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A significant population of patients with myelofibrosis (MF) develop anemia and either require red blood cell (RBC) transfusions or have an inadequate response to the currently available therapies and become transfusion-dependent. In patients with MF, elevated levels of serum hepcidin, a key iron regulatory hormone, is associated with increased dependence on RBC transfusions and reduced overall survival. Elevated hepcidin expression has also been observed to cause severe functional iron deficiency anemia and is central to the pathophysiology of anemia of chronic disease. Thus, to ensure proper maintenance of iron homeostasis, hepcidin levels are tightly regulated. Specifically, the production of hepcidin is controlled by the bone morphogenetic protein (BMP) type I receptor ACVR1, a gene that encodes the serine/threonine kinase ALK2. In preclinical models, knockdown or complete loss of ALK2 decreases hepcidin production resulting in elevated serum iron levels. In this study, we report characterization of INCB00928, a novel small molecule inhibitor of ALK2 for the treatment of anemia. INCB00928 was observed to have subnanomolar activity against ALK2 and selectivity over ALK1 and ALK3 in biochemical enzyme assays. In cell-based profiling studies, INCB00928 inhibited ALK2 potently and selectively over ALK1 and ALK3 as determined by the inhibition of ligand-induced SMAD pathway signaling. Importantly, in both an immortalized human liver cell line as well as primary human hepatocytes, INCB00928 inhibited BMP-induced production of hepcidin with nanomolar activity. INCB00928 was also observed to have suitable absorption, distribution, metabolism, and excretion properties to be dosed in in vivo rodent studies. In tumor- and inflammation-induced mouse models of anemia, INCB00928 improved RBC count, hemoglobin, and hematocrit levels while decreasing hepcidin levels in a dose-dependent manner. Additionally, consistent with the improved symptoms of anemia, pSMAD1/5 inhibition was observed in a dose-dependent manner in liver tissues collected from INCB00928-treated mice. In summary, INCB00928 is a potent, selective, and orally available small molecule inhibitor of ALK2, which significantly reduces the production of hepcidin in human liver cells, primary hepatocytes, and in rodent models of anemia. For the majority of patients with MF, the management of anemia remains an unmet need. The preclinical findings from this study suggest ALK2 kinase inhibition with INCB00928 may be a promising novel treatment to reduce the production of hepcidin and improve MF-related anemia in humans, thus warranting further investigation. Disclosures Chen: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Stubbs:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Pusey:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Wen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Collins:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kapilashrami:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Rupar:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Thekkat:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Lin:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Bowman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Diamond:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yeleswaram:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kim:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Koblish:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Chen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Wee:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company.

The electronic structures of carbon nanocages (CNCs) and nitrogen/phosphorus doped carbon nanocages (N-CNCs/P-CNCs) have been studied by X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), X-ray emission spectroscopy (XES) and resonant X-ray emission spectroscopy (RXES). The doping configurations for N/P dopants are identified from the experiments. The results have shown that there are three major doping configurations for nitrogen but only one doping configuration for phosphorus. The nitrogen doping reveals the complex coexistence of graphite-like, pyridine-like and pyrrole-like configurations that are proved by density functional theory (DFT) simulations, while the phosphorus doping presents only the “graphite-like” configuration. The different configuration profiles result in less atomic structure ordering of N-CNCs than that of P-CNCs. XAS spectra obtained from both surface and bulk sensitive detection suggest different chemical environments between the interior and shell for all types of nanocages. The electronic structure modifications show significant difference between nitrogen and phosphorus doping from the DOS calculations.

Unique experiments were designed to study the surface phenomena in steelmaking reactions. The concept of surface sulfide capacities and an understanding of the surface accumulation of surface-active species, based on experimental results, are presented. In order to understand the flow phenomenon at slag/metal interface, experiments were designed to measure the interfacial velocity of S on the surface of an iron drop immersed in an aluminosilicate slag using the X-ray sessile drop method. The oscillation of the iron drop in the slag due to the change in the surface concentration of sulfur at the slag–metal interface was monitored by X-ray imaging. From the observations, the interfacial velocity of sulfur was evaluated. Similar experiments were performed to measure the interfacial velocity of oxygen at the interface as well as the impact of oxygen potential on the interfacial velocity of sulfur. The interfacial shear viscosity and the dilatational modulus were also evaluated. In a study of the wetting of alumina base by iron drop at constant oxygen pressure under isothermal condition, the contact angle was found to be decreased with the progress of the reaction leading to the formation of hercynite as an intermediate layer creating non-wetting conditions. In the case of silica substrate, an intermediate liquid fayalite layer was formed.

The global pandemic caused by coronavirus disease 2019 is challenging health care workers and public health specialists around the world. Most data and policy, including recommendations for controlling the pandemic, measures of lockdown, and strategy to relaxing lockdown, all appear to emerge from the high income countries. We present the situation in the UK, and consider the inequalities globally, calling to attention critical concerns faced by vulnerable groups. Ethnic minorities, migrants, those in care homes, those in mental health services, and health staff from migrant or minority groups are all at higher risk of death and need for intensive care. We call for more comprehensive evidence base to be generated across nations, and for the global health community to be more cognisant of actions and approaches in the Global South, and translating these lessons to develop more sustainable recovery pathways. Learning across geopolitical and economic divides and addressing entrenched social inequalities are critical if we are to recommence international travel and business, and ensure that health protections are enforced globally.

Aim: To gain insight into community nurses’ experiences and how they make sense of the expertise they offer in their roleBackground: Globally, the spotlight is currently on community nursing expertise because of the movement of hospital-based to community- based care. Caring for people at home is no longer solely concerned with prevention, but delivering complex care to patients who are acutely unwell or at the end of their life. Little is known about the distinct expertise of community nurses, or their contribution to patient outcomes. There is a need to examine expertise in this group in order to inform current and future care provision within community settings.Design: A hermeneutic, phenomenological study.Method: Semi-structured interviews were conducted with eight community nurses in Scotland, UK, who hold an additional post-registration, professional qualification. Participants also kept audio-journals. Data were analysed using Interpretive Phenomenological Analysis. Findings: Participants described their expertise in three themes; negotiating a ‘way in’ to care, managing complexity, and ‘thinking on your feet’. They did not refer to themselves as specialist practitioners, nor did they perceive that they were viewed as specialist by colleagues or management. They appeared to dismiss their range of expertise which included forming trusting relationships, anticipating care needs and problem-solving, enabling them to undertake complex care management. Conclusions: Expertise of community nurses in this study is dynamic, contextualised and action-oriented enabling them to be creative problem-solvers. It reflects engagement with patients and families and all aspects of the setting where care is provided, rather than being solely an identifiable set of specialist skills, Relevance to clinical practice: It is vital to recognize community-based expertise internationally, especially if current WHO aims for community-based health care are to be achieved. Highlighting this expertise contributes to current discourse and may be considered in education and practice reviews.

Multiple structural, contextual and individual factors determine social disadvantage and affect health experience. There is limited understanding, however, of how this complex system works to shape access to health enabling resources (HER), especially for most marginalised or hard-to-reach populations. As a result, planning continues to be bereft of voices and lived realities of those in the margins. This paper reports on key findings and experience of a participatory action research (PAR) that aimed to deepen understanding of how multiple disadvantages (and structures of oppression) interact to produce difference in access to resources affecting well-being in disadvantaged communities in Edinburgh. An innovative approach combining intersectionality and PAR was adopted and operationalised in three overlapping phases. A preparatory phase helped establish relationships with participant groups and policy stakeholders, and challenge assumptions underlying the study design. Field-work and analysis was conducted iteratively in two phases: with a range of participants working in policy and community roles (or ‘bridge’ populations), followed by residents of one Edinburgh locality with relatively high levels of deprivation (As measured by the Scottish Index of Multiple Deprivation, a geographically-based indicator. See http://www.gov.scot/Topics/Statistics/SIMD/DataAnalysis/SPconstituencyprofile/EdinburghNorthern-Leith ). Traditional qualitative methods (interviews, focus groups) alongside participatory methods (health resource mapping, spider-grams, photovoice) were employed to facilitate action-oriented knowledge production among multiply disadvantaged groups. There was considerable agreement across groups and communities as to what healthful living (in general) means. This entailed a combination of material, environmental, socio-cultural and affective resources including: a sense of belonging and of purpose, feeling valued, self-esteem, safe/secure housing, reliable income, and access to responsive and sensitive health care when needed. Differences emerge in the value placed by people at different social locations on these resources. The conditions/aspects of their living environment that affected their access to and ability to translate these resources into improved health also appeared to vary with social location. Integrating intersectionality with PAR enables the generation of a fuller understanding of disparities in the distribution of, and access to, HER, notably from the standpoint of those excluded from mainstream policy and planning processes. Employing an intersectionality lens helped illuminate links between individual subjectivities and wider social structures and power relations. PAR on the other hand offered the potential to engage multiply disadvantaged groups in a process to collectively build local knowledge for action to develop healthier communities and towards positive community-led social change.

Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative l-asparaginase exhibits l-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that l-asparagine is a nutrient important for T cell activation and that l-asparagine deprivation, such as that mediated by the Salmonella Typhimurium l-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and l-lactate secretion. We also show that l-asparagine deprivation mediated by the Salmonella Typhimurium l-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.

Growing environmental concerns have renewed the interest for light induced catalytic reactions to synthesize cleaner chemical fuels from syngas. This, however, requires a sound understanding for the dynamics taking place at molecular level as a result of light – matter interaction. We present herein the principles of soft X-ray resonant emission spectroscopy (RXES) and resonant inelastic scattering (RIXS) and the importance of these spectroscopic techniques in materials science in light of their unique ability to emanate characteristic fingerprints on the geometric structure, chemical bonding charge and spin states in addition to chemical sensitivity. The addition of in situ/operando RXES and RIXS capability offers new opportunities to project important material properties and functionalities under conditions nearly identical to the operational modes.

International audience; Understanding the mechanisms of catalytic and reactions calls for in situ/operando spectroscopic characterization. Here we report the developments of in situ reaction cells at the Advanced Light Source for soft X-ray spectroscopic studies of nanoparticle catalysts during the catalytic reactions. The operation of these various cells and their capabilities are illustrated with examples from the studies of Co-based nanocatalysts.

Three hundred and one underfive children belonging to Armed Forces families were studied for their anthropometric and haemoglobin status. Their weights, MUAC and haemoglobin were superior as compared with the children in the general civil population as reported in various studies. 82.39% had weights above 80% of Harvard median. Chest circumference and head circumference crossing took place between 12–23 months. 69.56% had MUAC within normal limits and 59.81% had haemoglobin levels of 11 gm/dl or more. The healthier nutritional status of the underfives in the Armed Forces population is attributable to a healthier environment and an easy access to comprehensive health care facilities made available to them. It can be further improved by augmenting and modernising the MCH services with a view to provide quality care.

© Materials Research Society 2017. Recent advances in synchrotron based x-ray spectroscopy enable materials scientists to emanate fingerprints on important materials properties, e.g., electronic, optical, structural, and magnetic properties, in real-time and under nearly real-world conditions. This characterization in combination with optimized materials synthesis routes and tailored morphological properties could contribute greatly to the advances in solid-state electronics and renewable energy technologies. In connection to this, such perspective reflects the current materials research in the space of emerging energy technologies, namely photocatalysis, with a focus on transition metal oxides, mainly on the Fe2O3- and TiO2-based materials.

Protein lysine methyltransferases (PKMTs) catalyze the methylation of protein substrates, and their dysregulation has been linked to many diseases, including cancer. Accumulated evidence suggests that the reaction path of PKMT-catalyzed methylation consists of the formation of a cofactor(cosubstrate)–PKMT–substrate complex, lysine deprotonation through dynamic water channels, and a nucleophilic substitution (SN2) transition state for transmethylation. However, the molecular characters of the proposed process remain to be elucidated experimentally. Here we developed a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) method and corresponding mathematic matrix to determine precisely the ratios of isotopically methylated peptides. This approach may be generally applicable for examining the kinetic isotope effects (KIEs) of posttranslational modifying enzymes. Protein lysine methyltransferase SET8 is the sole PKMT to monomethylate histone 4 lysine 20 (H4K20) and its function has been implicated in normal cell cycle progression and cancer metastasis. We therefore implemented the MS-based method to measure KIEs and binding isotope effects (BIEs) of the cofactor S-adenosyl-l-methionine (SAM) for SET8-catalyzed H4K20 monomethylation. A primary intrinsic 13C KIE of 1.04, an inverse intrinsic α-secondary CD3 KIE of 0.90, and a small but statistically significant inverse CD3 BIE of 0.96, in combination with computational modeling, revealed that SET8-catalyzed methylation proceeds through an early, asymmetrical SN2 transition state with the C-N and C-S distances of 2.35–2.40 A and 2.00–2.05 A, respectively. This transition state is further supported by the KIEs, BIEs, and steady-state kinetics with the SAM analog Se-adenosyl-l-selenomethionine (SeAM) as a cofactor surrogate. The distinct transition states between protein methyltransferases present the opportunity to design selective transition-state analog inhibitors.

Selected IMPHOS heats, have been used to make observations on decarburising and dephosphorising performance, scrap melting and slag foaming characteristics during BOS refining. If it is assumed that decarburisation takes place solely in the slag/metal emulsion then maximum metal residence time in the emulsion is just under 9 seconds and at peak decarburisation time, the maximum amount of metal in the emulsion is ∼50% of the total metal content in the converter. To evaluate the effects of changes in slag component chemistry on phosphorus refining it is necessary to account for changes in slag weight, which can change substantially throughout a heat and be significantly different heat-to-heat. Dephosphorising performance depends on the thermodynamic stability of slag phases that are able to take up phosphorus and the distribution of phosphorus between these thermodynamically stable phases. The application of proprietary thermodynamic models such as MTDATA and FACTSage has helped to clarify such even...

Selected IMPHOS (IMproving PHOSphorus refining) heats ([1], [2]: Millman et al. in Proc. Scanmet 3, 2008; and Millman et al. in Ironmak Steelmak 38:499, 2011), have been used to make observations on decarburizing and dephosphorising performance characteristics during BOS refining. If it is assumed that decarburization takes place solely in the slag/metal emulsion then maximum metal residence time in the emulsion is just under 9 sec and at peak decarburisation time, the maximum amount of metal in the emulsion is ~ 50 % of the total metal content in the converter. To evaluate the effects of changes in slag component chemistry on phosphorus refining it is necessary to account for changes in slag weight, which can change substantially throughout a heat and be significantly different heat-to-heat. Dephosphorising performance depends on the thermodynamic stability of slag phases that are able to take-up phosphorus and the distribution of phosphorus between these thermodynamically stable phases. The application of proprietary thermodynamic models such as MTDATA and FACTSage has helped to clarify such events. The stability of the foamy slag/metal emulsion changes over the period of the blow. Slag height increases with an increase in FeO (tot) wt% and decreases with a decrease in decarburisation rate and the collapse of the foamy slag.

Thiolactomycin (TLM) is a natural product inhibitor of KasA, the β-ketoacyl synthase A from Mycobacterium tuberculosis. To improve the affinity of TLM for KasA, a series of TLM analogs have been synthesized based on interligand NOEs between TLM and a pantetheine analog when both are bound simultaneously to the enzyme. Kinetic binding data reveal that position 3 of the thiolactone ring is a suitable position for elaboration of the TLM scaffold, and the structure-activity relationship studies provide information on the molecular features that govern time-dependent inhibition in this enzyme system. These experiments also exemplify the utility of transient one-dimensional NOE spectroscopy for obtaining interligand NOEs compared with traditional steady state two-dimensional NOESY spectroscopy.

Epigenetic regulation requires site-specific modification of the genome and is involved in multiple physiological processes and disease etiology. Methyltransferases, which catalyze the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to various substrates, are critical components of the epigenetic machinery. This group of enzymes can methylate diverse substrates including DNA, RNA, proteins, and small-molecule metabolites. Their dysregulation has also been implicated in multiple disease states such as cancer, neurological, and cardiovascular disorders. Developing potent and selective small-molecule inhibitors of methyltransferases is valuable not only for therapeutic intervention but also for investigating the roles of these enzymes in disease progression. In this chapter, we will discuss the strategies of designing and synthesizing methyltransferases inhibitors based on the SAM scaffold. Following the section of inhibitor design, we will briefly review representative assays that are available to evaluate the potency of these inhibitors along with a detailed description of the most commonly used radiometric assay.

Significance Better understanding of the mechanisms used by bacteria to counter antibacterial agents is essential to cope with the rising prevalence of antimicrobial resistance. Here, we identified the mechanism of resistance of Mycobacterium tuberculosis to an antimycobacterial cyano-substituted fused pyrido-benzimidazole. Clones bearing mutations in a transcription factor, Rv2887, markedly up-regulated the expression of rv0560c , a putative methyltransferase. Rv0560c N -methylated the pyrido-benzimidazole in vitro and in Mycobacterium tuberculosis , abrogating its bactericidal activity. Resistant mutants selected in the absence of rv0560c led to the identification of the target of the compound, the essential oxidoreductase, decaprenylphosphoryl-β- d -ribose 2-oxidase (DprE1). Methylation of an antibacterial compound is a previously uncharacterized mode of antimicrobial resistance.

β-Ketoacyl-ACP synthases (KAS) are key enzymes involved in the type II bacterial fatty acid biosynthesis (FASII) pathway and are putative targets for antibacterial discovery. Several natural product KAS inhibitors have previously been reported, including thiolactomycin (TLM), which is produced by Nocardia spp. Here we describe the synthesis and characterization of optically pure 5R-thiolactomycin (TLM) analogues that show improved whole cell activity against bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and priority pathogens such as Francisella tularensis and Burkholderia pseudomallei. In addition, we identify TLM analogues with in vivo efficacy against MRSA and Klebsiella pneumoniae in animal models of infection.

The Framework Convention on Global Health comes amid wider recognition of health inequalities and several recent calls for greater democratisation of the world order. The framework suggests wider consensus on principles of human rights, equity and justice in addressing global health. In this paper we draw on our empirical research and wider literature to discuss the lessons learnt from application of global ‘ideas’ and ‘innovations’ and reveal institutional and political processes and structural constraints that affect their roll-out. We present our concerns with the approach on the basis of two key arguments. First, gross inequalities and unequal distributional effects of the current global political and economic environment do not offer a level playing field for nation states to translate principles enshrined in the framework into practice. Second, such a ‘view from above’ undermines processes of empowering communities for responsive health systems. Through a case vignette of the People’s Health Movement we then discuss substantive ways to facilitate local ideas and action.

Political conflicts create significant risks for women, as new forms and pathways of violence emerge, and existing patterns of violence may get amplified and intensified. The systematic use of sexual violence as a tactic of war is well-documented. Emergent narratives from the Middle East also highlight increasing risk and incidence of violence among displaced populations in refugee camps in countries bordering states affected by conflict. However, much less is known about the changing nature of violence and associated risks and lived experiences of women across a continuum of violence faced within the country and across national borders. Discussion on violence against women (VAW) in conflict settings is often stripped of an understanding of the changing political economy of the state and how it structures gender relations, before, during and after a conflict, creating particular risks of violence and shaping women's experiences. Drawing on a review of grey and published literature and authors' experiences, this paper examines this underexplored dimension of VAW in political conflicts, by identifying risk environments and lived realities of violence experienced by women in the Syrian conflict, a context that is itself poorly understood. We argue for multi-level analysis of women's experiences of violence, taking into account the impact of the political economy of the wider region as shaping the lived realities of violence and women's response, as well as their access to resources for resistance and recovery.

Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition P. aeruginosa is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.

Epigenetic regulation requires site-specific modification of the genome and is involved in multiple physiological processes and disease etiology. Methyltransferases, which catalyze the transfer of a methyl group from S-adenosyl-l-methionine (SAM) to various substrates, are critical components of the epigenetic machinery. This group of enzymes can methylate diverse substrates including DNA, RNA, proteins, and small-molecule metabolites. Their dysregulation has also been implicated in multiple disease states such as cancer, neurological, and cardiovascular disorders. Developing potent and selective small-molecule inhibitors of methyltransferases is valuable not only for therapeutic intervention but also for investigating the roles of these enzymes in disease progression. In this chapter, we will discuss the strategies of designing and synthesizing methyltransferases inhibitors based on the SAM scaffold. Following the section of inhibitor design, we will briefly review representative assays that are available to evaluate the potency of these inhibitors along with a detailed description of the most commonly used radiometric assay.