Towards an Ethics of Being-With: Intertwinements of Life in Post-Invasion Basra

In this paper, I turn to Oum Hassan, a woman who works as a cleaner in a hotel in Basra, and show that her life is as much a life for her niece and sister as it is about maintaining her own existence in the face of tremendous pressures. Where anthropologists have insisted on the primordiality of social relationship to the constitution of personhood, I am wanting to recast some of this interest into a language of an ethics of life and being-with.     

Drug repurposing for SARS-CoV-2 main protease: Molecular docking and molecular dynamics investigations

The current novel corona virus illness (COVID-19) is a developing viral disease that was discovered in 2019. There is currently no viable therapeutic strategy for this illness management. Because traditional medication development and discovery has lagged behind the threat of emerging and re-emerging illnesses like Ebola, MERS-CoV, and, more recently, SARS-CoV-2. Drug developers began to consider drug repurposing (or repositioning) as a viable option to the more traditional drug development method. The goal of drug repurposing is to uncover new uses for an approved or investigational medicine that aren't related to its original use. The main benefits of this strategy are that there is less developmental risk and that it takes less time because the safety and pharmacologic requirements are met. The main protease (Mpro) of corona viruses is one of the well-studied and appealing therapeutic targets. As a result, the current research examines the molecular docking of Mpro (PDB ID: 5R81) conjugated repurposed drugs. 12,432 approved drugs were collected from ChEMBL and drugbank libraries, and docked separately into the receptor grid created on 5R81, using the three phases of molecular docking including high throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP). Based on docking scores and MM-GBSA binding free energy calculation, top three drugs (kanamycin, sulfinalol and carvedilol) were chosen for further analyses for molecular dynamic simulations.     

N-Terminal Presequence-Independent Import of Phosphofructokinase into Hydrogenosomes of Trichomonas vaginalis

Mitochondrial evolution entailed the origin of protein import machinery that allows nuclear-encoded proteins to be targeted to the organelle, as well as the origin of cleavable N-terminal targeting sequences (NTS) that allow efficient sorting and import of matrix proteins. In hydrogenosomes and mitosomes, reduced forms of mitochondria with reduced proteomes, NTS-independent targeting of matrix proteins is known. Here, we studied the cellular localization of two glycolytic enzymes in the anaerobic pathogen Trichomonas vaginalis: PP_i-dependent phosphofructokinase (TvPP_i-PFK), which is the main glycolytic PFK activity of the protist, and ATP-dependent PFK (TvATP-PFK), the function of which is less clear. TvPP_i-PFK was detected predominantly in the cytosol, as expected, while all four TvATP-PFK paralogues were imported into T. vaginalis hydrogenosomes, although none of them possesses an NTS. The heterologous expression of TvATP-PFK in Saccharomyces cerevisiae revealed an intrinsic capability of the protein to be recognized and imported into yeast mitochondria, whereas yeast ATP-PFK resides in the cytosol. TvATP-PFK consists of only a catalytic domain, similarly to “short” bacterial enzymes, while ScATP-PFK includes an N-terminal extension, a catalytic domain, and a C-terminal regulatory domain. Expression of the catalytic domain of ScATP-PFK and short Escherichia coli ATP-PFK in T. vaginalis resulted in their partial delivery to hydrogenosomes. These results indicate that TvATP-PFK and the homologous ATP-PFKs possess internal structural targeting information that is recognized by the hydrogenosomal import machinery. From an evolutionary perspective, the predisposition of ancient ATP-PFK to be recognized and imported into hydrogenosomes might be a relict from the early phases of organelle evolution.     

A plate-based assay system for analyses and screening of the Leishmania major inositol phosphorylceramide synthase

Sphingolipids are key components of eukaryotic membranes, particularly the plasma membrane. The biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals, which produce sphingomyelin, organisms such as the pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. The key step involves the reaction of ceramide and phosphatidylinositol catalysed by IPC synthase, an essential enzyme with no mammalian equivalent encoded by the AUR1 gene in yeast and recently identified functional orthologues in the pathogenic kinetoplastid protozoa. As such this enzyme represents a promising target for novel anti-fungal and anti-protozoal drugs. Given the paucity of effective treatments for kinetoplastid diseases such as leishmaniasis, there is a need to characterize the protozoan enzyme. To this end a fluorescent-based cell-free assay protocol in a 96-well plate format has been established for the Leishmania major IPC synthase. Using this system the kinetic parameters of the enzyme have been determined as obeying the double displacement model with apparent V_max = 2.31 pmol min^?1 U^?1. Furthermore, inhibitory substrate analogues have been identified. Importantly this assay is amenable to development for use in high-throughput screening applications for lead inhibitors and as such may prove to be a pivotal tool in drug discovery.     

Studies on the antileishmanial properties of the antimicrobial peptides temporin A,B and 1Sa

Given the paucity and toxicity of available drugs for leishmaniasis, coupled with the advent of drug resistance, the discovery of new therapies for this neglected tropical disease is recognised as being of the utmost urgency. As such antimicrobial peptides (AMPs) have been proposed as promising compounds against the causative Leishmania species, insect vector‐borne protozoan parasites. Here the AMP temporins A, B and 1Sa have been synthesised and screened for activity against Leishmania mexicana insect stage promastigotes and mammalian stage amastigotes, a significant cause of human cutaneous disease. In contrast to previous studies with other species the activity of these AMPs against L. mexicana amastigotes was low. This suggests that amastigotes from different Leishmania species display varying susceptibility to peptides from the temporin family, perhaps indicating differences in their surface structure, the proposed target of these AMPs. In contrast, insect stage L. mexicana promastigotes were sensitive to two of the screened temporins which clearly demonstrates the importance of screening AMPs against both forms of the parasite. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Anti-genotoxic and free-radical scavenging activities of extracts from (Tunisian) Myrtus communis

The effect of extracts from leaves of Myrtus communis on the SOS reponse induced by Aflatoxin B1 (AFB1) and Nifuroxazide was investigated in a bacterial assay system, i.e. the SOS chromotest with Escherichia coli PQ37. Aqueous extract, the total flavonoids oligomer fraction (TOF), hexane, chloroform, ethyl acetate and methanol extracts and essential oil obtained from M. communis significantly decreased the SOS response induced by AFB1 (10 microg/assay) and Nifuroxazide (20 microg/assay). Ethyl acetate and methanol extracts showed the strongest inhibition of the induction of the SOS response by the indirectly genotoxic AFB1. The methanol and aqueous extracts exhibited the highest level of protection towards the SOS-induced response by the directly genotoxic Nifuroxazide. In addition to anti-genotoxic activity, the aqueous extract, the TOF, and the ethyl acetate and methanol extracts showed an important free-radical scavenging activity towards the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. These results suggest the future utilization of these extracts as additives in chemoprevention studies.     

Lack of significant influence for FcγRIIa-RH131 or hemoglobin AA/AS polymorphisms on immunity and susceptibility to uncomplicated malaria and existence of marked linkage between the two polymorphisms in Daraweesh

Malaria signature on human genome is marked by several gene polymorphisms. HemoglobinAS (HbAS) is known to protect against severe malaria, but barely proved to protect against uncomplicated malaria (UM). Similarly, the influence of FcγRIIa-RH131 polymorphism on malaria is controversial. Polymorphisms in both genes were examined and levels of IgG subclasses against four malaria antigens were measured for 250 Fulani’s from Daraweesh, eastern Sudan. Morbidity data for up to nine years was available for 214 donors. Number of malaria episodes experienced by each individual during the study period was used as indicator for susceptibility to UM. PCR and RFLP were used for donors DNA genotyping and ELISA for antibodies measurement. Results revealed that neither FcγRIIa-RH131 alleles/genotypes nor HbAA/AS was significantly associated with malaria morbidity or with levels of IgG to test antigens. Both polymorphisms were in Hardy–Weinberg Equilibrium, interestingly, there was strong association between the two polymorphisms (linkage disequilibrium – LD) with D′ = 0.89. The association between the two polymorphisms was confirmed by analysis of independent material from a neighboring village. In conclusion, in Daraweesh both FcγRIIa-RH131 and HbAA/AS genotypes, independently or together, were not major markers for UM susceptibility, however, marked LD was observed between the two polymorphisms.     

Reproductive performance of Farafra ewes in the subtropics

The present study was carried out to assess the reproductive performance of Farafra ewes—a breed with potential economic importance in the subtropics. A total of 262 ewes were categorized according to age, parity, and postpartum interval. Ewes were introduced for breeding in fall, winter and late spring seasons. Fertility, prolificacy, lamb birth weight, and ultrasonic fetal parameters were recorded. Results obtained showed that litter size was increased with age and parity. Lamb birth weight was affected by season. None of the parameters studied had a clear-cut effect on fertility. However, an interaction between season and parity was detected. Measurement of fetal size in the first half of gestation did not predict birth weight. The obtained data represents the first record of the reproductive performance of Farafra ewes in the subtropics, which could be used to anticipate their performance in different seasons.     

Adenovirus-induced liver pathology is mediated through TNF receptors I and II but is independent of TNF or lymphotoxin.

Mice infected with an adenovirus mutant in which the E3 region is deleted, including TNF-resistance genes, develop fatal liver pathology within 3-4 days after infection. At least 10-fold more wild-type virus was needed to cause comparable pathology. These results indicate that the E3 region is critically involved in modulating the pathogenesis of adenovirus infection and that TNF may play a role in liver damage. To explore the latter possibility, the course of disease was examined in infected mice lacking TNFR-I and/or TNFRII, TNF only, or both TNF and lymphotoxin-alpha. Only mice lacking both TNFRI and TNFRII were protected from the lethal affects of the mutant adenovirus. Mice deficient in TNF or TNF and lymphotoxin-alpha displayed the fatal pathology. This outcome is consistent with the existence of another related ligand that binds TNFRI/II to mediate liver damage during infection with this mutant.