Cyclin D 1‐induced proliferation is independent of beta‐catenin in H ead and N eck C ancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106775/1/odi12124.pd

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Multiplexed and scalable super-resolution imaging of three-dimensional protein localization in size-adjustable tissues

The biology of multicellular organisms is coordinated across multiple size scales, from the subnanoscale of molecules to the macroscale, tissue-wide interconnectivity of cell populations. Here we introduce a method for super-resolution imaging of the multiscale organization of intact tissues. The method, called magnified analysis of the proteome (MAP), linearly expands entire organs fourfold while preserving their overall architecture and three-dimensional proteome organization. MAP is based on the observation that preventing crosslinking within and between endogenous proteins during hydrogel-tissue hybridization allows for natural expansion upon protein denaturation and dissociation. The expanded tissue preserves its protein content, its fine subcellular details, and its organ-scale intercellular connectivity. We use off-the-shelf antibodies for multiple rounds of immunolabeling and imaging of a tissue's magnified proteome, and our experiments demonstrate a success rate of 82% (100/122 antibodies tested). We show that specimen size can be reversibly modulated to image both inter-regional connections and fine synaptic architectures in the mouse brain.United States. National Institutes of Health (1-U01-NS090473-01

Adult mortality of diseases and injuries attributable to selected metabolic, lifestyle, environmental, and infectious risk factors in Taiwan: A comparative risk assessment

Background: To facilitate priority-setting in health policymaking, we compiled the best available information to estimate the adult mortality (>30 years) burden attributable to 13 metabolic, lifestyle, infectious, and environmental risk factors in Taiwan. Methods: We obtained data on risk factor exposure from nationally representative health surveys, cause-specific mortality from the National Death Registry, and relative risks from epidemiological studies and meta-analyses. We applied the comparative risk assessment framework to estimate mortality burden attributable to individual risk factors or risk factor clusters. Results: In 2009, high blood glucose accounted for 14,900 deaths (95% UI: 11,850-17,960), or 10.4% of all deaths in that year. It was followed by tobacco smoking (13,340 deaths, 95% UI: 10,330-16,450), high blood pressure (11,190 deaths, 95% UI: 8,190-14,190), ambient particulate matter pollution (8,600 deaths, 95% UI: 7,370-9,840), and dietary risks (high sodium intake and low intake of fruits and vegetables, 7,890 deaths, 95% UI: 5,970-9,810). Overweight-obesity and physical inactivity accounted for 7,620 deaths (95% UI: 6,040-9,190), and 7,400 deaths (95% UI: 6,670-8,130), respectively. The cardiometabolic risk factors of high blood pressure, high blood glucose, high cholesterol, and overweight-obesity jointly accounted for 12,120 deaths (95% UI: 11,220-13,020) from cardiovascular diseases. For domestic risk factors, infections from hepatitis B virus (HBV) and hepatitis C virus (HCV) were responsible for 6,300 deaths (95% UI: 5,610-6,980) and 3,170 deaths (95% UI: 1,860-4,490), respectively, and betel nut use was associated with 1,780 deaths from oral, laryngeal, and esophageal cancer (95% UI: 1,190-2,360). The leading risk factors for years of life lost were similar, but the impact of tobacco smoking and alcohol use became larger because the attributable deaths from these risk factors occurred among young adults aged less than 60 years. Conclusions: High blood glucose, tobacco smoking, and high blood pressure are the major risk factors for deaths from diseases and injuries among Taiwanese adults. A large number of years of life would be gained if the 13 modifiable risk factors could be removed or reduced to the optimal level

Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci

Several recent studies have examined different aspects of mammalian higher order chromatin structure - replication timing, lamina association and Hi-C inter-locus interactions - and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution

The development of spontaneous facial responses to others’ emotions in infancy. An EMG study

Viewing facial expressions often evokes facial responses in the observer. These spontaneous facial reactions (SFRs) are believed to play an important role for social interactions. However, their developmental trajectory and the underlying neurocognitive mechanisms are still little understood. In the current study, 4- and 7-month old infants were presented with facial expressions of happiness, anger, and fear. Electromyography (EMG) was used to measure activation in muscles relevant for forming these expressions: zygomaticus major (smiling), corrugator supercilii (frowning), and frontalis (forehead raising). The results indicated no selective activation of the facial muscles for the expressions in 4-month-old infants. For 7-month-old infants, evidence for selective facial reactions was found especially for happy faces (leading to increased zygomaticus major activation) and fearful faces (leading to increased frontalis activation), while angry faces did not show a clear differential response. This suggests that emotional SFRs may be the result of complex neurocognitive mechanisms which lead to partial mimicry but are also likely to be influenced by evaluative processes. Such mechanisms seem to undergo important developments at least until the second half of the first year of life

Going means trouble and staying makes it double: the value of licensing recorded music online

This paper discusses whether a copyright compensation system (CCS) for recorded music—endowing private Internet subscribers with the right to download and use works in return for a fee—would be welfare increasing. It reports on the results of a discrete choice experiment conducted with a representative sample of the Dutch population consisting of 4986 participants. Under some conservative assumptions, we find that applied only to recorded music, a mandatory CCS could increase the welfare of rights holders and users in the Netherlands by over €600 million per year (over €35 per capita). This far exceeds current rights holder revenues from the market of recorded music of ca. €144 million per year. A monthly CCS fee of ca. €1.74 as a surcharge on Dutch Internet subscriptions would raise the same amount of revenues to rights holders as the current market for recorded music. With a voluntary CCS, the estimated welfare gains to users and rights holders are even greater for CCS fees below €20 on the user side. A voluntary CCS would also perform better in the long run, as it could retain a greater extent of market coordination. The results of our choice experiment indicate that a well-designed CCS for recorded music would simultaneously make users and rights holders better off. This result holds even if we correct for frequently observed rates of overestimation in contingent valuation studies

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers