International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. SIGNIFICANCE STATEMENT: Nuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets.

VerSoX B07-B: a high-throughput XPS and ambient pressure NEXAFS beamline at Diamond Light Source.

The beamline optics and endstations at branch B of the Versatile Soft X-ray (VerSoX) beamline B07 at Diamond Light Source are described. B07-B provides medium-flux X-rays in the range 45-2200 eV from a bending magnet source, giving access to local electronic structure for atoms of all elements from Li to Y. It has an endstation for high-throughput X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine-structure (NEXAFS) measurements under ultrahigh-vacuum (UHV) conditions. B07-B has a second endstation dedicated to NEXAFS at pressures from UHV to ambient pressure (1 atm). The combination of these endstations permits studies of a wide range of interfaces and materials. The beamline and endstation designs are discussed in detail, as well as their performance and the commissioning process.

Factors that influence participation in physical activity for people with bipolar disorder: a synthesis of qualitative evidence.

BACKGROUND: Mental health problems contribute significantly to the overall disease burden worldwide and are major causes of disability, suicide, and ischaemic heart disease. People with bipolar disorder report lower levels of physical activity than the general population, and are at greater risk of chronic health conditions including cardiovascular disease and obesity. These contribute to poor health outcomes. Physical activity has the potential to improve quality of life and physical and mental well-being. OBJECTIVES: To identify the factors that influence participation in physical activity for people diagnosed with bipolar disorder from the perspectives of service users, carers, service providers, and practitioners to help inform the design and implementation of interventions that promote physical activity. SEARCH METHODS: We searched MEDLINE, PsycINFO, and eight other databases to March 2021. We also contacted experts in the field, searched the grey literature, and carried out reference checking and citation searching to identify additional studies. There were no language restrictions. SELECTION CRITERIA: We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that focused on the experiences and attitudes of service users, carers, service providers, and healthcare professionals towards physical activity for bipolar disorder. DATA COLLECTION AND ANALYSIS: We extracted data using a data extraction form designed for this review. We assessed methodological limitations using a list of predefined questions. We used the "best fit" framework synthesis based on a revised version of the Health Belief Model to analyse and present the evidence. We assessed methodological limitations using the CASP Qualitative Checklist. We used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) guidance to assess our confidence in each finding. We examined each finding to identify factors to inform the practice of health and care professionals and the design and development of physical activity interventions for people with bipolar disorder. MAIN RESULTS: We included 12 studies involving a total of 592 participants (422 participants who contributed qualitative data to an online survey, 170 participants in qualitative research studies). Most studies explored the views and experiences of physical activity of people with experience of bipolar disorder. A number of studies also reported on personal experiences of physical activity components of lifestyle interventions. One study included views from family carers and clinicians. The majority of studies were from high-income countries, with only one study conducted in a middle-income country. Most participants were described as stable and had been living with a diagnosis of bipolar disorder for a number of years. We downgraded our confidence in several of the findings from high confidence to moderate or low confidence, as some findings were based on only small amounts of data, and the findings were based on studies from only a few countries, questioning the relevance of these findings to other settings. We also had very few perspectives of family members, other carers, or health professionals supporting people with bipolar disorder. The studies did not include any findings from service providers about their perspectives on supporting this aspect of care. There were a number of factors that limited people's ability to undertake physical activity. Shame and stigma about one's physical appearance and mental health diagnosis were discussed. Some people felt their sporting skills/competencies had been lost when they left school. Those who had been able to maintain exercise through the transition into adulthood appeared to be more likely to include physical activity in their regular routine. Physical health limits and comorbid health conditions limited activity. This included bipolar medication, being overweight, smoking, alcohol use, poor diet and sleep, and these barriers were linked to negative coping skills. Practical problems included affordability, accessibility, transport links, and the weather. Workplace or health schemes that offered discounts were viewed positively. The lack of opportunity for exercise within inpatient mental health settings was a problem. Facilitating factors included being psychologically stable and ready to adopt new lifestyle behaviours. There were positive benefits of being active outdoors and connecting with nature. Achieving balance, rhythm, and routine helped to support mood management. Fitting physical activity into a regular routine despite fluctuating mood or motivation appeared to be beneficial if practised at the right intensity and pace. Over- or under-exercising could be counterproductive and accelerate depressive or manic moods. Physical activity also helped to provide a structure to people's daily routines and could lead to other positive lifestyle benefits. Monitoring physical or other activities could be an effective way to identify potential triggers or early warning signs. Technology was helpful for some. People who had researched bipolar disorder and had developed a better understanding of the condition showed greater confidence in managing their care or providing care to others. Social support from friends/family or health professionals was an enabling factor, as was finding the right type of exercise, which for many people was walking. Other benefits included making social connections, weight loss, improved quality of life, and better mood regulation. Few people had been told of the benefits of physical activity. Better education and training of health professionals could support a more holistic approach to physical and mental well-being. Involving mental health professionals in the multidisciplinary delivery of physical activity interventions could be beneficial and improve care. Clear guidelines could help people to initiate and incorporate lifestyle changes. AUTHORS' CONCLUSIONS: There is very little research focusing on factors that influence participation in physical activity in bipolar disorder. The studies we identified suggest that men and women with bipolar disorder face a range of obstacles and challenges to being active. The evidence also suggests that there are effective ways to promote managed physical activity. The research highlighted the important role that health and care settings, and professionals, can play in assessing individuals' physical health needs and how healthy lifestyles may be promoted. Based on these findings, we have provided a summary of key elements to consider for developing physical activity interventions for bipolar disorder.

'Lifts your spirits, lifts your mind': A co-produced mixed-methods exploration of the benefits of green and blue spaces for mental wellbeing.

INTRODUCTION: Mental health problems are a considerable public health issue and spending time in nature has been promoted as a way to access a range of psychological benefits leading to the development of nature-based interventions for people with severe and enduring mental health problems. Less, however, is understood about the potential benefits and efficacy of day-to-day routine access to outdoor green and blue spaces for mental health service users. METHODS: Using a mixed-methods design between April and October 2021, we explored the benefits and barriers to spending time outdoors with a purposive sample of mental health service users (N = 11) using qualitative interviews and an online general population survey (N = 1791). Qualitative evidence highlighted the restorative benefits of nature and identified a number of barriers associated with fears around personal safety, social anxiety, fatigue and lack of motivation. COVID-19 had also restricted access to green and blue spaces. Having social contact and support encouraged people to spend time outdoors. In the quantitative survey, self-report and standardised measures (the Patient Health Questionnaire and the Warwick-Edinburgh Wellbeing Scale) were used to assess past and current mental wellbeing. FINDINGS: Statistically significant differences were found between wellbeing and the use of green and blue spaces. Those with mental health problems spent time outdoors because they: felt guilty; wanted to reduce their anxiety; or rely on someone for encouragement. Those without mental health problems endorsed more positively framed reasons including relaxation, improving physical health or getting exercise. Barriers for people with mental health problems involved safety concerns, feeling anxious and having a poor self-image. These findings give insight into motivations for an outdoor activity to help inform the design of public mental health interventions. CONCLUSION: Further work is required to improve access and safety to promote the benefits of green and blue spaces for everyone. PATIENT OR PUBLIC CONTRIBUTION: The research team included expert experienced researchers with a mental health service provider (Praxis Care) and they were involved in the development of the research idea, funding application, design, data collection, analysis, writing up and dissemination activities.

Fast-growing growth hormone transgenic coho salmon (Oncorhynchus kisutch) show a lower incidence of vaterite deposition and malformations in sagittal otoliths.

In fish otoliths, CaCO3 normally precipitates as aragonite, and more rarely as vaterite or calcite. A higher incidence of vaterite deposition in otoliths from aquaculture-reared fish has been reported and it is thought that high growth rates under farming conditions might promote its deposition. To test this hypothesis, otoliths from growth hormone (GH) transgenic coho salmon and non-transgenic fish of matching size were compared. Once morphometric parameters were normalized by animal length, we found that transgenic fish otoliths were smaller (-24%, -19%, -20% and -30% for length, width, perimeter and area, respectively; P<0.001) and rounder (-12%, +13.5%, +15% and -15.5% in circularity, form factor, roundness and ellipticity; P<0.001) than otoliths from non-transgenic fish of matching size. Interestingly, transgenic fish had smaller eyes (-30% eye diameter) and showed a strong correlation between eye and otolith size. We also found that the percentage of otoliths showing vaterite deposition was significantly smaller in transgenic fish (21-28%) than in non-transgenic fish (69%; P<0.001). Likewise, the area affected by vaterite deposition within individual otoliths was reduced in transgenic fish (21-26%) compared with non-transgenic fish (42.5%; P<0.001). Our results suggest that high growth rates per se are not sufficient to cause vaterite deposition in all cases, and that GH overexpression might have a protective role against vaterite deposition, a hypothesis that needs further investigation.

Pilot study to investigate the effect of long-term exposure to high pCO2 on adult cod (Gadus morhua) otolith morphology and calcium carbonate deposition.

To date the study of ocean acidification on fish otolith formation has been mainly focused on larval and juvenile stages. In the present pilot study, wild-captured adult Atlantic cod (Gadus morhua) were exposed to two different levels of pCO2, 422µatm (ambient, low pCO2) or 1091µatm (high pCO2), for a period of 30 weeks (from mid-October to early April 2014-2015) in order to study the effects on otolith size, shape and CaCO3 crystallization amongst other biological parameters. We found that otoliths from cod exposed to high pCO2 were slightly smaller (- 3.4% in length; - 3.3% in perimeter), rounder (- 2.9% circularity and + 4% roundness) but heavier (+ 5%) than the low pCO2 group. Interestingly, there were different effects in males and females; for instance, male cods exposed to high pCO2 exhibited significant changes in circularity (- 3%) and roundness (+ 4%) compared to the low pCO2 males, but without significant changes on otolith dimensions, while females exposed to high pCO2 had smaller otoliths as shown for length (- 5.6%), width (- 2%), perimeter (- 3.5%) and area (- 4.8%). Furthermore, while the majority of the otoliths analysed showed normal aragonite deposition, 10% of fish exposed to 1091µatm of pCO2 had an abnormal accretion of calcite, suggesting a shift on calcium carbonate polymorph crystallization in some individuals under high pCO2 conditions. Our preliminary results indicate that high levels of pCO2 in adult Atlantic cod might affect otolith growth in a gender-specific way. Our findings reveal that otoliths from adult cod are affected by ocean acidification, and we believe that the present study will prompt further research into this currently under-explored area.

An exercise intervention for people with serious mental illness: Findings from a qualitative data analysis using participatory theme elicitation.

BACKGROUND: People with severe mental illness (SMI) often have poorer physical health than the general population. A coproduced physical activity intervention to improve physical activity for people with SMI in Northern Ireland was evaluated by co-researchers (researchers with lived experience of SMI) and academic researchers using a new approach to participatory data analysis called participatory theme elicitation (PTE). OBJECTIVE: Co-researchers and academic researchers analysed the data from the pilot study using PTE. This paper aimed to compare these analyses to validate the findings of the study and explore the validity of the PTE method in the context of the evaluation of a physical activity intervention for individuals with SMI. RESULTS: There was alignment and congruence of some themes across groups. Important differences in the analyses across groups included the use of language, with the co-researchers employing less academic and clinical language, and structure of themes generated, with the academic researchers including subthemes under some umbrella themes. CONCLUSIONS: The comparison of analyses supports the validity of the PTE approach, which is a meaningful way of involving people with lived experience in research. PTE addresses the power imbalances that are often present in the analysis process and was found to be acceptable by co-researchers and academic researchers alike.

Strong Substrate Mediation of Attractive Lateral Interactions of CO on Cu(110).

The mechanism of chemical reactions between adsorbed species is defined by the combined effects of the adsorbate-substrate potential landscape and lateral interactions. Such lateral interactions are therefore integral to catalytic processes, but their study is often complicated by "substrate mediation", the regulation of a two-body potential between adsorbed particles by the surface itself. Substrate mediation can influence the sign and magnitude of lateral interactions. There are notable exceptions of ordered structures forming at low coverage, indicative of short-range attractive forces where repulsive forces are expected to dominate, suggesting a strong substrate-mediated contribution. To explore further the origins of such interactions, we have investigated the adsorption of CO on Cu(110) using a combination of low-temperature microscopy and first-principles calculations. Our studies reveal that lateral adsorbate interactions, which are constrained by the metal surface, regulate the bonding between the adsorbate and substrate. Anisotropic CO-CO coupling is seen to arise from a perfect balance between the intermolecular accumulation of charge that acts as a glue (chemical coupling) at sufficiently large distances to avoid repulsive effects (dipole-dipole coupling and Pauli's repulsion between electron clouds).

HBO1 directs histone H4 specific acetylation, potentiating mechano-transduction pathways and membrane elasticity in ovarian cancer cells.

New approaches to treat ovarian cancer, the fifth leading cause of cancer mortality among women, are being sought, with the targeting of epigenetic modulators now receiving much attention. The histone acetyltransferase HBO1 functions in regulating diverse molecular processes, including DNA repair, transcription and replication, and is highly expressed in primary ovarian cancer. Here we define both the molecular function and a role in cell biomechanics for HBO1 in ovarian cancer. HBO1 preferentially acetylates histone H4 through the concomitant overexpression of co-regulator JADE2, and is required for the expression of YAP1, an ovarian cancer oncogene and mechano-transductor signaling factor. HBO1 appears therefore to have a role in determining the mechano-phenotype in ovarian cancer cells, through both signal transduction processes, and the modulation of cell elasticity as observed using direct measurements on live cells via atomic force microscopy.

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs.

Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/ß-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cell-cycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.

BACKGROUND: Upregulation of estrogen receptor beta (ERß) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERß and breast carcinogenesis is still missing. METHODS: To study the role of ERß in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERß and p53 in the mammary gland epithelium. For epithelium-specific knockout of ERß and p53, ERß F/F and p53 F/F mice were crossed to transgenic mice that express the Cre recombinase under the control of the human keratin 14 promoter. RESULTS: Somatic loss of ERß significantly accelerated formation of p53-deficient mammary tumors. Loss of the receptor also resulted in the development of less differentiated carcinomas with stronger spindle cell morphology and decreased expression of luminal epithelial markers. CONCLUSIONS: Our results show that synergism between ERß and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression.

Structural and functional insight into TAF1-TAF7, a subcomplex of transcription factor II D.

Transcription factor II D (TFIID) is a multiprotein complex that nucleates formation of the basal transcription machinery. TATA binding protein-associated factors 1 and 7 (TAF1 and TAF7), two subunits of TFIID, are integral to the regulation of eukaryotic transcription initiation and play key roles in preinitiation complex (PIC) assembly. Current models suggest that TAF7 acts as a dissociable inhibitor of TAF1 histone acetyltransferase activity and that this event ensures appropriate assembly of the RNA polymerase II-mediated PIC before transcriptional initiation. Here, we report the 3D structure of a complex of yeast TAF1 with TAF7 at 2.9 Å resolution. The structure displays novel architecture and is characterized by a large predominantly hydrophobic heterodimer interface and extensive cofolding of TAF subunits. There are no obvious similarities between TAF1 and known histone acetyltransferases. Instead, the surface of the TAF1-TAF7 complex contains two prominent conserved surface pockets, one of which binds selectively to an inhibitory trimethylated histone H3 mark on Lys27 in a manner that is also regulated by phosphorylation at the neighboring H3 serine. Our findings could point toward novel roles for the TAF1-TAF7 complex in regulation of PIC assembly via reading epigenetic histone marks.

A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells.

Biological processes require close cooperation of multiple transcription factors that integrate different signals. Thyroid hormone receptors (TRs) induce Krüppel-like factor 9 (KLF9) to regulate neurogenesis. Here, we show that triiodothyronine (T3) also works through TR to induce KLF9 in HepG2 liver cells, mouse liver, and mouse and human primary hepatocytes and sought to understand TR/KLF9 network function in the hepatocyte lineage and stem cells. Knockdown experiments reveal that KLF9 regulates hundreds of HepG2 target genes and modulates T3 response. Together, T3 and KLF9 target genes influence pathways implicated in stem cell self-renewal and differentiation, including Notch signaling, and we verify that T3 and KLF9 cooperate to regulate key Notch pathway genes and work independently to regulate others. T3 also induces KLF9 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) and this effect persists during differentiation to definitive endoderm and hiPSC-derived hepatocytes. Microarray analysis reveals that T3 regulates hundreds of hESC and hiPSC target genes that cluster into many of the same pathways implicated in TR and KLF9 regulation in HepG2 cells. KLF9 knockdown confirms that TR and KLF9 cooperate to regulate Notch pathway genes in hESC and hiPSC, albeit in a partly cell-specific manner. Broader analysis of T3 responsive hESC/hiPSC genes suggests that TRs regulate multiple early steps in ESC differentiation. We propose that TRs cooperate with KLF9 to regulate hepatocyte proliferation and differentiation and early stages of organogenesis and that TRs exert widespread and important influences on ESC biology.

Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor ß/δ agonists with neuroprotective activity.

We report the pharmacophore of the peroxisome proliferator-activated receptor δ (PPARδ) agonist natural product phosphoiodyn A is the phosphonate core. Synthesis of simplified phosphonate esters 13 and 15 provide structurally novel, highly selective and potent PPARδ agonists (EC50=78 and 112 nM, respectively). Further, both compounds demonstrate significant neuroprotective activity in an in vitro cellular model indicating that phosphonates may be an effective novel scaffold for the design of therapeutics for the treatment of neurodegenerative disorders.

Phosphorylation of glucocorticoid receptor tau1c transactivation domain enhances binding to CREB binding protein (CBP) TAZ2.

The glucocorticoid receptor (GR) N-terminal domain (NTD) contains a transactivation domain (activation function 1; AF-1). GR AF-1 is phosphorylated, but effects of this modification upon AF-1 activity and cofactor recruitment are not completely clear. GR AF-1 activity is mostly confined to a short unstructured domain called tau1c (amino acids 187-244) that contains three phosphorylation sites and binds a short cysteine rich fragment (CH3) of the coactivator CREB binding protein (CBP). Since the CH3 domain overlaps the CBP transcriptional adaptor zinc binding (TAZ) 2 domain, implicated in phosphorylation dependent binding to other unstructured transcription factor domains, we set out to investigate whether GR interacts with TAZ2 and whether this binding event is modulated by phosphorylation. We find that GR tau1c is absolutely required for enhancement of GR function and GR/CBP association in cultured cells. Tau1c interacts with TAZ2 in vitro and peptide mapping reveals CBP binding determinants throughout tau1c. Phosphorylation at GR Ser203, not involved in transactivation, does not affect tau1c/TAZ2 interactions. However, phosphorylation at Ser211 and Ser226, markers of GR transcriptional activity, greatly enhances TAZ2 binding in a synergistic fashion. We propose that GR tau1c phosphorylation could promote CBP recruitment and enhance AF-1 activity.

PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes.

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16.

Assessing the susceptibility of transgenic mice overexpressing deer prion protein to bovine spongiform encephalopathy.

Several transgenic mouse models have been developed which facilitate the transmission of chronic wasting disease (CWD) of cervids and allow prion strain discrimination. The present study was designed to assess the susceptibility of the prototypic mouse line, Tg(CerPrP)1536(+/-), to bovine spongiform encephalopathy (BSE) prions, which have the ability to overcome species barriers. Tg(CerPrP)1536(+/-) mice challenged with red deer-adapted BSE resulted in 90% to 100% attack rates, and BSE from cattle failed to transmit, indicating agent adaptation in the deer.

The mechanism of CO2 insertion into iridium(I) hydroxide and alkoxide bonds: a kinetics and computational study.

The facile insertion of CO2 into iridium(I) hydroxide, alkoxide, and amide bonds was recently reported. In particular, [Ir(cod)(IiPr)(OH)] (IiPr = 1,3-bis(isopropyl)imidazol-2-ylidene) reacted with CO2 in solution and in the solid state in a matter of minutes to give the novel [{Ir(cod)(IiPr)}2(µ-κ(1)O:κ(2)O,O-CO3)] complex. In the present study, this reaction is probed using kinetics and theoretical studies, which enabled us to analyse its facile nature and to fully elucidate the reaction mechanism with excellent correlation between the two methods.

The application of inelastic neutron scattering to explore the significance of a magnetic transition in an iron based Fischer-Tropsch catalyst that is active for the hydrogenation of CO.

An iron based Fischer-Tropsch synthesis catalyst is evaluated using CO hydrogenation at ambient pressure as a test reaction and is characterised by a combination of inelastic neutron scattering (INS), powder X-ray diffraction, temperature-programmed oxidation, Raman scattering, and transmission electron microscopy. The INS spectrum of the as-prepared bulk iron oxide pre-catalyst (hematite, α-Fe2O3) is distinguished by a relatively intense band at 810 cm(-1), which has previously been tentatively assigned as a magnon (spinon) feature. An analysis of the neutron scattering intensity of this band as a function of momentum transfer unambiguously confirms this assignment. Post-reaction, the spinon feature disappears and the INS spectrum is characterised by the presence of a hydrocarbonaceous overlayer. A role for the application of INS in magnetic characterisation of iron based FTS catalysts is briefly considered.

Structural basis of coactivation of liver receptor homolog-1 by ß-catenin.

We report the three-dimensional structure of a ß-catenin armadillo repeat in complex with the liver receptor homolog-1 (LRH-1) ligand binding domain at 2.8 Å resolution as the first structure of ß-catenin in complex with any nuclear receptor. The surface of ß-catenin that binds LRH-1 partly overlaps defined contact sites for peptide segments of ß-catenin partners, including T-cell factor-4. The surface of LRH-1 that engages ß-catenin is comprised of helices 1, 9, and 10 and is distinct from known interaction surfaces of LRH-1, including corepressor and coactivator binding sites. Targeted mutagenesis of amino acids forming both sides of the LRH-1/ß-catenin interface reveals that they are essential for stable interactions between these proteins in solution. The LRH-1 binding site in ß-catenin is also required for association with androgen receptor, providing evidence that the observed LRH-1/ß-catenin interaction may be prototypic.