings reveal profound conformational flexibility of the pore in the slow-inactivated state. We find that the P1 and P2 pore helices undergo opposing movements with respect to the pore axis. These movements result in changes in volume of both the central and intersubunit cavities, which form pathways for lipophilic drugs that modulate slow inactivation. Our findings therefore provide novel insight into the molecular basis for state-dependent effects of lipophilic drugs on channel function.