Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Distribution of preoperative and postoperative astigmatism in a large population of patients undergoing cataract surgery in the UK

PURPOSE: To assess the prevalence and severity of preoperative and postoperative astigmatism in patients with cataract in the UK. SETTING: Data from 8 UK National Health Service ophthalmology clinics using MediSoft electronic medical records (EMRs). DESIGN: Retrospective cohort study. METHODS: Eyes from patients aged ≥65 years undergoing cataract surgery were analysed. For all eyes, preoperative (corneal) astigmatism was evaluated using the most recent keratometry measure within 2 years prior to surgery. For eyes receiving standard monofocal intraocular lens (IOLs), postoperative refractive astigmatism was evaluated using the most recent refraction measure within 2-12 months postsurgery. A power vector analysis compared changes in the astigmatic 2-dimensional vector (J0, J45) before and after surgery, for the subgroup of eyes with both preoperative and postoperative astigmatism measurements. Visual acuity was also assessed preoperatively and postoperatively. RESULTS: Eligible eyes included in the analysis were 110 468. Of these, 78% (n=85 650) had preoperative (corneal) astigmatism ≥0.5 dioptres (D), 42% (n=46 003) ≥1.0 D, 21% (n=22 899) ≥1.5 D and 11% (n=11 651) ≥2.0 D. After surgery, the refraction cylinder was available for 39 744 (36%) eyes receiving standard monofocal IOLs, of which 90% (n=35 907) had postoperative astigmatism ≥0.5 D and 58% (n=22 886) ≥1.0 D. Visual acuity tended to worsen postoperatively with increased astigmatism (ρ=-0.44, P<0.01). CONCLUSIONS: There is a significant burden of preoperative astigmatism in the UK cataract population. The available refraction data indicate that this burden is not reduced after surgery with implantation of standard monofocal IOLs. Measures should be taken to improve visual outcomes of patients with astigmatic cataract by simultaneously correcting astigmatism during cataract surgery

Consensus recommendations for clinical assessment tools for the diagnosis of posterior cortical atrophy syndrome from the Atypical AD PIA of ISTAART

INTRODUCTION: Delay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed. METHODS: Recommendations were developed using results from a web-based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA. RESULTS: Survey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria. DISCUSSION: These consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials

Control of microwave signals using circuit nano-electromechanics

Waveguide resonators are crucial elements in sensitive astrophysical detectors [1] and circuit quantum electrodynamics (cQED) [2]. Coupled to artificial atoms in the form of superconducting qubits [3, 4], they now provide a technologically promising and scalable platform for quantum information processing tasks [2, 5-8]. Coupling these circuits, in situ, to other quantum systems, such as molecules [9, 10], spin ensembles [11, 12], quantum dots [13] or mechanical oscillators [14, 15] has been explored to realize hybrid systems with extended functionality. Here, we couple a superconducting coplanar waveguide resonator to a nano-coshmechanical oscillator, and demonstrate all-microwave field controlled slowing, advancing and switching of microwave signals. This is enabled by utilizing electromechanically induced transparency [16-18], an effect analogous to electromagnetically induced transparency (EIT) in atomic physics [19]. The exquisite temporal control gained over this phenomenon provides a route towards realizing advanced protocols for storage of both classical and quantum microwave signals [20-22], extending the toolbox of control techniques of the microwave field.Comment: 9 figure

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target

Heavy Meson Production in Proton-Nucleus Reactions with Empirical Spectral Functions

We study the production of $K^+, \rho, \omega$ and $\phi$ mesons in $p + ^{12}C$ reactions on the basis of empirical spectral functions. The high momentum, high removal energy part of the spectral function is found to be negligible in all cases close to the absolute threshold. Furthermore, the two-step process ($pN \rightarrow \pi N N; \pi N \rightarrow N + K^+, \rho, \omega, \phi$) dominates the cross section at threshold energies in line with earlier calculations based on the folding model.Comment: 18 pages, LaTeX, plus 14 postscript figures, submitted to Z. Phys.

Effect of Biodiversity Changes in Disease Risk: Exploring Disease Emergence in a Plant-Virus System

The effect of biodiversity on the ability of parasites to infect their host and cause disease (i.e. disease risk) is a major question in pathology, which is central to understand the emergence of infectious diseases, and to develop strategies for their management. Two hypotheses, which can be considered as extremes of a continuum, relate biodiversity to disease risk: One states that biodiversity is positively correlated with disease risk (Amplification Effect), and the second predicts a negative correlation between biodiversity and disease risk (Dilution Effect). Which of them applies better to different host-parasite systems is still a source of debate, due to limited experimental or empirical data. This is especially the case for viral diseases of plants. To address this subject, we have monitored for three years the prevalence of several viruses, and virus-associated symptoms, in populations of wild pepper (chiltepin) under different levels of human management. For each population, we also measured the habitat species diversity, host plant genetic diversity and host plant density. Results indicate that disease and infection risk increased with the level of human management, which was associated with decreased species diversity and host genetic diversity, and with increased host plant density. Importantly, species diversity of the habitat was the primary predictor of disease risk for wild chiltepin populations. This changed in managed populations where host genetic diversity was the primary predictor. Host density was generally a poorer predictor of disease and infection risk. These results support the dilution effect hypothesis, and underline the relevance of different ecological factors in determining disease/infection risk in host plant populations under different levels of anthropic influence. These results are relevant for managing plant diseases and for establishing conservation policies for endangered plant species

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

Estimation of progression of multi-state chronic disease using the Markov model and prevalence pool concept

<p>Abstract</p> <p>Background</p> <p>We propose a simple new method for estimating progression of a chronic disease with multi-state properties by unifying the prevalence pool concept with the Markov process model.</p> <p>Methods</p> <p>Estimation of progression rates in the multi-state model is performed using the E-M algorithm. This approach is applied to data on Type 2 diabetes screening.</p> <p>Results</p> <p>Good convergence of estimations is demonstrated. In contrast to previous Markov models, the major advantage of our proposed method is that integrating the prevalence pool equation (that the numbers entering the prevalence pool is equal to the number leaving it) into the likelihood function not only simplifies the likelihood function but makes estimation of parameters stable.</p> <p>Conclusion</p> <p>This approach may be useful in quantifying the progression of a variety of chronic diseases.</p