Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear

We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock-down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKB beta, a dramatic increase in Akt1/PKB alpha protein and relocation of Akt1/PKB alpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing-Deafness-Renal anomaly syndrome

The Potential for pathogenicity was present in the ancestor of the Ascomycete subphylum Pezizomycotina

<p>Abstract</p> <p>Background</p> <p>Previous studies in Ascomycetes have shown that the function of gene families of which the size is considerably larger in extant pathogens than in non-pathogens could be related to pathogenicity traits. However, by only comparing gene inventories in extant species, no insights can be gained into the evolutionary process that gave rise to these larger family sizes in pathogens. Moreover, most studies which consider gene families in extant species only tend to explain observed differences in gene family sizes by gains rather than by losses, hereby largely underestimating the impact of gene loss during genome evolution.</p> <p>Results</p> <p>In our study we used a selection of recently published genomes of Ascomycetes to analyze how gene family gains, duplications and losses have affected the origin of pathogenic traits. By analyzing the evolutionary history of gene families we found that most gene families with an enlarged size in pathogens were present in an ancestor common to both pathogens and non-pathogens. The majority of these families were selectively maintained in pathogenic lineages, but disappeared in non-pathogens. Non-pathogen-specific losses largely outnumbered pathogen-specific losses.</p> <p>Conclusions</p> <p>We conclude that most of the proteins for pathogenicity were already present in the ancestor of the Ascomycete lineages we used in our study. Species that did not develop pathogenicity seemed to have reduced their genetic complexity compared to their ancestors. We further show that expansion of gained or already existing families in a species-specific way is important to fine-tune the specificities of the pathogenic host-fungus interaction.</p

Incidence and mortality of hip fracture among the elderly population in South Korea: a population-based study using the National Health Insurance claims data

<p>Abstract</p> <p>Background</p> <p>The lack of epidemiologic information on osteoporotic hip fractures hampers the development of preventive or curative measures against osteoporosis in South Korea. We conducted a population-based study to estimate the annual incidence of hip fractures. Also, we examined factors associated with post-fracture mortality among Korean elderly to evaluate the impact of osteoporosis on our society and to identify high-risk populations.</p> <p>Methods</p> <p>The Korean National Health Insurance (NHI) claims database was used to identify the incidence of hip fractures, defined as patients having a claim record with a diagnosis of hip fracture and a hip fracture-related operation during 2003. The 6-month period prior to 2003 was set as a 'window period,' such that patients were defined as incident cases only if their first record of fracture was observed after the window period. Cox's proportional hazards model was used to investigate the relationship between survival time and baseline patient and provider characteristics available from the NHI data.</p> <p>Results</p> <p>The age-standardized annual incidence rate of hip fractures requiring operation over 50 years of age was 146.38 per 100,000 women and 61.72 per 100,000 men, yielding a female to male ratio of 2.37. The 1-year mortality was 16.55%, which is 2.85 times higher than the mortality rate for the general population (5.8%) in this age group. The risk of post-fracture mortality at one year is significantly higher for males and for persons having lower socioeconomic status, living in places other than the capital city, not taking anti-osteoporosis pharmacologic therapy following fracture, or receiving fracture-associated operations from more advanced hospitals such as general or tertiary hospitals.</p> <p>Conclusion</p> <p>This national epidemiological study will help raise awareness of osteoporotic hip fractures among the elderly population and hopefully motivate public health policy makers to develop effective national prevention strategies against osteoporosis to prevent hip fractures.</p

The efficacy and safety study of dietary supplement PURIAM110 on non-insulin taking Korean adults in the stage of pre-diabetes and diabetes mellitus: protocol for a randomized, double-blind, placebo-controlled, and multicenter trial-pilot study

<p>Abstract</p> <p>Background</p> <p>Diabetes has already become a threat to the nation and the individual due to its high prevalence rates and high medical expenses. Therefore, preventing diabetes at an earlier stage is very important. Despite advances in antidiabetic agents, we have not yet achieved any satisfying results in treating diabetes. Among various treatments, medicinal herbs and supplements for diabetes are reported to show generally good efficacy and safety data. In particular, PURIAM110, a compound from orange fruits and mulberry leaves, is supposed to prevent the progress of type II diabetes mellitus and improve diabetic symptoms. This is the first reported pilot study about the protective effect of the orange fruits and mulberry leaves mixture against pre-diabetes on Korean adults. Based on these positive results of herb-derived components, extended studies of dietary supplements have to be done to suggest confirmative evidences.</p> <p>Methods/Design</p> <p>The efficacy and safety study of PURIAM110 is a double-blinded, placebo-controlled, randomized, and multi-center clinical trial. A total of 45 subjects will participate in this study for 6 weeks.</p> <p>Discussion</p> <p>The present protocol will confirm the efficacy and safety of PURIAM110 for pre-diabetes, suggesting more basic knowledge to conduct further randomized controlled trials (RCT). In addition, PURIAM110 can be an alternative dietary supplemental remedy for diabetes patients.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN44779824">ISRCTN44779824</a></p

Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

Transitions at CpG dinucleotides, referred to as “CpG substitutions”, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates

Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death

The ATP-dependent ClpQY protease system in Plasmodium falciparum is a prokaryotic machinery in the parasite. In the present study, we have identified the complete ClpQY system in P. falciparum and elucidated its functional importance in survival and growth of asexual stage parasites. We characterized the interaction of P. falciparum ClpQ protease (PfClpQ) and PfClpY ATPase components, and showed that a short stretch of residues at the C terminus of PfClpY has an important role in this interaction; a synthetic peptide corresponding to this region antagonizes this interaction and interferes with the functioning of this machinery in the parasite. Disruption of ClpQY function by this peptide caused hindrance in the parasite growth and maturation of asexual stages of parasites. Detailed analyses of cellular effects in these parasites showed features of apoptosis-like cell death. The peptide-treated parasites showed mitochondrial dysfunction and loss of mitochondrial membrane potential. Dysfunctioning of mitochondria initiated a cascade of reactions in parasites, including activation of VAD–FMK-binding proteases and nucleases, which resulted in apoptosis-like cell death. These results show functional importance of mitochondrial proteases in the parasite and involvement of mitochondria in programmed cell death in the malaria parasites

Metastatic lymph node in gastric cancer; Is it a real distant metastasis?

<p>Abstract</p> <p>Background</p> <p>Currently, the TNM staging system is a widely accepted method for assessing the prognosis of the disease and planning therapeutic strategies for cancer. Of the TNM system, the extent of lymph node involvement is the most important independent prognostic factor for gastric cancer. The aim of our study is to evaluate the survival and prognosis of gastric cancer patients with LN#12 or #13 involvement only and to assess the impact of anatomic regions of primary gastric tumor on survival in this particular subset of patients.</p> <p>Methods</p> <p>Among data of 1,008 stage IV gastric cancer patients who received curative R0 gastrectomy, a total of 79 patients with LN#12 (n = 68) and/or #13 (n = 11) were identified. All patients performed gastrectomy with D2 or D3 lymph node dissection.</p> <p>Results</p> <p>In 79 patients with LN#12/13 involvement, the estimated one-, three- and five-year survival rate was 77.2%, 41.8% and 26.6% respectively. When we compared the patients with LN#12/13 involvement to those without involvement, there was no significant difference in OS (21.0 months vs. 25.0 months, respectively; P = 0.140). However, OS was significantly longer in patients with LN#12/13 involvement only than in those with M1 lymph node involvement (14.3 months; P = 0.001). There was a significant difference in survival according to anatomic locations of the primary tumor (lower to mid-body vs. high body or whole stomach): 26.5 vs. 9.2 months (P = 0.009). In Cox proportional hazard analysis, only N stage (p = 0.002) had significance to predict poor survival.</p> <p>Conclusion</p> <p>In this study we found that curatively resected gastric cancer patients with pathologic involvement of LN #12 and/or LN #13 had favorable survival outcome, especially those with primary tumor location of mid-body to antrum. Prospective analysis of survival in gastric cancer patients with L N#12 or #13 metastasis is warranted especially with regards to primary tumor location.</p

The Association between Intrauterine Inflammation and Spontaneous Vaginal Delivery at Term: A Cross-Sectional Study

BACKGROUND:Different factors contribute to the onset of labor at term. In animal models onset of labor is characterized by an inflammatory response. The role of intrauterine inflammation, although implicated in preterm birth, is not yet established in human term labor. We hypothesized that intrauterine inflammation at term is associated with spontaneous onset of labor. METHODS/RESULTS:In two large urban hospitals in the Netherlands, a cross-sectional study of spontaneous onset term vaginal deliveries and elective caesarean sections (CS), without signs of labor, was carried out. Placentas and amniotic fluid samples were collected during labor and/or at delivery. Histological signs of placenta inflammation were determined. Amniotic fluid proinflammatory cytokine concentrations were measured using ELISA. A total of 375 women were included. In term vaginal deliveries, more signs of intrauterine inflammation were found than in elective CS: the prevalence of chorioamnionitis was higher (18 vs 4%, p = 0.02) and amniotic fluid concentration of IL-6 was higher (3.1 vs 0.37 ng/mL, p<0.001). Similar results were obtained for IL-8 (10.93 vs 0.96 ng/mL, p<0.001) and percentage of detectable TNF-alpha (50 vs 4%, p<0.001). CONCLUSIONS:This large cross-sectional study shows that spontaneous term delivery is characterized by histopathological signs of placenta inflammation and increased amniotic fluid proinflammatory cytokines