Structure based virtual screening and molecular simulation study of FDA-approved drugs to inhibit human HDAC6 and VISTA as dual cancer immunotherapy.

Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.

Occurrence, distribution, and pollution indices of potentially toxic elements within the bed sediments of the riverine system in Pakistan.

Potentially toxic elements (PTEs) are a major source of pollution due to their toxicity, persistence, and bio-accumulating nature in riverine bed sediments. The sediment, as the largest storage and source of PTEs, plays an important role in transformation of mercury (Hg), lead (Pb), nickel (Ni), chromium (Cr), copper (Cu), zinc (Zn), and other toxic PTEs. Several important industrial hubs that contain a large population along the banks of different rivers, such as Kabul, Sutlej, Ravi, Jhelum, and Chenab in Pakistan, are acting as major sources of PTEs. In this study, 150 bed sediment samples (n=30 from each river) were collected from different sites. Total (acid extracted) PTE (Hg, Cu, Cr, Ni, Zn, and Pb) concentrations in bed sediments were determined using inductively coupled plasma mass spectrometry (ICP-MS). Sediment pollution indices were calculated in the major rivers of Pakistan. The results demonstrated high levels of Hg and Ni concentrations which exceeded the guideline standards of river authorities in the world. The contamination factor (CF) and contamination degree (CD) indices for Hg, Ni, and Pb showed a moderate to high (CF≥6 and CD≥24) contamination level in all the selected rivers. The values of geo-accumulation index (Igeo) were also high (Igeo≥5) for Hg and Pb and heavily polluted for Ni, while Cr, Cu, and Zn showed low to unpolluted (Igeo) values. Similarly, the enrichment factor (EF) values were moderately severe (5≤EF≤10) for Hg, Pb, and Ni in Sutlej, Ravi, and Jhelum, and severe (10≤EF≤25) in Kabul and Jhelum. Moreover, Hg and Ni showed severe to very severe enrichment in all the sampling sites. The ecological risk index (ERI) values represented considerable, moderate, and low risks, respectively, for Hg (The ERI value should not be bold. Please unbold the  ERI in the whole paper. It should be same like RI, CD and EF. [Formula: see text]≥160), Pb and Ni (40≤[Formula: see text]≤80), and Cr, Cu, and Zn ([Formula: see text]≤40). Similarly, potential ecological risk index (PERI) values posed considerable (300≤RI≤600) risk in Ravi and moderate (150≤RI≤300) in Kabul and Jhelum, but low (RI≤150) risk in Ravi and Chenab. On the basis of the abovementioned results, it is concluded that bed sediment pollution can be dangerous for both ecological resources and human beings. Therefore, PTE contamination should be regularly monitored and a cost-effective and environmentally friendly wastewater treatment plant should be installed to ensure removal of PTEs before the discharge of effluents into the freshwater ecosystems.

Life Cycle and Genetic Identification of Argas persicus Infesting Domestic Fowl in Khyber Pakhtunkhwa, Pakistan.

Ticks transmit numerous pathogens to animals including humans; therefore, they are parasites of health concern. Soft ticks infesting domestic fowl in Pakistan are carriers of viruses and bacteria and cause unestimated economic losses in the poultry sector. The current study was intended to identify soft ticks infesting domestic fowl and understand their spatiotemporal distribution along 1 year. A sum of 7,219 soft ticks were collected from 608 domestic fowl in 58 infested shelters; 938 (12.9%) ticks were found on the host and 6,281 (87%) in the shelters. The collected ticks comprised 3,503 (48.52%) adults including 1,547 (21.42%) males and 1,956 (27.09%) females, 3,238 (44.85%) nymphs, and 478 (6.62%) larvae. The most prevalent life stages were adults, followed by nymphs and larvae. Overall tick prevalence considering all visited shelters was 38.66% (58/150). The highest tick prevalence was found in district Lakki Marwat (50.03%) followed by Peshawar (31.08%) and Chitral (18.88%) districts. All ticks were morpho-taxonomically identified as Argas persicus. To determine their life cycle, adult A. persicus were reared in the laboratory infesting domestic fowl (Gallus gallus domesticus). The life cycle was completed in 113-132 days (egg to egg) with a mean temperature of 33 ± 3°C and relative humidity of 65 ± 5%. Individual ticks were used for DNA extraction and subjected to polymerase chain reaction (PCR) using specific primers for the amplification of a partial fragment of mitochondrial cytochrome oxidase subunit I (cox1) and 16S ribosomal RNA (16S rRNA) genes. Obtained amplicons were compared using basic local alignment search tool (BLAST) to scan for homologous sequences. Phylogenetic trees showed A. persicus from Pakistan clustering with conspecific sequences reported from Australia, Chile, China, Kenya, and the United States. This is the first study aiming to reproduce the life cycle of A. persicus and genetically identify this tick in the region. Further studies are encouraged to investigate the pathogens associated with this soft tick species in Pakistan.

Correction: Ali, A., et al. Modeling Novel Putative Drugs and Vaccine Candidates against Tick-Borne Pathogens: A Subtractive Proteomics Approach. Vet. Sci. 2020, 7, 129.

The authors wish to make the following corrections to this paper [...].

Cutaneous leishmaniasis in male schoolchildren in the upper and lower Dir districts of Khyber Pakhtunkhwa, and a review of previous record in Pakistan.

Documented reports are limited, showing cutaneous leishmaniasis (CL) as a severe threat to schoolchildren in Pakistan. The present study aimed to investigate the clinico-epidemiology and associated risk factors of CL in local and Afghan male schoolchildren between 6 and 16 years of age. The experimental strategy involved a questionnaire for the collection of information and clinical diagnosis (microscopy and semi-nested PCR) of 113 CL symptomatic schoolchildren out of 8,833 schoolchildren (7,175 local and 1,658 Afghan refugees) studying in nineteen schools of the Upper and Lower Dir Districts, Khyber Pakhtunkhwa, Pakistan. Previous records of CL in Pakistan was studied, and spatial analysis was performed on elevation and agro-ecological maps using Arc-GIS v10.3.1. Active lesions were found predominant (n=113, 1.2%: cutaneous lesions, 97, 86%, and lesions with mucosal involvement, 16, 14%) than scars (20, 0.25%). Active lesions of both local (100, 88%) and Afghan refugees (13, 12%), and infected age groups were found significantly different. Majority of the lesions were dry crusted (98, 86.7%), single (83, 73%), and frequently infecting facial region (59, 52%). Avoiding bed nets, living in mud houses and animal shelters were highly associated with CL infection. Temergara (30, 26.5%) and Rabath (14, 12.3%) were hyperendemic CL foci. Microscopically, 71 (63%) cases were positive, while the PCR assay revealed Leishmania tropica in 110 (97.3%) cases. Previous record revealed that L. tropica is dominant throughout Pakistan, and dry mountains and plateaus of northwestern and southwestern regions are spatially at high-risk. Measures should be taken to reduce CL infection by eliminating the associated risk factors, promoting PCR-based diagnosis and basic medical facilities.