Comprehensive Sex Steroid Profiling in Multiple Tissues Reveals Novel Insights in Sex Steroid Distribution in Male Mice

A comprehensive atlas of sex steroid distribution in multiple tissues is currently lacking, and how circulating and tissue sex steroid levels correlate remains unknown. Here, we adapted and validated a gas chromatography tandem mass spectrometry method for simultaneous measurement of testosterone (T), dihydrotestosterone (DHT), androstenedione, progesterone (Prog), estradiol, and estrone in mouse tissues. We then mapped the sex steroid pattern in 10 different endocrine, reproductive, and major body compartment tissues and serum of gonadal intact and orchiectomized (ORX) male mice. In gonadal intact males, high levels of DHT were observed in reproductive tissues, but also in white adipose tissue (WAT). A major part of the total body reservoir of androgens (T and DHT) and Prog was found in WAT. Serum levels of androgens and Prog were strongly correlated with corresponding levels in the brain while only modestly correlated with corresponding levels in WAT. After orchiectomy, the levels of the active androgens T and DHT decreased markedly while Prog levels in male reproductive tissues increased slightly. In ORX mice, Prog was by far the most abundant sex steroid, and, again, WAT constituted the major reservoir of Prog in the body. In conclusion, we present a comprehensive atlas of tissue and serum concentrations of sex hormones in male mice, revealing novel insights in sex steroid distribution. Brain sex steroid levels are well reflected by serum levels and WAT constitutes a large reservoir of sex steroids in male mice. In addition, Prog is the most abundant sex hormone in ORX mice

Further evidence for a variable fine-structure constant from Keck/HIRES QSO absorption spectra

[Abridged] We previously presented evidence for a varying fine-structure constant, alpha, in two independent samples of Keck/HIRES QSO spectra. Here we present a detailed many-multiplet analysis of a third Keck/HIRES sample containing 78 absorption systems. We also re-analyse the previous samples, providing a total of 128 absorption systems over the redshift range 0.2<z_abs<3.7. All three samples separately yield consistent, significant values of da/a. The analyses of low- and high-z systems rely on different ions/transitions with very different dependencies on alpha, yet they also give consistent results. We identify additional random errors in 22 high-z systems characterized by transitions with a large dynamic range in apparent optical depth. Increasing the statistical errors on da/a for these systems gives our fiducial result, a weighted mean da/a=(-0.543+/-0.116)x10^-5, representing 4.7-sigma evidence for a smaller weighted mean alpha in the absorption clouds. Assuming that da/a=0 at z_abs=0, the data marginally prefer a linear increase in alpha with time: dota/a=(6.40+/-1.35)x10^-16 yr^-1. The two-point correlation function for alpha is consistent with zero over 0.2-13 Gpc comoving scales and the angular distribution of da/a shows no significant dipolar anisotropy. We therefore have no evidence for spatial variations in da/a. We extend our previous searches for possible systematic errors, identifying atmospheric dispersion and isotopic structure effects as potentially the most significant. However, overall, known systematic errors do not explain the results. Future many-multiplet analyses of QSO spectra from different telescopes and spectrographs will provide a now crucial check on our Keck/HIRES results.Comment: 31 pages, 25 figures (29 EPS files), 8 tables. Accepted by MNRAS. Colour versions of Figs. 6, 8 & 10 and text version of Table 3 available at http://www.ast.cam.ac.uk/~mim/pub.htm

Network Compression as a Quality Measure for Protein Interaction Networks

With the advent of large-scale protein interaction studies, there is much debate about data quality. Can different noise levels in the measurements be assessed by analyzing network structure? Because proteomic regulation is inherently co-operative, modular and redundant, it is inherently compressible when represented as a network. Here we propose that network compression can be used to compare false positive and false negative noise levels in protein interaction networks. We validate this hypothesis by first confirming the detrimental effect of false positives and false negatives. Second, we show that gold standard networks are more compressible. Third, we show that compressibility correlates with co-expression, co-localization, and shared function. Fourth, we also observe correlation with better protein tagging methods, physiological expression in contrast to over-expression of tagged proteins, and smart pooling approaches for yeast two-hybrid screens. Overall, this new measure is a proxy for both sensitivity and specificity and gives complementary information to standard measures such as average degree and clustering coefficients

A cryotransmission electron microscopy study of skin barrier formation

Direct visualization of the skin barrier formation process by cryotransmission electron microscopy of vitreous epidermal sections has been performed. The results obtained differ in many aspects from those of classical chemical fixation electron microscopy. Here we show that (i) a new "organelle or branched tubular structure" containing nonlamellar or partly lamellar material, and closely corresponding in numbers, dimensions, and localization to lamellar bodies of classical chemical fixation electron micrographs, and (ii) a new "ribosome complex-like structure", not preserved in classical electron micrographs, are omnipresent at apparent active sites of skin barrier formation. Evidence that skin barrier formation may not take place via extensive membrane fusion involving discrete lamellar bodies, but rather by a morphologically continuous membrane folding process are: (i) the often clearly nonlamellar content of structures corresponding to lamellar bodies with concomitant visualization of multilamellar membrane structures of the intercellular space; (ii) the "multifolded" appearance of the lipid matrix of the intercellular space; and (iii) the identification of extended "intracellular" multilamellar continuous structures with an optical density profile closely corresponding to that of the lipid matrix of the intercellular space. Based on the cryo-electron microscopic data presented in this study we propose that a membrane transition from cubic-like to multilamellar may take place already inside the "tubuloreticular cisternal membrane system" of upper granular cells recently reported by Elias et al

Recent Tree Mortality Dampens Semi‐Arid Forest Die‐Off During Subsequent Drought

Abstract Climate change is expected to increase drought intensity and frequency, which are commonly predicted will threaten the survival of forests. Most forest die‐off projections assume that recent tree mortality will not alter die‐off severity during subsequent droughts. We tested this assumption by comparing die‐off in semi‐arid conifer forest stands in California that were exposed to a single drought in 2012–2015 (“2nd Drought Only”) with forest stands that experienced drought in both 1999–2002 and 2012–2015 (“Both Droughts”). We quantified die‐off severity as a reduction in the satellite observed Normalized Difference Moisture Index, and cumulative moisture deficit as negative 4‐year Precipitation minus Evapotranspiration (4‐year Pr‐ET overdraft). Here we show that recent tree morality reduces die‐off severity in semi‐arid conifer forests exposed to subsequent drought. Stands in the 2nd Drought Only sample experienced severe die‐off associated with extreme 4‐year Pr‐ET overdraft in 2012–2015. Stands in the Both Droughts sample experienced severe die‐off and 4‐year Pr‐ET overdraft in 1999–2002, but comparatively little 2012–2015 die‐off despite continued 4‐year Pr‐ET overdraft. We interpret this as a dampening effect, where prior tree mortality reduces forest die‐off severity during subsequent drought exposure. As forests continue to experience disturbances linked to climate change, dampening effects will impose a transient, and perhaps long‐term, constraint on the impact of repeated drought

Cryo-electron microscopy of vitreous sections of native biological cells and tissues

Cryo-electron microscopy of vitreous sections (CEMOVIS) is, in principle, the ultimate method of specimen preparation. It consists in ultra-rapid cooling of a sizable sample of biological material that is cut into thin sections. These are subsequently observed at low temperature in their fully hydrated vitreous state. Here, we show that CEMOVIS reveals the native state of cells and tissues with unprecedented quality and resolution. What is seen differs considerably from what conventional electron microscopy has shown previously and it is seen with more details. Our findings are demonstrated with images of cyanobacteria and skin

A screening instrument for side dominance in competitive adolescent alpine skiers

Previous research has shown that high school ski students injure their left anterior cruciate ligament (ACL) more often than their right ACL, and that a prevention program focusing on equal load to the right and left ski turns prevents ACL injuries. Whether the injuries were in the dominant or non-dominant side of ski students was not determined but may be important knowledge to ski coaches for future design of ski-specific training programs. There is no gold standard on how to investigate the dominant side of alpine skiers. Therefore, the aim of this study was to develop a screening instrument consisting of five questions for identifying side dominance and to evaluate side dominance in competitive adolescent alpine skiers. First, 121 competitive adolescent alpine skiers answered the questions on side dominance using a test-retest design. The questions were: which hand/arm (left/right) or foot/leg (left/right) one uses as the first choice when writing, throwing, kicking a ball, jumping over a fence and stair-climbing. A question about safer/better ski turn to the left or to the right was also added. Second, 274 skiers answered the questions at one occasion. A very good agreement was shown in writing and throwing and kicking a ball, and a fair agreement was shown in jumping over a fence and stair climbing. A total of 243 skiers reported right-sided dominance, and seven skiers reported left-sided dominance. One hundred and nineteen of the 121 skiers who took part in the test-retest design answered the question safer/better ski turn, and of those 70 (59%) reported that they had a safer/better ski turn to one side than to the other side. However, the side was not consistent between the two test occasions, and the question did not correlate with side dominance. A combination of the three questions "What hand/arm do you use as first choice when writing?" "What hand/arm do you use as first choice when throwing?" and "What foot/leg do you use as first choice when kicking a ball?", may be used to decide side dominance in adolescent alpine skiers. Most adolescent alpine skiers reported right-sided dominance