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Henzell-Thomas, Jeremy, The Power of Education. Herndon: International Institute of Islamic Thought, 2018. pp. 36. ISBN: 978-56564-568-4

Microsoft Excel workbook containing the following gene lists and information; A) 500 most variable genes from Figure 1D, B) differentially expressed genes between ILC and IDC at baseline and 3 months of treatment using Rank Products with a cut-off of 0.05 PFP figure 2, C) differentially expressed genes after 3 months of letrozole in ILC and IDCILC tumors using pairwise Rank Products with a cut-off of 0.05 PFP (percent false positive) from figure 3, D) genes from Sikora et al. 2014 [5] that were represented in the combined Affymetrix/Illumina dataset, E) Additional sample information including the NCBI GEO Accession numbers of the Affymetrix data.

Nuclear magnetic resonance (NMR) probes using thin-film high temperature superconducting (HTS) resonators offer high sensitivity and are particularly suitable for small-sample applications. We are developing an improved 1.5 mm HTS NMR probe designed for operation at 14.1 T and optimized for (13)C detection. The total sample volume is about 35 μL and the active sample volume is 20 μL. The probe employs HTS resonators for (13)C and (1)H transmission and detection and the (2)H lock. We examine the interactions of multiple superconducting resonators and normal metal tuning loops on coil resonance frequency and probe sensitivity. We test a recently introduced (13)C resonator design, engineered to significantly increase (13)C detection sensitivity over previous all-HTS probes. At zero field, we observe a (13)C quality factor of 6000 which is several times higher than previous resonators. In this work the coil design considerations and probe build-out procedure are discussed.

The prognostic value of cytonuclear grade in ductal carcinoma in situ (DCIS) is debated, partly due to high interobserver variability and the use of multiple guidelines. The aim of this study was to evaluate interobserver agreement in grading DCIS between Dutch, British, and American pathologists. Haematoxylin and eosin-stained slides of 425 women with primary DCIS were independently reviewed by nine breast pathologists based in the Netherlands, the UK, and the USA. Chance-corrected kappa (kappa(ma)) for association between pathologists was calculated based on a generalised linear mixed model using the ordinal package in R. Overall kappa(ma) for grade of DCIS (low, intermediate, or high) was estimated to be 0.50 (95% confidence interval [CI] 0.44-0.56), indicating a moderate association between pathologists. When the model was adjusted for national guidelines, the association for grade did not change (kappa(ma) = 0.53; 95% CI 0.48-0.57); subgroup analysis for pathologists using the UK pathology guidelines only had significantly higher association (kappa(ma) = 0.58; 95% CI 0.56-0.61). To assess if concordance of grading relates to the expression of the oestrogen receptor (ER) and HER2, archived immunohistochemistry was analysed on a subgroup (n = 106). This showed that non-high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non-high grade cases, respectively). In conclusion, DCIS grade showed only moderate association using whole slide images scored by nine breast pathologists. As therapeutic decisions and inclusion in ongoing clinical trials are guided by DCIS grade, there is a pressing need to reduce interobserver variability in grading. ER and HER2 might be supportive to prevent the accidental and unwanted inclusion of high-grade DCIS in such trials.

In this article, we investigate the experiences of Latter-day Saint college students as they navigate and negotiate the complexities associated with maintaining their beliefs about homosexuality wh...

Significant sensitivity improvements have been achieved by utilizing high temperature superconducting (HTS) resonators in nuclear magnetic resonance (NMR) probes. Many nuclei such as (13)C benefit from strong excitation fields which cannot be produced by traditional HTS resonator designs. We investigate the use of double-sided, counter-wound multi-arm spiral HTS resonators with the aim of increasing the excitation field at the required nuclear Larmor frequency for (13)C. When compared to double-sided, counter-wound spiral resonators with similar geometry, simulations indicate that the multi-arm spiral version develops a more uniform current distribution. Preliminary tests of a two-arm resonator indicate that it may produce a stronger excitation field.

Background: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. Methods: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I–III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. Findings: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20–80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0–186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41–1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79–2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p

Over the last 30 years, there has been a growing trend among both professionals and nonprofessionals in applying an addiction framework to understand frequent sexual behavior and pornography viewin...

In this article, I introduce the concept of BDSM as trauma play, which is the practice of intentionally engaging in BDSM activities in order to “play” with one’s past trauma or abuse. I begin by offering a fuller definition of trauma play, and I then summarize some of the key scholarly discussions related to the topic, especially the themes of healing, therapy, play, and embodiment. Following this, I take an autoethnographic approach, and I investigate my own trauma play experiences, which I subsequently analyze and use to highlight the need for more systematic research into this understudied topic area that significantly impacts the lives of some BDSM practitioners.

Despite seemingly heightened curiosity in recent years among the general population, there is a reluctance among scholars to seriously explore consensual erotic practices generally falling under the broad umbrella of bondage and discipline, dominance and submission, and sadomasochism (BDSM). BDSM is typically performed by individuals, who after thorough negotiation and consent, control what will happen in a particular “scene,” and those who enjoy yielding to such control. People have long participated in the activities, dynamics, and relationships that people now refer to as BDSM. Despite scholars’ familiarity with Foucault’s classic documentation that science has largely taken over regulatory duties from religion concerning sexuality, modern sexuality scholars, for the most part, purposely continue to distance themselves from their topic, thus promoting the illusion of objectivity or neutrality. Despite tensions and challenges rooted in sex-negativity, the science of BDSM is shifting toward a much broader, multidisciplinary approach.

Forensic experts commonly state that many serial homicide offenders kill for the pleasure of it. At the same time, a small number of leisure scientists have suggested that serial murder may be a particular form of deviant leisure. Despite such suggestions, there has been little scholarly exploration of serial homicide from a leisure science perspective. This exploratory study adds to the existing literature by analyzing content of multiple key texts and documents that describe a large number of serial homicide cases in order to explore an understanding of murder as potential leisure. Leisure-related themes that emerged across case descriptions were (a) serial murder as a game, (b) murder for thrills and intense sensations, (c) murder for simple enjoyment and fun, and (d) murder as unique personal celebration. Subsequently, possible intrapersonal, interpersonal, and structural constraints to serial murder as possible leisure were identified. Implications for future research are also discussed.

Using a mixed methods design that compares quantitative content analysis of popular religious magazines with statistical analysis of national survey data, we show how the anti-pornography narratives that are predominant within different religious traditions can influence the effect that pornography viewing has on the marital happiness of husbands within those traditions. More specifically, we propose a causal chain that explains how meso-level anti-pornography narratives can influence micro-level pornography-effect scripts and, in turn, influence the effect that pornography viewing has on the marital happiness of husbands. We suggest, then, that this kind of causal chain can be thought of as a type of self-fulfilling prophecy. However, instead of operating exclusively at the micro-level as self-fulfilling prophecies have typically been theorized as doing, we apply the notion of the self-fulfilling prophecy to the meso-level, so that rather than just considering how individual thinking can lead to individual outcomes, we also consider how collective thinking can lead to collective outcomes.

There are many reports on the occurrence of anomalous changes in the ionosphere prior to large earthquakes. However, whether or not these changes are reliable precursors that could be useful for earthquake prediction is controversial within the scientific community. To test a possible statistical relationship between ionospheric disturbances and earthquakes, we compare changes in the total electron content (TEC) of the ionosphere with occurrences of M ≥ 6.0 earthquakes globally for 2000 - 2014. We use TEC data from the global ionosphere map (GIM) and an earthquake list declustered for aftershocks. For each earthquake, we look for anomalous changes in GIM-TEC within 2.5° latitude and 5.0° longitude of the earthquake location (the spatial resolution of GIM-TEC). Our analysis has not found any statistically significant changes in GIM-TEC prior to earthquakes. Thus, we have found no evidence that would suggest that monitoring changes in GIM-TEC might be useful for predicting earthquakes.

1. Maculinea (= Phengaris ) species of butterfly have complex life‐styles in which the larvae feed briefly on specific foodplants before entering the final instar, after which they live as social parasites within Myrmica ant colonies and acquire 98–99% of their ultimate biomass by either preying on ant brood (predatory species) or being fed by worker ants (cuckoo species). Cuckoo species demonstrate two growth forms, whereby some individuals develop to pupate in 11 months and others remain 23 months in the nest, a strategy that in theory represents the most efficient exploitation of resources within Myrmica societies. Early studies suggested that development rates in Maculinea rebeli (referred to by other authors as the xerophilous form of Maculinea alcon ) were not plastic but represented an unusual fixed polymorphism, in which eggs were genetically predetermined as 1‐ or 2‐year larvae. 2. We tested this idea in lab experiments using M. rebeli from the French Hautes‐Alpes, with these results: (i) the growth strategy of every individual larva is pre‐determined by the mother either genetically or, less probably, during oogenesis. (ii) Intra‐nest competition and host fitness affects survival and growth but does not influence the inherent growth strategy. (iii) The ratio of 1‐ and 2‐year developing larvae is initially about 50:50, although differential survival in crowded nests may alter the ratio of surviving individuals. (iv) All females tested laid eggs that hatched into both 1‐ or 2‐year developers. (v) Growth patterns vary between different regions. Larvae from the Spanish Pyrenees initially grow less than those from the Alps, with a smaller initial differentiation between the size classes.

1. The six papers in this Special Issue of Insect Conservation and Diversity are presented as a gedenkschrift honouring ground‐breaking contributions made by the late Graham Elmes towards understanding the biology of Myrmica ants and their social parasites. 2. A common theme is that each research paper contributes new knowledge applicable to the future survival of Maculinea (= Phengaris) species of butterflies, which have become flagships for insect conservation across Europe. All Maculinea species are highly specialised, with larvae that feed briefly on a specific foodplant before living underground for 11–23 months as social parasites of Myrmica colonies. 3. This introductory overview provides a brief history of the research that has led to the current collection, with emphasis on Graham Elmes' life and work. It is followed by three research papers that illustrate the diversity, socio‐biology and ecology of Myrmica ants. A fourth describes an extreme adaptation that increases the efficiency with which some populations of Maculinea larvae exploit the resources within Myrmica nests. A fifth, more theoretical, paper models the constraints that typically lead to host specificity among social parasites and explores why host switches are rare and quick.

1. The link between multi-host use and host switching in host–parasite interactions is a continuing area of debate. Lycaenid butterflies in the genus Maculinea, for example, exploit societies of different Myrmica ant species across their ranges, but there is only rare evidence that they simultaneously utilise multiple hosts at a local site, even where alternative hosts are present. 2. We present a simple population-genetic model accounting for the proportion of two alternative hosts and the fitness of parasite genotypes on each host. In agreement with standard models, we conclude that simultaneous host use is possible whenever fitness of heterozygotes on alternative hosts is not too low. 3. We specifically focus on host-shifting dynamics when the frequency of hosts changes. We find that (i) host shifting may proceed so rapidly that multiple host use is unlikely to be observed, (ii) back and forth transition in host use can exhibit a hysteresis loop, (iii) the parasites' host use may not be proportional to local host frequencies and be restricted to the rarer host under some conditions, and (iv) that a substantial decline in parasite abundance may typically precede a shift in host use. 4. We conclude that focusing not just on possible equilibrium conditions but also considering the dynamics of host shifting in non-equilibrium situations may provide added insights into host–parasite systems.

The range of hosts exploited by a parasite is determined by several factors, including host availability, infectivity and exploitability. Each of these can be the target of natural selection on both host and parasite, which will determine the local outcome of interactions, and potentially lead to coevolution. However, geographical variation in host use and specificity has rarely been investigated. Maculinea (= Phengaris ) butterflies are brood parasites of Myrmica ants that are patchily distributed across the Palæarctic and have been studied extensively in Europe. Here, we review the published records of ant host use by the European Maculinea species, as well as providing new host ant records for more than 100 sites across Europe. This comprehensive survey demonstrates that while all but one of the Myrmica species found on Maculinea sites have been recorded as hosts, the most common is often disproportionately highly exploited. Host sharing and host switching are both relatively common, but there is evidence of specialization at many sites, which varies among Maculinea species. We show that most Maculinea display the features expected for coevolution to occur in a geographic mosaic, which has probably allowed these rare butterflies to persist in Europe. This article is part of the theme issue ‘The coevolutionary biology of brood parasitism: from mechanism to pattern’.

Introduction Recent studies have suggested that, in contrast to traditional psychopathologic explanations, bondage and discipline, dominance and submission, and sadomasochism (BDSM) could be understood as recreational leisure. However, the theoretical framing of BDSM as potential leisure has not been empirically explored. Aim To conduct an initial empirical exploration to determine whether BDSM experience fits established characteristics of recreational leisure. Methods A convenience sample of BDSM participants (N = 935) completed an online survey (9 demographic questions and 17 leisure questions) that assessed BDSM experience according to important attributes of leisure. Responses also were assessed and statistically compared as being primarily casual or serious leisure according to general BDSM identities (ie, dominants vs submissives vs switches). Main outcome measures BDSM experiences were assessed as a form of potential leisure. Results Most BDSM experiences met leisure criteria. Participants reported that "most of the time or nearly always" BDSM was associated with a sense of personal freedom (89.7% of participants), pleasure or enjoyment (98.5%), sense of adventure (90.7%), use of personal skills (90.8%), relaxation or decreased stress (91.4%), self-expression or exploration (90.6%), and positive emotions (96.6%). BDSM seemed to function as primarily serious, rather than casual, leisure, but important statistical differences were observed based on specific BDSM identities. Conclusion A leisure science perspective could be valuable to researchers and clinicians in reinterpreting the wide range of diverse BDSM motivations and practices.

Based on an archival analysis of the popular evangelical magazine Christianity Today, the story of evangelical thinking about pornography during the course of the magazine's history from 1956 to 2014 is traced. This article shows how evangelicals have developed and deployed the idea of pornography addiction, and in doing so, have communicated messages about pornography that have made it more likely for evangelicals to perceive themselves as being addicted to pornography. This article investigates the motivations behind these messages, and suggests that these messages may, in fact, tell us less about individual pornography users and more about those who are developing and deploying such messages.

In natural ecosystems, relationships between organisms are often characterised by high levels of complexity, where vulnerabilities in multi-trophic systems are difficult to identify, yet variation in specific community modules can be traceable. Within the complex community interactions, we can shed new light on dynamics by which co-evolutionary outcomes can inform science-led conservation. Here we assessed host-ant use in six populations of the butterfly Phengaris (=Maculinea) rebeli, an obligate social parasite of Myrmica ants and a model system in evolutionary and conservation ecology. Starting from the initial distribution of eggs, we estimated the survival of the parasite in the wild in nests of seven Myrmica ant species, and analysed the chemical cues evolved by the parasites to subvert its host defences. We found local variations in host specificity that are consistent with similarities found in the chemical profiles of hosts and parasites on different sites. At some sites, only one ant species is successfully exploited; at others, multiple-host populations are used. Understanding how stable or adaptable these associations are is essential knowledge when devising conservation measures to maintain keystone species of ant and locally adapted populations of Phengaris butterfly species, which are rare, threatened and a high priority for conservation worldwide.

Introduction: Ductal Carcinoma In Situ (DCIS) is a proliferation of neoplastic cells confined to the ducto-lobular system. Due to uncertainty which DCIS lesions progress to invasive breast cancer women with DCIS receive surgery and radiotherapy. The PRECISION (PREvent ductal carcinoma In Situ Invasive Overtreatment Now) initiative intends to improve the management of DCIS including reduction of unnecessary treatment. Histological high grade is an unfavorable prognostic indicator used to guide treatment decisions, and used as an exclusion criterion for DCIS trials that randomize between active surveillance and standard treatment. Hence, accurate assessment of grade is important in current clinical practice. Pathologists within PRECISION setup this study to compare histological parameters of four retrospective DCIS cohorts from three different countries to investigate interobserver variability particularly in grading of DCIS. Method: Tissue slides from two population-based cohorts (UK Sloane cohort n=110; Dutch DCIS cohort n= 110) and two hospital based cohorts (Duke n=110; MDACC n=95) were included, leading to a total of 425 slides. All slides were reviewed by 9 breast pathologists originating from the UK, US and the Netherlands (NL) using the digital software platform Slidescore. The slides included were a representative selection of histological grades from all cases in these respective studies (see table 1 for distribution). Kappa (κ) values were calculated based on a generalized linear mixed model using the ordinal package in R. Results: The distribution of grade according to the majority opinion and originally assigned during diagnosis is shown in table 1. The cohort from NL demonstrated less grade 1 lesions according to the majority opinion compared to originally assigned grade. Table 2 shows the κ values of all evaluated histological variables. DCIS grade 1,2,3, grade 1/2 vs 3, necrosis and calcification show moderate agreement (κ between 0.4-0.6). Lymphocytic infiltrate, periductal fibrosis and mitoses demonstrate poor agreement (κ between 0.2-0.4). Conclusion: Histological factors including DCIS grade 1/2/3 and DCIS grade 1/2 versus 3 show only moderate agreement in this study using whole slide images. Preliminary analyses show no differences in κ values with the inclusion of country of the pathologist. However, the distribution of grade differs between the grading originally assigned and determined by majority opinion. Since clinical decisions are based on histological variables, it is important to realize that interobserver variability play a part in the diagnostic process. We are currently reviewing con- versus discordant cases and discussing how pathology guidelines can be improved. In addition, we are exploring whether artificial intelligence-based methods could be used to standardize grading of DCIS. Table 1. Distribution of grade of all slides and slides from participating centers. Slides were excluded if the majority opinion was equally divided between two grades or if originally grade 1-2/2-3 was assigned.Origin of tissue slidesGrade 1 (n)Grade 2 (n) Grade 3 (n)Excluded nAll tissue slides (n=425)Distribution according to majority opinion12% (49)40% (163)48% (197)16Distribution originally assigned12% (36)36% (111)53% (165)113Slides from Netherlands Cancer Institute (n=110)Distribution according to majority opinion6% (6)31% (33)64% (68)3Distribution originally assigned17% (19)33% (36)50% (55)0Slides from Sloane (n=110)Distribution according to majority opinion20% (20)51% (52)29% (30)8Distribution originally assigned11% (12)31% (34)58% (64)0Slides from Duke (n=110)Distribution according to majority opinion9% (10)44% (47)47% (50)3Distribution originally assigned5% (5)45% (41)50% (46)18Slides from MDAnderson (n=95)Distribution according to majority opinion14% (13)33% (31)53% (49)2Distribution originally assignedTo be collected Table 2. Kappa values of evaluated histological parametersVariableModel based weighted kappa (κma)95% confidence intervalDCIS grade 1/2/30.500.440.57DCIS grade 1/2 vs 30.520.440.60DCIS grade 1 vs 2/30.450.400.50DCIS grade low vs high0.520.440.59Necrosis absent vs present (manually dichotomized)0.550.510.59Calcification absent vs present0.510.480.55Lymphocytic infiltrate0.470.390.55Periductal fibrosis0.350.300.40Mitoses0.340.250.42 Citation Format: Maartje van Seijen, Katarzyna Jóźwiak, Sarah E Pinder, Allison Hall, Savitri Krishnamurthy, Jeremy SJ Thomas, Laura Collins, Jonathan Bijron, Joost Bart, Danielle Cohen, Wen Ng, Hilary Stobart, Jan Hudecek, Esther H Lips, Jelle Wesseling. Variability in ductal carcinoma in situ grading among an international group of pathologists [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-05.

Accurate assessment of estrogen receptor (ER) expression is crucial to ensure that patients with early breast cancer are accurately identified for appropriate treatment with endocrine therapy. Reverse transcriptase polymerase chain reaction (RT-PCR), compared with immunohistochemistry (IHC), may provide a more precise indication of ER status. Data were pooled and analyzed from two independent, but similarly designed, studies that examined ER status by IHC and the 21-gene Recurrence Score that employs RT-PCR-based methodology.Tumor tissue from patients with early stage breast cancer where ER status could be determined by both IHC and RT-PCR was included. ER status by IHC staining was defined as ER-negative ( 1%), ER-low+ (1-10%), or ER+ ( 10%). ER status by RT-PCR was defined as ER-negative (≤ 6.5) or ER+ ( 6.5). Recurrence Score results from the 21-gene assay were reported on a continuous scale from 0 to 100. A sub-analysis examined the association between ER expression (Allred score 2-7) and response to a 14-day pre-surgery pulse with an aromatase inhibitor. A separate sub-analysis examined the association between ER expression and human epidermal growth factor receptor 2 (HER2) expression.Tumor specimens from 192 patients (aged 25-92 years) were included in the pooled analysis. Correlation between IHC- and RT-PCR-measured ER was strong for IHC-defined ER-negative and ER+ samples (r = 0.646 [95% CI 0.553-0.720]). There was 100% concordance for ER+ tumors; however, 56% of the ER-low+ tumors were negative by RT-PCR. Allred score correlated better with ER status measured by RT-PCR at pre-treatment (r = 0.83) than at post-treatment (r = 0.76). The majority (77%) of ER-negative and ER-low+ tumors were HER2-negative.RT-PCR provided a more accurate assessment of ER expression in patients with ER-low+ tumors, and data support dual testing for patients with ER-low+ status to ensure appropriate treatment planning as it pertains to endocrine therapy.Genomic Health, Inc.

We examine the recent report of Febriani et al. (2014) in which the authors show changes in ULF magnetic field data prior to the M7.5 Tasikmalaya earthquake that occurred south of Java, Indonesia, on 2 September 2009. Febriani et al. (2014) state that the magnetic changes they found may be related to the impending earthquake. We do not agree that the pre-earthquake magnetic changes shown in Febriani et al. (2014) are seismogenic. These magnetic changes, indeed, are too closely related to global geomagnetic disturbances to be regarded as being of seismic origin.

Background The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model. Methods Consecutive tumour samples from 62 patients undergoing extended (4–45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13–120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as “dormant”, and the remaining 20 patients as “acquired resistant”. Results Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment. Conclusions This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy. Electronic supplementary material The online version of this article (10.1186/s13058-018-1089-5) contains supplementary material, which is available to authorized users.

Application of H2S (“sulfide”) elicits a complex contraction in rat pulmonary arteries (PAs) comprising a small transient contraction (phase 1; Ph1) followed by relaxation and then a second, larger, and more sustained contraction (phase 2; Ph2). We investigated the mechanisms causing this response using isometric myography in rat second-order PAs, with Na2S as a sulfide donor. Both phases of contraction to 1,000 μM Na2S were attenuated by the pan-PKC inhibitor Gö6983 (3 μM) and by 50 μM ryanodine; the Ca2+ channel blocker nifedipine (1 μM) was without effect. Ph2 was attenuated by the mitochondrial complex III blocker myxothiazol (1 μM), the NADPH oxidase (NOX) blocker VAS2870 (10 μM), and the antioxidant TEMPOL (3 mM) but was unaffected by the complex I blocker rotenone (1 μM). The bath sulfide concentration, measured using an amperometric sensor, decreased rapidly following Na2S application, and the peak of Ph2 occurred when this had fallen to ~50 μM. Sulfide caused a transient increase in NAD(P)H autofluorescence, the offset of which coincided with development of the Ph2 contraction. Sulfide also caused a brief mitochondrial hyperpolarization (assessed using tetramethylrhodamine ethyl ester), followed immediately by depolarization and then a second more prolonged hyperpolarization, the onset of which was temporally correlated with the Ph2 contraction. Sulfide application to cultured PA smooth muscle cells increased reactive oxygen species (ROS) production (recorded using L012); this was absent when the mitochondrial flavoprotein sulfide-quinone oxoreductase (SQR) was knocked down using small interfering RNA. We propose that the Ph2 contraction is largely caused by SQR-mediated sulfide metabolism, which, by donating electrons to ubiquinone, increases electron production by complex III and thereby ROS production.

A new storm-following tool continually watches for lightning over the open ocean. Combined with satellite microwave data, the new real-time observations will improve forecasts of tropical cyclones.

In this commentary, we show how self-disclosure can help elucidate the ways that the sexual desires of sex researchers can and do affect their research. We demonstrate this self-disclosure by exploring how our own sexual desires have affected some of our past research through influencing research project choices, methodological choices, methodological interactions, and research findings and conclusions. We propose that sex research of all kinds would benefit if sex researchers would be more willing to disclose their sexual desires and to consider and discuss how their sexual desires have affected their research.

The scientific literature includes many reports of ionospheric phenomena that are retrospectively identified prior to seismic events. These disturbances of the Earth's ionosphere are considered to be possible precursors of the impending earthquakes. However, a causal relationship between ionospheric phenomena and earthquakes has never been definitively demonstrated, and attempts at identifying precursory effects in the ionosphere have been called into question by several studies. Among the candidate indicators of ionospheric precursors there is the Spatial Scintillation Index (SSI) proposed by Pulinets et al. (2007). The usefulness of this index in the search for precursory effects of earthquakes has been criticized by Thomas et al. (2012) and Masci (2013). In a recent report, Pulinets and Davidenko (2014) attempt to briefly respond to the remarks of these researchers. Here we cast doubt that Pulinets and Davidenko (2014) have shown that SSI is a reliable indicator of precursory effects of earthquakes in the ionosphere.