Hidden breakpoints in genome alignments

During the course of evolution, an organism's genome can undergo changes that affect the large-scale structure of the genome. These changes include gene gain, loss, duplication, chromosome fusion, fission, and rearrangement. When gene gain and loss occurs in addition to other types of rearrangement, breakpoints of rearrangement can exist that are only detectable by comparison of three or more genomes. An arbitrarily large number of these "hidden" breakpoints can exist among genomes that exhibit no rearrangements in pairwise comparisons. We present an extension of the multichromosomal breakpoint median problem to genomes that have undergone gene gain and loss. We then demonstrate that the median distance among three genomes can be used to calculate a lower bound on the number of hidden breakpoints present. We provide an implementation of this calculation including the median distance, along with some practical improvements on the time complexity of the underlying algorithm. We apply our approach to measure the abundance of hidden breakpoints in simulated data sets under a wide range of evolutionary scenarios. We demonstrate that in simulations the hidden breakpoint counts depend strongly on relative rates of inversion and gene gain/loss. Finally we apply current multiple genome aligners to the simulated genomes, and show that all aligners introduce a high degree of error in hidden breakpoint counts, and that this error grows with evolutionary distance in the simulation. Our results suggest that hidden breakpoint error may be pervasive in genome alignments.Comment: 13 pages, 4 figure

Higher bone resorption excretion in South Asian women vs. White Caucasians and increased bone loss with higher seasonal cycling of vitamin D: Results from the D-FINES cohort study

Few data exist on bone turnover in South Asian women and it is not well elucidated as to whether Western dwelling South Asian women have different bone resorption levels to that of women from European ethnic backgrounds. This study assessed bone resorption levels in UK dwelling South Asian and Caucasian women as well as evaluating whether seasonal variation in 25-hydroxyvitamin D [25(OH)D] is associated with bone resorption in either ethnic group. Data for seasonal measures of urinary N-telopeptide of collagen (uNTX) and serum 25(OH)D were analysed from n = 373 women (four groups; South Asian postmenopausal n = 44, South Asian premenopausal n = 50, Caucasian postmenopausal n = 144, Caucasian premenopausal n = 135) (mean (± SD) age 48 (14) years; age range 18–79 years) who participated in the longitudinal D-FINES (Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England) cohort study (2006–2007). A mixed between-within subjects ANOVA (n = 192) showed a between subjects effect of the four groups (P < 0.001) on uNTX concentration, but no significant main effect of season (P = 0.163). Bonferroni adjusted Post hoc tests (P ≤ 0.008) suggested that there was no significant difference between the postmenopausal Asian and premenopausal Asian groups. Season specific age-matched-pairs analyses showed that in winter (P = 0.04) and spring (P = 0.007), premenopausal Asian women had a 16 to 20 nmol BCE/mmol Cr higher uNTX than premenopausal Caucasian women. The (amplitude/mesor) ratio (i.e. seasonal change) for 25(OH)D was predictive of uNTX, with estimate (SD) = 0.213 (0.015) and 95% CI (0.182, 0.245; P < 0.001) in a non-linear mixed model (n = 154). This showed that individuals with a higher seasonal change in 25(OH)D, adjusted for overall 25(OH)D concentration, showed increased levels of uNTX. Although the effect size was smaller than for the amplitude/mesor ratio, the mesor for 25(OH)D concentration was also predictive of uNTX, with estimate (SD) = − 0.035 (0.004), and 95% CI (− 0.043, − 0.028; P < 0.001). This study demonstrates higher levels of uNTX in premenopausal South Asian women than would be expected for their age, being greater than same-age Caucasian women, and similar to postmenopausal Asian women. This highlights potentially higher than expected bone resorption levels in premenopausal South Asian women which, if not offset by concurrent increased bone formation, may have future clinical and public health implications which warrant further investigation. Individuals with a larger seasonal change in 25(OH)D concentration showed an increased bone resorption, an association which was larger than that of the 25(OH)D yearly average, suggesting it may be as important clinically to ensure a stable and steady 25(OH)D concentration, as well as one that is high enough to be optimal for bone health

New incision rates along the Colorado River system based on cosmogenic burial dating of terraces: Implications for regional controls on Quaternary incision

New cosmogenic burial and published dates of Colorado and Green river terraces are used to infer variable incision rates along the rivers in the past 10 Ma. A knickpoint at Lees Ferry separates the lower and upper Colorado River basins. We obtained an isochron cosmogenic burial date of 1.5 ± 0.13 Ma on a 190-m-high strath terrace near Bullfrog Basin, Utah (upstream of Lees Ferry). This age yields an average incision rate of 126+12/-10m/Ma above the knickpoint and is three times older than a cosmogenic surface age on the same terrace, suggesting that surface dates inferred by exposure dating may be minimum ages. Incision rates below Lees Ferry are faster, ~170m/Ma-230m/Ma, suggesting upstream knickpoint migration over the past several million years. A terrace at Hite (above Lees Ferry) yields an isochron burial age of 0.29 ± 0.17 Ma, and a rate of ~300-900m/Ma, corroborating incision acceleration in Glen Canyon. Within the upper basin, isochron cosmogenic burial dates of 1.48 ± 0.12 Ma on a 60 m terrace near the Green River in Desolation Canyon, Utah, and 1.2 ± 0.3 Ma on a 120 m terrace upstream of Flaming Gorge, Wyoming, give incision rates of 41± 3m/Ma and 100+33/-20m/Ma, respectively. In contrast, incision rates along the upper Colorado River are 150m/Ma over 0.64 and 10 Ma time frames. Higher incision rates, gradient, and discharge along the upper Colorado River relative to the Green River are consistent with differential rock uplift of the Colorado Rockies relative to the Colorado Plateau

Search for varying constants of nature from astronomical observation of molecules

The status of searches for possible variation in the constants of nature from astronomical observation of molecules is reviewed, focusing on the dimensionless constant representing the proton-electron mass ratio $\mu=m_p/m_e$. The optical detection of H$_2$ and CO molecules with large ground-based telescopes (as the ESO-VLT and the Keck telescopes), as well as the detection of H$_2$ with the Cosmic Origins Spectrograph aboard the Hubble Space Telescope is discussed in the context of varying constants, and in connection to different theoretical scenarios. Radio astronomy provides an alternative search strategy bearing the advantage that molecules as NH$_3$ (ammonia) and CH$_3$OH (methanol) can be used, which are much more sensitive to a varying $\mu$ than diatomic molecules. Current constraints are $|\Delta\mu/\mu| < 5 \times 10^{-6}$ for redshift $z=2.0-4.2$, corresponding to look-back times of 10-12.5 Gyrs, and $|\Delta\mu/\mu| < 1.5 \times 10^{-7}$ for $z=0.88$, corresponding to half the age of the Universe (both at 3$\sigma$ statistical significance). Existing bottlenecks and prospects for future improvement with novel instrumentation are discussed.Comment: Contribution to Workshop "High Performance Clocks in Space" at the International Space Science Institute, Bern 201

Measurement of the Mass Splittings between the bbˉχb,J(1P)b\bar{b}\chi_{b,J}(1P) States

We present new measurements of photon energies and branching fractions for the radiative transitions: Upsilon(2S)->gamma+chi_b(J=0,1,2). The masses of the chi_b states are determined from the measured radiative photon energies. The ratio of mass splittings between the chi_b substates, r==(M[J=2]-M[J=1])/(M[J=1]-M[J=0]) with M the chi_b mass, provides information on the nature of the bbbar confining potential. We find r(1P)=0.54+/-0.02+/-0.02. This value is in conflict with the previous world average, but more consistent with the theoretical expectation that r(1P)<r(2P); i.e., that this mass splittings ratio is smaller for the chi_b(1P) triplet than for the chi_b(2P) triplet.Comment: 11 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Role of the microbiome in regulating bone metabolism and susceptibility to osteoporosis

The human microbiota functions at the interface between diet, medication-use, lifestyle, host immune development and health. It is therefore closely aligned with many of the recognised modifiable factors that influence bone mass accrual in the young, and bone maintenance and skeletal decline in older populations. While understanding of the relationship between micro-organisms and bone health is still in its infancy, two decades of broader microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and pathogenesis of osteoporosis as well as its prevention and treatment. Pre-clinical research has demonstrated biological interactions between the microbiome and bone metabolism. Furthermore, observational studies and randomized clinical trials have indicated that therapeutic manipulation of the microbiota by oral administration of probiotics may influence bone turnover and prevent bone loss in humans. In this paper, we summarize the content, discussion and conclusions of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in October, 2020. We provide a detailed review of the literature examining the relationship between the microbiota and bone health in animal models and in humans, as well as formulating the agenda for key research priorities required to advance this field. We also underscore the potential pitfalls in this research field that should be avoided and provide methodological recommendations to facilitate bridging the gap from promising concept to a potential cause and intervention target for osteoporosis

Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo

Breast cancer stem cells (BCSCs) are pan-resistant to different anticancer agents and responsible for cancer relapse. Disulfiram (DS), an antialcoholism drug, targets CSCs and reverses pan-chemoresistance. The anticancer application of DS is limited by its very short half-life in the bloodstream. This prompted us to develop a liposomeencapsulated DS (Lipo-DS) and examine its anticancer effect and mechanisms in vitro and in vivo. The relationship between hypoxia and CSCs was examined by in vitro comparison of BC cells cultured in spheroid and hypoxic conditions. To determine the importance of NFκB activation in bridging hypoxia and CSC-related pan-resistance, the CSC characters and drug sensitivity in BC cell lines were observed in NFκB p65 transfected cell lines. The effect of Lipo-DS on the NFκB pathway, CSCs and chemosensitivity was investigated in vitro and in vivo. The spheroid cultured BC cells manifested CSC characteristics and pan-resistance to anticancer drugs. This was related to the hypoxic condition in the spheres. Hypoxia induced activation of NFκB and chemoresistance. Transfection of BC cells with NFκB p65 also induced CSC characters and pan-resistance. Lipo-DS blocked NFκB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted the CSC population in vivo and showed very strong anticancer efficacy. Mice tolerated the treatment very well and no significant in vivo nonspecific toxicity was observed. Hypoxia induced NFκB activation is responsible for stemness and chemoresistance in BCSCs. Lipo-DS targets NFκB pathway and CSCs. Further study may translate DS into cancer therapeutics