Cell Cycle- and Cancer-Associated Gene Networks Activated by Dsg2: Evidence of Cystatin A Deregulation and a Potential Role in Cell-Cell Adhesion

This work was supported by grants from the National Institutes of Health (Mahoney, R01AR056067; Riobo, RO1 GM088256). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

lincRNAs act in the circuitry controlling pluripotency and differentiation

Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.Broad InstituteHarvard UniversityNational Human Genome Research Institute (U.S.)Merkin Family Foundation for Stem Cell Researc

Understanding emotionally relevant situations in primary dental practice. 2. Reported effects of emotionally charged situations

Background and aims. Dentistry is widely reported to be a stressful profession. There is a limited body of research relating to the coping strategies used by dentists whilst in clinical situations. This study aims to use qualitative methods to explore the full extent of the coping strategies associated with stressful events in primary dental practice. Method. Semi-structured interviews were conducted with 20 dentists within a 50 mile radius of Lincoln. A thematic analysis was conducted on verbatim transcriptions thereby identifying six themes and 35 codes. Results. Participants described both problem-focused and emotion-focused strategies. The strategies used had a variety of outcomes in the context of use. Most dentists denied that their emotions affected their decision-making, but then proceeded to describe how they were influential. Discussion and conclusion. Dentists use a wide variety of coping strategies some of which are maladaptive. Training in the development and recognition of appropriate coping decisions would be appropriate as they woul

Heterochromatin and the molecular mechanisms of 'parent-of-origin' effects in animals.

Twenty five years ago it was proposed that conserved components of constitutive heterochromatin assemble heterochromatinlike complexes in euchromatin and this could provide a general mechanism for regulating heritable (cell-to-cell) changes in gene expressibility. As a special case, differences in the assembly of heterochromatin-like complexes on homologous chromosomes might also regulate the parent-of-origin-dependent gene expression observed in placental mammals. Here, the progress made in the intervening period with emphasis on the role of heterochromatin and heterochromatin-like complexes in parent-of-origin effects in animals is reviewed

Exploring the effects of telehealth on medical human resources supply: a qualitative case study in remote regions

BACKGROUND: The availability of medical human resource supply is a growing concern for rural and remote communities in many countries. In the last decade, various telehealth experiences in Canada have highlighted the potential impact of this technology on professional practice. The purpose of this study was to explore physicians' and managers' perceptions regarding the potential of telehealth to support recruitment and retention of physicians in remote and rural regions. METHODS: A case study in Eastern Quebec was performed to explore this complex phenomenon. The analytical framework was based on two literature reviews and a Delphi study. Data were collected from semi-structured interviews with 41 physicians and 22 managers. Transcripts were produced and interview content was coded independently by two judges and validated by an expert panel. RESULTS: Interviews have highlighted the potential impact of telehealth on several factors influencing the recruitment and retention of physicians in rural and remote regions. The potential effects of telehealth on physicians' choice of practice location could be seen at the professional, organizational, educational and individual levels. For instance, telehealth could improve work satisfaction by allowing a regional on-call duty system and a better follow-up of patients. However, there are also certain limits related to telehealth, such as the fear that it would eventually replace all continuing medical education activities and onsite specialists in remoteregions. CONCLUSION: Telehealth is likely to have an impact on several factors related to medical workforce supply in remote and rural regions. However, the expected benefits will materialize if and only if this technology is properly integrated into organizations as a support to professional practice

Analysis of a sprint ski race and associated laboratory determinants of world-class performance

This investigation was designed to analyze the time-trial (STT) in an international cross-country skiing sprint skating competition for (1) overall STT performance and relative contributions of time spent in different sections of terrain, (2) work rate and kinematics on uphill terrain, and (3) relationships to physiological and kinematic parameters while treadmill roller ski skating. Total time and times in nine different sections of terrain by 12 world-class male sprint skiers were determined, along with work rate and kinematics for one specific uphill section. In addition, peak oxygen uptake (VO2peak), gross efficiency (GE), peak speed (Vpeak), and kinematics in skating were measured. Times on the last two uphill and two final flat sections were correlated to overall STT performance (r = ~−0.80, P < 0.001). For the selected uphill section, speed was correlated to cycle length (r = −0.75, P < 0.01) and the estimated work rate was approximately 160% of peak aerobic power. VO2peak, GE, Vpeak, and peak cycle length were all correlated to STT performance (r = ~−0.85, P < 0.001). More specifically, VO2peak and GE were correlated to the last two uphill and two final flat section times, whereas Vpeak and peak cycle length were correlated to times in all uphill, flat, and curved sections except for the initial section (r = ~−0.80, P < 0.01). Performances on uphill and flat terrain in the latter part were the most significant determinants of overall STT performance. Peak oxygen uptake, efficiency, peak speed, and peak cycle length were strongly correlated to overall STT performance, as well as to performance in different sections of the race

Epigenetic Silencing of Spermatocyte-Specific and Neuronal Genes by SUMO Modification of the Transcription Factor Sp3

SUMO modification of transcription factors is linked to repression of transcription. The physiological significance of SUMO attachment to a particular transcriptional regulator, however, is largely unknown. We have employed the ubiquitously expressed murine transcription factor Sp3 to analyze the role of SUMOylation in vivo. We generated mice and mouse embryonic fibroblasts (MEFs) carrying a subtle point mutation in the SUMO attachment sequence of Sp3 (IKEE553D mutation). The E553D mutation impedes SUMOylation of Sp3 at K551 in vivo, without affecting Sp3 protein levels. Expression profiling revealed that spermatocyte-specific genes, such as Dmc1 and Dnahc8, and neuronal genes, including Paqr6, Rims3, and Robo3, are de-repressed in non-testicular and extra-neuronal mouse tissues and in mouse embryonic fibroblasts expressing the SUMOylation-deficient Sp3E553D mutant protein. Chromatin immunoprecipitation experiments show that transcriptional de-repression of these genes is accompanied by the loss of repressive heterochromatic marks such as H3K9 and H4K20 tri-methylation and impaired recruitment of repressive chromatin-modifying enzymes. Finally, analysis of the DNA methylation state of the Dmc1, Paqr6, and Rims3 promoters by bisulfite sequencing revealed that these genes are highly methylated in Sp3wt MEFs but are unmethylated in Sp3E553D MEFs linking SUMOylation of Sp3 to tissue-specific CpG methylation. Our results establish SUMO conjugation to Sp3 as a molecular beacon for the assembly of repression machineries to maintain tissue-specific transcriptional gene silencing

Burn Injury Reduces Neutrophil Directional Migration Speed in Microfluidic Devices

Thermal injury triggers a fulminant inflammatory cascade that heralds shock, end-organ failure, and ultimately sepsis and death. Emerging evidence points to a critical role for the innate immune system, and several studies had documented concurrent impairment in neutrophil chemotaxis with these post-burn inflammatory changes. While a few studies suggest that a link between neutrophil motility and patient mortality might exist, so far, cumbersome assays have prohibited exploration of the prognostic and diagnostic significance of chemotaxis after burn injury. To address this need, we developed a microfluidic device that is simple to operate and allows for precise and robust measurements of chemotaxis speed and persistence characteristics at single-cell resolution. Using this assay, we established a reference set of migration speed values for neutrophils from healthy subjects. Comparisons with samples from burn patients revealed impaired directional migration speed starting as early as 24 hours after burn injury, reaching a minimum at 72–120 hours, correlated to the size of the burn injury and potentially serving as an early indicator for concurrent infections. Further characterization of neutrophil chemotaxis using this new assay may have important diagnostic implications not only for burn patients but also for patients afflicted by other diseases that compromise neutrophil functions

Population Genetic Analysis Infers Migration Pathways of Phytophthora ramorum in US Nurseries

Recently introduced, exotic plant pathogens may exhibit low genetic diversity and be limited to clonal reproduction. However, rapidly mutating molecular markers such as microsatellites can reveal genetic variation within these populations and be used to model putative migration patterns. Phytophthora ramorum is the exotic pathogen, discovered in the late 1990s, that is responsible for sudden oak death in California forests and ramorum blight of common ornamentals. The nursery trade has moved this pathogen from source populations on the West Coast to locations across the United States, thus risking introduction to other native forests. We examined the genetic diversity of P. ramorum in United States nurseries by microsatellite genotyping 279 isolates collected from 19 states between 2004 and 2007. Of the three known P. ramorum clonal lineages, the most common and genetically diverse lineage in the sample was NA1. Two eastward migration pathways were revealed in the clustering of NA1 isolates into two groups, one containing isolates from Connecticut, Oregon, and Washington and the other isolates from California and the remaining states. This finding is consistent with trace forward analyses conducted by the US Department of Agriculture's Animal and Plant Health Inspection Service. At the same time, genetic diversities in several states equaled those observed in California, Oregon, and Washington and two-thirds of multilocus genotypes exhibited limited geographic distributions, indicating that mutation was common during or subsequent to migration. Together, these data suggest that migration, rapid mutation, and genetic drift all play a role in structuring the genetic diversity of P. ramorum in US nurseries. This work demonstrates that fast-evolving genetic markers can be used to examine the evolutionary processes acting on recently introduced pathogens and to infer their putative migration patterns, thus showing promise for the application of forensics to plant pathogens

Electrophysiological evidence for an early processing of human voices

<p>Abstract</p> <p>Background</p> <p>Previous electrophysiological studies have identified a "voice specific response" (VSR) peaking around 320 ms after stimulus onset, a latency markedly longer than the 70 ms needed to discriminate living from non-living sound sources and the 150 ms to 200 ms needed for the processing of voice paralinguistic qualities. In the present study, we investigated whether an early electrophysiological difference between voice and non-voice stimuli could be observed.</p> <p>Results</p> <p>ERPs were recorded from 32 healthy volunteers who listened to 200 ms long stimuli from three sound categories - voices, bird songs and environmental sounds - whilst performing a pure-tone detection task. ERP analyses revealed voice/non-voice amplitude differences emerging as early as 164 ms post stimulus onset and peaking around 200 ms on fronto-temporal (positivity) and occipital (negativity) electrodes.</p> <p>Conclusion</p> <p>Our electrophysiological results suggest a rapid brain discrimination of sounds of voice, termed the "fronto-temporal positivity to voices" (FTPV), at latencies comparable to the well-known face-preferential N170.</p