Increasing picocyanobacteria success in shelf waters contributes to long-term food web degradation.

Continental margins are disproportionally important for global primary production, fisheries and CO2 uptake. However, across the Northeast Atlantic shelves, there has been an ongoing summertime decline of key biota-large diatoms, dinoflagellates and copepods-that traditionally fuel higher tropic levels such as fish, sea birds and marine mammals. Here, we combine multiple time series with in situ process studies to link these declines to summer nutrient stress and increasing proportions of picophytoplankton that can comprise up to 90% of the combined pico- and nanophytoplankton biomass in coastal areas. Among the pico-fraction, it is the cyanobacterium Synechococcus that flourishes when iron and nitrogen resupply to surface waters are diminished. Our field data show how traits beyond small size give Synechococcus a competitive edge over pico- and nanoeukaryotes. Key is their ability to grow at low irradiances near the nutricline, which is aided by their superior light-harvesting system and high affinity to iron. However, minute size and lack of essential biomolecules (e.g. omega-3 polyunsaturated fatty acids and sterols) render Synechococcus poor primary producers to sustain shelf sea food webs efficiently. The combination of earlier spring blooms and lower summer food quantity and quality creates an increasing period of suboptimal feeding conditions for zooplankton at a time of year when their metabolic demand is highest. We suggest that this nutrition-related mismatch has contributed to the widespread, ~50% decline in summer copepod abundance we observe over the last 60 years. With Synechococcus clades being prominent from the tropics to the Arctic and their abundances increasing worldwide, our study informs projections of future food web dynamics in coastal and shelf areas where droughts and stratification lead to increasing nutrient starvation of surface waters.

Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers.

PURPOSE: Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies. METHODS: Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan-Meier analyses were performed. RESULTS: 2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30-39 years. Kaplan-Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002). CONCLUSIONS: The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

Seasonal ITCZ migration dynamically controls the location of the (sub)tropical Atlantic biogeochemical divide.

Inorganic nitrogen depletion restricts productivity in much of the low-latitude oceans, generating a selective advantage for diazotrophic organisms capable of fixing atmospheric dinitrogen (N2). However, the abundance and activity of diazotrophs can in turn be controlled by the availability of other potentially limiting nutrients, including phosphorus (P) and iron (Fe). Here we present high-resolution data (∼0.3°) for dissolved iron, aluminum, and inorganic phosphorus that confirm the existence of a sharp north-south biogeochemical boundary in the surface nutrient concentrations of the (sub)tropical Atlantic Ocean. Combining satellite-based precipitation data with results from a previous study, we here demonstrate that wet deposition in the region of the intertropical convergence zone acts as the major dissolved iron source to surface waters. Moreover, corresponding observations of N2 fixation and the distribution of diazotrophic Trichodesmium spp. indicate that movement in the region of elevated dissolved iron as a result of the seasonal migration of the intertropical convergence zone drives a shift in the latitudinal distribution of diazotrophy and corresponding dissolved inorganic phosphorus depletion. These conclusions are consistent with the results of an idealized numerical model of the system. The boundary between the distinct biogeochemical systems of the (sub)tropical Atlantic thus appears to be defined by the diazotrophic response to spatial-temporal variability in external Fe inputs. Consequently, in addition to demonstrating a unique seasonal cycle forced by atmospheric nutrient inputs, we suggest that the underlying biogeochemical mechanisms would likely characterize the response of oligotrophic systems to altered environmental forcing over longer timescales.

The effect of select seminal plasma proteins on endometrial mRNA cytokine expression in mares susceptible to persistent mating-induced endometritis.

In the horse, breeding induces a transient endometrial inflammation. A subset of mares are unable to resolve this inflammation, and they are considered susceptible to persistent mating-induced endometritis PMIE Select seminal plasma proteins cysteine-rich secretory protein-3 (CRISP-3) and lactoferrin have been shown to affect the innate immune response to sperm in vitro. The objective of this study was to determine whether the addition of CRISP-3 and lactoferrin at the time of insemination had an effect on the mRNA expression of endometrial cytokines in susceptible mares after breeding. Six mares classified as susceptible to PMIE were inseminated during four consecutive oestrous cycles with treatments in randomized order of: 1 mg/ml CRISP-3, 150 µg/ml lactoferrin, seminal plasma (positive control) or lactated Ringer's solution (LRS; negative control) to a total volume of 10 ml combined with 1 × 109 spermatozoa pooled from two stallions. Six hours after treatment, an endometrial biopsy was obtained for qPCR analysis of selected genes associated with inflammation (pro-inflammatory cytokines interleukin (IL)-1ß, IL-8, tumour necrosis factor (TNF)-α, interferon (INF)-γ, anti-inflammatory cytokines IL-1RN and IL-10, and inflammatory-modulating cytokine IL-6). Seminal plasma treatment increased the mRNA expression of IL-1ß (p = .019) and IL-8 (p = .0068), while suppressing the mRNA expression of TNF (p = .0013). Lactoferrin also suppressed the mRNA expression of TNF (p = .0013). In conclusion, exogenous lactoferrin may be considered as one modulator of the complex series of events resulting in the poorly regulated pro-inflammatory response seen in susceptible mares.

Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.

The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status. If HER2+ only 2.5 % (4/156) and 3.2 % (5/156) of women had a BRCA1 or BRCA2 mutation identified respectively; compared to 27.7 % (115/415) and 8.2 % (34/415) with triple negative tumours. Only 2.1 % (4/195) women with BRCA1-related breast cancer had HER2 amplified breast cancers rising to 6.8 % (n = 12, p = 0.04) in BRCA2. These rates are in keeping with most of the existing literature except a recent large multicenter report which documented higher rates but with no control group. The study concluded that true HER2-amplified breast cancers are rare amongst BRCA1 mutation carriers and are less common in BRCA2 than background rates.

Distribution pattern(s) of sperm protein at 22 kDa (SP22) on fresh, cooled and frozen/thawed equine spermatozoa and expression of SP22 in tissues from the testes and epididymides of normal stallions.

The objectives of this study were to (i) verify localization of SP22 on fresh, cooled, and frozen/thawed equine spermatozoa and to (ii) determine SP22 mRNA and protein expression in equine testicular and epididymal tissues. Immunocytochemistry and Western blots were performed on the spermatozoa samples. Northern blots and Western blots were performed on the tissue samples. The immunocytochemistry revealed the presence of SP22 in all samples tested. The fresh spermatozoa stained predominantly over the equatorial segment as did the samples cooled for 1 and 2 days. The samples cooled for 3 days, and the frozen/thawed samples had an increased proportion of no staining. The Western blots revealed SP22 was present on all semen samples tested. The Northern blot of the tissues revealed a 1.0 kb mRNA transcript present in each of the tissues, and the Western blot revealed the presence of SP22 in each of the tissues. As expected, SP22 was found to be altered on cooled and frozen/thawed spermatozoa. Our results suggest that the equatorial pattern is the normal pattern in spermatozoa, while a complete loss of SP22 from the surface of spermatozoa seems to be the staining pattern indicating the most extreme abnormality with scattered staining of the head indicating intermediate damage.

Effects of topical application of misoprostol on cervical relaxation in mares.

Mares who have not delivered a foal early in life may experience limitations in cervical relaxation, primarily during oestrus. A closed cervix prevents intrauterine deposition of semen during natural breeding, may delay uterine clearance after insemination leading to intrauterine fluid accumulation in, and subsequent infertility. Therefore, a reliable pharmacological method of dilating the equine cervix would have practical application in veterinary medicine. The goal of this study was to investigate the effectiveness of topically applied, synthetic prostaglandin E1 analogue (PGE1 ) for stimulating dilation of the equine cervix. Ten mares in dioestrus were randomly assigned to one of two treatments in a single-blind crossover study: (treatment) PGE1 gel (1000 mcg compounded misoprostol cream) applied topically to the external cervical os (n = 5), and (control) a vehicle cream applied topically to the external cervical os (n = 5). Transrectal palpation and ultrasonographic measurements of the cervix were performed prior to, six and 24 h post-treatment. Digital measurements were taken, per vagina, at six and 24 h post-treatment. Mares were monitored through the subsequent oestrous cycle for ovulation. Mares were assigned to the opposite treatment group such that each mare served as her own control (crossover). Data were analysed using parametric (split-plot anova), as well as nonparametric (Kruskal-Wallis anova, Wilcoxon's rank-sum test) methods. At six and 24 h there were no significant differences for tone, length, height, degree of relaxation or echotexture between control and PGE1 treated groups at the measured time points (p > 0.05). Topical cervical application of PGE1 did not induce a measurable degree of cervical relaxation under the conditions of this experiment.

Endometrial inflammatory markers of the early immune response in mares susceptible or resistant to persistent breeding-induced endometritis.

Transient endometritis after breeding is necessary for clearance of bacteria and spermatozoa; however, in a subpopulation of mares, the inflammation fails to resolve in a timely fashion. The objective of this study was to describe the uterine inflammatory response in mares susceptible or resistant to persistent breeding-induced endometritis (PBIE) during the first 24 h after induction of uterine inflammation.Twelve mares were classified as susceptible (nZ6) or resistant (nZ6) to PBIE. Mares were inseminated over five estrous cycles and endometrial biopsies were collected at one time point per cycle before (0) and 2, 6, 12, and 24 h after insemination. qPCR analysis for IL1B, IL6, IL8, IFNG, TNF (TNFA), IL10, and IL1RN was performed, and endometrial inflammatory cells were counted for each sample. Relative quantification values reported fold changes in mRNA expression from 0 h values. A general pattern of expression post insemination was observed in both groups of mares. Cytokine mRNA increased at 2 h, peaked between 2 and 12 h, and then decreased.Differences were detected between groups of mares 6 h after challenge; resistant mares had higher mRNA expression of IL6, IL1RN,and IL10 than susceptible mares. Susceptible mares had an increased number of polymorphonuclear neutrophils in the endometrium 2 and 12 h after breeding when compared with resistant mares. These findings describe an inherent difference in the initial immune response to insemination and may help explain the transient nature of inflammation in resistant mares, whereas susceptible mares develop a persistent inflammation.

An investigation of uterine nitric oxide production in mares susceptible and resistant to persistent breeding-induced endometritis and the effects of immunomodulation.

The first objective of this study was to evaluate intrauterine nitric oxide (NO) and endometrial inducible NO synthase (iNOS) in mares susceptible or resistant to persistent breeding-induced endometritis (PBIE) within 24 h after breeding. Mares susceptible (n = 6) or resistant (n = 6) to PBIE were inseminated over five cycles, and uterine secretions and endometrial biopsies were collected before and 2, 6, 12 and 24 h after insemination. Uterine secretions were analysed for NO and biopsies were analyzed for iNOS expression. A second experiment evaluated the effect of treatment with dexamethasone or mycobacterial cell wall extract (MCWE) on uterine NO production and endometrial iNOS mRNA expression. Six susceptible mares were inseminated over three cycles with (i) killed spermatozoa without treatment (control), (ii) killed spermatozoa with 50 mg of dexamethasone IV or (iii) MCWE IV 24 h prior to insemination with killed spermatozoa. Six resistant mares were inseminated with killed spermatozoa as a control. Six hours after breeding, uterine biopsies and secretions were collected and evaluated for NO and iNOS mRNA. In Experiment 1, resistant mares had an increase in iNOS mRNA expression 2 h post-breeding compared to baseline (p = 0.045), 12 h (p = 0.014) and 24 h (p = 0.001). Susceptible mares had higher expression 2 h compared to 6 h (p = 0.046). No differences were observed in mRNA or protein expression of iNOS between resistant and susceptible mares. Resistant mares had a relatively steady amount of total intrauterine NO over 24 h, while susceptible mares had an increase over time, with a significantly higher increase in total NO than resistant mares at 6 (p = 0.04) and 12 h (p = 0.032). In Experiment 2, no differences were observed for iNOS mRNA expression. Susceptible mares had increased NO when compared to resistant mares (p = 0.008) and MCWE decreased NO (p = 0.047).

Phytoplankton responses to changing temperature and nutrient availability are consistent across the tropical and subtropical Atlantic.

Temperature and nutrient supply interactively control phytoplankton growth and productivity, yet the role of these drivers together still has not been determined experimentally over large spatial scales in the oligotrophic ocean. We conducted four microcosm experiments in the tropical and subtropical Atlantic (29°N-27°S) in which surface plankton assemblages were exposed to all combinations of three temperatures (in situ, 3 °C warming and 3 °C cooling) and two nutrient treatments (unamended and enrichment with nitrogen and phosphorus). We found that chlorophyll a concentration and the biomass of picophytoplankton consistently increase in response to nutrient addition, whereas changes in temperature have a smaller and more variable effect. Nutrient enrichment leads to increased picoeukaryote abundance, depressed Prochlorococcus abundance, and increased contribution of small nanophytoplankton to total biomass. Warming and nutrient addition synergistically stimulate light-harvesting capacity, and accordingly the largest biomass response is observed in the warmed, nutrient-enriched treatment at the warmest and least oligotrophic location (12.7°N). While moderate nutrient increases have a much larger impact than varying temperature upon the growth and community structure of tropical phytoplankton, ocean warming may increase their ability to exploit events of enhanced nutrient availability.

Enhanced mercury reduction in the South Atlantic Ocean during carbon remineralization.

Mercury (Hg) in seawater is subject to interconversions via (photo)chemical and (micro)biological processes that determine the extent of dissolved gaseous mercury (DGM) (re)emission and the production of monomethylmercury. We investigated Hg speciation in the South Atlantic Ocean on a GEOTRACES cruise along a 40°S section between December 2011 and January 2012 (354 samples collected at 24 stations from surface to 5250 m maximum depth). Using statistical analysis, concentrations of methylated mercury (MeHg, geometric mean 35.4 fmol L-1) were related to seawater temperature, salinity, and fluorescence. DGM concentrations (geometric mean 0.17 pmol L-1) were related to water column depth, concentrations of macronutrients and dissolved inorganic carbon (DIC). The first-ever observed linear correlation between DGM and DIC obtained from high-resolution data indicates possible DGM production by organic matter remineralization via biological or dark abiotic reactions. DGM concentrations projected from literature DIC data using the newly discovered DGM-DIC relationship agreed with published DGM observations.

Transcriptional responses of Trichodesmium to natural inverse gradients of Fe and P availability.

The filamentous diazotrophic cyanobacterium Trichodesmium is responsible for a significant fraction of marine di-nitrogen (N2) fixation. Growth and distribution of Trichodesmium and other diazotrophs in the vast oligotrophic subtropical gyres is influenced by iron (Fe) and phosphorus (P) availability, while reciprocally influencing the biogeochemistry of these nutrients. Here we use observations across natural inverse gradients in Fe and P in the North Atlantic subtropical gyre (NASG) to demonstrate how Trichodesmium acclimates in situ to resource availability. Transcriptomic analysis identified progressive upregulation of known iron-stress biomarker genes with decreasing Fe availability, and progressive upregulation of genes involved in the acquisition of diverse P sources with decreasing P availability, while genes involved in N2 fixation were upregulated at the intersection under moderate Fe and P availability. Enhanced N2 fixation within the Fe and P co-stressed transition region was also associated with a distinct, consistent metabolic profile, including the expression of alternative photosynthetic pathways that potentially facilitate ATP generation required for N2 fixation with reduced net oxygen production. The observed response of Trichodesmium to availability of both Fe and P supports suggestions that these biogeochemically significant organisms employ unique molecular, and thus physiological responses as adaptations to specifically exploit the Fe and P co-limited niche they construct.

Late effects in survivors of teenage and young adult cancer: does age matter?

BACKGROUND: Late effects (LEs) after cancer treatment are increasing. After childhood cancer, substantial risks include physical, psychological and social LE and vary with age. Teenagers and young adults (TYA) present with particular cancers; their risk of LE may relate to cancer site, treatment or their age itself. The LEs after TYA-onset cancers are described in relation to age at diagnosis of primary tumour. PATIENTS AND METHODS: Data were extracted from Medline English language articles, 1999-2009. Keywords were late effect/s, late toxicity and survivor and the frequent TYA cancer sites. Only those articles that reported the relation between LEs risks with age at diagnosis were included. RESULTS: The majority of known LEs are described after TYA cancer. No study primarily aimed to relate TYA age to LEs. Many studies did not report LE by age. TYA-specific risks are seen in cardiac toxicity, second malignancies, pulmonary complications and psychosocial difficulties when compared with older or younger cancer survivors. CONCLUSIONS: TYA age brings specific LE risks after cancer. Prospective population-based collection of LE data after TYA cancer will inform the development of appropriate services to effectively manage LE.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Risk of breast cancer in male BRCA2 carriers.

The risk of breast cancer for unaffected men who test positive for a BRCA2 mutation is based on very few retrospective studies. We have used both retrospective and prospective analysis in 321 families with pathogenic BRCA2 mutations. Three breast cancers occurred in male first-degree relatives after family ascertainment in 4140 years of follow-up suggesting a risk of breast cancer to 80 years of 8.9%. A second analysis excluding index cases identified 16 breast cancers in 905 first-degree male relatives on which Kaplan-Meier analysis was performed after assigning carrier status. This analysis confirmed that breast cancer risk in men was 7.1% (SE 5.2-8.6%) by age 70 years and 8.4% (SE 6.2-10.6%) by age 80 years.

COVID-19 related moral injury: Associations with pandemic-related perceived threat and risky and protective behaviors.

BACKGROUND: The coronavirus-2019 (COVID-19) pandemic is associated with increased potential for morally injurious events, during which individuals may experience, witness, or learn about situations that violate deeply held moral beliefs. However, it is unknown how pandemic risk and resilience factors are associated with COVID-related moral injury. METHODS: Individuals residing in the U.S. (N = 839; Mage = 37.09, SD = 11.06; 78% women; 63% White; 33% PTSD) participating in an online survey reported on COVID-19 related moral injury (modified Moral Injury Events Scale), perceived current and future threat of pandemic on life domains (social, financial, health), and COVID-19 risky and protective behaviors. Multivariate linear regressions examined associations of perceived threat and risky and protective behaviors on type of COVID-19 related moral injury (betrayal, transgression by others, self). RESULTS: Participants endorsed MI betrayal (57%, N = 482), transgression by other (59%, N = 497), and by self 17% (N = 145). Adjusting for sociodemographics, only future threat of COVID-19 to health was significantly associated with betrayal (B = 0.21, p = .001) and transgression by other (B = 0.16, p = .01), but not by self. In contrast, high frequency of risky behaviors was associated with transgressions by self (B = 0.23, p < .001). Sensitivity analyses showed PTSD did not moderate the observed effects. CONCLUSIONS: Betrayal and transgression by others was associated with greater perceived future threat of COVID-19 to health, but not financial or social domains. Stronger endorsement of transgression by self was associated with more frequently engaging in risky behaviors for contracting COVID-19. These findings may suggest the need for individual, community, and system level interventions to address COVID-19 related moral injury.

A multifaceted analytical approach for detecting effects on semen quality when using small sample sizes.

Driven by technical, logistical and economic limitations, detection of treatment effects on semen quality typically include the design and collection of small sample datasets. A consequence of these small sample studies is that they suffer low statistical power. Historically, researchers faced with small sample size studies have relied upon non-parametric analysis; however, this approach is still unlikely to tease out a true statistical significance based upon limited sample size. Here we propose a novel methodology that can be applied in small samples study situations that combines repeated measures ANOVA and Mixed-Effects linear regression models with Bayesian Linear regression modeling when evaluating for treatment effects on quantitative semen quality parameters. Using this methodology, we show that investigating the data with this multifaceted analytical technique results in improved reproducibility and sensitivity of the findings while minimizing the likelihood of Type 1 errors when combining the inference statistics from multiple models/methodologies using Bayes Factor analysis.