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Maxwell Korang-Yeboah,1 Yamini Gorantla,1 Simon A Paulos,1 Pankaj Sharma,2 Jaideep Chaudhary,2 Ravi Palaniappan1 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, 2Center for Cancer Research and Therapeutic Development (CCRTD), Clark Atlanta University, Atlanta, GA, USA Abstract: Prostate cancer (PCa) disease progression is associated with significant changes in intracellular and extracellular proteins, intracellular signaling mechanism, and cancer cell phenotype. These changes may have direct impact on the cellular interactions with nanocarriers; hence, there is the need for a much-detailed understanding, as nanocarrier cellular internalization and intracellular sorting mechanism correlate directly with bioavailability and clinical efficacy. In this study, we report the differences in the rate and mechanism of cellular internalization of a biocompatible polycaprolactone (PCL)/maltodextrin (MD) nanocarrier system for intracellular drug delivery in LNCaP, PC3, and DU145 PCa cell lines. PCL/MD nanocarriers were designed and characterized. PCL/MD nanocarriers significantly increased the intracellular concentration of coumarin-6 and fluorescein isothiocyanate-labeled bovine serum albumin, a model hydrophobic and large molecule, respectively. Fluorescence microscopy and flow cytometry analysis revealed rapid internalization of the nanocarrier. The extent of nanocarrier cellular internalization correlated directly with cell line aggressiveness. PCL/MD internalization was highest in PC3 followed by DU145 and LNCaP, respectively. Uptake in all PCa cell lines was metabolically dependent. Extraction of endogenous cholesterol by methyl-ß-cyclodextrin reduced uptake by 75%±4.53% in PC3, 64%±6.01% in LNCaP, and 50%±4.50% in DU145, indicating the involvement of endogenous cholesterol in cellular internalization. Internalization of the nanocarrier in LNCaP was mediated mainly by macropinocytosis and clathrin-independent pathways, while internalization in PC3 and DU145 involved clathrin-mediated endocytosis, clathrin-independent pathways, and macropinocytosis. Fluorescence microscopy showed a very diffused and non-compartmentalized subcellular localization of the PCL/MD nanocarriers with possible intranuclear localization and minor colocalization in the lysosomes with time. Keywords: endocytosis, prostate cancer, subcellular targeting, macropinocytosis, clathrin-mediated endocytosis

Purpose: To study the epidemiological characteristics and laboratory diagnosis of fungal keratitis seen at a tertiary eye care referral centre in South India. Methods: A retrospective review of all culture-proven fungal keratitis seen over a 3-year period, September 1999 through August 2002. Results: Fungal aetiology were confirmed in1095(34.4%) of 3183 corneal ulcers. The predominant fungal species isolated was Fusarium spp (471; 42.82%) followed by Aspergillus spp (286; 26%). Males (712; 65.08%) were more often affected (P< 0.0001). A large proportion of the patients (732; 66.85%) were in the younger age group (21 to 50 years). A majority (879; 80.27%) came from rural areas (P< 0.0001), and most patients (709; 64.75%) were farmers (P< 0.0001). Ocular trauma (1009; 92.15%) was a highly significant risk factor (P< 0.0001) and vegetative injuries (671; 61.28%) were identified as a significant cause for fungal keratitis (P< 0.0001). 172 (15.71%) patients had concurrent diabetes mellitus. The sensitivity of 10% potassium hydroxide (KOH) wet mount preparation was higher (99.23%) than Gram-stained smear (88.73%) (P< 0.0001). Incidence of fungal keratitis was higher between June and September. Conclusion: Agricultural activity and related ocular trauma were principal causes of mycotic keratitis. A potassium hydroxide (KOH) wet mount preparation is a simple, and sensitive, method for diagnosis.

PURPOSE: To analyse the in-vitro efficacy of commonly used antibacterials against bacterial pathogens from corneal ulcers. METHODS: We evaluated 596 patients seen over 18 months, period, September 1999 through March 2001. Corneal scrapings were subjected to microscopy and cultures using standard protocols. Antibacterial susceptibility of isolated bacteria were determined by the Kirby-Bauer disc-diffusion method. RESULTS: 626 bacterial pathogens were isolated from 596 corneal ulcer cases. 411(65.65%) were gram positive cocci Streptococcus pneumoniae (41.85%) was the predominant bacterial species. The antibacterial susceptibility was: 451(72.04%) to cefazolin, 471(75.24%) to chloramphenicol; 321(51.28%) to cephaloridine; 430(68.69%) to vancomycin; 564(90.09%) to ciprofloxacin; 429(68.53%) to norfloxacin; 464(74.12%) to gentamicin and 202(32.27%) to co.trimoxazole. CONCLUSION: This study provides information on the efficacy of ocular antibacterials commonly used against bacterial pathogens of keratitis. It is hoped that this information will help decision-making in empiric initial treatment of bacterial keratitis.

Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP.

The Farmer Producer Company (FPC), a subset of the Farmer Producer Organization (FPO), is an important institutional form designed to organize farmer groups towards better coordinated farming and marketing. In the Indian context, as FPCs have emerged as new forms of members-led agribusiness, their ability to identify prevailing social ties and tap them effectively towards business growth needs to be better understood. Although social capital is studied broadly for its potential to drive organizational performance, it has been poorly researched in farmer collectives such as FPCs. The current work examines the effect of social capital on benefits and business performance at the level of member groups in FPCs. An empirical analysis was conducted in which two FPCs, which differed significantly in their mobilization strategies, farming methods, and supply chain linkages, were surveyed. Data collected from the surveys were visualized and clustering analysis was carried out using Self Organizing Maps (SOM), an unsupervised Artificial Neural Network (ANN) tool. Insights from clustering reveal the importance of pre-existing social ties, leadership, participation in group activities and the geographical affinity of groups in benefits realization and business performance of FPCs. The importance of bottom-up approaches in establishing robust supply chain linkages in emerging FPCs was keyed out through this work. The inferences through SOM, distilled strategies for FPCs' stakeholders in prioritizing interventions for member groups and in generating broader implications for policy makers accounting social capital in new institutional models.

Abstract Respiratory tract vaccination has an advantage of needle-free delivery and induction of mucosal immune response in the portal of SARS-CoV-2 entry. We utilized human parainfluenza virus type 3 vector to generate constructs expressing the full spike (S) protein of SARS-CoV-2, its S1 subunit, or the receptor-binding domain, and tested them in hamsters as single-dose intranasal vaccines. The construct bearing full-length S induced high titers of neutralizing antibodies specific to S protein domains critical to the protein functions. Robust memory T cell responses in the lungs were also induced, which represent an additional barrier to infection and should be less sensitive than the antibody responses to mutations present in SARS-CoV-2 variants. Following SARS-CoV-2 challenge, animals were protected from the disease and detectable viral replication. Vaccination prevented induction of gene pathways associated with inflammation. These results indicate advantages of respiratory vaccination against COVID-19 and inform the design of mucosal SARS-CoV-2 vaccines.