Altered expression of Alzheimer\u27s disease-related proteins in male hypogonadal mice

Age-related depletion of estrogens and androgens is associated with an increase in Alzheimer\u27s disease (AD) brain pathology and diminished cognitive function. Here we investigated AD-associated molecular and cellular changes in brains of aged hypogonadal (hpg) male and female mice. hpg Mice have a spontaneous, inactivating genetic mutation in the GnRH gene resulting in lifelong deficiency of gonadotropins and gonadal sex hormones. Western blot analysis revealed low levels of amyloid precursor protein and high levels of presenilin 1, amyloid precursor protein C-terminal fragment, and β-amyloid 42 in brains of aged male, but not female, hpg mice. Changes were confined to the hippocampus and were not evident in the cerebellum or other brain tissues. Male hpg mice tended to have lower levels of IL-1β protein than male littermate controls. Immunohistochemical staining of the basal forebrain revealed that male hpg mice had lower choline acetyltransferase levels per neuron compared with controls. These AD-like changes specific to male hpg mice supports a link between androgen depletion and the development of AD pathology

Some Remarks on Effective Range Formula in Potential Scattering

In this paper, we present different proofs of very recent results on the necessary as well as sufficient conditions on the decrease of the potential at infinity for the validity of effective range formulas in 3-D in low energy potential scattering (Andr\'e Martin, private communication, to appear. See Theorem 1 below). Our proofs are based on compact formulas for the phase-shifts. The sufficiency conditions are well-known since long. But the necessity of the same conditions for potentials keeping a constant sign at large distances are new. All these conditions are established here for dimension 3 and for all angular momenta $\ell \geq 0$

Class of correlated random networks with hidden variables

We study a class models of correlated random networks in which vertices are characterized by \textit{hidden variables} controlling the establishment of edges between pairs of vertices. We find analytical expressions for the main topological properties of these models as a function of the distribution of hidden variables and the probability of connecting vertices. The expressions obtained are checked by means of numerical simulations in a particular example. The general model is extended to describe a practical algorithm to generate random networks with an \textit{a priori} specified correlation structure. We also present an extension of the class, to map non-equilibrium growing networks to networks with hidden variables that represent the time at which each vertex was introduced in the system

Features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age

STUDY QUESTION: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? SUMMARY ANSWER: Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder. WHAT IS KNOWN ALREADY: Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function. STUDY DESIGN, SIZE, DURATION: The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA \u3e4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk. MAIN RESULTS AND THE ROLE OF CHANCE: Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P \u3c 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P \u3c 0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR \u3e 4 was associated with a lower serum testosterone (P = LIMITATIONS, REASONS FOR CAUTION: This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment. WIDER IMPLICATIONS OF THE FINDINGS: Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume. STUDY FUNDING/ COMPETING INTEREST(S): This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.Aimee S. L. Caldwell, Melissa C. Edwards, Reena Desai, Mark Jimenez, Robert B. Gilchrist, David J. Handelsman and Kirsty A. Walter

Frequency and type of adverse analytical findings in athletics: Differences among disciplines.

Athletics is a highly diverse sport that contains a set of disciplines grouped into jumps, throws, races of varying distances, and combined events. From a physiological standpoint, the physical capabilities linked to success are quite different among disciplines, with varying involvements of muscle strength, muscle power, and endurance. Thus, the use of banned substances in athletics might be dictated by physical dimensions of each discipline. Thus, the aim of this investigation was to analyse the number and distribution of adverse analytical findings per drug class in athletic disciplines. The data included in this investigation were gathered from the Anti-Doping Testing Figure Report made available by the World Anti-Doping Agency (from 2016 to 2018). Interestingly, there were no differences in the frequency of adverse findings (overall, 0.95%, range from 0.77 to 1.70%) among disciplines despite long distance runners having the highest number of samples analysed per year ( 9812 samples/year). Sprinters and throwers presented abnormally high proportions of adverse analytical findings within the group of anabolic agents (p < 0.01); middle- and long-distance runners presented atypically high proportions of findings related to peptide hormones and growth factors (p < 0.01); racewalkers presented atypically high proportions of banned diuretics and masking agents (p = 0.05). These results suggest that the proportion of athletes that are using banned substances is similar among the different disciplines of athletics. However, there are substantial differences in the class of drugs more commonly used in each discipline. This information can be used to effectively enhance anti-doping testing protocols in athletics.post-print1.911 K

Evolutionary change in continuous reaction norms

Abstract Understanding the evolution of reaction norms remains a major challenge in ecology and evolution. Investigating evolutionary divergence in reaction norm shapes between populations and closely related species is one approach to providing insights. Here we use a meta-analytic approach to compare divergence in reaction norms of closely related species or populations of animals and plants across types of traits and environments. We quantified mean-standardized differences in overall trait means (Offset) and reaction norm shape (including both Slope and Curvature). These analyses revealed that differences in shape (Slope and Curvature together) were generally greater than differences in Offset. Additionally, differences in Curvature were generally greater than differences in Slope. The type of taxon contrast (species vs. population), trait, organism, and the type and novelty of environments all contributed to the best-fitting models, especially for Offset, Curvature, and the total differences (Total) between reaction norms. Congeneric species had greater differences in reaction norms than populations, and novel environmental conditions increased the differences in reaction norms between populations or species. These results show that evolutionary divergence of curvature is common and should be considered an important aspect of plasticity, together with slope. Biological details about traits and environments, including cryptic variation expressed in novel environmental conditions, may be critical to understanding how reaction norms evolve in novel and rapidly changing environments

Extending colonic mucosal microbiome analysis - Assessment of colonic lavage as a proxy for endoscopic colonic biopsies

This study was supported through GI Research funds and MRC Grant Ref: MR/M00533X/1 to GH.Peer reviewedPublisher PD

1, 2, 3, 4: Infusing Quantitative Literacy into Introductory Biology

Biology of the twenty-first century is an increasingly quantitative science. Undergraduate biology education therefore needs to provide opportunities for students to develop fluency in the tools and language of quantitative disciplines. Quantitative literacy (QL) is important for future scientists as well as for citizens, who need to interpret numeric information and data-based claims regarding nearly every aspect of daily life. To address the need for QL in biology education, we incorporated quantitative concepts throughout a semester-long introductory biology course at a large research university. Early in the course, we assessed the quantitative skills that students bring to the introductory biology classroom and found that students had difficulties in performing simple calculations, representing data graphically, and articulating data-driven arguments. In response to students' learning needs, we infused the course with quantitative concepts aligned with the existing course content and learning objectives. The effectiveness of this approach is demonstrated by significant improvement in the quality of students' graphical representations of biological data. Infusing QL in introductory biology presents challenges. Our study, however, supports the conclusion that it is feasible in the context of an existing course, consistent with the goals of college biology education, and promotes students' development of important quantitative skills