Self-Assembly Driven Formation of Functional Ultralong "Artificial Fibers" to Mitigate the Neuronal Damage Associated with Alzheimer's Disease.

Fibrillation of amyloid beta (Aß) is the key event in the amyloid neurotoxicity process that induces a chain of toxic events including oxidative stress, caspase activation, poly(ADP-ribose) polymerase cleavage, and mitochondrial dysfunction resulting in neuronal loss and memory decline manifesting as clinical dementia in humans. Herein, we report the development of a novel, biologically active supramolecular probe, INHQ, and achieve functional nanoarchitectures via a self-assembly process such that ultralong fibers are achieved spontaneously. With specifically decorated functional groups on INHQ such as imidazole, hydroxyquinoline, hydrophobic chain, and hydroxyquinoline molecules, these ultralong fibers coassembled efficiently with toxic Aß oligomers and mitigated the amyloid-induced neurotoxicity by blocking the aforementioned biochemical events leading to neuronal damage in mice. These functional ultralong "Artificial Fibers" morphologically resemble the amyloid fibers and provide a higher surface area of interaction that improves its clearance ability against the Aß aggregates. The efficacy of this novel INHQ molecule was ascertained by its high ability to interact with Aß. Moreover, this injectable, ultralong INHQ functional "artificial fiber" translocates through the blood-brain barrier and successfully attenuates the amyloid-triggered neuronal damage and pyknosis in the cerebral cortex of wild-type mouse. Utilizing various spectroscopic techniques, morphology analysis, and in vitro, in silico, and in vivo studies, these ultralong INHQ fibers are proven to hold great promise for treating neurological disorders at all stages with a potential to replace the existing medications, reduce complications in the brain, and eradicate the amyloid-triggered neurotoxicity implicated in numerous disorders in human through a rare synergistic mechanism.

Niclosamide inhibits Newcastle disease virus replication in chickens by perturbing the cellular glycolysis.

Newcastle disease virus (NDV), a member of Paramyxoviridae family, is one of the most important pathogens in poultry. To ensure optimal environments for their replication and spread, viruses rely largely on host cellular metabolism. In the present study, we evaluated the small drug molecule niclosamide for its anti-NDV activity. Our study has shown that a sublethal dose of 1 µM niclosamide could drastically reduce NDV replication. The results showed that niclosamide has antiviral activity against NDV infection during in vitro, in ovo and in vivo assays. Pharmacologically inhibiting the glycolytic pathway remarkably reduced NDV RNA synthesis and infectious virion production. Our results suggest that the effect of niclosamide on cellular glycolysis could be the possible reason for the specific anti-NDV effect. This study could help us understand antiviral strategies against similar pathogens and may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways.

Genetic diversity in mitochondrial DNA D-loop region of indigenous pig breeds of India.

India is home for at least 18 indigenous pig breeds; however, the genetic diversity of Indian pig, Sus scrofa domesticus, population is poorly known. Here, the hypervariable region (HVR) of mitochondrial DNA D-loop (~487 bp) of 214 pigs representing five indigenous and three exotic breeds was sequenced and analysed with reference sequences from other countries. A total of 54 segregating sites among the sequences revealed 56 different haplotypes. Two, 11, eight, seven and six haplotypes were identified with some haplotype sharing in indigenous breeds: Doom, Ghungroo, Mali, Niang-Megha and Tenyi-Vo, respectively. Population pairwise differences (PhiST) (0.409) were found significant (P<0.001), and variance within breeds (59.1%) was more than that of among breeds (40.9%). Similar topology was noted in phylogeny and median-joining network. Indian domestic pigs from this study were found to possess unique and highly differentiated haplotypes on network analysis. The diverse haplotypes and phylogenetic lineages identified here is the first report on Indian pig breeds that need to be further explored by complete mitochondrial DNA sequencing and analysis. These findings provide indicative insights for conservation and optimum utilization of the porcine genetic resources.

Evaluation of candidate genes related to litter traits in Indian pig breeds.

Improvement in litter traits is the key to profitable pig farming that directly enhances the economic standing of the farmers in developing countries. The present study aimed to explore oestrogen receptor (ESR), epidermal growth factor (EGF), follicle-stimulating hormone beta subunit (FSHß), prolactin receptor (PRLR) and retinol-binding protein 4 (RBP4) genes as possible candidate genetic markers for litter traits in indigenous pigs of India. The breeds included in the study were Ghungroo, Mali, Niang Megha and Tenyi Vo, and the reproductive traits considered were litter size at birth (LSB), number born alive (NBA), litter weight at birth (LWB), litter size at weaning (LSW) and litter weight at weaning (LWW) at their first parity. PCR-RFLP and primer-based mutation detection methods were used to identify polymorphism, and associations between the genotypes and the traits were analysed using a general linear model. The Ghungroo pigs recorded the best litter performances among the breeds (p < .05, LWB p < .01). Different alleles and genotypes of the genes under study were detected. Short interspersed nuclear element (SINE) -/- genotype of FSHß revealed significantly higher litter traits (p < .05, LSB p < .01). The LWW was also found to be significantly influenced by ESR BB and AB, EGF AB and BB, and PRLR CC genotypes (p < .05). Although we did not find statistically significant and consistently superior litter traits with respect to different genotypes of other studied genes than genotype SINE -/- of the FSHß, PRLR CC genotype demonstrated superior performances for all the litter traits. Our study revealed the FSHß as a potential candidate genetic marker for litter traits in indigenous pig breeds of India.

Analysis of the beak and feather disease viral genome indicates evidence of multiple introduction events into Saudi Arabia.

Psittacine beak and feather disease (PBFD), caused by beak and feather disease virus (BFDV) is a highly contagious disease in wild and captive psittacine populations and has an almost global presence. However, the BFDV infection in Saudi Arabia remains largely unknown. In the present study, we report the full genome sequence of BFDV strains from Saudi Arabia and its genetic diversity. The complete genome sequences were analyzed for 14 BFDV-infected birds representing 6 psittacine species. The complete genome sequence of BFDV strains was compared with 201 previously reported sequences to evaluate their diversity and possible recombination events, if any. Our analysis revealed that newly sequenced BFDV genomes from Saudi Arabia belonged to six different strains. Phylogenetic analysis suggested that the isolated BFDV genomes were highly recombinant with a high degree of diversity. It is evident from the study that psittacine species in Saudi Arabia are at risk from the spread of BFDV. As per the CITES trade database, about 190,000 parrots have been imported to Saudi Arabia since 1975 over a thousand instances. Presumably, during any of these trade events or unregulated trade of birds has predisposed the introduction of BFDV to Saudi Arabia. Understanding the epidemiology of BFDV is necessitated to address the threat posed by the virus to the psittacine population of Saudi Arabia.

Amyloid Targeting "Artificial Chaperone" Impairs Oligomer Mediated Neuronal Damage and Mitochondrial Dysfunction Associated with Alzheimer's Disease.

Alzheimer's disease (AD) is an irreversible memory disorder associated with multiple neuropathological events including amyloid aggregation that triggers oxidative stress and mitochondrial dysfunction in humans. Herein, a new artificial chaperone, benzimidazole functionalized polyfluorene (PFBZ) is reported to efficiently sequester toxic amyloid beta (Aß) by binding at their 'amyloidogenic domain' (Aß16-21) with unprecedented selectivity and prevent amyloid-mediated neuronal damage in a wild-type (WT) mouse model. An accurate dose of PFBZ chaperone successfully attenuated an amyloid triggered internal hemorrhage and pyknosis in the cerebral cortex of WT mice. The structural advantage of the polymer results in an efficient Cu(II) chelation arresting a redox cycle to prevent reactive oxygen species (ROS) generation and protect mitochondria from ROS mediated damage. This was further evidenced by caspase activation and mitochondrial membrane potential (MMP) biomarkers and was complemented by brain histology and electron microscopy data which revealed that the PFBZ chaperone provided a protective coating over the amyloid surface and resists from interacting with cell membrane and prevents inducing toxicity. This conjugated polymer artificial chaperone-based nanodrug showed exceptional properties such as its multipotent and highly biocompatible nature, the first of its kind with specific amyloid (Aß16-21) targeting behavior, bioimaging, and BBB permeability with a potential to suppress amyloid triggered neurotoxicity implicated in numerous human disorders through a rare synergistic mechanism.

Therapeutic potential of Nitazoxanide against Newcastle disease virus: A possible modulation of host cytokines.

Newcastle disease (ND) is prevalent among the domesticated and the wild birds and is caused by the avian paramyxovirus serotype-I (APMV-I). It is commonly known to affect chicken, pheasant, ostrich, pigeon and waterfowl. Depending on the virulence, the velogenic NDV strains cause severe respiratory and nervous disorders with a high mortality rate. The live and killed vaccines are available for the prevention of infection in the market, but the drug for the treatment is not available. Nitazoxanide (NTZ), a member of thiazolides, is an antiparasitic drug. In the present study, the effect of NTZ on the NDV replication was explored. The experiments were conducted in chicken fibroblast cells (DF-1), PBMC, embryonated chicken eggs, and two-week old chickens. The inhibition of the NDV was observed upon post-treatment of NTZ at a concentration of ~12.5 µM. Cytokine profiling of the DF-1, PBMC, and chicken embryonic tissue treated with NTZ revealed significant upregulation in all the cytokines studied except for IL-1ß in DF-1 cells. It is plausible that NTZ is involved in causing immune-modulatory effects in poultry. NTZ treatment in two weeks old chicken showed significant reduction in NDV replication in trachea, and lungs, respectively, at 72 h post-infection. Encouraging results from the present study warrants repurposing NTZ as a drug for the treatment of viral infection in poultry. It will also pave the way towards understanding of similar effect against other animal pathogens.

Understanding the B and T cell epitopes of spike protein of severe acute respiratory syndrome coronavirus-2: A computational way to predict the immunogens.

The 2019 novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak has caused a large number of deaths, with thousands of confirmed cases worldwide. The present study followed computational approaches to identify B- and T-cell epitopes for the spike (S) glycoprotein of SARS-CoV-2 by its interactions with the human leukocyte antigen alleles. We identified 24 peptide stretches on the SARS-CoV-2 S protein that are well conserved among the reported strains. The S protein structure further validated the presence of predicted peptides on the surface, of which 20 are surface exposed and predicted to have reasonable epitope binding efficiency. The work could be useful for understanding the immunodominant regions in the surface protein of SARS-CoV-2 and could potentially help in designing some peptide-based diagnostics. Also, identified T-cell epitopes might be considered for incorporation in vaccine designs.

Chloride Ion Transport by PITENINs across the Phospholipid Bilayers of Vesicles and Cells.

Small-molecule-based Cl- ion carriers are gaining revived attention because of their recently discovered role toward anticancer activity. Herein, we showed that the anticancer agents, PITENINs, have an efficient transmembrane Cl- ion transport activity. Theoretical calculations, 1H NMR titration, and spectrophotometric analysis suggest that the PITENINs strongly bind with a Cl- ion. In addition to the lipophilicity, the presence of both acylthiourea and phenolic OH moieties of the compounds plays a crucial role in the transport of Cl- ions. Among the tested compounds, PIT-1 and DM-PIT-1 showed higher Cl- ion selectivity and transport efficiency. Mechanistic studies demonstrated that the potent compounds follow the H+/Cl- transport pathway. Cellular activity studies showed that the disruption of Cl- ion homeostasis by PIT-1 and DM-PIT-1 preferentially promotes apoptotic cell death.

Dietary supplementation of n-3 polyunsaturated fatty acid alters endometrial expression of genes involved in prostaglandin biosynthetic pathway in breeding sows (Sus scrofa).

The present investigation was designed to study the effect of dietary supplementation of omega-3 (n-3) PUFA on endometrial expression of fertility-related genes in breeding sows. Sixteen crossbred sows were randomized to receive diets containing 4% (wt/wt) flaxseed oil as n-3 PUFA source (TRT group) or iso-nitrogenous, iso-caloric standard control diet (CON group), starting from the first day of estrus up to 40 days and were artificially bred on the second estrus. Endometrial samples were collected during days 10-11 and 15-16 post-mating for studying relative expression profile of candidate genes viz. Prostaglandin F Synthase (PGFS), microsomal Prostaglandin E Synthase-1 (mPGES-1) and Carbonyl Reductase-1 (CBR-1) using quantitative Real-Time PCR. Expression level of mPGES-1 gene transcript was 2.1-fold higher (P < 0.05) during 10-11 days of pregnancy and 1.4-fold higher (P > 0.05) during 15-16 days of pregnancy in TRT group as compared to CON group. Relative expression of PGFS gene transcript was significantly lower (P < 0.05) during 10-11 days of pregnancy in TRT group while there was no significant effect (P > 0.05) of dietary supplementation during 15-16 days of pregnancy. Endometrial mRNA level of CBR1 was significantly lower (P < 0.05) with 3.93-fold decrease in TRT group during 10-11 days of pregnancy whereas 2.82-fold reduction in expression (P > 0.05) was observed subsequently during 15-16 days of pregnancy as compared to CON group. Collectively, these results indicate that dietary n-3 PUFA supplementation can modulate gene expression of key enzymes in prostaglandin biosynthetic pathway during early gestation, which in turn might have beneficial impact on overall reproductive response in breeding sows. These findings partly support strategic dietary supplementation of plant-based source of n-3 PUFA with an aim to improve overall reproductive performance in sows.