The condition-dependent transcriptional landscape of Burkholderia pseudomallei

This is the final version of the article. Available from the publisher via the DOI in this record.Burkholderia pseudomallei (Bp), the causative agent of the often-deadly infectious disease melioidosis, contains one of the largest prokaryotic genomes sequenced to date, at 7.2 Mb with two large circular chromosomes (1 and 2). To comprehensively delineate the Bp transcriptome, we integrated whole-genome tiling array expression data of Bp exposed to >80 diverse physical, chemical, and biological conditions. Our results provide direct experimental support for the strand-specific expression of 5,467 Sanger protein-coding genes, 1,041 operons, and 766 non-coding RNAs. A large proportion of these transcripts displayed condition-dependent expression, consistent with them playing functional roles. The two Bp chromosomes exhibited dramatically different transcriptional landscapes--Chr 1 genes were highly and constitutively expressed, while Chr 2 genes exhibited mosaic expression where distinct subsets were expressed in a strongly condition-dependent manner. We identified dozens of cis-regulatory motifs associated with specific condition-dependent expression programs, and used the condition compendium to elucidate key biological processes associated with two complex pathogen phenotypes--quorum sensing and in vivo infection. Our results demonstrate the utility of a Bp condition-compendium as a community resource for biological discovery. Moreover, the observation that significant portions of the Bp virulence machinery can be activated by specific in vitro cues provides insights into Bp's capacity as an "accidental pathogen", where genetic pathways used by the bacterium to survive in environmental niches may have also facilitated its ability to colonize human hosts.This work was funded by a core grant provided by the Agency for Science, Technology and Research to the Genome Institute of Singapore, and funding from the Defence Medical and Environmental Research Institute, Singapore. This work was supported in part through NIAID contract HHSN266200400035C to BWS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The prognostic value of nestin expression in newly diagnosed glioblastoma: Report from the Radiation Therapy Oncology Group

<p>Abstract</p> <p>Background</p> <p>Nestin is an intermediate filament protein that has been implicated in early stages of neuronal lineage commitment. Based on the heterogeneous expression of nestin in GBM and its potential to serve as a marker for a dedifferentiated, and perhaps more aggressive phenotype, the Radiation Therapy Oncology Group (RTOG) sought to determine the prognostic value of nestin expression in newly diagnosed GBM patients treated on prior prospective RTOG clinical trials.</p> <p>Methods</p> <p>Tissue microarrays were prepared from 156 patients enrolled in these trials. These specimens were stained using a mouse monoclonal antibody specific for nestin and expression was measured by computerized quantitative image analysis using the Ariol SL-50 system. The parameters measured included both staining intensity and the relative area of expression within a specimen. This resulted into 3 categories: low, intermediate, and high nestin expression, which was then correlated with clinical outcome.</p> <p>Results</p> <p>A total of 153 of the 156 samples were evaluable for this study. There were no statistically significant differences between pretreatment patient characteristics and nestin expression. There was no statistically significant difference in either overall survival or progression-free survival (PFS) demonstrated, although a trend in decreased PFS was observed with high nestin expression (p = 0.06).</p> <p>Conclusion</p> <p>Although the correlation of nestin expression and histologic grade in glioma is of considerable interest, the presented data does not support its prognostic value in newly diagnosed GBM. Further studies evaluating nestin expression may be more informative when studied in lower grade glioma, in the context of markers more specific to tumor stem cells, and using more recent specimens from patients treated with temozolomide in conjunction with radiation.</p

Study on Resistance Switching Properties of Na0.5Bi0.5TiO3Thin Films Using Impedance Spectroscopy

The Na0.5Bi0.5TiO3(NBT) thin films sandwiched between Au electrodes and fluorine-doped tin oxide (FTO) conducting glass were deposited using a sol–gel method. Based on electrochemical workstation measurements, reproducible resistance switching characteristics and negative differential resistances were obtained at room temperature. A local impedance spectroscopy measurement of Au/NBT was performed to reveal the interface-related electrical characteristics. The DC-bias-dependent impedance spectra suggested the occurrence of charge and mass transfer at the interface of the Au/NBT/FTO device. It was proposed that the first and the second ionization of oxygen vacancies are responsible for the conduction in the low- and high-resistance states, respectively. The experimental results showed high potential for nonvolatile memory applications in NBT thin films

Determining level of care appropriateness in the patient journey from acute care to rehabilitation

Background: The selection of patients for rehabilitation, and the timing of transfer from acute care, are important clinical decisions that impact on care quality and patient flow. This paper reports utilization review data on inpatients in acute care with stroke, hip fracture or elective joint replacement, and other inpatients referred for rehabilitation. It examines reasons why acute level of care criteria are not met and explores differences in decision making between acute care and rehabilitation teams around patient appropriateness and readiness for transfer. Methods: Cohort study of patients in a large acute referral hospital in Australia followed with the InterQual utilization review tool, modified to also include reasons why utilization criteria are not met. Additional data on team decision making about appropriateness for rehabilitation, and readiness for transfer, were collected on a subset of patients. Results: There were 696 episodes of care (7189 bed days). Days meeting acute level of care criteria were 56% (stroke, hip fracture and joint replacement patients) and 33% (other patients, from the time of referral). Most inappropriate days in acute care were due to delays in processes/scheduling (45%) or being more appropriate for rehabilitation or lower level of care (30%). On the subset of patients, the acute care team and the utilization review tool deemed patients ready for rehabilitation transfer earlier than the rehabilitation team (means of 1.4, 1.3 and 4.0 days from the date of referral, respectively). From when deemed medically stable for transfer by the acute care team, 28% of patients became unstable. From when deemed stable by the rehabilitation team or utilization review, 9% and 11%, respectively, became unstable. Conclusions: A high proportion of patient days did not meet acute level of care criteria, due predominantly to inefficiencies in care processes, or to patients being more appropriate for an alternative level of care, including rehabilitation. The rehabilitation team was the most accurate in determining ongoing medical stability, but at the cost of a longer acute stay. To avoid inpatients remaining in acute care in a state of \u27terra nullius\u27, clinical models which provide rehabilitation within acute care, and more efficient movement to a rehabilitation setting, is required. Utilization review could have a decision support role in the determination of medical stability

In patient stroke rehabilitation efficiency: Influence of organization of service delivery and staff numbers

<p>Abstract</p> <p>Background</p> <p>Outcomes of inpatient stroke rehabilitation need to be reviewed in terms of optimal resource utilization (staff time, service organization, and duration of stay). We compared FIM efficiency scores between three hospitals, and also variation in FIM scores over a ten year period in one hospital undergoing reduction in staff numbers, to examine the relationship between outcome and service characteristics.</p> <p>Method</p> <p>This is a retrospective study comparing the mean FIM efficiency for stroke patients (FIM score – FIM admission score) divided by duration of stay for 2005 among three rehabilitation hospitals adjusting for age and baseline FIM score, and a longitudinal study of changes in mean FIM efficiency during a ten year period in one hospital, to examine the effects of different service organization and staff numbers.</p> <p>Results</p> <p>FIM efficiency (FIMEG) was inversely associated with age, and positively associated with admission FIM score. FIMEG was higher in the hospital with a coordinated care plan involving medical, nursing, occupational, physiotherapy staff and other healthcare providers working as a team, with a seamless interface with community rehabilitation services. Over a ten year period, reduction in staff numbers was associated with reduction in FIMEG, which may be offset to some extent by service re-engineering.</p> <p>Conclusion</p> <p>Within hospital organization of stroke rehabilitation services may influence outcome. A critical number of staff may be identified for the provision of services, below which rehabilitation efficiency may be affected.</p

Forced, not voluntary, exercise effectively induces neuroprotection in stroke

Previous treadmill exercise studies showing neuroprotective effects have raised questions as to whether exercise or the stress related to it may be key etiologic factors. In this study, we examined different exercise regimens (forced and voluntary exercise) and compared them with the effect of stress-only on stroke protection. Adult male Sprague-Dawley rats (n = 65) were randomly assigned to treatment groups for 3 weeks. These groups included control, treadmill exercise, voluntary running wheel exercise, restraint, and electric shock. Levels of the stress hormone, corticosterone, were measured in the different groups using ELISA. Animals from each group were then subjected to stroke induced by a 2-h middle cerebral artery (MCA) occlusion followed by 48-h reperfusion. Infarct volume was determined in each group, while changes in gene expression of stress-induced heat shock proteins (Hsp) 27 and 70 were compared using real-time PCR between voluntary and treadmill exercise groups. The level of corticosterone was significantly higher in both stress (P < 0.05) and treadmill exercise (P < 0.05) groups, but not in the voluntary exercise group. Infarct volume was significantly reduced (P < 0.01) following stroke in rats exercised on a treadmill. However, the amelioration of damage was not duplicated in voluntary exercise, even though running distance in the voluntary exercise group was significantly (P < 0.01) longer than that of the forced exercise group (4,828 vs. 900 m). Furthermore, rats in the electric shock group displayed a significantly increased (P < 0.01) infarct volume. Expression of both Hsp 27 and Hsp 70 mRNA was significantly increased (P < 0.01) in the treadmill exercise group as compared with that in the voluntary exercise group. These results suggest that exercise with a stressful component, rather than either voluntary exercise or stress alone, is better able to reduce infarct volume. This exercise-induced neuroprotection may be attributable to up-regulation of stress-induced heat shock proteins 27 and 70

Spatiotemporal cluster patterns of hand, foot, and mouth disease at the county level in Mainland China, 2008-2012

Background: Hand, foot, and mouth disease (HFMD) is known to be a highly contagious childhood illness. In recent years, the number of reported cases of HFMD has significantly increased in mainland China. This study aims at the epidemiological features, spatiotemporal patterns of HMFD at the county/district level in mainland China. Methods: Data on reported HFMD cases for each county from 1 January 2008 to 31 December 2012 were obtained from the Chinese Center for Disease Control and Prevention. Cluster analysis, spatial autocorrelation, and retrospective scan methods were used to explore the spatiotemporal patterns of the disease. Results: The annual incidences varied greatly among the counties, ranging from 0 to 74.31‰with the median of 5.42‰ (interquartile range: 1.54‰–13.55‰) during 2008–2012 in mainland China. Counties close to provincial capital cities generally had higher incidences than rural counties. A seasonal distribution was observed between the northern and southern China, of which dual epidemic were shown in southern China and usually only one in northern China. Based on the global and local spatial autocorrelation analysis, we found that the spatial distribution of HFMD was presented a significant clustering pattern for each year (P \u3c 0.001), and hotspots of the disease were mostly distributed in coastal provinces of China. The retrospective scan statistic further identified the dynamics of spatiotemporal clustering areas of the disease, which were mainly distributed in the counties of eastern and southern China, as well as provincial capitals and their surrounding counties. Conclusions: The spatiotemporal clustering areas of the disease identified in this way were relatively stable, and imminent public health planning and resource allocation should be focused within those areas

A genome-wide DNA methylation study in colorectal carcinoma

<p>Abstract</p> <p>Background</p> <p>We performed a genome-wide scan of 27,578 CpG loci covering 14,475 genes to identify differentially methylated loci (DML) in colorectal carcinoma (CRC).</p> <p>Methods</p> <p>We used Illumina's Infinium methylation assay in paired DNA samples extracted from 24 fresh frozen CRC tissues and their corresponding normal colon tissues from 24 consecutive diagnosed patients at a tertiary medical center.</p> <p>Results</p> <p>We found a total of 627 DML in CRC covering 513 genes, of which 535 are novel DML covering 465 genes. We also validated the Illumina Infinium methylation data for top-ranking genes by non-bisulfite conversion q-PCR-based methyl profiler assay in a subset of the same samples. We also carried out integration of genome-wide copy number and expression microarray along with methylation profiling to see the functional effect of methylation. Gene Set Enrichment Analysis (GSEA) showed that among the major "gene sets" that are hypermethylated in CRC are the sets: "inhibition of adenylate cyclase activity by G-protein signaling", "Rac guanyl-nucleotide exchange factor activity", "regulation of retinoic acid receptor signaling pathway" and "estrogen receptor activity". Two-level nested cross validation showed that DML-based predictive models may offer reasonable sensitivity (around 89%), specificity (around 95%), positive predictive value (around 95%) and negative predictive value (around 89%), suggesting that these markers may have potential clinical application.</p> <p>Conclusion</p> <p>Our genome-wide methylation study in CRC clearly supports most of the previous findings; additionally we found a large number of novel DML in CRC tissue. If confirmed in future studies, these findings may lead to identification of genomic markers for potential clinical application.</p