The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

Peer reviewedPublisher PD

Histoplasmosis infection in patients with rheumatoid arthritis, 1998-2009

<p>Abstract</p> <p>Background</p> <p>Patients with rheumatic diseases including rheumatoid arthritis (RA) are at increased risk for infections related to both the disease and its treatments. These include uncommonly reported infections due to histoplasmosis.</p> <p>Methods</p> <p>Medical record review of all patients with a diagnosis of RA who developed new histoplasmosis infection in an endemic region between Jan 1, 1998 and Jan 30, 2009 and who were seen at Mayo Clinic in Rochester, Minnesota was performed.</p> <p>Results</p> <p>Histoplasmosis was diagnosed in 26 patients. Most patients were on combination therapies; 15 were on anti-tumor necrosis factor (anti-TNF) agents, 15 on corticosteroids and 16 on methotrexate. Most received more than 6 months of itraconazole and/or amphotericin treatment. Two patients died of causes unrelated to histoplasmosis. Anti-TNF treatment was restarted in 4/15 patients, with recurrence of histoplasmosis in one.</p> <p>Conclusions</p> <p>In this largest single center series of patients with RA and histoplasmosis in the era of immunomodulatory therapy, we found that most patients had longstanding disease and were on multiple immunomodulatory agents. Most cases were pulmonary; typical signs and symptoms of disease were frequently lacking.</p

Molecular Dynamics Analysis Reveals Structural Insights into Mechanism of Nicotine N-Demethylation Catalyzed by Tobacco Cytochrome P450 Mono-Oxygenase

CYP82E4, a cytochrome P450 monooxygenase, has nicotine N-demethylase (NND) activity, which mediates the bioconversion of nicotine into nornicotine in senescing tobacco leaves. Nornicotine is a precursor of the carcinogen, tobacco-specific nitrosamine. CYP82E3 is an ortholog of CYP82E4 with 95% sequence identity, but it lacks NND activity. A recent site-directed mutagenesis study revealed that a single amino acid substitution, i.e., cysteine to tryptophan at the 330 position in the middle of protein, restores the NND activity of CYP82E3 entirely. However, the same amino acid change caused the loss of the NND activity of CYP82E4. To determine the mechanism of the functional turnover of the two molecules, four 3D structures, i.e., the two molecules and their corresponding cys–trp mutants were modeled. The resulting structures exhibited that the mutation site is far from the active site, which suggests that no direct interaction occurs between the two sites. Simulation studies in different biological scenarios revealed that the mutation introduces a conformation drift with the largest change at the F-G loop. The dynamics trajectories analysis using principal component analysis and covariance analysis suggests that the single amino acid change causes the opening and closing of the transfer channels of the substrates, products, and water by altering the motion of the F-G and B-C loops. The motion of helix I is also correlated with the motion of both the F-G loop and the B-C loop and; the single amino acid mutation resulted in the curvature of helix I. These results suggest that the single amino acid mutation outside the active site region may have indirectly mediated the flexibility of the F-G and B-C loops through helix I, causing a functional turnover of the P450 monooxygenase

A New Horned Crocodile from the Plio-Pleistocene Hominid Sites at Olduvai Gorge, Tanzania

BACKGROUND: The fossil record reveals surprising crocodile diversity in the Neogene of Africa, but relationships with their living relatives and the biogeographic origins of the modern African crocodylian fauna are poorly understood. A Plio-Pleistocene crocodile from Olduvai Gorge, Tanzania, represents a new extinct species and shows that high crocodylian diversity in Africa persisted after the Miocene. It had prominent triangular "horns" over the ears and a relatively deep snout, these resemble those of the recently extinct Malagasy crocodile Voay robustus, but the new species lacks features found among osteolaemines and shares derived similarities with living species of Crocodylus. METHODOLOGY/PRINCIPAL FINDINGS: The holotype consists of a partial skull and skeleton and was collected on the surface between two tuffs dated to approximately 1.84 million years (Ma), in the same interval near the type localities for the hominids Homo habilis and Australopithecus boisei. It was compared with previously-collected material from Olduvai Gorge referable to the same species. Phylogenetic analysis places the new form within or adjacent to crown Crocodylus. CONCLUSIONS/SIGNIFICANCE: The new crocodile species was the largest predator encountered by our ancestors at Olduvai Gorge, as indicated by hominid specimens preserving crocodile bite marks from these sites. The new species also reinforces the emerging view of high crocodylian diversity throughout the Neogene, and it represents one of the few extinct species referable to crown genus Crocodylus

Adherence to highly active antiretroviral therapy and its correlates among HIV infected pediatric patients in Ethiopia

BACKGROUND: The introduction of combination antiretroviral therapy (ART) has resulted in striking reductions in HIV-related mortality. Despite increased availability of ART, children remain a neglected population. This may be due to concerns that failure to adhere appears to be related to continued viral replication, treatment failure and the emergence of drug-resistant strains of HIV. This study determines the rates and factors associated with adherence to Antiretroviral (ARV) Drug therapy in HIV-infected children who were receiving Highly Active Antiretroviral Therapy (HAART) in Addis Ababa, Ethiopia in 2008. METHODS: A cross-sectional study was conducted in five hospitals in Addis Ababa from February 18 - April 28, 2008. The study population entailed parents/caretaker and index children who were following ART in the health facilities. A structured questionnaire was used for data collection. RESULTS: A total of 390 children respondents were included in the study with a response rate of 91%. The majority, equaling 205 (52.6%) of the children, were greater than 9 years of age. Fifty five percent of the children were girls. A total of 339 children (86.9%) as reported by caregivers were adherent to antiretroviral drugs for the past 7 days before the interview. Numerous variables were found to be significantly associated with adherence: children whose parents did not pay a fee for treatment [OR = 0.39 (95%CI: 0.16, 0.92)], children who had ever received any nutritional support from the clinic [OR = 0.34 (95%CI: 0.14, 0.79)] were less likely to adhere. Whereas children who took co-trimoxazole medication/syrup besides ARVs [OR = 3.65 (95%CI: 1.24, 10.74)], children who did not know their sero-status [OR = 2.53 (95%CI: 1.24, 5.19)] and children who were not aware of their caregiver's health problem [OR = 2.45 (95%CI: 1.25, 4.81)] were more likely to adhere than their counterparts. CONCLUSION: Adherence to HAART in children in Addis Ababa was higher than other similar set-ups. However, there are still significant numbers of children who are non-adherent to HAART

Chromosomal disorders:estimating baseline birth prevalence and pregnancy outcomes worldwide

Chromosomal disorders, of which Down syndrome is the most common, can cause multi-domain disability. In addition, compared to the general population, there is a higher frequency of death before the age of five. In many settings, large gaps in data availability have hampered policy-making, programme priorities and resource allocation for these important conditions. We have developed methods, which overcome this lack of data and allow estimation of the burden of affected pregnancies and their outcomes in different settings worldwide. For example, the methods include a simple equation relating the percentage of mothers 35 and over to Down syndrome birth prevalence. The results obtained provide a starting point for consideration of services that can be implemented for the care and prevention of these disorders

The Trypanosoma cruzi Sylvio X10 strain maxicircle sequence: the third musketeer

<p>Abstract</p> <p>Background</p> <p>Chagas disease has a diverse pathology caused by the parasite <it>Trypanosoma cruzi</it>, and is indigenous to Central and South America. A pronounced feature of the trypanosomes is the kinetoplast, which is comprised of catenated maxicircles and minicircles that provide the transcripts involved in uridine insertion/deletion RNA editing. <it>T. cruzi </it>exchange genetic material through a hybridization event. Extant strains are grouped into six discrete typing units by nuclear markers, and three clades, A, B, and C, based on maxicircle gene analysis. Clades A and B are the more closely related. Representative clade B and C maxicircles are known in their entirety, and portions of A, B, and C clades from multiple strains show intra-strain heterogeneity with the potential for maxicircle taxonomic markers that may correlate with clinical presentation.</p> <p>Results</p> <p>To perform a genome-wide analysis of the three maxicircle clades, the coding region of clade A representative strain Sylvio X10 (a.k.a. Silvio X10) was sequenced by PCR amplification of specific fragments followed by assembly and comparison with the known CL Brener and Esmeraldo maxicircle sequences. The clade A rRNA and protein coding region maintained synteny with clades B and C. Amino acid analysis of non-edited and 5'-edited genes for Sylvio X10 showed the anticipated gene sequences, with notable frameshifts in the non-edited regions of Cyb and ND4. Comparisons of genes that undergo extensive uridine insertion and deletion display a high number of insertion/deletion mutations that are likely permissible due to the post-transcriptional activity of RNA editing.</p> <p>Conclusion</p> <p>Phylogenetic analysis of the entire maxicircle coding region supports the closer evolutionary relationship of clade B to A, consistent with uniparental mitochondrial inheritance from a discrete typing unit TcI parental strain and studies on smaller fragments of the mitochondrial genome. Gene variance that can be corrected by RNA editing hints at an unusual depth for maxicircle taxonomic markers, which will aid in the ability to distinguish strains, their corresponding symptoms, and further our understanding of the <it>T. cruzi </it>population structure. The prevalence of apparently compromised coding regions outside of normally edited regions hints at undescribed but active mechanisms of genetic exchange.</p

Variation in WNT7A is unlikely to be a cause of familial Congenital Talipes Equinovarus

<p>Abstract</p> <p>Background</p> <p>Genetic factors make an important contribution to the aetiology of congenital talipes equinovarus (CTEV), the most common developmental disorder of the lower limb. WNT7A was suggested as a candidate gene for CTEV on the basis of a genome-wide scan for linkage in a large multi-case family. WNT7A is a plausible candidate gene for CTEV as it provides a signal for pattern formation during limb development, and mutation in WNT7A has been reported in a number of limb malformation syndromes.</p> <p>Methods</p> <p>We investigated the role of WNT7A using a family-based linkage approach in our large series of European multi-case CTEV families. Three microsatellite markers were used, of which one (D3S2385) is intragenic, and the other two (D3S2403, D3S1252) are 700 kb 5' to the start and 20 kb from the 3' end of the gene, respectively. Ninety-one CTEV families, comprising 476 individuals of whom 211 were affected, were genotyped. LOD scores using recessive and incomplete-dominant inheritance models, and non-parametric linkage scores, excluded linkage.</p> <p>Results</p> <p>No significant evidence for linkage was observed using either parametric or non-parametric models. LOD scores for the parametric models remained strongly negative in the regions between the markers, and in the 0.5 cM intervals outside the marker map. No significant lod scores were obtained when the data were analysed allowing for heterogeneity.</p> <p>Conclusion</p> <p>Our evidence suggests that the WNT7A gene is unlikely to be a major contributor to the aetiology of familial CTEV.</p