Conformational Preferences of cis-1,3-Cyclopentanedicarboxylic Acid and Its Salts by ^1H NMR Spectroscopy: Energetics of Intramolecular Hydrogen Bonds in DMSO

The conformational populations of cis-1,3- cyclopentanedicarboxylic acid (1) and its mono- and dianion were established in DMSO solution by comparing the vicinal proton−proton coupling constants (^3JHH) obtained in solution to their theoretical counterparts. Geometries used for ^3JHH theoretical estimation (using Karplus-type equations) were obtained from optimized structures at the B3LYP/6-31G-(2d,2p) level. The diacid (1) adopted many conformations, whereas the ionized species (1A mono- and 1B dianion) assumed single conformations. A downfield chemical shift of 19.45 ppm (Δδ_H = 7.43 ppm) observed at −60 °C was indicative of intramolecular hydrogen bonding in 1A, which was later corroborated by determining the ratio of the first (K_1) to the second (K_2) ionization constants. K_1/K_2 in DMSO (1.3 × 10^7) was significantly larger than the value in water (2 × 10). In addition, K_1/K_E = 200 (where K_E is the acidity constant of the monomethylester of 1) was greater than the intramolecular hydrogen bonding threshold value of 2. The calculated intramolecular hydrogen bond strength of 1A was ∼3.1 kcal mol^(−1), which is ∼2.7 kcal mol^(−1) more stable than the values for cis- 1,3-cyclohexanedicarboxylic acid (2A). Thus, the relative energies of intramolecular hydrogen bonding in the monoanions 1A and 2A suggests that 1,3-diaxial conformers are more favored for cyclopentane than for cyclohexane rings

Links between energy budgets, somatic condition, and life history reveal heterogeneous energy management tactics in a group-living mesocarnivore

Peer reviewe

MitoNeoD:a mitochondria-targeted superoxide probe

Mitochondrial superoxide (O2⋅−) underlies much oxidative damage and redox signaling. Fluorescent probes can detect O2⋅−, but are of limited applicability in vivo, while in cells their usefulness is constrained by side reactions and DNA intercalation. To overcome these limitations, we developed a dual-purpose mitochondrial O2⋅− probe, MitoNeoD, which can assess O2⋅− changes in vivo by mass spectrometry and in vitro by fluorescence. MitoNeoD comprises a O2⋅−-sensitive reduced phenanthridinium moiety modified to prevent DNA intercalation, as well as a carbon-deuterium bond to enhance its selectivity for O2⋅− over non-specific oxidation, and a triphenylphosphonium lipophilic cation moiety leading to the rapid accumulation within mitochondria. We demonstrated that MitoNeoD was a versatile and robust probe to assess changes in mitochondrial O2⋅− from isolated mitochondria to animal models, thus offering a way to examine the many roles of mitochondrial O2⋅−production in health and disease

Identification of pathogen genomic variants through an integrated pipeline

Background: Whole-genome sequencing represents a powerful experimental tool for pathogen research. We present methods for the analysis of small eukaryotic genomes, including a streamlined system (called Platypus) for finding single nucleotide and copy number variants as well as recombination events. Results: We have validated our pipeline using four sets of Plasmodium falciparum drug resistant data containing 26 clones from 3D7 and Dd2 background strains, identifying an average of 11 single nucleotide variants per clone. We also identify 8 copy number variants with contributions to resistance, and report for the first time that all analyzed amplification events are in tandem. Conclusions: The Platypus pipeline provides malaria researchers with a powerful tool to analyze short read sequencing data. It provides an accurate way to detect SNVs using known software packages, and a novel methodology for detection of CNVs, though it does not currently support detection of small indels. We have validated that the pipeline detects known SNVs in a variety of samples while filtering out spurious data. We bundle the methods into a freely available package

Mitotic Evolution of Plasmodium falciparum Shows a Stable Core Genome but Recombination in Antigen Families

Malaria parasites elude eradication attempts both within the human host and across nations. At the individual level, parasites evade the host immune responses through antigenic variation. At the global level, parasites escape drug pressure through single nucleotide variants and gene copy amplification events conferring drug resistance. Despite their importance to global health, the rates at which these genomic alterations emerge have not been determined. We studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure. A combination of whole-genome microarray analysis and next-generation deep resequencing (totaling 14 terabases) revealed a stable core genome with only 38 novel single nucleotide variants appearing in seventeen evolved clones (avg. 5.4 per clone). In clones exposed to atovaquone, we found cytochrome b mutations as well as an amplification event encompassing the P. falciparum multidrug resistance associated protein (mrp1) on chromosome 1. We observed 18 large-scale (greater than 1 kb on average) deletions of telomere-proximal regions encoding multigene families, involved in immune evasion (9.5×10−6 structural variants per base pair per generation). Six of these deletions were associated with chromosomal crossovers generated during mitosis. We found only minor differences in rates between genetically distinct strains and between parasites cultured in the presence or absence of drug. Using these derived mutation rates for P. falciparum (1.0–9.7×10−9 mutations per base pair per generation), we can now model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions. Further, the detection of mitotic recombination events in var gene families illustrates how multigene families can arise and change over time in P. falciparum. These results will help improve our understanding of how P. falciparum evolves to evade control efforts within both the individual hosts and large populations

The Globular Cluster Systems of the Sculptor Group

We use CTIO 4-m Mosaic II images taken with the Washington $CM$ and Harris $R$ filters to identify candidate globular clusters in the six major galaxies of the Sculptor group: NGC 45, NGC 55, NGC 247, NGC 254, NGC 300, and NGC 7793. From follow-up spectroscopy with Hydra-CTIO, we find 19 new globular clusters in NGC 55, NGC 247, NGC 253, and NGC 300, bringing the total number of known Sculptor group globular clusters to 36. The newly discovered clusters have spectroscopic ages consistent with those of old Milky Way globular clusters, and the majority are metal-poor. Their luminosity function closely resembles that of the Milky Way's globular clusters; their metallicity distribution is somewhat more metal-rich, but this may be the result of our color selection of candidates. The mean [$\alpha$/Fe] ratio in the clusters is $-0.2\pm0.3$, which is lower than the Milky Way average. The specific frequencies $S_N$ are similar to those of other late-type galaxies. However, if we calculate the specific frequency using the $K$-band total magnitudes of the host galaxies, we find values that are more than a factor of two higher. The kinematics of the globular cluster systems are consistent with rotation with the \ion{H}{1} disk in each of the four galaxies; however, only in NGC 253 is this result based on more than seven objects. We suggest that the Sculptor group galaxies add to evidence indicating that many of the first generation globular clusters formed in disks, not halos.Comment: 22 pages, 13 figures, 7 Tables. Full Table 3 available electronically at http://www.ctio.noao.edu/~olsen/tab3.tex. To appear in May 2004 issue of the Astronomical Journa

Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

<div><p>Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.</p></div