Genetic basis of human circadian rhythm disorders.

Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health

Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.

Posttranslational modifications play central roles in myriad biological pathways including circadian regulation. We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. Modulating O-GlcNAcylation levels alter circadian period length in both mice and Drosophila; conversely, protein O-GlcNAcylation is circadianly regulated. Central clock proteins, Clock and Period, are reversibly modified by O-GlcNAcylation to regulate their transcriptional activities. In addition, O-GlcNAcylation of a region in PER2 known to regulate human sleep phase (S662-S674) competes with phosphorylation of this region, and this interplay is at least partly mediated by glucose levels. Together, these results indicate that O-GlcNAcylation serves as a metabolic sensor for clock regulation and works coordinately with phosphorylation to fine-tune circadian clock

Is clopidogrel better than aspirin following breakthrough strokes while on aspirin? A retrospective cohort study.

ObjectiveThere is insufficient evidence on which to base a recommendation for optimal antiplatelet therapy following a stroke while on aspirin. The objective was to compare clopidogrel initiation vs aspirin reinitiation for vascular risk reduction among patients with ischaemic stroke on aspirin at the time of their index stroke.DesignRetrospective.SettingWe conducted a nationwide cohort study by retrieving all hospitalised patients (≥18 years) with a primary diagnosis of ischaemic stroke between 2003 and 2009 from Taiwan National Health Insurance Research Database.ParticipantsAmong 3862 patients receiving aspirin before the index ischaemic stroke and receiving either aspirin or clopidogrel after index stroke during follow-up period, 1623 were excluded due to a medication possession ratio <80%. Also, 355 were excluded due to history of atrial fibrillation, valvular heart disease or coagulopathy. Therefore, 1884 patients were included in our final analysis.InterventionsPatients were categorised into two groups based on whether clopidogrel or aspirin was prescribed during the follow-up period. Follow-up was from time of the index stroke to admission for recurrent stroke or myocardial infarction, death or the end of 2010.Primary and secondary outcome measuresThe primary end point was hospitalisation due to a new-onset major adverse cardiovascular event (MACE: composite of any stroke or myocardial infarction). The leading secondary end point was any recurrent stroke.ResultsCompared to aspirin, clopidogrel was associated with a lower occurrence of future MACE (HR=0.54, 95% CI 0.43 to 0.68, p<0.001, number needed to treat: 8) and recurrent stroke (HR=0.54, 95% CI 0.42 to 0.69, p<0.001, number needed to treat: 9) after adjustment of relevant covariates.ConclusionsAmong patients with an ischaemic stroke while taking aspirin, clopidogrel initiation was associated with fewer recurrent vascular events than aspirin reinitiation

Leukocyte Subset Changes in Response to a 164-km Road Cycle Ride in a Hot Environment

International Journal of Exercise Science 9(1): 34-46, 2016. The purpose of this observational study was to determine the circulating leukocyte subset response to completing the 2013 Hotter’N Hell Hundred recreational 164-km road cycle event in a hot and humid environmental condition. Twenty-eight men and four women were included in this study. Whole blood samples were obtained 1-2 hours before (PRE) and immediately after (POST) the event. Electronic sizing/sorting and cytometry were used to determine complete blood counts (CBC) including neutrophil, monocyte, and lymphocyte subsets. The concentration of circulating total leukocytes (103·µL-1) increased 134% from PRE to POST with the greatest increase in neutrophils (319%, p\u3c0.0001). Circulating monocytes (including macrophages) increased 24% (p=0.004) and circulating lymphocytes including B and T cells increased 53% (p\u3c0.0001). No association was observed between rolling time or relative intensity and leukocyte subset. Completing the Hotter n’ Hell Hundred (HHH), a 100 mile recreational cycling race in extreme (hot and humid) environmental conditions, induces a substantial increase in total leukocytes in circulation. The contribution of increases in specific immune cell subsets is not equal, with neutrophils increasing to greater than 4-fold starting values from PRE to POST race. It is likely that exercise in stressful environmental conditions affects the complement of circulating immune cells, although activational state and characterization of specific leukocyte subsets remains unclear. The observed increase in circulating cell sub-populations suggests that the circulating immune surveillance system may be acutely affected by exercise in hot and humid conditions

GPER-induced signaling is essential for the survival of breast cancer stem cells.

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs

Morning versus Afternoon Body Mass in Free-Living or Controlled Euhydration

The standard protocol to assess hydration status is by measuring body mass in the early morning without controlling fluid intake. However, obtaining first-morning body mass is not necessarily feasible for many situations, for example, most physical activities take place in the afternoon. Thus, first-morning body mass might not be practical to assess hydration status. PURPOSE: To investigate first-morning body mass versus afternoon body mass in free- living and controlled euhydration. METHODS: 9 males (age: 21 ± 2; mass: 79.7 ± 17.8 kg) and 5 females (age: 22 ± 2; mass: 60.5 ± 13.6 kg) visited the laboratory in the morning (7:00-9:00am) and afternoon (2:00-4:00pm) for six days to measure their nude body mass and urine specific gravity (USG). Participants were in the free-living (FL) condition for the first three consecutive days, and then in a euhydrated (EUH) state (USGRESULTS: There were no interactions between FL and EUH with morning and afternoon in USG (Morning-FL, 1.017±0.005; Afternoon-FL, 1.012±0.006; Morning-EUH, 1.011±0.004; Afternoon-EUH, 1.007±0.004; p=0.390). No statistically significant differences were found between morning and afternoon in both FL and EUH controlled (Morning-FL, 72.7±18.3 kg; Afternoon-FL, 72.0±18.1 kg; Morning-EUH, 72.9±18.1 kg; Afternoon-EUH, 73.1±18.1 kg, p=0.661). CONCLUSION: There is no difference between morning and afternoon body mass, regardless of the hydration status. This means that first morning body mass is no more, or less, accurate than afternoon

Exact Analysis of Scaling and Dominant Attractors Beyond the Exponential Potential

By considering the potential parameter $\Gamma$ as a function of another potential parameter $\lambda$[47], We successfully extend the analysis of two-dimensional autonomous dynamical system of quintessence scalar field model to the analysis of three-dimension, which makes us be able to research the critical points of a large number of potentials beyond the exponential potential exactly. We find that there are ten critical points in all, three points $P_{3, 5, 6}$} are general points which are possessed by all quintessence models regardless of the form of potentials and the rest points are closely connected to the concrete potentials. It is quite surprising that, apart from the exponential potential, there are a large number of potentials which can give the scaling solution when the function $f(\lambda)(=\Gamma(\lambda)-1)$ equals zero for one or some values of $\lambda_{*}$ and if the parameter $\lambda_{*}$ also satisfies the condition Eq.(16) or Eq.(17) at the same time. We give the differential equations to derive these potentials $V(\phi)$ from $f(\lambda)$. We also find that, if some conditions are satisfied, the de-Sitter-like dominant point $P_4$ and the scaling solution point $P_9$(or $P_{10}$) can be stable simultaneously but $P_9$ and $P_{10}$ can not be stable simultaneity. Although we survey scaling solutions beyond the exponential potential for ordinary quintessence models in standard general relativity, this method can be applied to other extensively scaling solution models studied in literature[46] including coupled quintessence, (coupled-)phantom scalar field, k-essence and even beyond the general relativity case $H^2 \propto\rho_T^n$. we also discuss the disadvantage of our approach.Comment: 16 pages,no figure, this new revision has taken the suggestions from CQG referees and has been accepted for publication in Classical and Quantum Gravit