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Emotional stress activates the sympathetic nervous system (SNS) and release of the neurotransmitter norepinephrine to promote breast tumor pathogenesis. We demonstrate here that the metastatic mammary adenocarcinoma cell line 4T1 does not express functional adrenergic receptors (AR), the receptors activated by norepinephrine, yet stimulation of adrenergic receptor in vivo altered 4T1 tumor progression in vivo. Chronic treatment with the antidepressant desipramine (DMI) to inhibit norepinephrine reuptake increased 4T1 tumor growth but not metastasis. Treatment with a highly selective α2-adrenergic receptor agonist, dexmedetomidine (DEX), increased tumor growth and metastasis. Neither isoproterenol (ISO), a β-AR agonist, nor phenylephrine, an α1-AR agonist, altered tumor growth or metastasis. Neither DMI- nor DEX-induced tumor growth was associated with increased angiogenesis. In DMI-treated mice, tumor VEGF, IL-6, and the prometastatic chemokines RANTES, M-CSF, and MIP-2 were reduced. Tumor collagen microstructure was examined using second harmonic generation (SHG), a nonabsorptive optical scattering process to highlight fibrillar collagen. In DMI- and DEX-treated mice, but not ISO-treated mice, tumor SHG was significantly altered without changing fibrillar collagen content, as detected by immunofluorescence. These results demonstrate that α2-AR activation can promote tumor progression in the absence of direct sympathetic input to breast tumor cells. The results also suggest that SNS activation may regulate tumor progression through alterations in the extracellular matrix, with outcome dependent on the combination of adrenergic receptor activated. These results underscore the complexities underlying SNS regulation of breast tumor pathogenesis, and suggest that the therapeutic use of adrenergic receptor blockers, tricyclic antidepressants, and adrenergic receptor agonists must be approached cautiously in patients with breast cancer. Cancer Prev Res; 6(12); 1262–72. ©2013 AACR.

Supplemental Fig. S1. 4T1 Cells Do Not Express Functional a2-AR. High dose DEX-induced effects on 4T1 (A) proliferation and (B) VEGF production in vitro are not blocked by the a2-AR antagonist yohimbine (YOH). (C) The alpha2-AR agonists clonidine (CLON) and dexmedetomidine (DEX) do not inhibit forskolin (FORSK)-induced cAMP in 4T1 cells. (D) CLON and DEX reduced FORSK-induced cAMP in human foreskin fibroblasts (HFF). Groups labeled with same letter are not significantly different from each other, but are significantly different from groups labeled with different letters, p{less than or equal to}0.01, Tukey's post-hoc test. Supplemental Fig. S2. DMI Elevates Spleen Norepinephrine (NE) and the NE Metabolite, Normetanephrine (NMN). Spleen (A) NE and (B) NMN were increased 3 days post-DMI pellet implantation. (C) Spleen weight was decreased day 3 post-DMI implantation. *** indicates significant differences versus corresponding placebo group, Holm-Sidak multiple comparison test, p

Palladium-catalyzed reactions are among the most commonly used procedures in organic synthesis. The products have a range of uses, including as intermediates in total synthesis and as screening compounds for drug discovery or agrochemical projects. Despite the known and potentially deleterious effects of low-level metal impurities in biological assays, the quantification of metal remaining in reaction products to verify the effective removal of the transition element is rarely reported. Using palladium as an exemplar, we describe a pilot study that for the first time quantifies residual metal levels in reaction products following increasingly rigorous purification protocols. Our results demonstrate that significant levels of residual palladium can remain in isolated reaction products following chromatographic purification, and only by using a subsequent metal scavenging step are they reliably reduced to a low level. Finally, we provide a set of simple guidelines that should minimize the potential for issues associated with residual palladium in reaction products.

The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR’s constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimized in terms of activity and physicochemical properties to yield OXS007417, a proof-of-concept tool compound, which was also able to decrease tumor volume in a murine in vivo xenograft model.

Introduction Undergraduate career aspirations are accurately translated to chosen career paths. Understanding what influences these decisions has implications for future workforce planning. The aim of this study was to identify future career intentions in Northern Irish Medical Students. Method An anonymous voluntary survey consisting of binominal, Likert and free text responses was distributed to all medical students registered at Queen’s University Belfast (QUB). Data was collected over 6 weeks in April-May 2021. The primary outcome was future career aspiration and secondary outcome was the reported attrition rate from medicine. Local Ethical approval was obtained. Results 202 responses were received (Response rate 15%). Two thirds (n = 135) were female. One third of respondents remained undecided about their future career choice, with senior students demonstrating greatest certainty in future career choice. Respondents were least likely to choose a career in Surgery (33%). Factors influencing these decisions were a lack of academic interest in the speciality, perceived workload, and the length of the training scheme. 10% of respondents were unsure or unlikely to pursue a career in Medicine after they graduated. Thematic analysis demonstrated, fear of making mistakes, poor work life balance and poor working environments as reasons for leaving medicine. Conclusions Uncertainty over future career intention remains common with surgery the least popular speciality. The rate of potential attrition is concerning which warrants further investigation.

Introduction Decisions made by medical students on future career choice have demonstrated consistency with resulting postgraduate career path. The aim of this qualitative study was to identify factors influencing career choice amongst medical students in Northern Ireland. Method An anonymous voluntary non-monetised survey consisting of binominal, Likert and free text responses was distributed to all medical students registered at Queen’s University Belfast (QUB). Data was collected over 6 weeks in April-May 2021. Primary outcomes were factors influencing future career choice and the secondary outcomes were the impact of finance and mentorship on ultimate career choice. Local ethical approval was obtained. Results 202 responses were received (Response rate 15%). 67% (n = 135) were female. One third of respondents remained undecided about their future career choice. Respondents were least likely to choose a career in Surgery (33%). Factors positively influencing career choice were academic interest and flexibility in working hours. Negative predictors of career choice were lack of interest in the area, perceived workload, and duration of training schemes. 71% (n = 144) of respondents reported that a subspecialty mentor would positively influence their career choice and two-thirds of respondents reported that financial factors would not influence their career decision. Conclusions Surgery was the least the popular specialty. Mentorship, integrating flexibility in training and enhancing academic interest may create greater traction for prospective trainees to surgery.

Mass wasting plays an important role on carbon cycling and sequestration by exposing fresh, weatherable bedrock and delivering hillslope sediments to lowlands and fluvial systems. Chemical weatheri...

We explore the use of femtosecond laser pulses to clean a variety of colors of spray paint from the Moruya granite, a stone with high heritage value that is widely used for monuments and sculptures in Sydney and New South Wales (Australia). The efficiency of the cleaning treatment and the effects on the stone substrate are evaluated using optical microscopy, optical profilometry, Raman spectroscopy, energy-dispersive X-ray spectroscopy, and colorimetry. We demonstrate that femtosecond laser cleans granite without damaging it and without discoloration when the laser fluence is set below the damage threshold of the stone.

The reconnection of the scientific community with phenotypic drug discovery has created exciting new possibilities to develop therapies for diseases with highly complex biology. It promises to revolutionise fields such as neurodegenerative disease and regenerative medicine, where the development of new drugs has consistently proved elusive. Arguably, the greatest challenge in readopting the phenotypic drug discovery approach exists in establishing a crucial chain of translatability between phenotype and benefit to patients in the clinic. This remains a key stumbling block for the field which needs to be overcome in order to fully realise the potential of phenotypic drug discovery. Excellent quality chemical probes and chemistry-based target deconvolution techniques will be a crucial part of this process. In this review, we discuss the current capabilities of chemical probes and chemistry-based target deconvolution methods and evaluate the next advances necessary in order to fully support phenotypic screening approaches in drug discovery., High quality chemical probes and chemistry-based target deconvolution techniques will be crucial to the advancement of phenotypic drug discovery, providing new hope for treatment of diseases with highly complex biology.

Acute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therapies that can target specific vulnerabilities of AML while having fewer toxic side effects. However, despite much recent progress in developing better drugs, many patients with AML still die within a year of diagnosis, partly due to the fact that it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Thus screening for compounds that can overcome this block in genetically diverse AML models should allow for the identification of agents that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify novel compounds that stimulate differentiation in several AML cell lines. Lead compounds were shown to decrease tumour burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimised in terms of activity and physicochemical properties to yield OXS007417, which was also able to decrease tumour volume in a murine in vivo xenograft model.

Barriers to the ready adoption of biocatalysis into asymmetric synthesis for early stage medicinal chemistry are addressed, using ketone reduction by alcohol dehydrogenase as a model reaction. An efficient substrate screening approach is used to show the wide substrate scope of commercial alcohol dehydrogenase enzymes, with a high tolerance to chemical groups employed in drug discovery (heterocycle, trifluoromethyl and nitrile/nitro groups) observed. We use our screening data to build a preliminary predictive pharmacophore-based screening tool using Forge software, with a precision of 0.67/1, demonstrating the potential for developing substrate screening tools for commercially available enzymes without publically available structures. We hope that this work, combined with our simple protocols for scaleable H2-driven biocatalytic ketone reduction, will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods.

Preclinical models of breast cancer have established mechanistic links between psychological stress and cancer progression. However, epidemiological evidence linking stress and cancer is equivocal. We tested the impact of stress exposure in female mice expressing the mouse mammary tumor virus polyoma middle-T antigen (MMTV-PyMT), a spontaneous model of mammary adenocarcinoma that mimics metastatic hormone receptor–positive human breast cancer development. MMTV-PyMT mice were socially isolated at 6 to 7 weeks of age during premalignant hyperplasia. To increase the potency of the stressor, singly housed mice were exposed to acute restraint stress (2 hours per day for 3 consecutive days) at 8 to 9 weeks of age during early carcinoma. Exposure to this dual stressor activated both major stress pathways, the sympathetic nervous system and hypothalamic-pituitary-adrenal axis throughout malignant transformation. Stressor exposure reduced mammary tumor burden in association with increased tumor cleaved caspase-3 expression, indicative of increased cell apoptosis. Stress exposure transiently increased tumor vascular endothelial growth factor and reduced tumor interleukin-6, but no other significant alterations in immune/inflammation-associated chemokines and cytokines or changes in myeloid cell populations were detected in tumors. No stress-induced change in second-harmonic generation-emitting collagen, indicative of a switch to a metastasis-promoting tumor extracellular matrix, was detected. Systemic indicators of slowed tumor progression included reduced myeloid-derived suppressor cell (MDSC) frequency in lung and spleen, and decreased transforming growth factor β (TGF-β) content in circulating exosomes, nanometer-sized particles associated with tumor progression. Chronic β-adrenergic receptor (β-AR) blockade with nadolol abrogated stress-induced alterations in tumor burden and cleaved caspase-3 expression, lung MDSC frequency, and exosomal TGF-β content. Despite the evidence for reduced tumor growth, metastatic lesions in the lung were not altered by stress exposure. Unexpectedly, β-blockade in nonstressed mice increased lung metastatic lesions and splenic MDSC frequency, suggesting that in MMTV-PyMT mice, β-AR activation also inhibits tumor progression in the absence of stress exposure. Together, these results suggest stress exposure can act through β-AR signaling to slow primary tumor growth in MMTV-PyMT mice.

The experimental shearing of granitic faults revealed complex evolution of strength and microstructure. We use a rotary shear apparatus to shear three types of granitic rocks at moderate slip-velocity of 0.01 - 0.11 m/s, normal stress of 1.0 - 6.8 MPa, and slip distance up to 60 m. Three stages of strength evolution with slip-distance were systematically observed. In Stage I, faults exhibited initial weakening in which the friction coefficient dropped to a steady-state level of μ ≈ 0.3. This weakening is associated with powder lubrication and the development of cohesive gouge layers. Stage II included strengthening to μ ≈ 0.5 associated with volumetric expansion, melting of fault patches, and viscous braking at these patches. In Stage III, fault weakening is due to melt lubrication when the melted patches reach a critical fraction of the fault surface area. We show that this complex weakening-strengthening-weakening evolution is controlled by thermally activated deformation processes that can explain the friction behavior of igneous rocks at seismic velocity range.

Pyroxene minerals are a significant component of Shergottite-Nakhlite-Chassignite (SNC) meteorites (e.g., Velbel 2012) and detected across large areas of Mars’ surface (e.g., Mustard et al. 2005). These minerals are associated with chloride, sulfate, and perchlorate salts that may represent briny waters present in Mars’ history. Previous textural analyses by Velbel and Losiak (2010) comparing pyroxenes and amphiboles from various natural weathering environments showed no correlation between apparent apical angles (describing the morphology of denticular weathering textures) and mineralogy or aqueous alteration history in relatively dilute solutions. However, high-salinity brines preferentially dissolve surface species, potentially leading to different textures dependent on the brine chemistry. In this study, we performed controlled pyroxene dissolution experiments in the laboratory on a well-characterized diopside to determine if aqueous alteration in different high-salinity brines, representative of potential weathering fluids on Mars, produce unique textural signatures. Following two months of dissolution in batch reactors, we observed denticles on etch pit margins and pyroxene chip boundaries in all of the solutions investigated: ultrapure water (18 MΩ cm −1 ; a H 2 O = 1); low-salinity solutions containing 0.35 M NaCl ( a H 2 O = 0.99), 0.35 M Na 2 SO 4 ( a H 2 O = 0.98), and 2 M NaClO 4 ( a H 2 O = 0.9); and near-saturated brines containing 1.7 M Na 2 SO 4 ( a H 2 O = 0.95), 3 M NaCl ( a H 2 O = 0.75), and 4.5 M CaCl 2 ( a H 2 O = 0.35). No systematic change in denticle length or apical angle was observed between any of the solutions investigated, even when altered in brines with significantly different salinity, activity of water, and anion composition. Based on these and previous results from natural systems, apical angle measurements are not a useful proxy for determining the extent or nature of aqueous alteration. However, since denticles form relatively slowly during weathering at circum-neutral pH, denticle length may be a useful proxy for chemical weathering duration. All of the experimental solutions produced median denticle lengths ≤1 μm, likely due to the brief weathering experiments. However, perchlorate brines produced a significantly wider range of denticle lengths than those observed in all the other experimental solutions tested. Since perchlorate is likely a common constituent in martian soils (Glotch et al. 2016), denticle length measurements should be used cautiously as proxies for extent of aqueous alteration on Mars, particularly in samples that also contain perchlorate.

Talc is present in several large-scale fault zones world-wide, and is mineralogically stable at temperature of the upper crust. It is therefore necessary to gain a better understanding of the frictional behavior of talc under a wide range of slip velocity conditions occurring during the seismic cycle. We analyzed the frictional and structural characteristics of room-dry and water-saturated talc gouge by shear experiments on a confined gouge layer at slip-velocity range of 0.002 – 0.66 m/s and normal stress up to 4.1 MPa. Room-dry talc showed a distinct slip-strengthening with the initial friction coefficient of μ ~ 0.4 increased systematically to μ ~ 1 at slip distance D > 1 m. Room-dry talc also displayed velocity-strengthening at slip-distances shorter than 1 m. The water-saturated talc gouge displayed systematic low frictional strength of μ = 0.1 - 0.3 for the entire experimental range, with clear velocity-strengthening behavior with positive (a-b) values (rate dependence parameter of rate- state- friction) of 0.01-0.04. The microstructural analyses revealed distributed shear and systematic dilation (up to 50%) for the room-dry talc, in contrast to the extreme slip localization and strong shear compaction for water-saturated talc. We propose that talc frictional strength is controlled by lubrication along cleavage surfaces that is facilitated by adsorbed water (room-dry) and surplus water (water-saturated). This mechanism can explain our experimental observations of slip-strengthening and velocity-strengthening for both types of talc gouge, as well as other clay minerals. It is thus expected that talc presence in fault-zones would enhance creep and inhibit unstable slip.

This review will highlight recently discovered mechanisms underlying sympathetic nervous system (SNS) regulation of the immune system in hematopoiesis, thermogenesis, and inflammation. This work in mammals illuminates potential mechanisms by which the nervous and immune systems may interact in invertebrate and early vertebrate species and allow diverse organisms to thrive under varying and extreme conditions and ultimately improve survival.

Approaches to the polyene natural product xanthomonadin, an octaenyl electron-deficient bacterial photoprotective agent, and its debromo analogue, were developed. These involved the iterative cross-coupling of multiple C2-fragments, using a vinylboronate ester as a formal vinyl dianion equivalent. Vinyl iodide starting materials undergo Heck-Mizoroki cross-coupling at ambient temperatures, allowing further iododeboronation to derive the next vinyl iodide. This works in a highly effective manner to access systems of up to pentaene chain length. However, final assembly of polyenylboronates with such polyenyl iodides through their Suzuki-Miyaura cross-coupling was less successful, even at lower temperatures, reflecting the extreme sensitivity of such octaenylxanthomonadin analogues. Despite this, the mild cross-coupling conditions could be effectively applied to the assembly of a range of useful polyenyl building blocks, as well as a truncated pentaenyl-debromoxanthomonadin analogue.

Two truncated analogues of the polyenyl photoprotective xanthomonadin pigments have been synthesised utilising an iterative Heck-Mizoroki/iododeboronation cross coupling approach and investigated as models of the natural products as photoprotective agents in bacteria. Use of this methodology enabled the construction of a key unsubstituted tetraenyl iodide building block, despite the instability of this type of compound. Both analogues proved to be sufficiently stable to allow isolation, spectroscopic analysis and biological studies into their photoprotective behaviour. Analysis of the spectroscopic properties of these analogues provided support for the limited structural characterisation previously reported for some of the xanthomonadins and also fitted their expected behaviour despite their shorter polyene chain length. This behaviour also extended to their ability to protect bacteria from photochemical damage: incorporation of one compound into E. coli provided photoprotective activity against singlet oxygen analogous to the natural photoprotective mechanisms employed by Xanthomonas bacteria. This answers some key questions about what minimal functionality is required to impart photoprotection and opens up an exciting avenue of research into new classes of photoprotective and antioxidants.

The zodiacal dust complex, a population of dust and small particles that pervades the Solar System, provides important insight into the formation and dynamics of planets, comets, asteroids, and other bodies. Here we present a new set of data obtained using a novel technique: direct measurements of momentum transfer to a spacecraft from individual particle impacts. This technique is made possible by the extreme precision of the instruments flown on the LISA Pathfinder spacecraft, a technology demonstrator for a future space-based gravitational wave observatory that operated near the first Sun-Earth Lagrange point from early 2016 through Summer of 2017. Using a simple model of the impacts and knowledge of the control system, we show that it is possible to detect impacts and measure properties such as the transferred momentum (related to the particle's mass and velocity), direction of travel, and location of impact on the spacecraft. In this paper, we present the results of a systematic search for impacts during 4348 hours of Pathfinder data. We report a total of 54 candidates with momenta ranging from 0.2$\,\mu\textrm{Ns}$ to 230$\,\mu\textrm{Ns}$. We furthermore make a comparison of these candidates with models of micrometeoroid populations in the inner solar system including those resulting from Jupiter-family comets, Oort-cloud comets, Hailey-type comets, and Asteroids. We find that our measured population is consistent with a population dominated by Jupiter-family comets with some evidence for a smaller contribution from Hailey-type comets. This is in agreement with consensus models of the zodiacal dust complex in the momentum range sampled by LISA Pathfinder., Comment: 22 pages, 14 figures, accepted in ApJ

Most radiative transfer models assume that dust in spiral galaxies is distributed exponentially. In this paper our goal is to verify this assumption by analysing the two-dimensional large-scale distribution of dust in galaxies from the DustPedia sample. For this purpose, we have made use of Herschel imaging in five bands, from 100 to 500 μm, in which the cold dust constituent is primarily traced and makes up the bulk of the dust mass in spiral galaxies. For a subsample of 320 disc galaxies, we successfully performed a simultaneous fitting with a single Srsic model of the Herschel images in all five bands using the multi-band modelling code galfitm. We report that the Srsic index n, which characterises the shape of the Srsic profile, lies systematically below 1 in all Herschel bands and is almost constant with wavelength. The average value at 250 μm is 0:67 ± 0:37 (187 galaxies are fitted with n 250 = 0:75, 87 galaxies have 0:75 < n 250 = 1:25, and 46 with n 250 > 1:25). Most observed profiles exhibit a depletion in the inner region (at r < 0:3-0:4 of the optical radius r 25 ) and are more or less exponential in the outer part. We also find breaks in the dust emission profiles at longer distances (0:5-0:6) r25 which are associated with the breaks in the optical and near-infrared. We assumed that the observed deficit of dust emission in the inner galaxy region is related to the depression in the radial profile of the Hi surface density in the same region because the atomic gas reaches high enough surface densities there to be transformed into molecular gas. If a galaxy has a triggered star formation in the inner region (for example, because of a strong bar instability, which transfers the gas inwards to the centre, or a pseudobulge formation), no depletion or even an excess of dust emission in the centre is observed. © 2019 ESO.

Observations of evolution in the dust-to-metal ratio allow us to constrain the dominant dust processing mechanisms. In this work, we present a study of the dust-to-metal and dust-to-gas ratios in a sub-sample of ~500 DustPedia galaxies. Using literature and MUSE emission line fluxes, we derived gas-phase metallicities (oxygen abundances) for over 10 000 individual regions and determine characteristic metallicities for each galaxy. We study how the relative dust, gas, and metal contents of galaxies evolve by using metallicity and gas fraction as proxies for evolutionary state. The global oxygen abundance and nitrogen-to-oxygen ratio are found to increase monotonically as galaxies evolve. Additionally, unevolved galaxies (gas fraction >60%, metallicity 12 + log(O H) < 8.2) have dust-to-metal ratios that are about a factor of 2.1 lower (a factor of six lower for galaxies with gas fraction >80%) than the typical dust-to-metal ratio (Md MZ ~ 0.214) for more evolved sources. However, for high gas fractions, the scatter is larger due to larger observational uncertainties as well as a potential dependence of the dust grain growth timescale and supernova dust yield on local conditions and star formation histories. We find chemical evolution models with a strong contribution from dust grain growth describe these observations reasonably well. The dust-to-metal ratio is also found to be lower for low stellar masses and high specific star formation rates (with the exception of some sources undergoing a starburst). Finally, the metallicity gradient correlates weakly with the HI-to-stellar mass ratio, the effective radius and the dust-to-stellar mass ratio, but not with stellar mass. © 2019 ESO.

Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression.

Aims. We aim to study the fraction of stellar radiation absorbed by dust, fabs, in 814 galaxies of different morphological types. The targets constitute the vast majority (93%) of the DustPedia sample, including almost all large (optical diameter larger than 10), nearby (v ≤ 3000 km s-1) galaxies observed with the Herschel Space Observatory. Methods. For each object, we modelled the spectral energy distribution from the ultraviolet to the sub-millimetre using the dedicated, aperture-matched DustPedia photometry and the Code Investigating GALaxy Evolution (CIGALE). The value of fabs was obtained from the total luminosity emitted by dust and from the bolometric luminosity, which are estimated by the fit. Results. On average, 19% of the stellar radiation is absorbed by dust in DustPedia galaxies. The fraction rises to 25% if only late-type galaxies are considered. The dependence of fabs on morphology, showing a peak for Sb-Sc galaxies, is weak; it reflects a stronger, yet broad, positive correlation with the bolometric luminosity, which is identified for late-type, disk-dominated, high-specific-starformation rate, gas-rich objects. We find no variation of fabs with inclination, at odds with radiative transfer models of edge-on galaxies. These results call for a self-consistent modelling of the evolution of the dust mass and geometry along the build-up of the stellar content. We also provide template spectral energy distributions in bins of morphology and luminosity and study the variation of fabs with stellar mass and specific star-formation rate. We confirm that the local Universe is missing the high fabs, luminous and actively star-forming objects necessary to explain the energy budget in observations of the extragalactic background light. © ESO 2018.

Natural examples demonstrate uranyl-phosphate minerals can maintain extremely low levels of aqueous uranium in groundwaters due to their low solubility. Therefore, greater understanding of the geochemical factors leading to uranyl phosphate precipitation may lead to successful application of phosphate-based remediation methods. However, the solubility of uranyl phosphate phases varies over >3 orders of magnitude, with the most soluble phases typically observed in lab experiments. To understand the role of common soil/sediment mineral surfaces in the nucleation and transformation of uranyl phosphate minerals under environmentally relevant conditions, batch experiments were carried out with goethite and mica at pH 6 in mixed electrolyte solutions ranging from 1–800 μM U and 1–800 μM P. All experiments ended with uranium concentrations below the USEPA MCL for U, but with 2–3 orders of magnitude difference in uranium concentrations. Despite the presence of many cations that are well known to incorporate into less soluble autunite-group minerals, chernikovite rapidly precipitated in all experiments containing U and P, except for solutions with 1 μM U and 1 μM P that were calculated to be undersaturated. Textures of uranyl phosphates observed by AFM and TEM indicate that nucleation was homogenous and independent of the initial mineral content. Comparison of time-course U and P concentrations from the experiments with thermodynamic modeling of solution equilibria demonstrated that aqueous uranium concentrations in the experimental systems evolved as increasingly sparingly soluble uranyl phosphate phases nucleated over time, with sorption accelerating the transition between phases by influencing solution chemistry. Aqueous uranium concentrations consistent with partially dehydrated (meta-) autunite were achieved only in experiments containing goethite and/or mica. These dynamic nucleation-growth-sorption-nucleation-growth-sorption cycles occur over the time scales of weeks, not hours or days at room temperature. Lab experiments and field-based investigations of uranium phosphate should consider these or longer time scales for the greatest long-term relevance.

Jarosite flow-through dissolution experiments were conducted in ultrapure water (UPW), pH 2 sulfuric acid, and saturated NaCl and CaCl2 brines at 295–298 K to investigate how hydrologic variables may affect jarosite preservation and reaction products on Mars. K+-based dissolution rates in flowing UPW did not vary significantly with flow rate, indicating that mineral surface reactions control dissolution rates over the range of flow rates investigated. In all of the solutions tested, hydrologic variables do not significantly affect extent of jarosite alteration; therefore, jarosite is equally likely to be preserved in flowing or stagnant waters on Mars. However, increasing flow rate did affect the mineralogy and accumulation of secondary reaction products. Iron release rates in dilute solutions increased as the flow rate increased, likely due to nanoscale iron (hydr)oxide transport in flowing water. Anhydrite formed in CaCl2 brine flow-through experiments despite low temperatures, while metastable gypsum and bassanite were observed in batch experiments. Therefore, observations of the hydration state of calcium sulfate minerals on Mars may provide clues to unravel past salinity and hydrologic conditions as well as temperatures and vapor pressures.

Vinyliodide reacts chemoselectively under Heck–Mizoroki conditions with terminal alkenes to give diene products, including vinyl boronate esters, and the resulting dienylboronate undergoes Suzuki–Miyaura coupling with aryl, heteroaryl and alkenyl halides to access dienes and trienes.

This paper describes a methodology to analyze, in the frequency domain, the steady-state control performances of the LISA Pathfinder mission. In particular, it provides a technical framework to give a comprehensive understanding of the spectra of all the degrees of freedom by breaking them down into their various physical origins, hence bringing out the major contributions of the control residuals. A reconstruction of the measured in-loop output, extracted from a model of the closed-loop system, is shown as an instance to illustrate the potential of such a model breakdown of the data.

LISA Pathfinder, the European Space Agency's technology demonstrator mission for future spaceborne gravitational wave observatories, was launched on 3 December 2015, from the European space port of Kourou, French Guiana. After a short duration transfer to the final science orbit, the mission has been gathering science data since. This data has allowed the science community to validate the critical technologies and measurement principle for low frequency gravitational wave detection and thereby confirming the readiness to start the next generation gravitational wave observatories, such as LISA. This paper will briefly describe the mission, followed by a description of the science operations highlighting the performance achieved. Details of the various experiments performed during the nominal science operations phase can be found in accompanying papers in this volume.

We report on electrostatic measurements made on board the European Space Agency mission LISA Pathfinder. Detailed measurements of the charge-induced electrostatic forces exerted on free-falling test masses (TMs) inside the capacitive gravitational reference sensor are the first made in a relevant environment for a space-based gravitational wave detector. Employing a combination of charge control and electric-field compensation, we show that the level of charge-induced acceleration noise on a single TM can be maintained at a level close to 1.0 fm/s^2/sqrt(Hz) across the 0.1-100 mHz frequency band that is crucial to an observatory such as LISA. Using dedicated measurements that detect these effects in the differential acceleration between the two test masses, we resolve the stochastic nature of the TM charge build up due to interplanetary cosmic rays and the TM charge-to-force coupling through stray electric fields in the sensor. All our measurements are in good agreement with predictions based on a relatively simple electrostatic model of the LISA Pathfinder instrument., Comment: 9 Pages, 3 figures

Genes predicted to by dysregulated in the studied PC3 model of Docetaxel Resistance. AG = aged matched control, D8 = docetaxel resistant subline, D12 = docetaxel resistant subline. FC = fold change. (DOCX 79 kb)

Characteristics of patient cohort and differences between Docetaxel naïve and Docetaxel resistant patients. N = 42. Values are presented as mean (standard deviation). * P-values

A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.

Conventional SBF (simulated/synthetic body fluid) solutions are buffered at pH 7.4 degrees C and 37 degrees C using 50mM Tris [(HOCH2)(3)CNH2]. Tris is not present in human blood or metabolism and its high concentration makes it the third major component of SBF solutions. All three crystalline polymorphs of calcium carbonate (calcite, aragonite and vaterite) have never been tested simultaneously in an SBF solution. This study presents the SBF-testing of the particles of these polymorphs at 37 degrees C in Na-L-lactate (22mM)-buffered Lac-SBF solution. While the calcite rhombohedra remained completely inert in the solution, vaterite spherulites and aragonite needles accrued apatitic CaP (calcium phosphate) deposits on their surfaces. Mg-doped (1050ppm) synthetic aragonite particles did not transform into calcite for 96h in the Lac-SBF solution while increasing their BET surface area by about 560% via the apatitic CaP deposits. Given the well-established use of calcite powders in CaP cement formulations, synthetic aragonite particles may be a potential replacement for calcite due to their rapid response to blood plasma-like solutions in between 24 and 48h at 37 degrees C.

Emotional stress activates the sympathetic nervous system (SNS) and release of the neurotransmitter norepinephrine to promote breast tumor pathogenesis. We demonstrate here that the metastatic mammary adenocarcinoma cell line 4T1 does not express functional adrenergic receptors (AR), the receptors activated by norepinephrine, yet stimulation of adrenergic receptor in vivo altered 4T1 tumor progression in vivo. Chronic treatment with the antidepressant desipramine (DMI) to inhibit norepinephrine reuptake increased 4T1 tumor growth but not metastasis. Treatment with a highly selective α2-adrenergic receptor agonist, dexmedetomidine (DEX), increased tumor growth and metastasis. Neither isoproterenol (ISO), a β-AR agonist, nor phenylephrine, an α1-AR agonist, altered tumor growth or metastasis. Neither DMI- nor DEX-induced tumor growth was associated with increased angiogenesis. In DMI-treated mice, tumor VEGF, IL-6, and the prometastatic chemokines RANTES, M-CSF, and MIP-2 were reduced. Tumor collagen microstructure was examined using second harmonic generation (SHG), a nonabsorptive optical scattering process to highlight fibrillar collagen. In DMI- and DEX-treated mice, but not ISO-treated mice, tumor SHG was significantly altered without changing fibrillar collagen content, as detected by immunofluorescence. These results demonstrate that α2-AR activation can promote tumor progression in the absence of direct sympathetic input to breast tumor cells. The results also suggest that SNS activation may regulate tumor progression through alterations in the extracellular matrix, with outcome dependent on the combination of adrenergic receptor activated. These results underscore the complexities underlying SNS regulation of breast tumor pathogenesis, and suggest that the therapeutic use of adrenergic receptor blockers, tricyclic antidepressants, and adrenergic receptor agonists must be approached cautiously in patients with breast cancer. Cancer Prev Res; 6(12); 1262–72. ©2013 AACR.

Slip during large earthquakes occurs along faults that are hundreds of kilometers long, yet the dynamic weakening that drives these earthquakes is controlled by nano- to micro-scale frictional processes. We analyzed these processes along experimental faults that slipped at rates approaching seismic velocity, and which displayed intense dynamic weakening of 50%–70%. Sheared fault surfaces were extracted, and then atomic force microscopy was used to (1) measure friction on a sub-micron scale, and (2) determine the three-dimensional morphology at the nano- to micro-scale. The sheared surfaces developed a prevalent anisotropy with a weaker and smoother axis along the slip direction. The nanoscale friction coefficient correlates well with sheared-surface roughness: the friction coefficients dropped only on surfaces with root mean square (RMS) values of

Hydroxyapatite-like (apatitic) calcium phosphate (Ap-CaP) powders are usually synthesized in stirred solutions containing the highly soluble salts of calcium, such as calcium nitrate, calcium acetate and calcium chloride as the Ca-source. The current study tested the ideas of simultaneously using (i) precipitated calcite (CaCO3) powders as the Ca-source and (ii) non-stirred, static solutions for synthesizing carbonated, Na+- and Mg2+-doped apatitic calcium phosphate (Ap-CaP) powders. 0.5 M phosphate buffer (non-saline) solutions were used as the sole phosphate source. The synthesized Ap-CaP powders were found to consist of micron-size carnation-like crystalline particles. Samples were characterized by FE-SEM, XRD, FTIR, ICP-AES, dynamic light scattering (DLS), carbon percentage and BET surface area analyses.

In this paper, we describe the current status of the LISA Pathfinder mission, a precursor mission aimed at demonstrating key technologies for future space-based gravitational wave detectors, like LISA. Since much of the flight hardware has already been constructed and tested, we will show that performance measurements and analysis of these flight components lead to an expected performance of the LISA Pathfinder which is a significant improvement over the mission requirements, and which actually reaches the LISA requirements over the entire LISA Pathfinder measurement band. © 2012 IOP Publishing Ltd.