Xeno Amino Acids: A look into biochemistry as we don't know it

Would another origin of life resemble Earth's biochemical use of amino acids? Here we review current knowledge at three levels: 1) Could other classes of chemical structure serve as building blocks for biopolymer structure and catalysis? Amino acids now seem both readily available to, and a plausible chemical attractor for, life as we don't know it. Amino acids thus remain important and tractable targets for astrobiological research. 2) If amino acids are used, would we expect the same L-alpha-structural subclass used by life? Despite numerous ideas, it is not clear why life favors L-enantiomers. It seems clearer, however, why life on Earth uses the shortest possible (alpha-) amino acid backbone, and why each carries only one side chain. However, assertions that other backbones are physicochemically impossible have relaxed into arguments that they are disadvantageous. 3) Would we expect a similar set of side chains to those within the genetic code? Not only do many plausible alternatives exist and evidence exists for both evolutionary advantage and physicochemical constraint for those encoded by life. Overall, as focus shifts from amino acids as a chemical class to specific side chains used by post-LUCA biology, the probable role of physicochemical constraint diminishes relative to that of biological evolution. Exciting opportunities now present themselves for laboratory work and computing to explore how changing the amino acid alphabet alters the universe of protein folds. Near-term milestones include: a) expanding evidence about amino acids as attractors within chemical evolution; b) extending characterization of other backbones relative to biological proteins; c) merging computing and laboratory explorations of structures and functions unlocked by xeno peptides.Comment: Submitted to Life (ISSN 2075-1729), 26 pages (without references), 8 figures, 1 table, 1 bo

Progesterone significantly enhances the mobility of boar spermatozoa

Progesterone released from the cumulus cells of the oocyte causes a number of physiological responses in human sperm cells including hyperactivation, acrosome reaction and chemotaxis. We employed a validated sperm mobility assay, which involves measuring the ability of sperm to penetrate an inert cell separation solution over time, to assess the ability of progesterone to enhance the mobility of boar spermatozoa. Cells maximally penetrate the solution over 50 minutes. 100nM progesterone significantly (P = 0.01) increased the mobility of non-capacitated sperm cells causing a doubling in the rate at which the cells penetrated through the cell separation solution (control half maximal penetration rate [Km] = 18.0±2.2; +100nM progesterone Km = 8.8±0.8min). Similarly, capacitated cells penetrated at a rate (Km = 19.2±3.0 min) not significantly different from non-capacitated cells and 100nM progesterone also significantly increased the rate of penetration of capacitated cells (Km = 9.5±1.0 min, P<0.05). The T-type voltage gated calcium channel blocker mibefradil (30mM) significantly inhibited both the control and progesterone enhanced mobility in non-capacitated and capacitated sperm. Only capacitated cells showed a significant increase in the acrosome reaction in response to 100nM progesterone (control non-reacted = 75±4%, +100nM progesterone non-reacted = 47±10%). Western blot analysis confirmed that there was an increase in the total protein tyrosine phosphorylation levels in capacitated cells. In conclusion, we have demonstrated that 100nM progesterone accelerates the mobility of boar sperm cells through an inert cell separation solution in an extracellular calcium dependent manner

An ALMA Constraint on the GSC 6214-210 B Circum-Substellar Accretion Disk Mass

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of GSC 6214-210 A and B, a solar-mass member of the 5-10 Myr Upper Scorpius association with a 15 $\pm$ 2 Mjup companion orbiting at $\approx$330 AU (2.2"). Previous photometry and spectroscopy spanning 0.3-5 $\mu$m revealed optical and thermal excess as well as strong H$\alpha$ and Pa~$\beta$ emission originating from a circum-substellar accretion disk around GSC 6214-210 B, making it the lowest mass companion with unambiguous evidence of a subdisk. Despite ALMA's unprecedented sensitivity and angular resolution, neither component was detected in our 880 $\mu$m (341 GHz) continuum observations down to a 3-$\sigma$ limit of 0.22 mJy/beam. The corresponding constraints on the dust mass and total mass are <0.15 Mearth and <0.05 Mjup, respectively, or <0.003% and <0.3% of the mass of GSC 6214-210 B itself assuming a 100:1 gas-to-dust ratio and characteristic dust temperature of 10-20 K. If the host star possesses a putative circum-stellar disk then at most it is a meager 0.0015% of the primary mass, implying that giant planet formation has certainly ceased in this system. Considering these limits and its current accretion rate, GSC 6214-210 B appears to be at the end stages of assembly and is not expected to gain any appreciable mass over the next few Myr.Comment: Accepted to ApJ

Proposal for a low cost close air support aircraft for the year 2000: The Raptor

The Raptor is a proposed low cost Close Air Support (CAS) aircraft for the U.S. Military. The Raptor incorporates a 'cranked arrow' wing planform, and uses canards instead of a traditional horizontal tail. The Raptor is designed to be capable of responsive delivery of effective ordnance in close proximity to friendly ground forces during the day, night, and 'under the weather' conditions. Details are presented of the Raptor's mission, configuration, performance, stability and control, ground support, manufacturing, and overall cost to permit engineering evaluation of the proposed design. A description of the design process and analysis methods used is also provided

Single-cell analysis of [Ca²⁺]i signalling in sub-fertile men:characteristics and relation to fertilization outcome

STUDY QUESTIONWhat are the characteristics of progesterone-induced (CatSper-mediated) single cell [Ca2+]i signals in spermatozoa from sub-fertile men and how do they relate to fertilizing ability?SUMMARY ANSWERSingle cell analysis of progesterone-induced (CatSper-mediated) [Ca2+]i showed that reduced progesterone-sensitivity is a common feature of sperm from sub-fertile patients and is correlated with fertilization rate.WHAT IS KNOWN ALREADYStimulation with progesterone is a widely used method for assessing [Ca2+]i mobilization by activation of CatSper in human spermatozoa. Although data are limited, sperm population studies have indicated an association of poor [Ca2+]i response to progesterone with reduced fertilization ability.STUDY DESIGN, SIZE, DURATIONThis was a cohort study using semen samples from 21 donors and 101 patients attending the assisted conception unit at Ninewells Hospital Dundee who were undergoing ART treatment. Patients were recruited from January 2016 to June 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSSemen donors and patients were recruited in accordance with local ethics approval (13/ES/0091) from the East of Scotland Research Ethics Service (EoSRES) REC1. [Ca2+]i responses were examined by single cell imaging and motility parameters assessed by computer-assisted sperm analysis (CASA).MAIN RESULTS AND THE ROLE OF CHANCEFor analysis, patient samples were divided into three groups IVF(+ve) (successful fertilization; 62 samples), IVF-FF (failed fertilization; eight samples) and ICSI (21 samples). A further 10 IVF samples showed large, spontaneous [Ca2+]i oscillations and responses to progesterone could not be analysed. All patient samples loaded with the [Ca2+]i-indicator fluo4 responded to progesterone stimulation with a biphasic increase in fluorescence (transient followed by plateau) which resembled that seen in progesterone-stimulated donor samples. The mean normalized response (progesterone-induced increase in fluorescence normalized to resting level) was significantly smaller in IVF-FF and ICSI patient groups than in donors. All samples were further analysed by plotting, for each cell, the relationship between resting fluorescence intensity and the progesterone-induced fluorescence increment. In donor samples these plots overlaid closely and had a gradient of ≈ 2 and plots for most IVF(+ve) samples closely resembled the donor distribution. However, in a subset (≈ 10%) of IVF(+ve) samples, 3/8 IVF-FF samples and one-third of ICSI samples the gradient of the plot was significantly lower, indicating that the response to progesterone of the cells in these samples was abnormally small. Examination of the relationship between gradient (regression coefficient of the plot) in IVF samples and fertilization rate showed a positive correlation. In IVF-FF and ICSI groups, the proportion of cells in which a response to progesterone could be detected was significantly lower than in donors and IVF (+ve) patients. Approximately 20% of cells in donor, IVF(+ve) and ICSI samples generated [Ca2+]i oscillations when challenged with progesterone but in IVF-FF samples only ≈ 10% of cells generated oscillations and there was a significantly greater proportion of samples where no oscillations were observed. Levels of hyperactivated motility were lower in IVF(+ve) and IVF-FF groups compared to controls, IVF-FF also having lower levels than IVF(+ve).LIMITATIONS, REASONS FOR CAUTIONThis is an in vitro study and caution must be taken when extrapolating these results in vivo.WIDER IMPLICATIONS OF THE FINDINGSThis study reveals important details of impaired [Ca2+]i signalling in sperm from sub-fertile men that cannot be detected in population studies

Microscopic crystallographic analysis of dislocations in molecular crystals

Organic molecular crystals encompass a vast range of materials from pharmaceuticals to organic optoelectronics and proteins to waxes in biological and industrial settings. Crystal defects from grain boundaries to dislocations are known to play key roles in mechanisms of growth and also in the functional properties of molecular crystals. In contrast to the precise analysis of individual defects in metals, ceramics, and inorganic semiconductors enabled by electron microscopy, significantly greater ambiguity remains in the experimental determination of individual dislocation character and slip systems in molecular materials. In large part, nanoscale dislocation analysis in molecular crystals has been hindered by the severely constrained electron exposures required to avoid irreversibly degrading these crystals. Here, we present a low-dose, single-exposure approach enabling nanometre-resolved analysis of individual extended dislocations in molecular crystals. We demonstrate the approach for a range of crystal types to reveal dislocation character and operative slip systems unambiguously.Comment: Manuscript (14 pages, 4 figures) and Supplementary Material (32 pages, 19 figures) in a single PDF fil

Edmonton Obesity Staging System Prevalence and Association with Weight Loss in a Publicly Funded Referral-Based Obesity Clinic

Objectives. To determine the distribution of EOSS stages and differences in weight loss achieved according to EOSS stage, in patients attending a referral-based publically funded multisite weight management clinic. Subjects/Methods. 5,787 obese patients were categorized using EOSS staging using metabolic risk factors, medication use, and severity of doctor diagnosis of obesity-related physiological, functional, and psychological comorbidities from electronic patient files. Results. The prevalence of EOSS stages 0 (no risk factors or comorbidities), 1 (mild conditions), 2 (moderate conditions), and 3 (severe conditions) was 1.7%, 10.4%, 84.0%, and 3.9%, respectively. Prehypertension (63%), hypertension (76%), and knee replacement (33%) were the most common obesity-related comorbidities for stages 1, 2, and 3, respectively. In the models including age, sex, initial BMI, EOSS stage, and treatment time, lower EOSS stage and longer treatment times were independently associated with greater absolute (kg) and percentage of weight loss relative to initial body weight P<0.05. Conclusions. Patients attending this publicly funded, referral-based weight management clinic were more likely to be classified in the higher stages of EOSS. Patients in higher EOSS stages required longer treatment times to achieve similar weight outcomes as those in lower EOSS stages

Patterns of genomic and phenomic diversity in wine and table grapes.

Grapes are one of the most economically and culturally important crops worldwide, and they have been bred for both winemaking and fresh consumption. Here we evaluate patterns of diversity across 33 phenotypes collected over a 17-year period from 580 table and wine grape accessions that belong to one of the world's largest grape gene banks, the grape germplasm collection of the United States Department of Agriculture. We find that phenological events throughout the growing season are correlated, and quantify the marked difference in size between table and wine grapes. By pairing publicly available historical phenotype data with genome-wide polymorphism data, we identify large effect loci controlling traits that have been targeted during domestication and breeding, including hermaphroditism, lighter skin pigmentation and muscat aroma. Breeding for larger berries in table grapes was traditionally concentrated in geographic regions where Islam predominates and alcohol was prohibited, whereas wine grapes retained the ancestral smaller size that is more desirable for winemaking in predominantly Christian regions. We uncover a novel locus with a suggestive association with berry size that harbors a signature of positive selection for larger berries. Our results suggest that religious rules concerning alcohol consumption have had a marked impact on patterns of phenomic and genomic diversity in grapes