Sex allocation theory reveals a hidden cost of neonicotinoid exposure in a parasitoid wasp

P.R.W. was funded by the University of Stirling, C.V.B. and S.M.G. were funded by Nuffield Research Placements and N.C., J.G. and D.M.S. were funded by NERC (NE/J024481/1).Sex allocation theory has proved to be one the most successful theories in evolutionary ecology. However, its role in more applied aspects of ecology has been limited. Here we show how sex allocation theory helps uncover an otherwise hidden cost of neonicotinoid exposure in the parasitoid wasp Nasonia vitripennis. Female N. vitripennis allocate the sex of their offspring in line with Local Mate Competition (LMC) theory. Neonicotinoids are an economically important class of insecticides, but their deployment remains controversial, with evidence linking them to the decline of beneficial species. We demonstrate for the first time to our knowledge, that neonicotinoids disrupt the crucial reproductive behaviour of facultative sex allocation at sub-lethal, field-relevant doses in N. vitripennis. The quantitative predictions we can make from LMC theory show that females exposed to neonicotinoids are less able to allocate sex optimally and that this failure imposes a significant fitness cost. Our work highlights that understanding the ecological consequences of neonicotinoid deployment requires not just measures of mortality or even fecundity reduction among non-target species, but also measures that capture broader fitness costs, in this case offspring sex allocation. Our work also highlights new avenues for exploring how females obtain information when allocating sex under LMC.Publisher PDFPeer reviewe

Enteric helminths promote Salmonella co-infection by altering the intestinal metabolome

Intestinal helminth infections occur pre dominantly in regions where exposure to enteric bacterial pathogens is also common. Helminth infections inhibit host immunity against microbial pathogens, which has largely been attributed to the induction of regulatory or type 2 (Th2) immune responses. Here we demonstrate an additional three-way interaction in which helminth infection alters the metabolic environment of the host intestine to enhance bacterial pathogenicity. We show that an ongoing helminth infection increased colonization by Salmonella independently of T regulatory or Th2 cells. Instead, helminth infection altered the metabolic profile of the intestine, which directly enhanced bacterial expression of Salmonella pathogenicity island 1 (SPI-1) genes and increased intracellular invasion. These data reveal a novel mechanism by which a helminth-modified metabolome promotes susceptibility to bacterial co-infection

Impact of Risk Factors for Specific Causes of Death in the First and Subsequent Years of Antiretroviral Therapy Among HIV-Infected Patients

Among HIV-infected patients who initiated antiretroviral therapy (ART), patterns of cause-specific death varied by ART duration and were strongly related to age, sex, and transmission risk group. Deaths from non-AIDS malignancies were much more frequent than those from cardiovascular diseas

Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients.

BACKGROUND: Patterns of cause-specific mortality in individuals infected with human immunodeficiency virus type 1 (HIV-1) are changing dramatically in the era of antiretroviral therapy (ART). METHODS: Sixteen cohorts from Europe and North America contributed data on adult patients followed from the start of ART. Procedures for coding causes of death were standardized. Estimated hazard ratios (HRs) were adjusted for transmission risk group, sex, age, year of ART initiation, baseline CD4 count, viral load, and AIDS status, before and after the first year of ART. RESULTS: A total of 4237 of 65 121 (6.5%) patients died (median, 4.5 years follow-up). Rates of AIDS death decreased substantially with time since starting ART, but mortality from non-AIDS malignancy increased (rate ratio, 1.04 per year; 95% confidence interval [CI], 1.0-1.1). Higher mortality in men than women during the first year of ART was mostly due to non-AIDS malignancy and liver-related deaths. Associations with age were strongest for cardiovascular disease, heart/vascular, and malignancy deaths. Patients with presumed transmission through injection drug use had higher rates of all causes of death, particularly for liver-related causes (HRs compared with men who have sex with men: 18.1 [95% CI, 6.2-52.7] during the first year of ART and 9.1 [95% CI, 5.8-14.2] thereafter). There was a persistent role of CD4 count at baseline and at 12 months in predicting AIDS, non-AIDS infection, and non-AIDS malignancy deaths. Lack of viral suppression on ART was associated with AIDS, non-AIDS infection, and other causes of death. CONCLUSIONS: Better understanding of patterns of and risk factors for cause-specific mortality in the ART era can aid in development of appropriate care for HIV-infected individuals and inform guidelines for risk factor management

NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

<p>Abstract</p> <p>Background</p> <p>A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)⁺versus ER^-cancer.</p> <p>Results</p> <p>We found association between SNP rs11249433 and expression of the <it>NOTCH2 </it>gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of <it>NOTCH2 </it>was found to be lowest in tumors with <it>TP53 </it>mutations and highest in <it>TP53 </it>wild-type/ER⁺tumors (p = 0.0059). In the latter group, the <it>NOTCH2 </it>expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between <it>NOTCH2 </it>expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of <it>NOTCH2</it>, a truncated version of <it>NOTCH2 </it>consisting of only the extracellular domain.</p> <p>Conclusion</p> <p>This is the first study to show that the expression of <it>NOTCH2 </it>differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER⁺luminal cells in the breast. Therefore, increased expression of <it>NOTCH2 </it>in carriers of rs11249433 may promote development of ER⁺luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of <it>NOTCH2 </it>expression by rs11249433 and the role of <it>NOTCH2 </it>splicing forms in breast cancer development.</p

CASCADE protocol: exploring current viral and host characteristics, measuring clinical and patient-reported outcomes, and understanding the lived experiences and needs of individuals with recently acquired HIV infection through a multicentre mixed-methods observational study in Europe and Canada

Introduction: Despite the availability of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART), 21 793 people were newly diagnosed with HIV in Europe in 2019. The Concerted action on seroconversion to AIDS and death in Europe study aims to understand current drivers of the HIV epidemic; factors associated with access to, and uptake of prevention methods and ART initiation; and the experiences, needs and outcomes of people with recently acquired HIV. / Methods and analysis: This longitudinal observational study is recruiting participants aged ≥16 years with documented laboratory evidence of HIV seroconversion from clinics in Canada and six European countries. We will analyse data from medical records, self-administered questionnaires, semistructured interviews and participatory photography. We will assess temporal trends in transmitted drug resistance and viral subtype and examine outcomes following early ART initiation. We will investigate patient-reported outcomes, well-being, and experiences of, knowledge of, and attitudes to HIV preventions, including PrEP. We will analyse qualitative data thematically and triangulate quantitative and qualitative findings. As patient public involvement is central to this work, we have convened a community advisory board (CAB) comprising people living with HIV. / Ethics and dissemination: All respective research ethics committees have approval for data to contribute to international collaborations. Written informed consent is required to take part. A dissemination strategy will be developed in collaboration with CAB and the scientific committee. It will include peer-reviewed publications, conference presentations and accessible summaries of findings on the study’s website, social media and via community organisations

Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies

BACKGROUND: The life expectancy of people with HIV taking antiretroviral therapy (ART) has increased substantially over the past 25 years. Most previous studies of life expectancy were based on data from the first few years after starting ART, when mortality is highest. However, many people with HIV have been successfully treated with ART for many years, and up-to-date prognosis data are needed. We aimed to estimate life expectancy in adults with HIV on ART for at least 1 year in Europe and North America from 2015 onwards. METHODS: We used data for people with HIV taking ART from the Antiretroviral Therapy Cohort Collaboration and the UK Collaborative HIV Cohort Study. Included participants started ART between 1996 and 2014 and had been on ART for at least 1 year by 2015, or started ART between 2015 and 2019 and survived for at least 1 year; all participants were aged at least 16 years at ART initiation. We used Poisson models to estimate the associations between mortality and demographic and clinical characteristics, including CD4 cell count at the start of follow-up. We also estimated the remaining years of life left for people with HIV aged 40 years who were taking ART, and stratified these estimates by variables associated with mortality. These estimates were compared with estimates for years of life remaining in a corresponding multi-country general population. FINDINGS: Among 206 891 people with HIV included, 5780 deaths were recorded since 2015. We estimated that women with HIV at age 40 years had 35·8 years (95% CI 35·2-36·4) of life left if they started ART before 2015, and 39·0 years (38·5-39·5) left if they started ART after 2015. For men with HIV, the corresponding estimates were 34·5 years (33·8-35·2) and 37·0 (36·5-37·6). Women with CD4 counts of fewer than 49 cells per μL at the start of follow-up had an estimated 19·4 years (18·2-20·5) of life left at age 40 years if they started ART before 2015 and 24·9 years (23·9-25·9) left if they started ART after 2015. The corresponding estimates for men were 18·2 years (17·1-19·4) and 23·7 years (22·7-24·8). Women with CD4 counts of at least 500 cells per μL at the start of follow-up had an estimated 40·2 years (39·7-40·6) of life left at age 40 years if they started ART before 2015 and 42·0 years (41·7-42·3) left if they started ART after 2015. The corresponding estimates for men were 38·0 years (37·5-38·5) and 39·2 years (38·7-39·7). INTERPRETATION: For people with HIV on ART and with high CD4 cell counts who survived to 2015 or started ART after 2015, life expectancy was only a few years lower than that in the general population, irrespective of when ART was started. However, for people with low CD4 counts at the start of follow-up, life-expectancy estimates were substantially lower, emphasising the continuing importance of early diagnosis and sustained treatment of HIV. FUNDING: US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council