The effect of mating on female reproduction across hermaphroditic freshwater snails

Sexual conflicts often arise between mating partners because each sex tries to maximize its own reproductive success. One major male strategy to influence a partner's resource allocation is the transfer of accessory gland proteins. This has been shown to occur in simultaneous hermaphrodites as well as in organisms with separate sexes. Although accessory gland proteins affect the investment of resources in both male and female function, we here specifically focus on female investment. In the great pond snail, Lymnaea stagnalis, previous studies found that the accessory gland protein ovipostatin reduced female fecundity by suppressing egg laying in the partner in the short term (days). To investigate whether this reduction in egg laying is a commonly found effect of mating in freshwater snails, we compared egg output for evidence of suppression in isolated and paired snails of eight pulmonate species. Furthermore, we determined whether the suppression of egg laying caused a shift in resource allocation to the eggs. We found that in five of the eight species egg laying was suppressed, with fewer and lighter egg masses being laid when they had access to a mating partner. In mated pairs of L. stagnalis and Biomphalaria alexandrina, allocation of resources to the eggs was altered in opposite ways: individuals of L. stagnalis laid fewer but larger and heavier eggs; individuals of B. alexandrina laid smaller and lighter eggs, with no change in egg numbers. Such changes in the female function are most likely the result of combined effects of receiving accessory gland proteins, and the cost of mating in both male and female roles. Thus, effects of the maternal environment, including the receipt of accessory gland proteins, on offspring investment are not restricted to species with separate sexes.     

Fibrin Clot Structure and Platelet Aggregation in Patients with Aspirin Treatment Failure

Background

Aspirin is a cornerstone in prevention of cardiovascular events and modulates both platelet aggregation and fibrin clot formation. Some patients experience cardiovascular events whilst on aspirin, often termed aspirin treatment failure (ATF). This study evaluated both platelet aggregation and fibrin clot structure in patients with ATF.

Methods

We included 177 stable coronary artery disease patients on aspirin monotherapy. Among these, 116 (66%) had ATF defined as myocardial infarction (MI) whilst on aspirin. Platelet aggregation was assessed by Multiplate® aggregometry and VerifyNow®, whereas turbidimetric assays and scanning electron microscopy were employed to study fibrin clot characteristics.

Results

Enhanced platelet aggregation was observed in patients with ATF compared with non-MI patients following stimulation with arachidonic acid 1.0 mM (median 161 (IQR 95; 222) vs. 97 (60; 1776) AU*min, p = 0.005) and collagen 1.0 µg/mL (293 (198; 427) vs. 220 (165; 370) AU*min, p = 0.03). Similarly, clot maximum absorbance, a measure of fibrin network density, was increased in patients with ATF (0.48 (0.41; 0.52) vs. 0.42 (0.38; 0.50), p = 0.02), and this was associated with thinner fibres (mean ± SD: 119.7±27.5 vs. 127.8±31.1 nm, p = 0.003) and prolonged lysis time (552 (498; 756) vs. 519 (468; 633) seconds; p = 0.02). Patients with ATF also had increased levels of C-reactive protein (CRP) (1.34 (0.48; 2.94) and 0.88 (0.32; 1.77) mg/L, p = 0.01) compared with the non-MI group. Clot maximum absorbance correlated with platelet aggregation (r = 0.31–0.35, p-values<0.001) and CRP levels (r = 0.60, p<0.001).

Conclusions

Patients with aspirin treatment failure showed increased platelet aggregation and altered clot structure with impaired fibrinolysis compared with stable CAD patients without previous MI. These findings suggest that an increased risk of aspirin treatment failure may be identified by measuring both platelet function and fibrin clot structure.     

Optimal Triage Test Characteristics to Improve the Cost-Effectiveness of the Xpert MTB/RIF Assay for TB Diagnosis: A Decision Analysis

Background

High costs are a limitation to scaling up the Xpert MTB/RIF assay (Xpert) for the diagnosis of tuberculosis in resource-constrained settings. A triaging strategy in which a sensitive but not necessarily highly specific rapid test is used to select patients for Xpert may result in a more affordable diagnostic algorithm. To inform the selection and development of particular diagnostics as a triage test we explored combinations of sensitivity, specificity and cost at which a hypothetical triage test will improve affordability of the Xpert assay.

Methods

In a decision analytical model parameterized for Uganda, India and South Africa, we compared a diagnostic algorithm in which a cohort of patients with presumptive TB received Xpert to a triage algorithm whereby only those with a positive triage test were tested by Xpert.

Findings

A triage test with sensitivity equal to Xpert, 75% specificity, and costs of US$5 per patient tested reduced total diagnostic costs by 42% in the Uganda setting, and by 34% and 39% respectively in the India and South Africa settings. When exploring triage algorithms with lower sensitivity, the use of an example triage test with 95% sensitivity relative to Xpert, 75% specificity and test costs $5 resulted in similar cost reduction, and was cost-effective by the WHO willingness-to-pay threshold compared to Xpert for all in Uganda, but not in India and South Africa. The gain in affordability of the examined triage algorithms increased with decreasing prevalence of tuberculosis among the cohort.

Conclusions

A triage test strategy could potentially improve the affordability of Xpert for TB diagnosis, particularly in low-income countries and with enhanced case-finding. Tests and markers with lower accuracy than desired of a diagnostic test may fall within the ranges of sensitivity, specificity and cost required for triage tests and be developed as such.     

CD98 marks a subpopulation of head and neck squamous cell carcinoma cells with stem cell properties

Patients with advanced head and neck squamous cell carcinomas (HNSCCs) are often treated with concomitant chemotherapy and radiotherapy, but only 50% is cured. A possible explanation for treatment failure is therapy resistance of the cancer stem cells (CSCs). The application of compounds specifically targeting these CSCs, in addition to routinely used therapeutics, would likely improve clinical outcome. We demonstrate that the previously described monoclonal antibody K984 recognizes the CD98 cell surface protein, which is specifically expressed by cells forming the squamous basal cell layer, the region where the squamous stem cells reside. Moreover, CD98 is highly resistant to the proteolytic enzymes required for CSC enrichment procedures. We show that CD98^high cells, in contrast to CD98^low cells, are able to generate tumors in immunodeficient mice, indicating that CD98^high cells have stem cell characteristics. Furthermore, the CD98^high subpopulation expresses high levels of cell cycle control and DNA repair genes, while the CD98^low fraction shows expression patterns that represent the more differentiated cells forming the bulk of the tumor. CD98 is a promising CSC enrichment marker in HNSCC. Our data support the CSC concept in head and neck cancer and the potential relevance of these cells for treatment outcome.     

Physiological Response of Adipocytes to Weight Loss and Maintenance

Background

Metabolic processes in adipose tissue are dysregulated in obese subjects and, in response to weight loss, either normalize or change in favor of weight regain.

Objective

To determine changes in adipocyte glucose and fatty acid metabolism in relation to changes in adipocyte size during weight loss and maintenance.

Methods

Twenty-eight healthy subjects (12 males), age 20–50 y, and BMI 28–35 kg/m², followed a very low energy diet for 2 months, followed by a 10-month period of weight maintenance. Body weight, body composition (deuterium dilution and BodPod), protein levels (Western blot) and adipocyte size were assessed prior to and after weight loss and after the 10-month follow-up.

Results

A 10% weight loss resulted in a 16% decrease in adipocyte size. A marker for glycolysis decreased (AldoC) during weight loss in association with adipocyte shrinking, and remained decreased during follow-up in association with weight maintenance. A marker for fatty acid transport increased (FABP4) during weight loss and remained increased during follow-up. Markers for mitochondrial beta-oxidation (HADHsc) and lipolysis (ATGL) were only increased after the 10-month follow-up. During weight loss HADHsc and ATGL were coordinately regulated, which became weaker during follow-up due to adipocyte size-related changes in HADHsc expression. AldoC was the major denominator of adipocyte size and body weight, whereas changes in ATGL during weight loss contributed to body weight during follow-up. Upregulation of ATGL and HADHsc occured in the absence of a negative energy balance and was triggered by adipocyte shrinkage or indicated preadipocyte differentiation.

Conclusion

Markers for adipocyte glucose and fatty acid metabolism are changed in response to weight loss in line with normalization from a dysregulated obese status to an improved metabolic status.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01015508","term_id":"NCT01015508"}}NCT01015508     

Interferon lambda 4 signals via the IFNλ receptor to regulate antiviral activity against HCV and coronaviruses

The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFNλ4 ORF. The expression of IFNλ4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFNλ4, which signals through the IFNλR1 and IL‐10R2 receptor chains. Recombinant IFNλ4 is antiviral against both HCV and coronaviruses at levels comparable to IFNλ3. However, the secretion of IFNλ4 is impaired compared to that of IFNλ3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFNλ4 gets N‐linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFNλ4 is strongly antiviral but a disadvantage during HCV infection.     

Phylogenetic beta diversity in bacterial assemblages across ecosystems: deterministic versus stochastic processes

Increasing evidence has emerged for non-random spatial distributions of microbes, but knowledge of the processes that cause variation in microbial assemblage among ecosystems is lacking. For instance, some studies showed that deterministic processes such as habitat specialization are important, while other studies hold that bacterial communities are assembled by stochastic forces. Here we examine the relative influence of deterministic and stochastic processes for bacterial communities from subsurface environments, stream biofilm, lake water, lake sediment and soil using pyrosequencing of the 16S ribosomal RNA gene. We show that there is a general pattern in phylogenetic signal in species ecological niches across recent evolutionary time for all studied habitats, enabling us to infer the influences of community assembly processes from patterns of phylogenetic turnover in community composition. The phylogenetic dissimilarities among-habitat types were significantly higher than within them, and the communities were clustered according to their original habitat types. For communities within-habitat types, the highest phylogenetic turnover rate through space was observed in subsurface environments, followed by stream biofilm on mountainsides, whereas the sediment assemblages across regional scales showed the lowest turnover rate. Quantifying phylogenetic turnover as the deviation from a null expectation suggested that measured environmental variables imposed strong selection on bacterial communities for nearly all sample groups. For three sample groups, spatial distance reflected unmeasured environmental variables that impose selection, as opposed to spatial isolation. Such characterization of spatial and environmental variables proved essential for proper interpretation of partial Mantel results based on observed beta diversity metrics. In summary, our results clearly indicate a dominant role of deterministic processes on bacterial assemblages and highlight that bacteria show strong habitat associations that have likely emerged through evolutionary adaptation.     

Using phylogeny to improve genome-wide distant homology recognition

The gap between the number of known protein sequences and structures continues to widen, particularly as a result of sequencing projects for entire genomes. Recently there have been many attempts to generate structural assignments to all genes on sets of completed genomes using fold-recognition methods. We developed a method that detects false positives made by these genome-wide structural assignment experiments by identifying isolated occurrences. The method was tested using two sets of assignments, generated by SUPERFAMILY and PSI-BLAST, on 150 completed genomes. A phylogeny of these genomes was built and a parsimony algorithm was used to identify isolated occurrences by detecting occurrences that cause a gain at leaf level. Isolated occurrences tend to have high e-values, and in both sets of assignments, a sudden increase in isolated occurrences is observed for e-values >10⁻⁸ for SUPERFAMILY and >10⁻⁴ for PSI-BLAST. Conditions to predict false positives are based on these results. Independent tests confirm that the predicted false positives are indeed more likely to be incorrectly assigned. Evaluation of the predicted false positives also showed that the accuracy of profile-based fold-recognition methods might depend on secondary structure content and sequence length. We show that false positives generated by fold-recognition methods can be identified by considering structural occurrence patterns on completed genomes; occurrences that are isolated within the phylogeny tend to be less reliable. The method provides a new independent way to examine the quality of fold assignments and may be used to improve the output of any genome-wide fold assignment method.     

Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants

BackgroundWomen’s reproductive factors have been associated with the risk of dementia; however, these findings remain uncertain. This study aimed to examine the risk of incident all-cause dementia associated with reproductive factors in women and the number of children in both sexes and whether the associations vary by age, socioeconomic status (SES), smoking status, and body mass index (BMI) in the UK Biobank.Methods and findingsA total of 273,240 women and 228,957 men without prevalent dementia from the UK Biobank were included in the analyses. Cox proportional hazard regressions estimated hazard ratios (HRs) for reproductive factors with incident all-cause dementia. Multiple adjusted models included age at study entry, SES, ethnicity, smoking status, systolic blood pressure, BMI, history of diabetes mellitus, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. Over a median of 11.8 years follow-up, 1,866 dementia cases were recorded in women and 2,202 in men. Multiple adjusted HRs ((95% confidence intervals (CIs)), p-value) for dementia were 1.20 (1.08, 1.34) (p = 0.016) for menarche <12 years and 1.19 (1.07, 1.34) (p = 0.024) for menarche >14 years compared to 13 years; 0.85 (0.74, 0.98) (p = 0.026) for ever been pregnant; 1.43 (1.26, 1.62) (p < 0.001) for age at first live birth <21 compared to 25 to 26 years; 0.82 (0.71, 0.94) (p = 0.006) for each abortion; 1.32 (1.15, 1.51) (p = 0.008) for natural menopause at <47 compared to 50 years; 1.12 (1.01, 1.25) (p = 0.039) for hysterectomy; 2.35 (1.06, 5.23) (p = 0.037) for hysterectomy with previous oophorectomy; and 0.80 (0.72, 0.88) (p < 0.001) for oral contraceptive pills use. The U-shaped associations between the number of children and the risk of dementia were similar for both sexes: Compared with those with 2 children, for those without children, the multiple adjusted HR ((95% CIs), p-value) was 1.18 (1.04, 1.33) (p = 0.027) for women and 1.10 (0.98, 1.23) (p = 0.164) for men, and the women-to-men ratio of HRs was 1.09 (0.92, 1.28) (p = 0.403); for those with 4 or more children, the HR was 1.14 (0.98, 1.33) (p = 0.132) for women and 1.26 (1.10, 1.45) (p = 0.003) for men, and the women-to-men ratio of HRs was 0.93 (0.76, 1.14) (p = 0.530). There was evidence that hysterectomy (HR, 1.31 (1.09, 1.59), p = 0.013) and oophorectomy (HR, 1.39 (1.08, 1.78), p = 0.002) were associated with a higher risk of dementia among women of relatively lower SES only. Limitations of the study include potential residual confounding and self-reported measures of reproductive factors, as well as the limited representativeness of the UK Biobank population.ConclusionsIn this study, we observed that some reproductive events related to shorter cumulative endogenous estrogen exposure in women were associated with higher dementia risk, and there was a similar association between the number of children and dementia risk between women and men.

In a cohort study, Jessica Gong and colleagues investigate associations between reproductive factors, number of children, and dementia among individuals in the UK Biobank.