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How do parties mobilise cultural expertise in Indigenous rights litigation in Scandinavia? Recently, Sami groups have litigated to claim Indigenous rights to land and natural resources, winning some remarkable victories in the Supreme Courts of Norway and Sweden. In this paper, we draw on socio-legal mobilisation theory to analyse the epistemic strategies of Sami litigants and their adversaries in two recent landmark Supreme Court cases on Indigenous rights to usage of land: the 2020 Girjascase in Sweden and the 2021 Fosencase in Norway. Conceptualising cultural expertise as a strategic framing contest, we analyse how the parties struggled over the epistemic basis of the respective case by legitimating their claims to cultural knowledge, drawing on academic research, and discrediting their opponents’ epistemic claims. Our findings suggest that in both cases, Sami claimants successfully established an epistemic basis where their traditional, experiential knowledge combined with independent academic expertise effectively challenged the knowledge claims of their adversaries. Yet, both cases also demonstrate how the linkage between Sami Indigeneity and reindeer husbandry in the national law of both countries excludes non-reindeer herding Sami persons from the Indigenous rights affirmed by the courts.

In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease.

Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.

ABSTRACT Lime-hemp concrete (LHC) is a sustainable building material that combines hemp shiv and building limes. Moisture fixation and thermal properties of LHC were determined so as to gain knowledge [...]

The most common malignancies that develop in carriers of BAP1germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAFmutations in cutaneous melanoma and enrichment for CRKLamplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13genes. This positional gene programme synergized with CRKLto amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

Internet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom.

Das Wissen über die genetischen Treiber und therapeutischen Zielstrukturen von Melanomen der Schleimhäute ist bisher lückenhaft, weil nur wenig umfassende Daten zu den Mutationen bei dieser seltenen Tumorart vorliegen. Um die genomische Landschaft des mukosalen Melanoms besser zu verstehen, beschreiben wir hier die Analyse von 67 Tumoren mittels Whole-Genome-Sequenzierung nebst Validierung von Treibermutationen durch Whole-Exome-Sequenzierung von 45 Tumoren. Die Tumoren zeigten eine geringe Punktmutationslast und eine hohe Zahl von Strukturvarianten, einschließlich rekurrenter Rearrangements im Bereich von TERT, CDK4und MDM2. Signifikant mutierte Gene sind NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-Aund CHD8. SF3B1-Mutationen kamen mit erhöhter Häufigkeit in Melanomen des weiblichen Genitaltrakts und der Anorektalregion vor, und CTNNB1-Mutationen deuten auf den Beitrag einer gestörten WNT-Signaltransduktion zur Entstehung eines Teils der Schleimhautmelanome hin. TERT-Aberrationen und ATRX-Mutationen sind mit Veränderungen der Telomerlängen assoziiert. Die Mutationsprofile eines Großteils der Schleimhautmelanome deuten auf eine mögliche Empfindlichkeit gegenüber CDK4/6- und/oder MEK-Inhibitoren hin.

Supplemental Digital Content is available in the text.

A core plant should be a centre of excellence, have a central role for knowledge creation, and ensure that the latest knowledge is diffused in the organisation's production network. Core plants can yield a range of benefits, such as increased resource efficiency and decreased costs in the production network. However, core plants face immense challenges in performing their roles, given the different interests of the different stakeholders that need to be satisfied. We use data gathered from an in-depth study of six core plants in Sweden to analyse the prerequisites. We conclude that the core plant prerequisites are influenced by human, organisational, and technological aspects, i.e., successful development of core plant capabilities can only be achieved if all the three components are considered together. Our findings are relevant to operation managers, plant managers, and others interested in developing and maintaining core plant excellence. [Submitted 01 March 2018; Accepted 18 March 2019]

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The Laser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy, and, as such, it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and space-born instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA’s first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed; ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or interme-diate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help making progress in the different areas. New research avenues that LISA itself, or its joint exploitation with upcoming studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe.

Supplemental Digital Content is available in the text.Germline mutations of BRCA1and BRCA2predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1or BRCA2by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1and BRCA2germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N= 763). We identified one individual with a deleterious BRCA1variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2mutations and UM susceptibility represents a rare source of increased risk.

The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signaling pathway, either BRAFV600E or NRASQ61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with UVR exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind E26 transformation-specific family transcription factors, as well as subclonal mutations in the TERTpromoter. This paper presents whole genome data from melanocytic nevi. We confirm that UVR is involved in the etiology of a subset of nevi. This study also establishes that TERTpromoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE–TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function.

Particles that diffuse in close proximity to a surface are expected to behave differently than in free solution because the surface interaction will influence a number of physical properties, including the hydrodynamic, optical, and thermal characteristics of the particle. Understanding the influence of such effects is particularly important in view of the increasing interest in laser tweezing of colloidal resonant nanoparticles for applications such as nanomotors and optical printing and for investigations of unconventional optical forces. Therefore, we used total internal reflection microscopy to probe the interaction between a glass surface and individual ∼100 nm gold nanoparticles trapped by laser tweezers. The results show that particles can be optically confined at controllable distances ranging between ∼30 and ∼90 nm from the surface, depending on the radiation pressure of the trapping laser and the ionic screening of the surrounding liquid. Moreover, the full particle–surface distance probability distribution can be obtained for single nanoparticles by analyzing temporal signal fluctuations. The experimental results are in excellent agreement with Brownian dynamics simulations that take the full force field and photothermal heating into account. At the observed particle–surface distances, translational friction coefficients increase by up to 60% compared to freely diffusing particles, whereas the rotational friction and thermal dissipation are much less affected. The methodology used here is general and can be adapted to a range of single nanoparticle–surface interaction investigations.

Supplemental Digital Content is available in the text.

Tumors are often polyclonal and are therefore heterogenous in their genomic and molecular profiles, which contributes to drug resistance and treatment failure. The methods used to detect these heterogenous differences in tumor samples are critical, but findings have been hindered by methodological inability to detect low-frequency subclones in bulk DNA. Chang et al.(2020) have addressed some of these methodological issues.

Purpose: The purpose of the study is to explore potential value conflicts between information security work and whistleblowing activities by analysing attitudes to whistleblowing among white-collar workers in Swedish organisations. Design/methodology/approach: The study is conducted using survey data among (n= 674) Swedish white-collar workers. Statistical analyses are conducted to explore variations in acceptance of whistleblowing and analyse the relationship between acceptance for whistleblowing and information security attitudes and behaviours. Findings: The study finds strong support for whistleblowing in both public and private spheres, and by both private and public sector employees. The study also finds stronger acceptance for intra-organisational whistleblowing, while support for external whistleblowing is low. Finally, the study shows that the whistleblowing activities might be perceived as coming in conflict with information security work, even as the support for including whistleblowing functions in information security practices is high. Research limitations/implications: With a focus on one country, the study is limited in terms of empirical scope. It is also limited by a relatively small number of respondents and survey items relating to whistleblowing, which in turn affects its explanatory value. However, the study does provide unique new insight into a specific form of “non-compliance”, i.e. whistleblowing, which merits further investigation. Originality/value: Few studies exist that combine insights from the fields of whistleblowing and information security research. Thus, this study provides a basis for further investigation into attitudes and behaviours linked to whistleblowing in public and private organisations, as well as attendant value conflicts related to information security management and practice.

Plasmonic gold nanorods are prime candidates for a variety of biomedical, spectroscopy, data storage, and sensing applications. It was recently shown that gold nanorods optically trapped by a focused circularly polarized laser beam can function as extremely efficient nanoscopic rotary motors. The system holds promise for applications ranging from nanofluidic flow control and nanorobotics to biomolecular actuation and analysis. However, to fully exploit this potential, one needs to be able to control and understand heating effects associated with laser trapping. We investigated photothermal heating of individual rotating gold nanorods by simultaneously probing their localized surface plasmon resonance spectrum and rotational Brownian dynamics over extended periods of time. The data reveal an extremely slow nanoparticle reshaping process, involving migration of the order of a few hundred atoms per minute, for moderate laser powers and a trapping wavelength close to plasmon resonance. The plasmon spectroscopy and Brownian analysis allows for separate temperature estimates based on the refractive index and the viscosity of the water surrounding a trapped nanorod. We show that both measurements yield similar effective temperatures, which correspond to the actual temperature at a distance of the order 10–15 nm from the particle surface. Our results shed light on photothermal processes on the nanoscale and will be useful in evaluating the applicability and performance of nanorod motors and optically heated nanoparticles for a variety of applications.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

This paper critically reviews the national strategies on e-health development in Sweden during the last decade. The aim is to identify the discourses that drive the development and implementation of eHealth in Sweden, with a particular focus on the rationales behind the government initiated PHR platform HälsaFörMig (HealthForMe), and discuss them in relation to health equity.

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

The identification of recurrent driver mutations by whole-exome sequencing (WES) of fresh-frozen human cancers and the subsequent development of novel targeted therapies have recently transformed the treatment of many cancers including melanoma. In routine clinical practice, fresh-frozen tissue is rarely available and mutation testing usually needs to be carried out on archival formalin fixed, paraffin embedded (FFPE) tissue, from which DNA is typically fragmented, cross-linked and of lower quality.

Efficient and robust artificial nanomotors could provide a variety of exciting possibilities for applications in physics, biology and chemistry, including nanoelectromechanical systems, biochemical sensing, and drug delivery. However, the application of current man-made nanomotors is limited by their sophisticated fabrication techniques, low mechanical output power and severe environmental requirements, making their performance far below that of natural biomotors. Here we show that single-crystal gold nanorods can be rotated extremely fast in aqueous solutions through optical torques dominated by plasmonic resonant scattering of circularly polarized laser light with power as low as a few mW. The nanorods are trapped in 2D against a glass surface, and their rotational dynamics is highly dependent on their surface plasmon resonance properties. They can be kept continuously rotating for hours with limited photothermal side effects and they can be applied for detection of molecular binding with high sensitivity. Because of their biocompatibility, mechanical and thermal stability, and record rotation speeds reaching up to 42 kHz (2.5 million revolutions per minute), these rotary nanomotors could advance technologies to meet a wide range of future nanomechanical and biomedical needs in fields such as nanorobotics, nanosurgery, DNA manipulation and nano/microfluidic flow control.

Whole genome sequencing (WGS) of cancer patients’ tumours offers the most comprehensive method of identifying both novel and known clinically-actionable genomic targets. However, the practicalities of performing WGS on clinical samples are poorly defined. This study was designed to test sample preparation, sequencing specifications and bioinformatic algorithms for their effect on accuracy and cost-efficiency in a large WGS analysis of human melanoma samples. WGS was performed on melanoma cell lines (n=15) and melanoma fresh frozen tumours (n=222). The appropriate level of coverage and the optimal mutation detection algorithm for the project pipeline were determined. An incremental increase in sequencing coverage from 36X to 132X in melanoma tissue samples and 30X to 103X for cell lines only resulted in a small increase (1–2%) in the number of mutations detected, and the quality scores of the additional mutations indicated a low probability that the mutations were real. The results suggest that 60X coverage for melanoma tissue and 40X for melanoma cell lines empower the detection of 98–99% of informative single nucleotide variants (SNVs), a sensitivity level at which clinical decision making or landscape research projects can be carried out with a high degree of confidence in the results. Likewise the bioinformatic mutation analysis methodology strongly influenced the number and quality of SNVs detected. Detecting mutations in the blood genomes separate to the tumour genomes generated 41% more SNVs than if the blood and melanoma tissue genomes were analysed simultaneously. Therefore, simultaneous analysis should be employed on matched melanoma tissue and blood genomes to reduce errors in mutation detection. This study provided valuable insights into the accuracy of SNV with WGS at various coverage levels in human clinical cancer specimens. Additionally, we investigated the accuracy of the publicly available mutation detection algorithms to detect cancer specific SNVs which will aid researchers and clinicians in study design and implementation of WGS for the identification of somatic mutations in other cancers.

Optical trapping using focused laser beams (laser tweezers) has been proven to be extremely useful for contactless manipulation of a variety of small objects, including biological cells, organelles within cells, and a wide range of other dielectric micro- and nano-objects. Colloidal metal nanoparticles have drawn increasing attention in the field of optical trapping because of their unique interactions with electromagnetic radiation, caused by surface plasmon resonance effects, enabling a large number of nano-optical applications of high current interest. Here we try to give a comprehensive overview of the field of laser trapping and manipulation of metal nanoparticles based on results reported in the recent literature. We also discuss and describe the fundamentals of optical forces in the context of plasmonic nanoparticles, including effects of polarization, optical angular momentum, and laser heating effects, as well as the various techniques that have been used to trap and manipulate metal nanoparticles. We conclude by suggesting possible directions for future research.

This paper attempts to explore an analogy between individual and organizational learning within experiential learning theory (ELT). The focus is on both the possibility of identifying a learning subject that learns in action, and on the genesis process behind the learning of a suggested learning subject at organizational level. The exploration uses an empirical study of a global software communication organization. The research adopts a qualitative approach, with data from three middle-management layers of a research and development (R&D) unit with 5,000 employees. During the study, shifts of emphasis occurred between two organizational logics, which required work-integrated learning. Metaphorically speaking, the organization was portrayed as ‘teeming with interaction’, and a growing wave of change decisively altered both the thinking and work processes within the organization. The organizational learning process is theoretically understood as an ‘augmented intense interaction’ around a specific content. The subject that learns and upholds the outcome is suggested to be the teeming activity, comprehended as a living organism. In practice, the awareness of an organization as a body that teems with interaction has potential to offer new understanding about how to manage change.

Localized surface-plasmon resonance (LSPR) sensors are typically based on tracing resonance peak shifts that precisely follow changes in the local refractive index. Such measurements usually require a spectrometer, a stable light source, and an accurate LSPR position tracing technique. As a simple but efficient alternative, we investigated a self-referenced single-wavelength sensing scheme based on angle-dependent and highly directional radiation patterns originating from a monolayer of asymmetric gold nanodimers. We found that one could easily trace a model biotin–neutravidin recognition reaction as well as minute bulk refractive index changes, by measuring the intensity ratio between the light scattered in two different directions with respect to the dimers. The refractometric resolution of the methodology was estimated to be on the order of Δn≈ 10–5RIU. These results may be particularly useful for label-free biosensing applications that require a combination of simple and cost-effective optical readout with a reasonable sensitivity.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1–risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

We have measured the angular distribution of light scattered off 2D plasmonic Al nanoparticle ensembles. We created these samples with disk-like nanoparticles, 175 and 500 nm in diameter, respectively, using hole-mask colloidal lithography and electron beam lithography. The nanoparticle arrangements in the samples display the short-range order (but no long-range order) characteristic for an ensemble formed by random sequential adsorption. As a consequence of this, the ensemble scattering patterns can be quantitatively well described by combining the single-particle scattering pattern with a static structure factor that carries information about the diffraction effects caused by the short-range order of the ensemble. We also performed sensing experiments in which we monitored changes in the angle-resolved scattering intensity for a fixed wavelength as a function of the thickness of an ultrathin SiO2coating covering the Al nanoparticles. The data show that the angle and strength of the main diffraction peak vary linearly with SiO2coating thickness in the range 1.5–4.5 nm and suggest that measurements of the scattering profile could be a competitive alternative to traditional transmission measurements in terms of sensitivity.

Symptomatic burden in myeloproliferative neoplasms is present in most patients and compromises quality of life. We sought to validate a broadly applicable 18-item instrument (Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF], coadministered with the Brief Fatigue Inventory) to assess symptoms of myelofibrosis, essential thrombocythemia, and polycythemia vera among prospective cohorts in the United States, Sweden, and Italy. A total of 402 MPN-SAF surveys were administered (English [25%], Italian [46%], and Swedish [28%]) in 161 patients with essential thrombocythemia, 145 patients with polycythemia vera, and 96 patients with myelofibrosis. Responses among the 3 administered languages showed great consistency after controlling for MPN subtype. Strong correlations existed between individual items and key symptomatic elements represented on both the MPN-SAF and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Enrolling physicians' blinded opinion of patient symptoms (6 symptoms assessed) were highly correlated with corresponding patients' responses. Serial administration of the English MPN-SAF among 53 patients showed that most MPN-SAF items are well correlated (r> 0.5, P< .001) and highly reproducible (intraclass correlation coefficient > 0.7). The MPN-SAF is a comprehensive and reliable instrument that is available in multiple languages to evaluate symptoms associated with all types of MPNs in clinical trials globally.

Cosmological simulations of galaxy formation appear to show a "two-phase" character with a rapid early phase at z [?] 2 during which "in situ" stars are formed within the galaxy from infalling cold gas followed by an extended phase since z [?] 3 during which "ex situ" stars are primarily accreted. In the latter phase, massive systems grow considerably in mass and radius by accretion of smaller satellite stellar systems formed at quite early times (z>3) outside of the virial radius of the forming central galaxy. These tentative conclusions are obtained from high-resolution re-simulations of 39 individual galaxies in a full cosmological context with present-day virial halo masses ranging from 7 x 1011 M h -1 [?]M vir [?] 2.7 x 1013 M h -1 (h = 0.72) and central galaxy masses between 4.5 x 1010 M h -1 [?] M * [?] 3.6 x 1011 M h -1. The simulations include the effects of a uniform UV background, radiative cooling, star formation, and energetic feedback from Type II supernova. The importance of stellar accretion increases with galaxy mass and toward lower redshift. In our simulations, lower mass galaxies (M * [?] 9 x 1010 M h -1) accrete about 60% of their present-day stellar mass. High-mass galaxy (M * [?] 1.7 x 1011 M h -1) assembly is dominated by accretion and merging with about 80% of the stars added by the present day. In general the simulated galaxies approximately double their mass since z = 1. For massive systems this mass growth is not accompanied by significant star formation. The majority of the in situ created stars are formed at z>2, primarily out of cold gas flows. We recover the observational result of "archaeological downsizing," where the most massive galaxies harbor the oldest stars. We find that this is not in contradiction with hierarchical structure formation. Most stars in the massive galaxies are formed early on in smaller structures; the galaxies themselves are assembled late.

To provide an overview of factors related to quality of life and symptoms of depression in heart failure patients and their partners. Furthermore, to give an overview of interventions that can be effective in improving their quality of life and decrease depressive symptoms.

We use a series of idealized, numerical smoothed particle hydrodynamics simulations to study the formation and evolution of galactic, gas-rich disks forming from gas infall within dark matter halos. The temperature and density structure of the gas is varied in order to differentiate between (1) simultaneous gas infall at a large range of radii and (2) the inside-out buildup of a disk. In all cases, the disks go through phases of ring formation, gravitational instability and break-up into massive clumps. Ring formation can be enhanced by a focal point effect. The position of the ring is determined by the angular momentum distribution of the material it forms from. We study the ring and clump morphologies, the characteristic properties of the resulting velocity dispersion field and the effect of star formation. In the early phases, gas accretion leads to a high vertical velocity dispersion. We find that the disk fragmentation by gravitational instability and the subsequent clump-clump interactions drive high velocity dispersions mainly in the plane of the disk while at the same time the vertical velocity dispersion dissipates. The result is a strong variation of the line-of-sight velocity dispersion with inclination angle. For a face-on view, clumps appear as minima in the (vertical) dispersion, whereas for a more edge-on view, they tend to correspond to maxima. There exists observational evidence of a systematic variation of the velocity dispersion with inclination angle in high-redshift disks, which could be partly explained by our simulation results. Additional energetic sources to drive velocity dispersion that are not included in our models are also expected to contribute to the observational results.

We present calculations of the optical forces between two metal nanospheres forming a hybridized plasmonic dimer. We consider homo- and heterodimers and investigate different plane wave illumination configurations. The forces between the particles are calculated using full Mie theory combined with the Maxwell stress tensor (MST) formalism, as well as by approximate methods, such as the Lorentz force (LF) approach taken in the dipole limit and calculations based on an optical potential. We show that the simplified calculation schemes can lead to serious errors in the case of strongly interacting particles and low damping. In particular, we find that equilibrium configurations, corresponding to vanishing optical forces, only are possible for homodimers illuminated in the end-fire configuration and for heterodimers, although multipolar effects and damping radically reduce the repulsive interactions in the latter case.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at ≤ 10 μM concentration. More interestingly, 17 compounds are active at ≤ 1 μM concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, 11 compounds are not currently used to treat NB. Among them, 9 are FDA approved compounds, and 3 agents are undergoing clinical trials for various malignancies. Furthermore, we identified 4 agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic.

We find that the amount and nature of the assumed ionizing background can strongly affect galaxy formation and evolution. Galaxy evolution simulations typically incorporate an ultraviolet background which falls off rapidly above z = 3; e.g., that of Haardt & Madau. However, this decline may be too steep to fit the Wilkinson Microwave Anistropy Probe constraints on electron scattering optical depth or observations of intermediate redshift (z [?] 2-4) Lya forest transmission. As an alternative, we present simulations of the cosmological formation of individual galaxies with UV backgrounds that decline more slowly at high redshift: both a simple intensity rescaling and the background recently derived by Faucher-Giguere, which softens the spectrum at higher redshifts. We also test an approximation of the X-ray background with a similar z dependence. We find for the test galaxies that an increase in either the intensity or hardness of ionizing radiation generically pushes star formation toward lower redshifts: although overall star formation in the simulation boxes is reduced by 10%-25%, the galaxies show a factor of [?]2 increase in the fraction of stars within a 30 kpc radius that are formed after z = 1. Other effects include late gas inflows enhanced up to 30 times, stellar half-mass radii decreased by up to 30%, central velocity dispersions increased up to 40%, and a strong reduction in substructure. The magnitude of the effects depends on the environmental/accretion properties of the particular galaxy.

We present binary galaxy merger simulations with varying mass ratios and different progenitor morphologies. The simulations include mergers of gas-rich disks (Sp-Sp), of early-type galaxies and disks (E-Sp, mixed mergers), and mergers of early-type galaxies (E-E, dry mergers). We follow the dynamics of gas, stars, and dark matter, and include radiative cooling, star formation and black hole (BH) accretion, and the associated feedback processes as in Springel et al. We study the mass assembly of the BHs and discuss technical issues of the implemented model in detail. For Sp-Sp mergers, the peak star formation rate and BH accretion rate decrease and the growth timescales of the central BHs and newly formed stars increase with higher progenitor mass ratios. The peak BH accretion rate typically occurs shortly after the time of BH merging for low progenitor mass ratios (e.g., 3:1 and lower), whereas for higher progenitor mass ratios there is no clear correlation between the peak BH accretion rate and the BH merging time. The termination of star formation by BH feedback in disk mergers is significantly less important for higher progenitor mass ratios (e.g., 3:1 and higher). In addition, the inclusion of BH feedback efficiently suppresses star formation in dry E-E mergers and mixed E-Sp mergers. All merger remnants, independent of their progenitors, follow the observed relations between the central BH mass and the stellar velocity dispersion (M BH - s), the bulge mass (M BH - M *), and the bulge binding energy (M BH - M *s2), with the dominant source of scatter arising from variations in the initial gas mass fraction. The normalizations for all relations and the simulated slope of the M BH - s and M BH - M *s2 relations are in good agreement with the observations, whereas the simulated slope of the M BH - M * relation is slightly steeper compared to the observations. This indicates that the simple BH feedback model self-regulates the mass growth of the BHs in accordance with the observed relations for a very wide range of merger progenitors.

Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.

Background: Fatigue is a common symptom associated with paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab, a C5 inhibitor approved for treatment of PNH, has been shown to significantly alleviate fatigue, as indicated by reduced scores on the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-Fatigue). FACIT-Fatigue scores range from 0-52 (higher scores indicate less fatigue); this assessment is validated for use in patients with PNH and has been used extensively both in clinical trials and in the International PNH Registry. In patients with cancer, the FACIT-Fatigue clinically important difference (CID) is estimated to be improvement of 3-5 points. This CID is commonly applied in PNH studies; however, no disease-specific CID for FACIT-Fatigue has been estimated in patients with PNH. A PNH-specific CID would be informative in evaluating changes in fatigue impact and could serve as a more robust criterion for evaluating treatment efficacy. The objective of this analysis was to determine the FACIT-Fatigue CID for patients with PNH using distribution- and anchor-based approaches and real-world data from the International PNH Registry.

The intrinsic anisotropy d and flattening [?] of simulated merger remnants is compared with elliptical galaxies that have been observed by the SAURON collaboration, and that were analyzed using axisymmetric Schwarzschild models. Collisionless binary mergers of stellar disks and disk mergers with an additional isothermal gas component, neglecting star formation, cannot reproduce the observed trend d = 0.55[?] (SAURON relationship). An excellent fit of the SAURON relationship for flattened ellipticals with [?] [?] 0.25 is, however, found for merger simulations of disks with gas fractions [?]20%, including star formation and stellar energy feedback. Massive black hole feedback does not strongly affect this result. Subsequent dry merging of these merger remnants does not generate the slowly rotating SAURON ellipticals, which are characterized by low ellipticities [?] < 0.25 and low anisotropies. These objects therefore might not have been shaped by a final major merger of either early-type galaxies or disks. We show, however, that stellar spheroids resulting from multiple, hierarchical mergers of star-bursting subunits in a cosmological context are in excellent agreement with the low ellipticities and anisotropies of the slowly rotating SAURON ellipticals and their observed trend of d with [?]. The numerical simulations indicate that the SAURON relation might be a result of strong violent relaxation and phase mixing of multiple, kinematically cold stellar subunits, with the angular momentum of the system determining its location on the relation.

We present a simple set of kinematic criteria that can distinguish between galaxies dominated by ordered rotational motion and those involved in major merger events. Our criteria are based on the dynamics of the warm ionized gas (as traced by Ha) within galaxies, making this analysis accessible to high-redshift systems, whose kinematics are primarily traceable through emission features. Using the method of kinemetry (developed by Krajnovic and coworkers), we quantify asymmetries in both the velocity and velocity dispersion maps of the warm gas, and the resulting criteria enable us to empirically differentiate between nonmerging and merging systems at high redshift. We apply these criteria to 11 of our best-studied rest-frame UV/optical-selected z [?] 2 galaxies for which we have near-infrared integral-field spectroscopic data from SINFONI on the VLT. Of these 11 systems, we find that >50% have kinematics consistent with a single rotating disk interpretation, while the remaining systems are more likely undergoing major mergers. This result, combined with the short formation timescales of these systems, provides evidence that rapid, smooth accretion of gas plays a significant role in galaxy formation at high redshift.

We describe high-resolution smoothed particle hydrodynamics (SPH) simulations of three approximately M* field galaxies starting from LCDM initial conditions. The simulations are made intentionally simple, and include photoionization, cooling of the intergalactic medium, and star formation, but not feedback from AGNs or supernovae. All of the galaxies undergo an initial burst of star formation at z [?] 5, accompanied by the formation of a bubble of heated gas. Two out of three galaxies show early-type properties at present, whereas only one of them experienced a major merger. Heating from shocks and PdV work dominates over cooling so that for most of the gas the temperature is an increasing function of time. By z [?] 1 a significant fraction of the final stellar system is in place and the spectral energy distribution resembles those of observed massive red galaxies. The galaxies have grown from z = 1 - 0 on average by 25% in mass and in size by gas-poor (dry) stellar mergers. By the present day the simulated galaxies are old ([?]10 Gyr), kinematically hot stellar systems surrounded by hot gaseous haloes. Stars dominate the mass of the galaxies up to [?]4 effective radii ([?]10 kpc). Kinematic and most photometric properties are in good agreement with those of observed elliptical galaxies. The galaxy with a major merger develops a counter-rotating core. Our simulations show that realistic intermediate-mass giant elliptical galaxies with plausible formation histories can be formed from LCDM initial conditions even without requiring recent major mergers or feedback from supernovae or AGNs.