A nanoemulsified formulation of dolutegravir and epigallocatechin gallate inhibits HIV-1 replication in cellular models.

Nanotechnology offers promising avenues for enhancing drug delivery systems, particularly in HIV-1 treatment. This study investigates a nanoemulsified formulation combining epigallocatechin gallate (EGCG) with dolutegravir (DTG) for managing HIV-1 infection. The combinatorial interaction between EGCG and DTG was explored through cellular, enzymatic, and molecular studies. In vitro assays demonstrated the potential of a dual drug-loaded nanoemulsion, NE-DTG-EGCG, in inhibiting HIV-1 replication, with EGCG serving as a supplementary treatment containing DTG. In silico molecular interaction studies highlighted EGCG's multifaceted inhibitory potential against HIV-1 integrase and reverse transcriptase enzymes. Further investigations are needed to validate the formulation's efficacy across diverse contexts. Overall, by integrating nanotechnology into drug delivery systems, this study represents a significant advancement in managing HIV-1 infection.

A metagenome-wide association study of gut microbiome in patients with AMD, ASD, RA, T2D & VKH diseases.

Clinical studies have already illustrated the associations between gut microbes and diseases, yet fundamental questions remain unclear that how we can universalize this knowledge. Considering the important role of human gut microbial composition in maintaining overall health, it is important to understand the microbial diversity and altered disease conditions of the human gut. Metagenomics provides a way to analyze and understand the microbes and their role in a community manner. It provides qualitative as well as quantitative measurements, in terms of relative abundance. Various studies are already going on to find out the association between microbes and diseases; still, the mined knowledge is limited. Considering the current scenario, using the targeted metagenomics approach, we analyzed the gut microbiome of 99 samples from healthy and diseased individuals. Our metagenomic analysis mainly targeted five diseased microbiomes (i.e., Age-related macular degeneration, Autism spectrum disorder, Rheumatoid arthritis, Type 2 diabetes and Vogt-Koyanagi harada), with compare to healthy microbiome, and reported disease-associated microbiome shift in different conditions.

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. In vivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

In-silico mining to glean SNPs of pharmaco-clinical importance: an investigation with reference to the Indian populated SNPs.

Drugs pharmacology is defined by pharmacokinetics and pharmacodynamics and both of them are affected by genetic variability. Genetic variability varies from population to population, and sometimes even within the population, it exists. Single nucleotide polymorphisms (SNPs) are one of the major genetic variability factors which are found to be associated with the pharmacokinetics and pharmacodynamics process of a drug and are responsible for variable drug response and clinical phenotypes. Studies of SNPs can help to perform genome-wide association studies for their association with pharmacological and clinical events, at the same time; their information can direct genome-wide association studies for their use as biomarkers. With the aim to mine and characterize Indian populated SNPs of pharmacological and clinical importance. Two hundred six candidate SNPs belonging to 43 genes were retrieved from Indian Genome Variation Database. The distribution pattern of considered SNPs was observed against all five world super-populations (AFR, AMR, EAS, EUR, and SAS). Further, their annotation was done through SNP-nexus by considering Human genome reference builds - hg38, pharmacological and clinical information was supplemented by PharmGKB and ClinVar database. At last, to find out the association between SNPs linkage disequilibrium was observed in terms of r2. Overall, the study reported 53 pharmaco-clinical active SNPs and found 24 SNP-pairs as potential markers, and recommended their clinical and experimental validation. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00154-4.

Development of a person-centred digital platform for the long-term support of people living with an adult-onset genetic disease predisposition: a mixed-methods study protocol.

INTRODUCTION: Individuals at an inherited high-risk of developing adult-onset disease, such as breast cancer, are rare in the population. These individuals require lifelong clinical, psychological and reproductive assistance. After a positive germline test result, clinical genetic services provide support and care coordination. However, ongoing systematic clinical follow-up programmes are uncommon. Digital health solutions offer efficient and sustainable ways to deliver affordable and equitable care. This paper outlines the codesign and development of a digital health platform to facilitate long-term clinical and psychological care, and foster self-efficacy in individuals with a genetic disease predisposition. METHODS AND ANALYSIS: We adopt a mixed-methods approach for data gathering and analysis. Data collection is in two phases. In phase 1, 300 individuals with a high-risk genetic predisposition to adult disease will undertake an online survey to assess their use of digital health applications (apps). In phase 2, we will conduct focus groups with 40 individuals with a genetic predisposition to cardiac or cancer syndromes, and 30 clinicians from diverse specialities involved in their care. These focus groups will inform the platform's content, functionality and user interface design, as well as identify the barriers and enablers to the adoption and retention of the platform by all endusers. The focus groups will be audiorecorded and transcribed, and thematic and content data analysis will be undertaken by adopting the Unified Theory of Acceptance and Use of Technology. Descriptive statistics will be calculated from the survey data. Phase 3 will identify the core skillsets for a novel digital health coordinator role. Outcomes from phases 1 and 2 will inform development of the digital platform, which will be user-tested and optimised in phase 4. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee (HREC/88892/PMCC). Results will be disseminated in academic forums, peer-reviewed publications and used to optimise clinical care.

Current Market Potential and Prospects of Copper-based Pyridine Derivatives: A Review.

Nicotine, minodronic acid, nicotinamide (niacin), zolpidem, zolimidine, and other pyridine-based chemicals play vital roles in medicine and biology. Pyridine-containing drugs are widely available on the market to treat a wide range of human ailments. As a result of these advances, pyridine research is continually expanding, and there are now higher expectations for how it may aid in the treatment of numerous ailments. This evaluation incorporates data acquired from sources, like PubMed, to provide a thorough summary of the approved drugs and bioactivity data for compounds containing pyridine. Most of the reactions discussed in this article will provide readers with a deeper understanding of various pyridine-related examples, which is necessary for the creation of copper catalysis-based synthetic processes that are more accessible, secure, environmentally friendly, and practical, and that also have higher accuracy and selectivity. This paper also discusses significant innovations in the multi-component copper-catalyzed synthesis of N-heterocycles (pyridine), with the aim of developing precise, cost-effective, and environmentally friendly oxygenation and oxidation synthetic methods for the future synthesis of additional novel pyridine base analogs. Therefore, the review article will serve as a novel platform for researchers investigating copper-based pyridine compounds.

Industrial Design education in Australia: a competence analysis across primary, secondary and tertiary education levels.

Industrial Design education is poorly understood by laypeople but is present in Australian curricula from primary through to tertiary education levels. Designers and design researchers have long recognised the value of the broad-ranging skills, knowledge fields, and personal qualities design education imparts, but this understanding is generally not shared by the wider community who may see design as surface decoration. This research identifies indicators of value and relevance taken from the twenty-first century competences literature, then measures their presence in four different Industrial Design education settings. Two studies were undertaken. First, Industrial Design educators from primary, secondary, and tertiary levels were surveyed. Then diverse Industrial Design education stakeholders from education and non-education settings were interviewed. The studies gathered both quantitative and qualitative data on the value and relevance of current Industrial Design education in Australia. The result is a comprehensive analysis of the twenty-first century competences present in Australian Industrial Design education, which concludes with recommendations for ways Industrial Design education can benefit twenty-first century learners, as well as ways it should evolve to remain relevant.

Copper removal from aqueous solution using chemical precipitation and adsorption by Himalayan Pine Forest Residue as Biochar.

This research deals with the use of pine residue biochar as an adsorbent for the removal of copper from aqueous solution which is a major component of printed circuit boards from E-waste. Biochar was produced from pine residue such as bark, cone and needle through pyrolysis, and the effect of temperature on biochar properties was assessed. The biochar yield of about 33% and maximum surface area of 368 m2/g was obtained at pyrolysis temperature of 650°C. FTIR analysis revealed the existence of C-O, O-H and C = C functional groups on the surface of biochars. The point of zero charge of pine biochars were in the range 5.55 to 5.75. Batch adsorption studies revealed maximum copper adsorption capacity of 60-81 mg/g at near neutral pH. The batch adsorption data fitted well with Langmuir isotherm and followed the pseudo-second order kinetics. Adsorption of copper onto the biochar surface mainly followed physisorption which was reversible in nature. Desorption study revealed that pine biochar could be reused up to three cycles. Column adsorption data fitted well with Thomas model. These investigations revealed that the pine residue, which otherwise results in adverse environmental impacts, can be converted into useful resource like biochar as a heavy metal adsorbent.

Comparative Analysis of Three Surface Treatments on the Bond Strength of Zirconia to Resin-luting Agents: An In Vitro Study.

AIM: To study the impact of three different surface treatments namely sandblasting, silane-coupling agent, and laser on the retention of zirconia prosthesis and bond strength of zirconia to a resin-luting agent. MATERIALS AND METHODS: Sixty zirconia crowns were fabricated and were divided into four groups of 15 samples each on the basis of surface treatments. A control group with no surface treatment (group A), laser-treated (group B), treatment with silane-coupling agent (group C), and sandblasting with aluminium oxide (Al2O3) particles (group D). Testing was then carried out using a universal testing machine (0.5 mm/min crosshead speed). At a point where the crown got separated from the tooth, the reading in kilogram force (kgF) was recorded. The data were collected and analyzed statistically. RESULTS: Group D produced the highest mean bond strength (17.5233 kgF) followed by group B (10.0067 kgF), group C (8.6907 kgF), and group A (3.3773 kgF). One-way ANOVA test showed a p-value more than 0.05, concluding no significant difference among the groups. Tukey's HSD post hoc test gave the p-value corresponding to the F-statistic of one-way ANOVA lower than 0.01 when intergroup comparison was done confirming a significant difference among the groups. CONCLUSION: The bond strength significantly increased in the samples treated by sandblasting compared with those treated with laser and silane-coupling agents. CLINICAL SIGNIFICANCE: The success of a zirconia prosthesis lies on its bonding with the tooth structure. Bond failure leads to loss of function and hence ends up in failure. Selection of the proper surface treatment will not only improve the bond strength but also amplify the retention of zirconia-based prosthesis, thereby reducing the failure of the final prosthesis. It also improves the longevity of the prosthesis and restores the lost function which is the basic clinical aim of a prosthodontic treatment.

Challenges and Perspectives of Polyhydroxyalkanoate Production From Microalgae/Cyanobacteria and Bacteria as Microbial Factories: An Assessment of Hybrid Biological System.

Polyhydroxyalkanoates (PHAs) are the biopolymer of choice if we look for a substitute of petroleum-based non-biodegradable plastics. Microbial production of PHAs as carbon reserves has been studied for decades and PHAs are gaining attention for a wide range of applications in various fields. Still, their uneconomical production is the major concern largely attributed to high cost of organic substrates for PHA producing heterotrophic bacteria. Therefore, microalgae/cyanobacteria, being photoautotrophic, prove to have an edge over heterotrophic bacteria. They have minimal metabolic requirements, such as inorganic nutrients (CO2, N, P, etc.) and light, and they can survive under adverse environmental conditions. PHA production under photoautotrophic conditions has been reported from cyanobacteria, the only candidate among prokaryotes, and few of the eukaryotic microalgae. However, an efficient cultivation system is still required for photoautotrophic PHA production to overcome the limitations associated with (1) stringent management of closed photobioreactors and (2) optimization of monoculture in open pond culture. Thus, a hybrid system is a necessity, involving the participation of microalgae/cyanobacteria and bacteria, i.e., both photoautotrophic and heterotrophic components having mutual interactive benefits for each other under different cultivation regime, e.g., mixotrophic, successive two modules, consortium based, etc. Along with this, further strategies like optimization of culture conditions (N, P, light exposure, CO2 dynamics, etc.), bioengineering, efficient downstream processes, and the application of mathematical/network modeling of metabolic pathways to improve PHA production are the key areas discussed here. Conclusively, this review aims to critically analyze cyanobacteria as PHA producers and proposes economically sustainable production of PHA from microbial autotrophs and heterotrophs in "hybrid biological system."

Genetics, genomics and personalized medicine in Type 2 diabetes: a perspective on the Arab region.

Type 2 diabetes (T2D) is a wide-spread, chronic metabolic disorder, affecting millions of people worldwide. The epidemic of diabetes has placed a huge strain on public health, longevity and economy. T2D occurs as a result of both genetic and environmental factors and is heterogeneous in its presentation across individuals. This review gives an overview of the genetic variations identified by genome-wide association studies which predispose individuals to T2D and those which are responsible for variable drug response across patients, and the necessity to adopt a personalized approach to diabetes management. We also include a perspective on diabetes in Arabs, given the high incidence of T2D and consanguineous marriages, and the need to understand associated genetic components in this vulnerable population.

Spectrum of large copy number variations in 26 diverse Indian populations: potential involvement in phenotypic diversity.

Copy number variations (CNVs) have provided a dynamic aspect to the apparently static human genome. We have analyzed CNVs larger than 100 kb in 477 healthy individuals from 26 diverse Indian populations of different linguistic, ethnic and geographic backgrounds. These CNVRs were identified using the Affymetrix 50K Xba 240 Array. We observed 1,425 and 1,337 CNVRs in the deletion and amplification sets, respectively, after pooling data from all the populations. More than 50% of the genes encompassed entirely in CNVs had both deletions and amplifications. There was wide variability across populations not only with respect to CNV extent (ranging from 0.04-1.14% of genome under deletion and 0.11-0.86% under amplification) but also in terms of functional enrichments of processes like keratinization, serine proteases and their inhibitors, cadherins, homeobox, olfactory receptors etc. These did not correlate with linguistic, ethnic, geographic backgrounds and size of populations. Certain processes were near exclusive to deletion (serine proteases, keratinization, olfactory receptors, GPCRs) or duplication (homeobox, serine protease inhibitors, embryonic limb morphogenesis) datasets. Populations having same enriched processes were observed to contain genes from different genomic loci. Comparison of polymorphic CNVRs (5% or more) with those cataloged in Database of Genomic Variants revealed that 78% (2473) of the genes in CNVRs in Indian populations are novel. Validation of CNVs using Sequenom MassARRAY revealed extensive heterogeneity in CNV boundaries. Exploration of CNV profiles in such diverse populations would provide a widely valuable resource for understanding diversity in phenotypes and disease.

SCA-LSVD: a repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias.

Repeat expansion has been implicated in 10 out of 17 candidate genes identified for autosomal dominant cerebellar ataxias (ADCAs)-commonly referred as spinocerebellar ataxias (SCAs). Though genetically distinct, the SCAs share a large number of features that confound their clinical classification. In addition, there is a difference in the prevalence and phenotypic expression of ataxias between different ethnic groups. We have created a new SCA-locus-specific variation database (LSVD) that aims to catalog and integrate information on SCAs associated with trinucleotide repeat expansion (SCA1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, SCA 12, SCA 17, Friedreich's ataxia [FRDA], and dentatorubral-pallidoluysian atrophy [DRPLA]) from all over the world. The database has been developed using the Leiden Open (source) Variation Database (LOVD) software (Leiden University Medical Center, Leiden, the Netherlands). The database houses detailed information on clinical features, such as age and symptom at onset, mode of inheritance, and genotype information, pertaining to the SCA patients from more than 400 families across India. All the compiled genotype data conforms to the HGVS Nomenclature guidelines. This would be a very useful starting point for understanding the molecular correlates of phenotypes in ataxia-a multilocus disease in which related molecular mechanisms converge to overlapping phenotypes.

SCA 1, SCA 2 & SCA 3/MJD mutations in ataxia syndromes in southern India.

BACKGROUND & OBJECTIVE: Spinocerebellar ataxias (SCAs) are often caused by expansions of CTG/ CAG trinucleotide repeat in the genome. Expansions at the SCA1, 2 and 3 loci are the most frequent, but differences in their relative proportion in regions occur across the world. We carried out this study to assess the occurrence of SCA1, 2 and 3, at a tertiary neuro-psychiatric center in Bangalore, Karnataka. METHODS: Probands (N=318) who were diagnosed to have an ataxia syndrome (progressive degenerative ataxia of unknown cause) attending the clinical services of the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, were evaluated over a period of three years. Standard protocols were used for both clinical and molecular diagnosis. RESULTS: Genotyping established that SCA1, 2 and 3 accounted for more than one third of the ataxia cases seen in the clinic. In the cases with established family history and autosomal dominant inheritance SCA1 was most prevalent followed by SCA2 and SCA3. INTERPRETATION & CONCLUSION: Our findings suggested SCA1 rather than SCA2 to be the more common mutation in southern India. Large numbers of SCA3 probands were also identified. Differences in prevalence of these syndromes within India need to be explored further for founder effects, correlations with phenotype, and patterns of outcome. Family history was not apparent in almost a fifth of those tested positive, highlighting the value of testing even in the absence of family history. Molecular testing should be extended to cover the other forms of ataxia, of which a large number are now known. Combined efforts to confirm the presence of these less common forms, as well as family studies to detect novel mutations, are necessary in this context in India.