UV Index monitoring in Europe.

The UV Index was established more than 20 years ago as a tool for sun protection and health care. Shortly after its introduction, UV Index monitoring started in several countries either by newly acquired instruments or by converting measurements from existing instruments into the UV Index. The number of stations and networks has increased over the years. Currently, 160 stations in 25 European countries deliver online values to the public via the Internet. In this paper an overview of these UV Index monitoring sites in Europe is given. The overview includes instruments as well as quality assurance and quality control procedures. Furthermore, some examples are given about how UV Index values are presented to the public. Through these efforts, 57% of the European population is supplied with high quality information, enabling them to adapt behaviour. Although health care, including skin cancer prevention, is cost-effective, a proportion of the European population still doesn't have access to UV Index information.

Coordinated expression of DNAM-1 and LFA-1 in educated NK cells.

The functional capacity of NK cells is dynamically tuned by integrated signals from inhibitory and activating cell surface receptors in a process termed NK cell education. However, the understanding of the cellular and molecular mechanisms behind this functional tuning is limited. In this study, we show that the expression of the adhesion molecule and activation receptor DNAX accessory molecule 1 (DNAM-1) correlates with the quantity and quality of the inhibitory input by HLA class I-specific killer cell Ig-like receptors and CD94/NKG2A as well as with the magnitude of functional responses. Upon target cell recognition, the conformational state of LFA-1 changed in educated NK cells, associated with rapid colocalization of both active LFA-1 and DNAM-1 at the immune synapse. Thus, the coordinated expression of LFA-1 and DNAM-1 is a central component of NK cell education and provides a potential mechanism for controlling cytotoxicity by functionally mature NK cells.

Nuclear IGF1R is a transcriptional co-activator of LEF1/TCF.

Recent findings suggest that nuclear IGF1R binds to enhancer regions and functions as a transcriptional cofactor. However, the downstream transcriptional regulators of this pathway remain to be defined. Here, we show that nuclear IGF1R associates with the transcription factor LEF1 and increases promoter activity of LEF1 downstream target genes cyclin D1 and axin2. Furthermore, nuclear IGF1R augments protein levels of cyclin D1 and axin2. Our findings suggest a novel function for IGF1R, thus further emphasizing the important role of this receptor in cancer biology.

Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education.

Natural killer (NK) cells are lymphocytes of the innate immune system that, following differentiation from CD56(bright) to CD56(dim) cells, have been thought to retain fixed functional and phenotypic properties throughout their lifespan. In contrast to this notion, we here show that CD56(dim) NK cells continue to differentiate. During this process, they lose expression of NKG2A, sequentially acquire inhibitory killer cell inhibitory immunoglobulin-like receptors and CD57, change their expression patterns of homing molecules, and display a gradual decline in proliferative capacity. All cellular intermediates of this process are represented in varying proportions at steady state and appear, over time, during the reconstitution of the immune system, as demonstrated in humanized mice and in patients undergoing hematopoietic stem cell transplantation. CD56(dim) NK-cell differentiation, and the associated functional imprint, occurs independently of NK-cell education by interactions with self-human leukocyte antigen class I ligands and is an essential part of the formation of human NK-cell repertoires.

KIR acquisition probabilities are independent of self-HLA class I ligands and increase with cellular KIR expression.

Inhibitory killer cell immunoglobulin-like receptors (KIRs) preserve tolerance to self and shape the functional response of human natural killer (NK) cells. Here, we have evaluated the influence of selection processes in the formation of inhibitory KIR repertoires in a cohort of 44 donors homozygous for the group A KIR haplotype. Coexpression of multiple KIRs was more frequent than expected by the product rule that describes random association of independent events. In line with this observation, the probability of KIR acquisition increased with the cellular expression of KIRs. Three types of KIR repertoires were distinguished that differed in frequencies of KIR- and NKG2A-positive cells but showed no dependency on the number of self-HLA class I ligands. Furthermore, the distribution of self- and nonself-KIRs at the cell surface reflected a random combination of receptors rather than a selection process conferred by cognate HLA class I molecules. Finally, NKG2A was found to buffer overall functional responses in KIR repertoires characterized by low-KIR expression frequencies. The results provide new insights into the formation of inhibitory KIR repertoires on human NK cells and support a model in which variegated KIR repertoires are generated through sequential and random acquisition of KIRs in the absence of selection.

Tolerant and diverse natural killer cell repertoires in the absence of selection.

Natural killer (NK) cells are innate lymphocytes that participate in the early control of viruses and tumors. The function of NK cells is under tight regulation by two complementary inhibitory receptor families that bind to classical and non-classical HLA class I molecules: the CD94/NKG2A receptors and the killer cell immunoglobulin-like receptors (KIRs). In this mini-review, recent data on the structure of human NK cell receptor repertoires and its relation to functional responses and tolerance to self are discussed. We propose that no active selection is required to generate diverse NK cell repertoires characterized by a dominant expression of receptors with specificity for self-HLA class I. Instead, the primary consequence of interactions with HLA class I molecules is a functional tuning of randomly generated NK cell repertoires.

Fathers' experiences of feeding their extremely preterm infants in family-centred neonatal intensive care: a qualitative study.

BACKGROUND: Extremely preterm infants need advanced intensive care for survival and are usually not discharged before they reach the time of expected birth. In a family-centred neonatal intensive care unit both parents are involved at all levels of care including the feeding process. However, studies focusing on fathers in this situation are scarce. The purpose of this study was to explore the experiences of feeding extremely preterm infants in a neonatal intensive care unit from fathers' perspectives. METHODS: The study adopts a qualitative inductive method, reported according to the COREQ checklist. Seven fathers of extremely preterm infants (gestational age 24-27 weeks) in neonatal intensive care in Sweden were interviewed by telephone after discharge in 2013-2014. The interviews were analysed using a qualitative content analysis and confirmed by triangulation in 2021. RESULTS: Six sub-categories and two generic categories formed the main category: "a team striving towards the same goal". The fathers were equally involved and engaged members of the feeding team all hours of the day. The fathers shared responsibility and practical duties with the mothers, and they provided as much support to the mothers as they could. However, the fathers found it difficult to support and encourage the mothers to breastfeed and express breastmilk when the breastmilk production was low. The fathers experienced a loss when breastfeeding was not successful. CONCLUSIONS: The findings indicate that fathers want to be involved with infant care, including night-time feeds, and long and demanding feeding processes. Fathers and staff need to collaborate to provide the best support to mothers during the feeding process. This study may inspire hospital staff to acknowledge and support fathers to become more involved in the oral feeding process when an infant is born extremely preterm.

Estimation of the size of the alloreactive NK cell repertoire: studies in individuals homozygous for the group A KIR haplotype.

Stem cell transplantation across HLA barriers may trigger NK cell-mediated graft-vs-leukemia effects leading to improved survival for patients with hematological malignancies. However, the genetic algorithm based on killer cell Ig-like receptor (KIR) and HLA genes used to predict NK cell alloreactivity have yielded discrepant results. Accordingly, it has been difficult to define transplantation settings that favor NK cell alloreactivity. In this study, we have used multiparameter flow cytometry to simultaneously analyze the cell surface expression of all four major inhibitory KIR and CD94/NKG2A to determine the size of the alloreactive NK cell repertoires in 31 individuals homozygous for the group A KIR haplotype. We observed a vast variability in the frequencies of cells with an alloreactive potential, ranging from 0 to 62% of the total NK cell population depending on which, and how many, KIR ligands were missing in theoretical recipients. This analysis required a functional examination of KIR3DL2-single positive NK cells, showing that this subset was hyporesponsive in individuals harboring the cognate ligands HLA-A3/A11. The results provide new insights into the variability of the functional alloreactive NK cell repertoire and have implications for donor selection in hematopoietic stem cell transplantation and adoptive NK cell-based immunotherapy.

Life Finds a Way: Young Adults With Lesbian Mothers Reflect on Their Childhood Prior to Legal Recognition of Same-Sex Parents in Sweden.

The strapline "life finds a way," from the classic movie Jurassic Park, referred to how the all-female dinosaurs in a theme park had been able to reproduce, despite the laws of nature. Similarly, the participants in the present study described how their lesbian mothers had shown that "life finds a way," when having children and forming a family, prior to the legal recognition of same-sex parents in Sweden. The study draws on interviews with eight young Swedish adults, aged 17-30 (average age 25). They had been raised by lesbian couples but were born prior to the legal recognition of same-sex parenthood. Prior to a legal change in 2003, a same-sex couple could not share legal parenthood. Further, female couples were excluded from Swedish assisted reproduction programs until 2005. The interviews have been analyzed thematically, and the article presents the results in four themes. The first theme, circumvent, oppose, or adapt to legal obstacles, shows the participants' reflections on how their parents navigated legal obstacles in order to have children and to live together as a family. The second theme, legal obstacles do not affect everyday life, depicts a common experience of how a lack of legal recognition seldom mattered to the participants during their childhood. Rather, they explained how their parents had been able to form parenthood and close relations without legal recognition. In contrast, the third theme describes occasions when legal parenthood matters. This theme highlights occasions when the lack of legal parenthood was problematic or devastating for the participants, such as when parents divorced, or one parent died. The final theme, the meaning of legal parents in adulthood, explores the participants' reflections on the meaning and impact of legal ties (or lack of legal ties) between themselves as young adults and their parents. The findings are discussed in relation to previous research on children and young adults with same-sex parents.

Focal adhesion kinase (FAK) activates and stabilizes IGF-1 receptor.

Recent studies have shown a direct association between IGF-1R and FAK, two important mediators of cell growth, survival and migration. However, the mechanism by which FAK affects IGF-1R function remains unknown. This study investigates the potential role of FAK in mediating activation and stability of IGF-1R. Autophosphorylation and phosphorylation capacities of wild type and mutant IGF-1R were studied. Surprisingly, we found that the mutant IGF-1R lacking the three core tyrosine residues in the activation-loop can be phosphorylated although it is unable to undergo autophosphorylation, suggesting that another kinase possesses the ability to phosphorylate IGF-1R. By using wild type MEFs and FAK-/- MEFs we could demonstrate that FAK mediates activation-loop independent phosphorylation, as well as Akt and ERK activation. Furthermore, the stability of IGF-1R was decreased upon FAK siRNA or inactivation. Taken together, our data suggest a role for FAK in phosphorylation, signaling and stability of the IGF-1R.

A novel strategy based on histological protein profiling in-silico for identifying potential biomarkers in urinary bladder cancer.

OBJECTIVE: To screen a publicly available immunohistochemistry (IHC) based web-atlas, to identify key proteins in bladder cancer that might serve as potential biomarkers. MATERIALS AND METHODS: The first version of the Human Protein Atlas (HPA 1.0), with 660 proteins, was visually examined to identify proteins with a variable staining pattern among the 12 tissue samples representing bladder cancer. None or limited previous characterization in bladder cancer, as well as a supportive Western blot, were also required. The selected proteins were then evaluated in an independent set of patient samples (106 tumour samples of differing stage and grade) represented in a tissue microarray (TMAi). The IHC expression of the identified proteins in the TMAi was scored and related to tumour stage and grade. RESULTS: The expression profiles of the 13 proteins selected from the web-atlas were confirmed in the TMAi. Expression patterns for seven proteins were significantly altered (P < 0.05) with higher stage and/or grade. Three of those (CN130, DSG3, PHF6) lack characterization in bladder cancer, whereas the remaining four proteins have previously been suggested as key proteins/potential biomarkers in cancer, some of them also in bladder cancer. CONCLUSION: New candidate proteins for urinary bladder cancer were identified through screening of the publicly available HPA 1.0. Although further evaluation is necessary, this strategy is promising in the search for new biomarkers, with potential to improve the management of patients with this disease.

Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma.

PURPOSE: The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulinlike growth factor-1 receptor (IGF-1R) and inhibits the growth of uveal melanoma cells in vitro and in vivo. In this study, the authors investigated the efficiency of orally administered PPP on the growth of uveal melanoma xenografts. In addition, they focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established antitumor agents in vitro. METHODS: Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-fluorouracil, and doxorubicin. Cell viability was determined by XTT assay. SCID mice that underwent xenografting with uveal melanoma cells were used to determine antitumor efficacy of oral PPP in vivo. Five mice were used per group. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by Western blotting. RESULTS: PPP was found to be superior to the other antitumor agents in killing uveal melanoma cells in all four cell lines (IC50 < 0.05 microM). Oral PPP inhibited uveal melanoma growth in vivo in OCM-3 (P = 0.03) and OCM-8 (P = 0.01) xenografts and was well tolerated by the animals. PPP decreased VEGF expression in the OCM-1 (P = 0.006) and OCM-8 (P = 0.01) tumors. CONCLUSIONS: Oral PPP was well tolerated in vivo, caused total growth inhibition of uveal melanoma xenografts, and decreased VEGF levels in the tumors.

Corrigendum: Insufficient antibody validation challenges oestrogen receptor beta research.

This corrects the article DOI: 10.1038/ncomms15840.

Insufficient antibody validation challenges oestrogen receptor beta research.

The discovery of oestrogen receptor ß (ERß/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ERα (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ERß antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ERß in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ERß protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

Estrogen actions in the brain.

Understanding of the mechanisms of estrogen action in the brain has always been poor. Neurons in several brain regions do not harbor estrogen receptor alpha (ERalpha) and yet are estrogen responsive. It was formerly thought that these responses represented indirect actions of estrogen. It is now evident that these neurons express ERbeta and that estrogen receptors have diverse actions in the central nervous system. By clear delineation of the cellular expression and function of the two estrogen receptors, it is likely that, in the future, selective ERalpha and ERbeta ligands will be developed and used for treatment of depression and behavioral disorders and may be useful in preventing degenerative diseases, such as Alzheimer's and Parkinson's disease.

Loss of Serglycin Promotes Primary Tumor Growth and Vessel Functionality in the RIP1-Tag2 Mouse Model for Spontaneous Insulinoma Formation.

The serglycin proteoglycan is mainly expressed by hematopoietic cells where the major function is to retain the content of storage granules and vesicles. In recent years, expression of serglycin has also been found in different forms of human malignancies and a high serglycin expression level has been correlated with a more migratory and invasive phenotype in the case of breast cancer and nasopharyngeal carcinoma. Serglycin has also been implicated in the development of the tumor vasculature in multiple myeloma and hepatocellular carcinoma where reduced expression of serglycin was correlated with a less extensive vasculature. To further investigate the contribution of serglycin to tumor development, we have used the immunocompetent RIP1-Tag2 mouse model of spontaneous insulinoma formation crossed into serglycin deficient mice. For the first time we show that serglycin-deficiency affects orthotopic primary tumor growth and tumor vascular functionality of late stage carcinomas. RIP1-Tag2 mice that lack serglycin develop larger tumors with a higher proliferative activity but unaltered apoptosis compared to normal RIP1-Tag2 mice. The absence of serglycin also enhances the tumor vessel functionality, which is better perfused than in tumors from serglycin wild type mice. The presence of the pro-angiogenic modulators vascular endothelial growth factor and hepatocyte growth factor were decreased in the serglycin deficient mice which suggests a less pro-angiogenic environment in the tumors of these animals. Taken together, we conclude that serglycin affects multiple aspects of spontaneous tumor formation, which strengthens the theory that serglycin acts as an important mediator in the formation and progression of tumors.

Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome.

5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-γ production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67+ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells.

A probabilistic model for hydrokinetic turbine collision risks: exploring impacts on fish.

A variety of hydrokinetic turbines are currently under development for power generation in rivers, tidal straits and ocean currents. Because some of these turbines are large, with rapidly moving rotor blades, the risk of collision with aquatic animals has been brought to attention. The behavior and fate of animals that approach such large hydrokinetic turbines have not yet been monitored at any detail. In this paper, we conduct a synthesis of the current knowledge and understanding of hydrokinetic turbine collision risks. The outcome is a generic fault tree based probabilistic model suitable for estimating population-level ecological risks. New video-based data on fish behavior in strong currents are provided and models describing fish avoidance behaviors are presented. The findings indicate low risk for small-sized fish. However, at large turbines (≥5 m), bigger fish seem to have high probability of collision, mostly because rotor detection and avoidance is difficult in low visibility. Risks can therefore be substantial for vulnerable populations of large-sized fish, which thrive in strong currents. The suggested collision risk model can be applied to different turbine designs and at a variety of locations as basis for case-specific risk assessments. The structure of the model facilitates successive model validation, refinement and application to other organism groups such as marine mammals.

Significant radiative impact of volcanic aerosol in the lowermost stratosphere.

Despite their potential to slow global warming, until recently, the radiative forcing associated with volcanic aerosols in the lowermost stratosphere (LMS) had not been considered. Here we study volcanic aerosol changes in the stratosphere using lidar measurements from the NASA CALIPSO satellite and aircraft measurements from the IAGOS-CARIBIC observatory. Between 2008 and 2012 volcanism frequently affected the Northern Hemisphere stratosphere aerosol loadings, whereas the Southern Hemisphere generally had loadings close to background conditions. We show that half of the global stratospheric aerosol optical depth following the Kasatochi, Sarychev and Nabro eruptions is attributable to LMS aerosol. On average, 30% of the global stratospheric aerosol optical depth originated in the LMS during the period 2008-2011. On the basis of the two independent, high-resolution measurement methods, we show that the LMS makes an important contribution to the overall volcanic forcing.

Update on estrogen signaling.

Our understanding of estrogen signaling has undergone a true paradigm shift over recent years, following the discovery in 1995 of a second estrogen receptor, estrogen receptor beta (ERbeta). In many contexts ERbeta appears to antagonize the actions of ERalpha (yin/yang relationship) although there also exist genes that are specifically regulated by one of the two receptors. Studies of ERbeta knockout mice have shown that ERbeta exerts important functions in the ovary, central nervous system, mammary gland, prostate gland, hematopoiesis, immune system, vessels and bone. The use of ERbeta-specific ligands against certain forms of cancer represents one of the many pharmaceutical possibilities that have been created thanks to the discovery of ERbeta.