Long-term deaths from melanoma according to tumor thickness at diagnosis

There is little long-term follow-up information about how the number of melanoma deaths and case fatality vary over time according to the measured thickness of melanoma at diagnosis. This population-based longitudinal cohort study examines patterns and trends in case fatality among 44,531 people in Queensland (Australia) diagnosed with a single invasive melanoma (International Classification of Diseases for Oncology, third revision [ICD-O-3], C44, Morphology 872–879) between 1987 and 2011, including 11,883 diagnosed between 1987 and 1996, with up to 20 years follow-up (to December 2016). The 20-year case fatality increased by thickness, with the percentage of melanoma deaths within 20 years of diagnosis being up to 4.8% for melanomas with measured thickness <0.80 mm, 10.6% for tumors 0.8 to <1.0 mm and generally more than 30% for melanomas measuring 3 mm and more. For melanomas <1.0 mm, most deaths occurred between 5 and 20 years after diagnosis, whereas for thicker melanomas the reverse was true with most deaths occurring within the first 5 years. Five-year case fatality decreased over successive calendar time periods for melanomas <1.0 mm, but not for melanomas ≥1.0 mm. These findings demonstrate that the time course for fatal melanomas varies markedly according to tumor thickness at diagnosis. Improved understanding of the patient factors and characteristics of melanomas, in addition to tumor thickness, which increase the likelihood of progression, is needed to guide clinical diagnosis, communication with patients and ongoing surveillance pathways of patients with potentially fatal lesions.     

Are sperm capacitation and apoptosis the opposite ends of a continuum driven by oxidative stress?

This chapter explores the possibility that capacitation and apoptosis are linked processes joined by their common dependence on the continued generation of reactive oxygen species (ROS). According to this model capacitation is initiated in spematozoa following their release into the female reproductive tract as a consequence of intracellular ROS generation, which stimulates intracellular cAMP generation, inhibits tyrosine phosphatase activity and enhances the formation of oxysterols prior to their removal from the sperm surface by albumin. The continued generation of ROS by capacitating populations of spermatozoa eventually overwhelms the limited capacity of these cells to protect themselves from oxidative stress. As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial ROS generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization. The latter may be particularly important in instructing phagocytic leukocytes that the removal of senescent, moribund spermatozoa should be a silent process unaccompanied by the generation of proinflammatory cytokines. These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa. A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.     

The effect of gender on mental health service use: an examination of mediation through material,social and health-related pathways

Purpose

We aimed to understand how much of the gender difference in mental health service use could be due to the joint mediation of employment, behavioural and material factors, social support and mental health need.

Methods

We used data from employed individuals aged 18–65 years who participated in the 2015–2017 waves of the Household, Income and Labour Dynamics in Australia survey. The exposure (male, female) and confounders were measured in 2015, mediators in 2016 and the outcome—whether a person had seen a mental health professional in the previous year—was measured in 2017. We estimated natural mediation effects using weighted counterfactual predictions from a logistic regression model.

Results

Men were less likely to see a mental health care provider than women. The total causal effect on the risk difference scale was  − 0.045 (95% CI  − 0.056,  − 0,034). The counterfactual of men taking the mediator values of women explained 28% (95% CI 1.7%, 54%) of the total effect, with the natural direct effect estimated to represent an absolute risk difference of  − 0.033 (95% CI  − 0.048,  − 0.018) and the natural indirect effect  − 0.012 (95% CI  − 0.022,  − 0.0027).

Conclusion

Gendered differences in the use of mental health services could be reduced by addressing inequalities in health, employment, material and behavioural factors, and social support.

     

Genome-wide shifts in climate-related variation underpin responses to selective breeding in a widespread conifer

Locally adapted temperate tree populations exhibit genetic trade-offs among climate-related traits that can be exacerbated by selective breeding and are challenging to manage under climate change. To inform climatically adaptive forest management, we investigated the genetic architecture and impacts of selective breeding on four climate-related traits in 105 natural and 20 selectively bred lodgepole pine populations from western Canada. Growth, cold injury, growth initiation, and growth cessation phenotypes were tested for associations with 18,600 single-nucleotide polymorphisms (SNPs) in natural populations to identify “positive effect alleles” (PEAs). The effects of artificial selection for faster growth on the frequency of PEAs associated with each trait were quantified in breeding populations from different climates. Substantial shifts in PEA proportions and frequencies were observed across many loci after two generations of selective breeding for height, and responses of phenology-associated PEAs differed strongly among climatic regions. Extensive genetic overlap was evident among traits. Alleles most strongly associated with greater height were often associated with greater cold injury and delayed phenology, although it is unclear whether potential trade-offs arose directly from pleiotropy or indirectly via genetic linkage. Modest variation in multilocus PEA frequencies among populations was associated with large phenotypic differences and strong climatic gradients, providing support for assisted gene flow polices. Relationships among genotypes, phenotypes, and climate in natural populations were maintained or strengthened by selective breeding. However, future adaptive phenotypes and assisted gene flow may be compromised if selective breeding further increases the PEA frequencies of SNPs involved in adaptive trade-offs among climate-related traits.

Local adaptation of climate-related traits in widespread temperate conifers has been demonstrated for centuries using extensive long-term common garden experiments (1, 2). As early as the 17th century, foresters were instructed to recognize variation in desirable traits and select seed from trees with favorable phenotypes (3). Modern tree improvement programs systematically select upon genetic variation, primarily to achieve growth gains and meet economic objectives. Estimates of genetic variation and gains from selection made using quantitative genetic models assume many anonymous loci of small effect underlie both variation in continuously distributed phenotypes and their responses to selective breeding. However, the type, quantity, effect size, distribution, and dynamics of genes underlying locally adaptive phenotypic variation and responses to selective breeding in forest trees are still poorly understood (4).Directional selection over hundreds or thousands of generations has led to genomic features of domestication in agricultural crops including simplified genetic architectures underlying many traits, reduced genome-wide diversity, and numerous selective sweeps (5–7). Beyond high-gain, short-rotation clonal forestry [e.g., Eucalyptus spp. (8)], we know little about the effects of artificial selection on adaptive genetic variation in forest trees, yet many tree species undergo some degree of selective breeding. Two or three generations of conifer breeding is not expected to have the same magnitude of genetic effects seen in domesticated crops, but if artificial selection for increased productivity is detectable in conifer genomes, it may expose genetic relationships and potential sources of trade-offs between growth and climatically adaptive phenotypes.Climate-related adaptive traits are often intercorrelated due to pleiotropy, natural selection, or linkage disequilibrium (LD), so that strong directional selection on one trait can cause correlated responses in others. Pleiotropic allelic variants associated with phenotypes do not function in isolation. Antagonistic pleiotropic effects among traits can generate adaptive trade-offs among traits within populations, and limit gains from selection on a focal trait (9). Trait–trait correlations can also arise through strong selection acting in parallel on unlinked loci or from LD mediated by physical linkage of loci on chromosomes. Average genome-wide LD estimates in conifers appear to be low (10, 11) but may be greater (r² of 0.2–0.4) within genes under strong selection (12).Conifer studies have identified putatively adaptive phenotype-associated alleles on a locus-by-locus basis using quantitative trait loci (QTL) mapping or genotype–phenotype associations (GPAs) (also known as genome-wide association studies [GWAS]) (13). Genotype–environment association analyses in conifers have identified putatively adaptive environmentally associated loci (e.g., 14, 15), but loci are usually anonymous relative to adaptive phenotypes. All of these approaches are biased toward detecting loci with large phenotypic effects, but expectations that genome scans will discover individual adaptive loci with large effects or frequency differences among populations may be biologically and statistically unrealistic (16, 17). Conifer GPA studies typically detect relatively few statistically significant loci, and locus-by-locus analyses are insufficient to characterize adaptive genome-wide variation associated with adaptive traits and signatures of selective breeding. Multilocus tests for adaptive polygenic signatures of selection have been developed (e.g., refs. 18 and 19), but significant limitations remain (reviewed in refs. 20 and 21).Uncertainty about the effects of selective breeding on adaptive genetic variation is layered upon expectations that forest trees will become maladapted as climates shift (22). Efforts are being made to estimate maladaptation using genome-wide variation associated with adaptive traits and climate (23, 24), because conserving, managing, and efficiently redeploying genetic variation associated with adaptive phenotypes will be a necessary element of strategies to mitigate the effects of shifting climates on forest resources (25). Assisted gene flow strategies in temperate and subboreal forests generally aim to move trees to cooler climates in anticipation of future warming, but trees must then contend with the increased short- to medium-term risk of maladaptation to damaging frost. This means cold tolerance is, perhaps surprisingly, an important trait when planning for warming climates.Genetic approaches have the potential to efficiently and accurately characterize local adaptation to climate. Understanding whether this potential can be realized in a technically robust and operationally feasible way, and whether selection for faster growth compromises genetic variation associated with phenotypic adaptation to climate, has far-reaching implications for developing effective assisted gene flow strategies that mitigate negative climate change impacts on forest health and timber production (26, 27). In this context, our research objectives are to 1) identify the genetic architecture of climate-related adaptive traits in interior lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.); 2) identify genome-wide effects of artificial selection for increased productivity on climate-related traits; and 3) assess the implications of genetic responses to selection for assisted gene flow strategies.Our study combines climatic data, genotype data from ∼50,000 lodgepole pine single-nucleotide polymorphisms (SNPs), and seedling phenotypic data for height, cold injury, growth initiation, and growth cessation traits. These data were collected from a seedling common garden that sampled reforestation seed lots from 105 natural populations and 20 breeding populations from across the species’ range in Alberta (AB) and British Columbia (BC), Canada (Fig. 1 and SI Appendix, Table S1). For each of the four traits, we identify range-wide GPAs using 929 seedlings from all 105 natural populations. Then for the 1% most strongly phenotype-associated SNPs, we examine how artificial selection within breeding populations has changed allele frequencies at individual SNP loci, within individual seedlings, populations (breeding zones), and three climatic regions (Fig. 1). Using elements from the approach of Turchin et al. (18), we study changes in frequency of the alleles that have a positive effect on adaptive traits (positive effect alleles [PEAs]). At each SNP locus, a PEA is the allele associated with increasing numeric values of the respective phenotype, determined in this case through GPA analyses in the natural seedling populations. PEAs reported here are associated with greater seedling height, greater cold injury, delayed growth initiation, and delayed growth cessation. To parse physical genetic linkage from allelic associations due to other causes, we compare LD estimated from our natural seedlings with estimates of recombination among haploid megagametophytes from a single maternal parent, where physical linkage is the only cause of LD. Integrating genetic, climatic, and phenotypic data gives us a robust basis to detect the effects of artificial selection on climate-related genotypes that are relevant to breeding and assisted gene flow strategies.Open in a separate windowFig. 1.Geographic origins of the natural and selected seedling populations sampled from across the range of lodgepole pine in Alberta (AB) and British Columbia (BC). Natural populations are represented by filled circles; selected seedling breeding zones are represented by filled polygons. The three climatic regions we used were AB, BC-Central, and BC-South. AB breeding zones are formally identified as A, B1, B2, C, J, and K1. BC-Central breeding zone abbreviations are as follows: BV, Bulkley Valley; CP, Central Plateau; and PG, Prince George. BC-South breeding zone abbreviations are as follows: EK, East Kootenay; NE, Nelson; and TO, Thompson–Okanagan. Reprinted from ref. 35, with permission from Elsevier.     

Remodeling of the plasma membrane in preparation for sperm–egg recognition: roles of acrosomal proteins

The interaction of sperm with the egg''s extracellular matrix, the zona pellucida (ZP) is the first step of the union between male and female gametes. The molecular mechanisms of this process have been studied for the past six decades with the results obtained being both interesting and confusing. In this article, we describe our recent work, which attempts to address two lines of questions from previous studies. First, because there are numerous ZP binding proteins reported by various researchers, how do these proteins act together in sperm–ZP interaction? Second, why do a number of acrosomal proteins have ZP affinity? Are they involved mainly in the initial sperm–ZP binding or rather in anchoring acrosome reacting/reacted spermatozoa to the ZP? Our studies reveal that a number of ZP binding proteins and chaperones, extracted from the anterior sperm head plasma membrane, coexist as high molecular weight (HMW) complexes, and that these complexes in capacitated spermatozoa have preferential ability to bind to the ZP. Zonadhesin (ZAN), known as an acrosomal protein with ZP affinity, is one of these proteins in the HMW complexes. Immunoprecipitation indicates that ZAN interacts with other acrosomal proteins, proacrosin/acrosin and sp32 (ACRBP), also present in the HMW complexes. Immunodetection of ZAN and proacrosin/acrosin on spermatozoa further indicates that both proteins traffic to the sperm head surface during capacitation where the sperm acrosomal matrix is still intact, and therefore they are likely involved in the initial sperm–ZP binding step.     

Hydrolytic and depolymerising enzyme activity of Prevotella intermedia and Prevotella nigrescens

OBJECTIVE: Prevotella intermedia has been reported to be associated with periodontal disease whilst P. nigrescens has predominantly been isolated from more specific conditions and healthy sites. The aim of the present study was to compare the enzyme activity of these species.
MATERIALS AND METHODS Nine strains of P. intermedio and 12 strains of P. nigrescens were studied. Lipolytic. saccharolytic, nucleolytic and proteolytic activity was determined by traditional microbiological and chromo-genic substrate methods.
RESULTS: All strains hydrolysed gelatine, casein. DNA and RNA. Lipase activity was produced by all strains except P. nigrescens ATCC 33563^T. Lipolytic activity of P. nigrescens strains decreased as the environmental glucose concentration was increased. Only two strains, both P. intermedia , hydrolysed benzyl-arg-p-nitroanilide. All strains hydrolysed alkaline pnitrophenolphosphate (except P. intermedia DAL 100). produced glycylprolyl dipeptidase activity and demonstrated elastase-like activity. All but three strains (2 P. intermedia and I P. nigrescens) hydrolysed suc-ala-ala-pro-phe-p-nitroanilide. Overall, no qualitatively analysed enzyme activity was exclusive to all strains of either species. Quantitatively analysed activity exhibited a high degree of variability both within and between species.
CONCLUSIONS: P. intermedia and P. nigrescens degrade natural and synthetic substrates, but intra- and interspec-ies activity is variable.     

HCV avidity as a tool for detection of recent HCV infection: Sensitivity depends on HCV genotype

Accurate detection of incident hepatitis C virus (HCV) infection is required to target and evaluate public health interventions, but acute infection is largely asymptomatic and difficult to detect using traditional methods. Our aim was to evaluate a previously developed HCV avidity assay to distinguish acute from chronic HCV infection. Plasma samples collected from recent seroconversion subjects in two large Australian cohorts were tested using the avidity assay, and the avidity index (AI) was calculated. Demographic and clinical characteristics of patients with low/high AI were compared via logistic regression. Sensitivity and specificity of the assay for recent infection and the mean duration of recent infection (MDRI) were estimated stratified by HCV genotype. Avidity was assessed in 567 samples (from 215 participants), including 304 with viraemia (defined as ≥250 IU/mL). An inverse relationship between AI and infection duration was found in viraemic samples only. The adjusted odds of a low AI (<30%) decreased with infection duration (odds ratio [OR] per week of 0.93; 95% CI:0.89‐0.97), and were lower for G1 compared with G3 samples (OR = 0.14; 95% CI:0.05‐0.39). Defining recent infection as <26 weeks, sensitivity (at AI cut‐off of 20%) was estimated at 48% (95% CI:39‐56%), 36% (95% CI:20‐52%), and 65% (95% CI:54‐75%) and MDRI was 116, 83, and 152 days for all genotypes, G1, and G3, respectively. Specificity (≥52 weeks infection duration, all genotypes) was 96% (95% CI:90‐98%). HCV avidity testing has utility for detecting recent HCV infection in patients, and for assessing progress in reaching incidence targets for eliminating transmission, but variation in assay performance across genotype should be recognized.