Discovery of a new prokaryotic type I GTP cyclohydrolase family

GTP cyclohydrolase I (GCYH-I) is the first enzyme of the de novo tetrahydrofolate biosynthetic pathway present in bacteria, fungi, and plants, and encoded in Escherichia coli by the folE gene. It is also the first enzyme of the biopterin (BH4) pathway in Homo sapiens, where it is encoded by a homologous folE gene. A homology-based search of GCYH-I orthologs in all sequenced bacteria revealed a group of microbes, including several clinically important pathogens, that encoded all of the enzymes of the tetrahydrofolate biosynthesis pathway but GCYH-I, suggesting that an alternate family was present in these organisms. A prediction based on phylogenetic occurrence and physical clustering identified the COG1469 family as a potential candidate for this missing enzyme family. The GCYH-I activity of COG1469 family proteins from a variety of sources (Thermotoga maritima, Bacillus subtilis, Acinetobacter baylyi, and Neisseria gonorrhoeae) was experimentally verified in vivo and/or in vitro. Although there is no detectable sequence homology with the canonical GCYH-I, protein fold recognition based on sequence profiles, secondary structure, and solvation potential information suggests that, like GCYH-I proteins, COG1469 proteins are members of the tunnel-fold (T-fold) structural superfamily. This new GCYH-I family is found in approximately 20% of sequenced bacteria and is prevalent in Archaea, but the family is to this date absent in Eukarya.     

Investigate the chronic neurotoxic effects of diquat

Chronic exposure to agricultural chemicals (pesticides/herbicides) has been shown to induce neurotoxic effects or results in accumulation of various toxic metabolic by-products. These substances have the relevant ability to cause or increase the risk for neurodegeneration. Diquat is an herbicide that has been extensively used in the United States of America and other parts of the world. Diquat is constantly released into the environment during its use as a contact herbicide. Diquat structurally resembles 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and paraquat. Rotenone, paraquat, maneb and MPTP reproduce features of movement disorders in experimental animal models. Based on the structural similarity to other neurotoxins, chronic exposure of diquat can induce behavioral and neurochemical alterations associated with dopaminergic neurotoxicity. However, in the present study, diquat unlike other neurotoxins (rotenone, 6-hydroxydopamine, MPTP, paraquat and maneb) did not induce dopamine depletion in the mouse striatum. Although, notable exacerbation in motor impairment (swimming score, akinesia and open field) were evident that may be due to the decreased dopamine turnover and mild nigrostriatal neurodegeneration. These data indicate that, despite the apparent structural similarity to other dopaminergic neurotoxins, diquat did not exert severe deleterious effects on dopamine neurons in a manner that is unique to rotenone and MPTP.     

Prion protein and shadoo are involved in overlapping embryonic pathways and trophoblastic development

The potential requirement of either the Prion or Shadoo protein for early mouse embryogenesis was recently suggested. However, the current data did not allow to precise the developmental process that was affected in the absence of both proteins and that led to the observed early lethal phenotype. In the present study, using various Prnp transgenic mouse lines and lentiviral vectors expressing shRNAs that target the Shadoo-encoding mRNA, we further demonstrate the specific requirement of at least one of these two PrP-related proteins at early developmental stages. Histological analysis reveals developmental defect of the ectoplacental cone and important hemorrhage surrounding the Prnp-knockout-Sprn-knockdown E7.5 embryos. By restricting the RNA interference to the trophoblastic cell lineages, the observed lethal phenotype could be attributed to the sole role of these proteins in this trophectoderm-derived compartment. RNAseq analysis performed on early embryos of various Prnp and Sprn genotypes indicated that the simultaneous down-regulation of these two proteins affects cell-adhesion and inflammatory pathways as well as the expression of ectoplacental-specific genes. Overall, our data provide biological clues in favor of a crucial and complementary embryonic role of the prion protein family in Eutherians and emphasizes the need to further evaluate its implication in normal and pathological human placenta biology.     

Genomic network analysis of environmental and livestock F-type plasmid populations

F-type plasmids are diverse and of great clinical significance, often carrying genes conferring antimicrobial resistance (AMR) such as extended-spectrum β-lactamases, particularly in Enterobacterales. Organising this plasmid diversity is challenging, and current knowledge is largely based on plasmids from clinical settings. Here, we present a network community analysis of a large survey of F-type plasmids from environmental (influent, effluent and upstream/downstream waterways surrounding wastewater treatment works) and livestock settings. We use a tractable and scalable methodology to examine the relationship between plasmid metadata and network communities. This reveals how niche (sampling compartment and host genera) partition and shape plasmid diversity. We also perform pangenome-style analyses on network communities. We show that such communities define unique combinations of core genes, with limited overlap. Building plasmid phylogenies based on alignments of these core genes, we demonstrate that plasmid accessory function is closely linked to core gene content. Taken together, our results suggest that stable F-type plasmid backbone structures can persist in environmental settings while allowing dramatic variation in accessory gene content that may be linked to niche adaptation. The association of F-type plasmids with AMR may reflect their suitability for rapid niche adaptation.Subject terms: Environmental microbiology, Genomics     

Can pennation angles be predicted from EMGs for the primary ankle plantar and dorsiflexors during isometric contractions?

Ultrasonography was used to measure pennation angle and electromyography (EMG) to record muscle activity of the human tibialis anterior (TA), lateral gastrocnemius (LG), medial gastrocnemius (MG), and soleus (SOL) muscles during graded isometric ankle plantar and dorsiflexion contractions done on a Biodex dynamometer. Data from 8 male and 8 female subjects were collected in increments of approximately 25% of maximum voluntary contraction (MVC) ranging from rest to MVC. A significant positive linear relationship (p<0.05) between normalized EMG and pennation angle for all muscles was observed when subject specific pennation angles at rest and MVC were included in the analysis. These were included to account for gender differences and inter-subject variability in pennation angle. The coefficient of determination, R(2), ranged between 0.76 for the TA and 0.87 for the SOL. The EMG-pennation angle relationships have ramifications for use in EMG-driven models of muscle force. The regression equations can be used to characterize fiber pennation angle more accurately and to determine how it changes with contraction intensity, thus providing improved estimates of muscle force when using musculoskeletal models.     

Assessment of Fluoride in Three Selected Polluted Environments along the Egyptian Mediterranean Sea: Effects on Local Populations

Fluoride ion (F^?) is a relevant component of concern due to its potential toxicity for humankind. This study clarifies the status of F^? for human health in three polluted regions along the Egyptian Mediterranean Sea coast, and determining its contents in seawater and different fish tissues (muscle, skin, brain, and bone). Fluoride ion concentrations in different fish tissues had a descending trend of brain > skin > muscle > bone with averages of 26.8 ± 26.0, 24.8 ± 6.5, 12.7 ± 2.3, and 9.0 ± 1.6 μg F^?/g wet wt, respectively. The bioconcentration factor for fluoride ion in different fish tissues was determined and multivariate analyses were conducted. The human health hazard assessment from fish consumption and seawater contact using hazard quotient (HQ) and ingestion and dermal absorption dose of whole body for different ages of females and males as well as the specified body parts (legs, arms, and hands) were calculated. Although the calculated daily intake values for ingestion of fish in the present study were lower than some established tolerable daily intake values, their hazard quotients were within 1 ≥ HQ < 10 and may reflect a possible fluoride adverse effect on human health from the consumption of the gathered fish species.     

A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.