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Remdesivir, a C-nucleotide prodrug binds to the viral RNA-dependent-RNA polymerase (RdRp) and inhibits the viral replication by terminating RNA transcription prematurely. It is reported in literature that interaction between the C-1’β–CN moiety of Remdesivir (RDV) and the Ser861 residue in RdRp enzyme, causes a delayed chain termination during the RNA replication process and is one of the important aspect of its mechanism of action. In the pursuance of increasing the biological activity of RDV and enhancing the SAR studies, against RNA viruses, we have designed its fourteen C1’β substituted analogs, 10 –23 bearing 4/5-membered heterocyclic rings. The docking and 100 ns molecular dynamics (MD) simulations of 10-23 to the RdRp protein (PDB ID: 7L1F) revealed important interactions between 2’,3’-diol, oxo group of phosphoramidate, nitrogen residues of heterocyclic rings of synthetic molecules with Arg555, Arg553, Ser759, Cys622, Asn691, Asp623 amino acid residues of protein. The docking score of 2-ethylbutyl ((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(1H-1,2,3-triazol-4-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, 11 was found to be the higher than RDV among 14 new compounds i.e. -5.20 kcal/mol. Out of 3 compounds, 10, 12 and 13 submitted for MD simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis, trifluoro-oxadiazole derivative, 13 showed higher binding energy as compared to Remdesivir. The predicted ADMET properties of 14 compounds showed their potential for being drug candidates. The present study suggests that substitution at the C1’β position by 4/5-membered rings plays an important role in the interactions between nucleoside/tide and target protein.

Small cell lung cancer (SCLC) is known for its rapid growth with high metastatic spread. Its treatment remains a major challenge for oncologists due to the high mutation rate and other clinical disadvantages. The survival rate of these patients is very poor but there is no significant progress over the last few decades in the treatment protocols. Hence there is an urgency to design new clinical trials with novel drug combinations that can specifically and effectively target key pathways for proper treatment of SCLC. There have been several indications that developmental signalling pathways are involved in tumor growth, progression, metastasis and invasion of SCLC. Thus, it is anticipated that deciphering the signalling cascades of these embryonic signalling pathways may reveal novel therapeutic breakthroughs in SCLC. In this context, we have tried to assemble all the relevant information to give an updated overview of the various signalling pathways involved in the development of SCLC.

Summary: The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31–36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%–50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

The presence of T regulatory (Treg) cells in the tumor microenvironment is associated with poor prognosis and resistance to therapies aimed at reactivating anti-tumor immune responses. Therefore, depletion of tumor-infiltrating Tregs is a potential approach to overcome resistance to immunotherapy. However, identifying Treg-specific targets to drive such selective depletion is challenging. CCR8 has recently emerged as one of these potential targets. Here, we describe GS-1811, a novel therapeutic monoclonal antibody that specifically binds to human CCR8 and is designed to selectively deplete tumor-infiltrating Tregs. We validate previous findings showing restricted expression of CCR8 on tumor Tregs, and precisely quantify CCR8 receptor densities on tumor and normal tissue T cell subsets, demonstrating a window for selective depletion of Tregs in the tumor. Importantly, we show that GS-1811 depleting activity is limited to cells expressing CCR8 at levels comparable to tumor-infiltrating Tregs. Targeting CCR8 in mouse tumor models results in robust anti-tumor efficacy, which is dependent on Treg depleting activity, and synergizes with PD-1 inhibition to promote anti-tumor responses in PD-1 resistant models. Our data support clinical development of GS-1811 to target CCR8 in cancer and drive tumor Treg depletion in order to promote anti-tumor immunity.

The disease COVID-19 caused by SARS-CoV-2 is the third highly infectious human Coronavirus epidemic in the 21s⁢t century due to its high transmission rate and quick evolution of its pathogenicity. Genomic studies indicate that it is zoonotic from bats. The COVID-19 has led to significant loss of lives and a tremendous economic decline in the world. Generally, the population at risk of a fatal outcome are the elderly and those who are debilitated or are immune compromised. The fatality rate is high, but now is reduced after the development of preventive vaccine although an effective treatment by drug against the virus is yet to be developed. The treatment is narrowed to the use of several anti-viral drugs, or other re-purposed drugs. Social distancing, therefore, has emerged as a putative method to decrease the rate of infection. In this review, we summarize the aspects of the disease that is so far have come to light and review the impact of the infection on our society, healthcare, economy, education, and environment.

Color vision deficiency (CVD) is a condition that results in individuals being unable to distinguish differences between certain colors. Occupational color vision standards were introduced in aviation in 1919 by The Aeronautical Commission of the International Civil Air Navigation Authority. Concern has been expressed during the last few years that the current color vision standards in aviation may be too stringent and, at the same time, also variable across the world. The tests employed do not always reflect the tasks pilots encounter in today's aviation environment. This ambiguity leads to the possible exclusion of deserving applicants for selection as aircrew. The compatibility of CVD with aircraft crew is assessed by medical personnel using clinical diagnosis tests on the ground level. These clinical tests were developed specifically to detect the presence, nature, and severity of CVD. No clinical tests yet provide a measure of operational performance in operating an aircraft. Arbitrary pass marks have been assigned to clinical tests such that a failing candidate will either be subject to operational restrictions or excluded completely. The prescribed clinical tests and associated pass marks vary considerably between regulators. While an individual may be subject to no restrictions in one jurisdiction, they may be excluded in another. This article highlights newer diagnostic techniques adopted by different countries for assessing color vision to see for the scope of evidence-based guidelines for minimum color vision requirements for flight crew as well as for civil aviation in India.

Purpose: Association of peripheral neuropathy with diabetic retinopathy is known but the relationship of preclinical neuropathy with various grades of retinopathy is not well documented. This study evaluated the association of preclinical peripheral neuropathy using nerve conduction studies with various grades of retinopathy. Methods: Cases of diabetic retinopathy of various grades but asymptomatic for peripheral neuropathy underwent nerve conduction studies of the lower limbs using Caldwell machine and Sierra wave software. The risk factors for retinopathy and association of neuropathy with various grades of retinopathy were analyzed by bivariate and multivariate regression analysis. Results: The overall prevalence of neuropathy was 75.6% (sensory 58.54% and combined motor and sensory 17.1%) with increase in prevalence with increase in severity of retinopathy. Duration was positively associated with neuropathy (OR = 1.13, 95% CI = 1.02–1.24; P = 0.012); moderate nonproliferative diabetic retinopathy (NPDR) (OR = 5.60, P = 0.002), severe and very severe NPDR (OR = 5.8, P = 0.041), and PDR (OR = 16.05, P = 0.000) were significantly at higher risk for having neuropathy as compared to mild NPDR. Conclusion: Duration and severity of retinopathy are important risk factors for peripheral neuropathy. There is a high prevalence of peripheral neuropathy among diabetics with retinopathy especially with severe grades, when neuropathy is diagnosed using nerve conduction studies.

Due to development of bacterial resistance to the conventional antibiotics, the treatment of bacterial infections has become a major issue of concern. The unprescribed and uncontrolled use of antibiotics has lead to the rapid development of antibiotic resistance in bacterial strains. Therefore, the development of novel and potent bactericidal agents is of great clinical importance. Interestingly, metallic nanoparticles (NPs) have been proven to be promising alternative to antibiotics. NPs interact with the important cellular organelles and biomolecules like DNA, enzymes, ribosomes, and lysosomes that can affect cell membrane permeability, oxidative stress, gene expression, protein activation, and enzyme activation. Since, NPs target multiple biomolecules concurrently; it becomes very difficult for bacteria to develop resistance against them. Currently, there are different physical and chemical methods utilized for NPs synthesis. However, most of these processes are costly and potentially hazardous for the living organisms and environment. Therefore, there is a need to develop an eco-friendly and cost-effective method of synthesis. Recently, the ‘green synthesis’ approaches are gaining a lot of attention. It is demonstrated that living organisms like bacteria, yeast, fungi, and plant cells can reduce inorganic metal ions into metal NPs by their cellular metabolites. Both the yield and stability of biogenic NPs are quite satisfactory. In the current article, we have addressed the green synthesis of various metal NPs reported till date and highlighted their different modes and mechanisms of antibacterial properties. It is highly anticipated that biogenic metallic NPs could be viable and economical alternatives for treating drug resistant bacterial infections in near future. Keywords: Metallic nanoparticles, Green synthesis, Antibacterial property, Antibiotics resistance

Gasification has played an important role in the sustainable use of waste biomass, providing useful combustible gases in the process. Gasification has an important role in waste management and promotes energy independence for many oil-deficit countries. The gasification process has been studied by various researchers, and improvements have been achieved in its sub-processes such as devolatilization, feed input methods, and so on. We examined the influence of gasifier operation parameters, such as oxidizer content, moisture content in the feedstock, and solar flux input inside the gasifier, on the temperature distribution, velocity distribution, and product gas yields of the gasifier. The results indicate that inducing solar energy at different stages of the gasifier leads to different yields of product gas composition (CO and H2).

Purpose: Strabismus and anisometropia are the most common causes of amblyopia. It can be easily prevented or treated if detected early. With the changing socio-cultural-economic milieu of the society, the perspectives of strabismus in society are gradually changing but still adequate knowledge, awareness, and attitude of parents toward strabismus will help in preventing amblyopia and aid in the proper psychosocial adaptation of such children. This study aimed to assess knowledge and attitude of parents toward children suffering from strabismus. Methods: A prospective study was carried out from January 1 to February 29, 2016, through a structured questionnaire to assess the level of knowledge and attitude of parents of children suffering from strabismus. Results: One hundred and twenty parents of children with strabismus were interviewed through a questionnaire. Education level of 78 parents was less than graduation (60%) and of 42 parents (40%) was graduation or higher. The majority of the parents, i.e., 116 (96.67%) were bothered due to strabismus. One hundred and one (84.17%) parents felt that their child's strabismus was noticed by others during interaction. Seventy-four (61.67%) parents felt that their children will have difficulty in making friends. Ninety (75%) parents felt uncomfortable if someone asked something about their child's strabismus. One hundred and ten (91.67%) parents considered strabismus as cosmetic stigma. Conclusion: Some parents, especially from the lower educated segment, had poor understanding of strabismus, thus resulting in late presentation and ineffective countermeasures. The key to prevent strabismic amblyopia and its psychosocial impacts is to provide health education regarding strabismus.

Aim: To evaluate stereoacuity in patients with acquired esotropia and determine the factors associated with favorable outcomes. Materials and Methods: A total of 68 subjects aged 6 years and above were included in the study. Thorough clinical evaluation including binocular status examination using the Bagolini-striated glass test, The Netherland Organization (TNO), and Randot stereo test were done. The subjects were divided into two groups 1 and 2, based on the amount of deviation. Statistical analysis of the result was performed. Result: The duration of misalignment in the group with deviation less than or equal to 8 prism diopters (PD) was 1.49 ± 0.86 years, whereas in the group with deviation more than or equal to 10 PD was 4.64 ± 2.99 years (P = 0.000). Among the subjects in group 1, 89.5% achieved fusion and 52.6% had stereoacuity on both TNO and Randot, whereas in group 2 40% achieved fusion and 3.3% stereopsis on both TNO and Randot (one case with only coarse stereopsis). A subanalysis within group 1 revealed a statistically significant difference for the duration of misalignment (P = 0.02), but a marginal difference for the amount of deviation (P = 0.3). Conclusion: A horizontal deviation up to 8 PD was compatible with stereopsis. Also, the duration of constant misalignment affects the attainment of stereopsis despite successful realignment.

We report a case of the primary deep orbital venous varix treated by endovascular coil embolization procedure by transfemoral catheterization. This method of treatment has the advantage of image-guided localization of the pathology, real-time management and confirmation of the success of the procedure in the sitting.

Due to the failure of the continuum hypothesis for higher Knudsen numbers, rarefied gases and microflows of gases are particularly difficult to model. Macroscopic transport equations compete with particle methods, such as the Direct Simulation Monte Carlo method (DSMC), to find accurate solutions in the rarefied gas regime. Due to growing interest in micro flow applications, such as micro fuel cells, it is important to model and understand evaporation in this flow regime. Here, evaporation boundary conditions for the R13 equations, which are macroscopic transport equations with applicability in the rarefied gas regime, are derived. The new equations utilize Onsager relations, linear relations between thermodynamic fluxes and forces, with constant coefficients, that need to be determined. For this, the boundary conditions are fitted to DSMC data and compared to other R13 boundary conditions from kinetic theory and Navier–Stokes–Fourier (NSF) solutions for two one-dimensional steady-state problems. Overall, the suggested fittings of the new phenomenological boundary conditions show better agreement with DSMC than the alternative kinetic theory evaporation boundary conditions for R13. Furthermore, the new evaporation boundary conditions for R13 are implemented in a code for the numerical solution of complex, two-dimensional geometries and compared to NSF solutions. Different flow patterns between R13 and NSF for higher Knudsen numbers are observed.

A 13-year-old child presenting with gross visual impairment was diagnosed as a case of optic atrophy. However, radiological investigations revealed osteopetrosis, which, though rare, can result in optic atrophy. The aim of this case report is to highlight this possibility while evaluating cases of optic atrophy in young patients.

The study utilizes a two-temperature model to analyze non-equilibrium in normal shocks within hypersonic flows in polyatomic rarefied gases. Derived from the extended second law of thermodynamics, this model separates translational and internal temperatures in polyatomic gases, providing a more accurate depiction of non-equilibrium gas flow compared to classical theories like the Navier–Stokes and Fourier (NSF) system. Notably, the analysis reveals that the two-temperature model incorporates an additional contribution to the heat flux due to the gradient of the dynamic temperature, resulting in improved accuracy, especially for high Mach numbers. Results show that the model gives satisfactory shock density and temperature profiles up to Mach 10, with very good agreement observed up to Mach 6.1 compared to the classical NSF model. We conduct an order of magnitude analysis on the dynamic temperature and heat flux gradients appearing in the new constitutive equation using the Mott-Smith method. This analysis highlights the impact of these terms on accurately modeling polyatomic gas behavior in high-speed flows. The effects of bulk viscosity and incoming temperature on shock profiles are also investigated, contributing to a better understanding of shock wave structures in polyatomic gases and their implications for hypersonic flow dynamics. [ABSTRACT FROM AUTHOR]

In this study, an efficient meshfree numerical method is introduced for solving the nonlinear boundary value problems. The method of fundamental solutions (MFS) is one of the most popular among meshfree methods. While traditionally limited to linear and homogeneous problems, this study extends the applicability of the MFS to include nonhomogeneous and nonlinear equations. To achieve this, an extended MFS is combined with a fixed-point iteration scheme. This developed framework is benchmarked to address two different flow problems. The first involves fluid flow through porous media in a channel governed by the nonlinear Brinkman-Forchheimer equation. The second problem pertains to electrohydrodynamic (EHD) flow in a circular conduit. The obtained solutions are compared with the finite element method and the solutions available in the existing literature. [ABSTRACT FROM AUTHOR]

Some phenomena pertaining to rarefied gases are beyond the reach of traditional fluid dynamics described, e.g., by the Euler or Navier–Stokes–Fourier equations. Therefore we adopt a recently developed model—referred to as the CCR model—to investigate thermally-induced transport in rarefied gases. To this end, the method of fundamental solutions is employed on the CCR model to investigate two problems: (i) a rarefied gas flow confined between two coaxial cylinders having different temperatures with the inner cylinder being circular while the outer being elliptical, and (ii) evaporation/condensation process in a rarefied vapor confined between two coaxial cylinders, again with the inner cylinder being circular and the outer being elliptical. Through a comprehensive analysis, the efficiency of the method of fundamental solutions is assessed. The work contributes toward a better understanding of thermally-induced confined rarefied gas flows. [ABSTRACT FROM AUTHOR]