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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.

The COVID-19 pandemic had a major impact on UK deceased organ donation and transplantation activity. We used national audit data from NHS Blood and Transplant to explore in detail the effects of the pandemic in comparison with 12 months pre-pandemic, and to consider the impact of the mitigating strategies and challenges placed on ICU by 'waves' of patients with COVID-19. Between 11 March 2020 and 10 March 2021, referrals to NHS Blood and Transplant of potential organ donors were initially inversely related to the number of people with COVID-19 undergoing mechanical ventilation in intensive care (incident rate ratio (95%CI) per 1000 patients 0.93 (0.88-0.99), p = 0.018), although this pattern reversed during the second wave (additional incident rate ratio (95%CI) 1.12 (1.05-1.19), p 0.001). Adjusted numbers of donors (incident rate ratio (95%CI) 0.71 (0.61-0.81), p 0.001) and organs retrieved (incident rate ratio (95%CI) 0.89 (0.82-0.97), p = 0.007) were inversely dependent on COVID-19 workload, though weekly numbers of transplants were unrelated (incident rate ratio (95%CI) 0.95 (0.86-1.04), p = 0.235). Non-COVID-19 mortality fell from 15,007 to 14,087 during the first wave (rate ratio (95%CI) 0.94 (0.92-0.96), p 0.001) but climbed from 18,907 to 19,372 during the second wave (rate ratio (95%CI) 1.02 (1.00-1.05), p = 0.018). There were fewer in-hospital deaths from cardiac arrest and intracranial catastrophes throughout (rate ratio (95%CI) 0.83 (0.81-0.86), p 0.001 and rate ratio (95%CI) 0.88 (0.85-0.91), p 0.001, respectively). There were overall fewer eligible donors (n = 4282) when compared with pre-pandemic levels (n = 6038); OR (95%CI) 0.58 (0.51-0.66), p 0.001. The total number of donations during the year fell from 1620 to 1140 (rate ratio (95%CI) 0.70 (0.65-0.76), p 0.001), but the proportion of eligible donors who proceeded to donation (27%) was unchanged (OR (95%CI) 0.99 (0.91-1.08), p = 0.821). The reduction in donations and transplantation during the pandemic was multifactorial, but these data highlight the impact in the UK of a fall in eligible donors and an inverse relationship of referrals to COVID-19 workload. Despite the challenges faced, the foundations underpinning the UK deceased organ donation programme remained strong.

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...

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

Both high and low calcium pyroxene minerals have been detected over large portions of the martian surface in addition to widespread salts in martian soils and dust. Calcium pyroxenes in martian meteorites are associated with secondary evaporite phases, including sulfates, chlorides, and perchlorates, suggesting the pyroxene may have been altered in saline solutions. Therefore, understanding pyroxene mineral weathering in high salinity brines may provide insight into past aqueous alteration on Mars. This study examines both solute-based dissolution rates and qualitative assessments of weathering textures developed during pyroxene-brine alteration experiments to link dissolution rates and textures and aid in interpreting weathering features observed in Mars meteorites and future pyroxene samples returned from Mars. Batch reactor dissolution experiments were conducted at 298 K to compare diopside (a high Ca-pyroxene) dissolution rates in water (18 MΩ cm−1 ultrapure water (UPW); activity of water (ɑH2O) = 1.0), 0.35 mol kg−1 NaCl (ɑH2O = 0.99), 0.35 mol kg−1 Na2SO4 (ɑH2O = 0.98), 2 mol kg−1 NaClO4 (ɑH2O = 0.90), 2.5 mol kg−1 Na2SO4 (ɑH2O = 0.95), 5.7 mol kg−1 NaCl (ɑH2O = 0.75), and 9 mol kg−1 CaCl2 (ɑH2O = 0.35) brines at pH 5–6.6 to determine how changing solution chemistry and activity of water influence pyroxene dissolution. Aqueous Si release rates and qualitative textural analyses indicate diopside dissolution rates are influenced by both solution chemistry and activity of water, with diopside weathering increasing along a trend from: 9 mol kg−1 CaCl2

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.

Summary Subsalt imaging is an industry-level challenge that has existed for many years in the Gulf of Mexico. This is due to the irregular shape of salt bodies, combined with poor illumination below top of salt. Both correct shape of salt and kinematically correct detailed sediment velocity are required to successfully image the reservoir level below salt bodies. The conventional method in the industry is to build the model from top to bottom with flooding of sediment or salt and then delineate the salt bodies by manual interpretation. This process requires intensive labour and usually creates suboptimal subsalt images in the presence of complex salt geometries. The template-matching full-waveform inversion (TM-FWI), which minimizes both the temporal and spatial shift between observation and prediction, is designed to automate the salt velocity model building by updating both sediment and salt simultaneously. This data-driven TM-FWI workflow reveals reliable salt geometry as well as greatly reduces turnaround time for salt model building. This workflow was tested in the extremely complex Campeche region in the Southern Gulf of Mexico and the resulting image is much superior to legacy, which validated the effectiveness of the workflow proposed herein.

Perchlorate salts and the ferric sulfate mineral jarosite have been detected at multiple locations on Mars by both landed instruments and orbiting spectrometers. Many perchlorate brines have eutectic temperatures −12 ± 0.85 × 10 −12 mol m −2 s −1 ) were slightly slower than the jarosite dissolution rate measured in ultrapure (18.2 MΩ cm −1 ) water (5.06 × 10 −12 mol m −2 s −1 ) using identical methods. No additional secondary phases were observed in XRD analyses of the reaction products. The observed decrease in dissolution rate may be due to lower activity of water (ɑH 2 O = 0.9) in the 2 M NaClO 4 brine compared with ultrapure water (ɑH 2 O = 1). This suggests that the perchlorate anion does not facilitate iron release, unlike chloride anions which accelerated Fe release rates in previously reported jarosite and hematite dissolution experiments. Since dissolution rates are slower in perchlorate-rich solutions, jarosite is expected to persist longer in perchlorate brines than in dilute waters or chloride-rich brines. Therefore, if perchlorate brines dominate aqueous fluids on the surface of Mars, jarosite may remain preserved over extended periods of time, despite active aqueous processes.

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.