Chelating Agents and the Regulation of Metal Ions

Up to about the early 1980s it was perhaps still possible to summarize in a review of a moderate length the development of the medicinal applications of chelation chemistry and the exploitation of such chemistry in regulating the metal ion concentrations in the body. However, in the last few years there has a great surge in the development of chelation chemistry and its usage in medicine and related areas of life sciences research. It is no longer the case that such a review primarily concentrates upon the use of chelating agents in removing toxic metals from the body but it must now cover the use of chelating agents in the imaging procedures nuclear medicine and magnetic resonance imaging (MRI), the use of chelating agents in unravelling the biochemistry of reactive oxidative species (ROS) and the control and measurement of intracellular calcium ions. It is in the recent applications that there have been the greatest developments over the last ten years

Aspects of the chemistry of differentiation in some protista

Several species of Actinomyces viscosus were examined using the scanning electron microscope and considerable morphological heterogeneity was seen and one species, Actinomyces viscosus WVU 398B, was observed to undergo a form of differentiation, for which the term 'vacuolation' has been introduced. This form of differentiation can be regulated by inhibitors of peptidyl transferase or translocase. Further examples of the regulation of differentiation were provided by an examination of the interaction of antibiotics and antimetabolites with a species of Bacillus cereus isolated from laboratory dust. 3-chloropropane-1-2-diol exhibited an ability to impair cell division in Staphylococcus aureus and Escherichia coli and this action may be due to the glycerol antagonism of 3-chloropropane-1,2-diol. [Continues.

Effect of ionic strength on complexation of Pu(IV) with humic acid

International audienceSuccessful geochemical modelling of the migration of radioactive materials, such as the transuranic elements, from nuclear waste repositories is dependent upon an understanding of their interaction with biogeopolymers such as humic acids, the most likely complexing agents in groundwaters. An established silica/humic acid composite has been evaluated as a model substrate for naturally occurring humate-coated minerals that are likely to be present in the vicinity of the repositories. The binding of Pu(IV), the highly likely oxidation station, by the silica/humic substrate was examined at pH 4 in the range 0.02 to 3.00M NaClO$_4$ by the titration method. Pu(IV)-humate conditional stability constants have been evaluated from data obtained from these experiments by using non-linear regression of binding isotherms. The results have been interpreted in terms of complexes of 1:1 stoichiometry. Analysis of the complex formation dependency with ionic strength shows that the effect of ionic strength on humate complexation of Pu(IV) is not dramatically pronounced. The complexation constants are evaluated for the humate interaction with Pu$^{4+}$ and Pu(OH)$_3^+$ at pH 4. The complexation constants are found, respectively, to be log$^{HA}$$\beta ^0$(Pu$^{4+}$)=16.6$\pm$0.3 and log$\beta ^0_{1.3.1}$=46.6$\pm$2.3. The estimations through analogy from previous results are in agreement with these new experimental data

A Revolutionary Lunar Space Transportation System Architecture Using Extraterrestrial Lox-augmented NTR Propulsion

The concept of a liquid oxygen (LOX)-augmented nuclear thermal rocket (NTR) engine is introduced, and its potential for revolutionizing lunar space transportation system (LTS) performance using extraterrestrial 'lunar-derived' liquid oxygen (LUNOX) is outlined. The LOX-augmented NTR (LANTR) represents the marriage of conventional liquid hydrogen (LH2)-cooled NTR and airbreathing engine technologies. The large divergent section of the NTR nozzle functions as an 'afterburner' into which oxygen is injected and supersonically combusted with nuclear preheated hydrogen emerging from the NTR's choked sonic throat: 'scramjet propulsion in reverse.' By varying the oxygen-to-fuel mixture ratio (MR), the LANTR concept can provide variable thrust and specific impulse (Isp) capability with a LH2-cooled NTR operating at relatively constant power output. For example, at a MR = 3, the thrust per engine can be increased by a factor of 2.75 while the Isp decreases by only 30 percent. With this thrust augmentation option, smaller, 'easier to develop' NTR's become more acceptable from a mission performance standpoint (e.g., earth escape gravity losses are reduced and perigee propulsion requirements are eliminated). Hydrogen mass and volume is also reduced resulting in smaller space vehicles. An evolutionary NTR-based lunar architecture requiring only Shuttle C and/or 'in-line' shuttle-derived launch vehicles (SDV's) would operate initially in an 'expandable mode' with NTR lunar transfer vehicles (LTV's) delivering 80 percent more payload on piloted missions than their LOX/LH2 chemical propulsion counterparts. With the establishment of LUNOX production facilities on the lunar surface and 'fuel/oxidizer' depot in low lunar orbit (LLO), monopropellant NTR's would be outfitted with an oxygen propellant module, feed system, and afterburner nozzle for 'bipropellant' operation. The LANTR cislunar LTV now transitions to a reusable mode with smaller vehicle and payload doubling benefits on each piloted round trip mission. As the initial lunar outposts grow to centralized bases and settlements with a substantial permanent human presence, a LANTR-powered shuttle capable of 36 to 24 hour 'one-way' trip times to the moon and back becomes possible with initial mass in low earth orbit (IMLEO) requirements of approximately 160 to 240 metric tons, respectively

Potential protein activity modifications of amino acid variants in the human transcriptome

Background: The occurrence of widespread RNA and DNA sequence differences in the human transcriptome was reported in 2011. Similar findings were described in a second independent publication on personal omics profiling investigating the occurrence of dynamic molecular and related medical phenotypes. The suggestion that the RNA sequence variation was likely to affect disease susceptibility prompted us to investigate with a range of algorithms the amino acid variants reported to be present in the identified peptides to determine if they might be disease-causing. Results: The predictive qualities of the different algorithms were first evaluated by using nonsynonymous single-base nucleotide polymorphism (nsSNP) datasets, using independently established data on amino acid variants in several proteins as well as data obtained by mutational mapping and modelling of binding sites in the human serotonin transporter protein (hSERT). Validation of the used predictive algorithms was at a 75% level. Using the same algorithms, we found that widespread RNA and DNA sequence differences were predicted to impair the function of the peptides in over 57% of cases. Conclusions: Our findings suggest that a proportion of edited RNAs which serve as templates for protein synthesis is likely to modify protein function, possibly as an adaptive survival mechanism in response to environmental modifications

Seeking for Genetic Signature of Radiosensitivity- Methods for Data Analysis

Abstract. The aim of the study was to develop a data analysis strategy capable of discovering the genetic background of radiosensitivity. Radiosensitivity is the relative predisposition of cells, tissues, organs or organisms to the harmful effect of radiation. Effects of radiation include the mutation of DNA . Identification of polymorphisms and genes responsible for an organism's radiosensitivity increases the knowledge about the cell cycle and the mechanism of radiosensitivity, possibly providing the researchers with a better understanding of the process of carcinogenesis. To obtain this information, mathematical modelling and data mining methods were used

A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder

Background: To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing. Methods and results. We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C \u3e T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C \u3e T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling. Conclusions: This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development. © 2013 Lahiry et al.; licensee BioMed Central Ltd

A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder

Background: To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing. Methods and results. We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C \u3e T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C \u3e T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling. Conclusions: This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development. © 2013 Lahiry et al.; licensee BioMed Central Ltd

Intellectual disability associated with a homozygous missense mutation in THOC6

BACKGROUND: We recently described a novel autosomal recessive neurodevelopmental disorder with intellectual disability in four patients from two related Hutterite families. Identity-by-descent mapping localized the gene to a 5.1 Mb region at chromosome 16p13.3 containing more than 170 known or predicted genes. The objective of this study was to identify the causative gene for this rare disorder. METHODS AND RESULTS: Candidate gene sequencing followed by exome sequencing identified a homozygous missense mutation p.Gly46Arg, in THOC6. No other potentially causative coding variants were present within the critical region on chromosome 16. THOC6 is a member of the THO/TREX complex which is involved in coordinating mRNA processing with mRNA export from the nucleus. In situ hybridization showed that thoc6 is highly expressed in the midbrain and eyes. Cellular localization studies demonstrated that wild-type THOC6 is present within the nucleus as is the case for other THO complex proteins. However, mutant THOC6 was predominantly localized to the cytoplasm, suggesting that the mutant protein is unable to carry out its normal function. siRNA knockdown of THOC6 revealed increased apoptosis in cultured cells. CONCLUSION: Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment