Melatonin attenuates the effects of sub-acute administration of lead on kidneys in rats without altering the lead-induced reduction in nitric oxide

Exposure to lead induces oxidative stress and renal damage. Although most forms of oxidative stress are characterized by simultaneous elevation of nitrogen and oxidative species, lead-induced oxidative stress is unusual in that it is associated with a reduction in nitric oxide (NO) levels in the kidney. The role of NO in kidney injury is controversial; some studies suggest that it is associated with renal injury, whereas others show that it exerts protective effects. Concentration-dependent effects have also been proposed, linking low levels with vasodilatation and high levels with toxicity. The aim of this study was to evaluate the effects of melatonin co-exposure on the lead-induced reduction in renal NO levels. We found that sub-acute intraperitoneal administration of 10 mg/kg/day of lead for 15 days induced toxic levels of lead in the blood and caused renal toxicity (pathological and functional). Under our experimental conditions, lead induced an increase in lipid peroxidation and a decrease in NO. Melatonin co-treatment decreased lead-induced oxidative stress (peroxidation level) and toxic effects on kidneys without altering the lead-induced reduction in renal NO. These results suggest that, in our experimental model, the reduction in renal NO levels by lead exposure is not the only responsible factor for lead-induced kidney damage.     

Catalytic and regulatory roles of species involved in metal–nucleotide equilibriums in human pyridoxal kinase

Pyridoxal 5′-phosphate is the active form of vitamin B₆ and its deficiency is directly related with several human disorders, which make human pyridoxal kinase (hPLK) an important pharmacologic target. In spite of this, a carefully kinetic characterization of hPLK including the main species that regulates the enzymatic activity is at date missing. Here we analyse the catalytic and regulatory mechanisms of hPLK as a function of a precise determination of the species involved in metal–nucleotide equilibriums and describe new regulatory mechanisms for this enzyme. hPLK activity is supported by several metals, being Zn²⁺ the most effective, although the magnitude of the effect observed is highly dependent on the relative concentrations of metal and nucleotide used. The true substrate for the reaction catalyzed by hPLK is the metal nucleotide complex, while ATP^4? and HATP^3? did not affect the activity. The enzyme presents substrate inhibition by both pyridoxal (PL) and ZnATP^2?, although the latter behaves as a weakly inhibitor. Our study also established, for the first time, a dual role for free Zn²⁺; as an activator at low concentrations (19 μM optimal concentration) and as a potent inhibitor with a IC₅₀ of 37 μM. These results highlighted the importance of an accurate estimation of the actual concentration of the species involved in metal–nucleotide equilibriums in order to obtain reliable values for the kinetic parameters, and for determine the true regulators of the PLK activity. They also help to explain the dissimilar kinetic parameters reported in the literature for this enzyme.     

Use of a Novel Probiotic Formulation to Alleviate Lactose Intolerance Symptoms—a Pilot Study

Probiotics and Antimicrobial Proteins - Lactose intolerance is a common condition caused by lactase deficiency and may result in symptoms of lactose malabsorption (bloating, flatulence, abdominal...     

Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase

Journal of Molecular Modeling - There is a wide variety of ion channel types with various types of blockers, making research in this field very complicated. To reduce this complexity, it is...     

The macroecology of infectious diseases: a new perspective on global‐scale drivers of pathogen distributions and impacts

Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence.     

A mutation in the Cdon gene potentiates congenital nevus development mediated by NRASQ61K

Congenital nevi develop before birth and sometimes cover large areas of the body. They are presumed to arise from the acquisition of a gene mutation in an embryonic melanocyte that becomes trapped in the dermis during development. Mice bearing the Cdk4^R24C::Tyr‐NRAS^Q61K transgenes develop congenital nevus‐like lesions by post‐natal day 10, from melanocytes escaping the confines of hair follicles. We interbred these mice with the collaborative cross (CC), a resource that enables identification of modifier genes for complex diseases (those where multiple genes are involved). We examined variation in nevus cell density in 66 CC strains and mapped a large‐effect quantitative trait locus (QTL) controlling nevus cell density to murine chromosome 9. The best candidate for a gene that exacerbates congenital nevus development in the context of an NRAS mutation is Cdon, a positive regulator of sonic hedgehog (Shh) that is expressed mainly in keratinocytes.     

Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4

Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3′-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.     

Variations in Abundance,Genome Size,Morphology, and Functional Role of the Virioplankton in Lakes Annecy and Bourget over a 1-Year Period

We sampled the surface waters (2–50 m) of two deep peri-alpine lakes over a 1-year period in order to examine (1) the abundance, vertical distribution, genome size, and morphology structures of the virioplankton; (2) the virus-mediated bacterial mortality; and (3) the specific genome size range of double-stranded DNA (dsDNA) phytoplankton viruses. Virus-like particle (VLP) concentrations varied between 4.16?×?10⁷ (January) and 2.08?×?10⁸ part mL^?1 (May) in Lake Bourget and between 2.7?×?10⁷ (June) and 8.39?×?10⁷ part mL^?1 (November) in Lake Annecy. Our flow cytometry analysis revealed at least three viral groups (referred to as virus-like particles 1, 2, and 3) that exhibited distinctive dynamics suggestive of different host types. Phage-induced bacterial mortality varied between 6.1 % (June) and 33.2 % (October) in Lake Bourget and between 7.4 % (June) and 52.6 % (November) in Lake Annecy, suggesting that viral lysis may be a key cause of mortality of the bacterioplankton. Virioplankton genome size ranged from 27 to 486 kb in Lake Bourget, while it reached 620 kb in Lake Annecy for which larger genome sizes were recorded. Our analysis of pulsed field gel electrophoresis bands using different PCR primers targeting both cyanophages and algal viruses showed that (1) dsDNA viruses infecting phytoplankton may range from 65 to 486 kb, and (2) both cyanophage and algal “diversity” were higher in Lake Annecy. Lakes Annecy and Bourget also differed regarding the proportions of both viral families (with the dominance of myoviruses vs. podoviruses) and infected bacterial morphotypes (short rods vs. elongated rods), in each of these lakes, respectively. Overall, our results reveal that (1) viruses displayed distinct temporal and vertical distribution, dynamics, community structure in terms of genome size and morphology, and viral activity in the two lakes; (2) the Myoviridae seemed to be the main cause of bacterial mortality in both lakes and this group seemed to be related to VLP2; and (3) phytoplankton viruses may have a broader range of genome size than previously thought. This study adds to growing evidence that viruses are diverse and play a significant role in freshwater microbial dynamics and more globally lake functioning. It highlights the importance of further considering this biological compartment for a better understanding of plankton ecology in peri-alpine lakes.