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Supplementary Table from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

Supplementary Figure from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies.Significance:We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach.See related commentary by Capparelli and Aplin, p. 1413.This article is highlighted in the In This Issue feature, p. 1397

Supplementary Data from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

Mobility patterns in South Asia are complex, defined by temporary and circular migration of low waged labourers within and across national borders. They move, live and work in conditions that expose them to numerous hazards and health risks that result in chronic ailments and physical and mental health problems. Yet, public policies and discourses either ignore migrants’ health needs or tend to pathologise them, framing them as carriers of diseases. Their structural neglect was exposed by the ongoing pandemic crisis. In this paper, we take stock of the evidence on the health of low-wage migrants in South Asia and examine how their health is linked to their social, political and work lives. The paper derives from a larger body of work on migration and health in South Asia and draws specifically on content analysis and scoping review of literature retrieved through Scopus from 2000 to 2021 on health of low-income migrants. Utilising the lens of precarity and building on previous applications, we identify four dimensions of precarity and examine how these influence health: i) Work-based, concerned with hazardous and disempowering work conditions, ii) Social position-based, pertaining to the social stratification and intersecting oppressions faced by migrants, iii) Status-based, derived from vulnerabilities arising from the mobile and transient nature of their lives and livelihoods, and iv) Governmentality-based, relating to the formal policies and informal procedures of governance that disenfranchise migrants. We illustrate how these collectively produce distinct yet interrelated and interlocking oppressive states of insecurity, disempowerment, dispossession, exclusion, and disposability that define health outcomes, health-seeking pathways, and lock migrants in a continuing cycle of precarity, impoverishment and ill-health.

This paper examines determinants of ethnic disparities in workplace risks of COVID-19 among health and social care workers (HCWs) in the UK. This was undertaken to inform public health policy in the management of COVID-19 relating to health and social care provision. A cross-sectional survey was administered in July–August 2020 (n = 456) to elicit HCWs’ experiences of COVID-19 management in the workplace and their perceptions of exposure, personal protection against infection, involvement in local clinical management, and other workplace hazards. Findings suggest minority ethnic HCWs were twice as likely as White HCWs to be in a patient-facing role (OR = 2.14, 95% CI:1.21; 3.78, P < 0.01) and twice as likely (63% vs 39%) to be caring for COVID-19 positive patients (OR = 2.68, 95% CI: 1.77; 4.06, P < 0.01). Those in nursing, were three times as likely to be redeployed to a COVID-19 care setting (OR = 3.33, 95%CI: 1.23; 9.02, P= 0.02). Minority ethnic HCWs within lower- and mid-level roles carried a higher burden of frontline clinical management of COVID-19 positive patients than their White counterparts. This study found evidence of ethnic disparities across several workplace hazards, with increased exposure to and less protection against infection, more responsibility for the clinical management of infection, and evidence of systemic racial bias in the disproportionate redeployment of minority ethnic nursing staff to COVID-19 areas. An NHS-wide review is required to assess procedural fairness, ensure safe practices now, and to avert future crises.

Magnetism in wide band gap materials is of great interests for future spintronic device applications. We prepared MgO and Fe-doped MgO films ‘in-situ’ on substrates by inkjet printing, and investigated the ferromagnetism tuned by the doping of Fe, the annealing temperature and the film thickness. It is found that the Fe-doping improves the crystallinity of the films with lattice structure changed by annealing temperature. The saturation magnetization (Ms) of the films enhanced by ~5 times comparing with the pure MgO thin film of similar thickness (~90 nm), because of both the long-range ordering of localized 3d electrons in Fe and the defects induced magnetism. The Ms at 5 K decreases with the film thickness, which is mainly attributed to the interface induced ferromagnetism. The Fe-doped MgO films with ferromagnetism in this work can be used in future spintronic devices.

The UK’s response to COVID-19 has been widely criticized by scientists and the public. According to EuroMOMO, a European mortality monitoring initiative, the excess mortality that may be attributable to COVID-19 in England is one of the highest in Europe, second only to Spain. While critiqued from a public health perspective, much less attention is given to the implications of the pandemic outbreak for the right to health as defined under international human rights law and ratified by member states. Using the UK as a case study, we examine critically the extent to which the government’s response to COVID-19 complied with the legal framework of the right to health. We review further key states’ obligations on the right to health and assess its suitability in times of pandemic. Finally, we offer some recommendations for an update of the right to health. This paper adds to the body of literature on the right to health and human rights based-approaches to health.

Significant progress has been achieved in the field of sexual and reproductive health (SRH) in the last three decades as evident in global commitments and national legislative, policy and programme level reforms. However, such progress is truncated by decades of low prioritisation, weak political commitment and funding,1 political backlash, and systematic assault on the broader set of socioeconomic and civil-political rights necessary for SRH. Amid these challenges, adoption of the Sustainable Development Goals (SDGs) is promising for its explicit recognition of the importance of SRH rights for development, and for offering an integrated framework of goals that address both entitlements (ie, positive right to services, medicines and information) and freedoms (from violence and discrimination) necessary for full realisation of the broad spectrum of sexual and reproductive health and rights (SRHR) (see box 1). Their ‘universal’ premise, however, calls for a more nuanced assessment of how systems and provisions can be made more responsive to the SRH needs of those who are left behind and remain excluded from mainstream policy and planning. Such assessment will benefit from an explicit adoption of the ‘lens’ of intersectionality in examining and tackling SRH challenges. Box 1 ### Synergies between SRHR and SDGs #### Goal 3: Ensure healthy lives and promote well-being for all at all ages. Target 3.1 By 2030, reduce the global maternal mortality ratio to less than 70 per 100 000 births. Target 3.7 By 2030, ensure universal access to sexual and reproductive health care services, including for family planning, information and education, and the integration of reproductive health into national strategies and programmes. Target 3.8 Achieve universal health coverage, including financial risk protection, access to quality essential healthcare services and access to safe, effective, quality and affordable essential medicines and vaccines for all. #### Goal 4: Ensure inclusive and equitable quality education and promote lifelong learning opportunities for all. Target 4.7 By 2030, ensure that all learners acquire the knowledge and skills needed to promote sustainable development, including, among others, through education for sustainable development and sustainable lifestyles, human …

This column addresses the need to strengthen human rights in global health, looking to violations of human rights law in the pandemic response to recommend rights-based reforms in global health law. The column opens by examining the fundamental importance of human rights, recognizing the centrality of human rights in global health governance. Notwithstanding the evolution of health-related human rights under international law, the COVID-19 pandemic response has posed sweeping implications for the realization of human rights, with state responses failing to comply with their domestic and international human rights obligations. Raising an imperative to strengthen human rights in global health law, this column presents recommendations to advance health through the United Nations (UN) human rights system, extend human rights in revisions of the International Health Regulations (IHR), and mainstream human rights in WHO governance.

The identification of lattice multiphases in TiO2 nanocrystals is studied by high resolution transmission electron microscope and electron diffraction patterns. Based on the spectroscopic analysis using soft x-ray absorption and resonant inelastic soft x-ray scattering, it is believed that the oxygen vacancies at the interface exhibit structural distortion of the TiO68−cluster around the defect site as for the multiphase lattice. We elucidate that the extra 3d electrons nearby induce the inelastic scattering features with the excitation energy dependence owing to different energy relaxation processes, a characteristic of the electron-phonon coupling or the nature of the electron-hole pair at the intermediate state. The manifold dd excitations driven by the strong interaction between Ti-3d and O-2p electrons are noticeably rich, coexisting on both Ti and O sites. This sophisticated experiment can advance the perspective of nanocomposite TiO2 for various interactions of surface Ti3+ in applications of future devices.

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. Significance: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397

SummaryCOVID-19 has changed our lives and it appears to be especially harmful for some groups more than others. Black and Asian ethnic minorities are at particular risk and have reported greater mortality and intensive care needs. Mental illnesses are more common among Black and ethnic minorities, as are crisis care pathways including compulsory admission. This editorial sets out what might underlie these two phenomena, explaining how societal structures and disadvantage generate and can escalate inequalities in crises.

Non-state actors, including humanitarian agencies, play a prominent role in providing health care in low- and middle-income countries. Between 2007 and 2009, Musina, a South African municipality bordering Zimbabwe, became the site of several interventions by non-state organisations as an unprecedented number of Zimbabweans crossed the border, putting strain on already burdened local systems. After the initial need for humanitarian relief dissipated, organisations started to implement projects that were more developmental in nature. For example, Médecins sans Frontières developed a mobile clinic programme to improve health care access for migrant farm workers, a programme that was subsequently integrated into the Department of Health. Since the handover of the programme, it has faced multiple challenges. Using qualitative methodology and a case study approach, this paper traces the development of the programme, exploring the changing relationship between MSF and the state during this time. This research raises questions about the implications of short-term ‘innovative’ interventions targeting the access that migrants have to care, within a context in which policy and programmatic responses to health are not migration aware. Furthermore, it highlights the ways in which the energies and resources of local DoH employees were redirected by MSF's involvement in the area.

The observation of a spontaneous electron enrichment at the apexes of bismuth vanadate (BiVO4) nanopyramidal arrays is achieved by performing synchrotron-based angular dependent X-ray absorption spectroscopy. In accordance with density function theory calculations, the formation of (112) facets enriched apexes is proposed. Such intrinsically electron-enriched (112) facets at the apexes produce a potential facilitating the diffusion of photoexcited holes, which not only mitigates the recombination with the photoexcited electrons, but also provide an active reaction site for the photoassisted selective growth of cobalt phosphate (CoPi), a well known and highly active co-catalyst for water oxidation at the apex of BiVO4 nanopyramids. Benefiting from the element-resolved properties of synchrotron-based X-ray spectroscopy, 3d electrons on the vanadium site are directly resolved by resonant inelastic X-ray scattering measurements. Due to this unique morphology, the charge at the apex is expected to induce a strong interaction with CoPi, as a result of the metal-to-ligand charge transfer spectroscopy feature observed from the cobalt site. Substantial evidences are collected by means of comprehensive soft X-ray spectroscopy techniques with high spectral resolution revealing the atomic-scale origin and the nature of the synergy as well as the strong correlation between its unique structural properties and the electronic structure of this novel highly-ordered hybrid photocatalyst and its significantly improved photoelectrochemical performance.

Summary box Relations of power are intrinsic to the social determinants of sexual and reproductive health (SRH); they influence the content, quality and outcomes of SRH care; and they shape the negotiation and realisation of sexual and reproductive health and rights (SRHR) more broadly. Power dynamics pervade how SRHR is understood, studied and acted on, in ways that are distinct from other health issues.1 For example, the deeply held personal beliefs about women’s sexuality and childbearing, cultural mores regarding adolescent sexuality and state goals related to fertility all mark SRHR as a sphere with distinct and deeply contested power dynamics. Unmasking power as a central element in SRHR research is therefore crucial to developing a research agenda that can produce …

Indian cities attract a considerable number of low-income migrants from marginal rural households experiencing difficult economic, political and social conditions at home. Based on fieldwork in Jalandhar and Guwahati, this article focuses on the precarity of low-income migrants in Indian cities. It argues that the concept of precarity, used in the context of migrant labour, should be extended to capture multiple and reinforcing forms of vulnerability, examining the relationship between structural inequalities, including difficult conditions at home, exclusion from public services and poor access to justice. It puts forward a proposition that the widespread media representations of migrant workers returning home in the context of COVID-19 are not simply a result of the sudden outbreak of the coronavirus but that these journeys must be seen as part of the history of the circulatory system of labour.

The UK's response to COVID-19 has been widely criticized by scientists and the public. According to EuroMOMO, a European mortality monitoring initiative, the excess mortality that may be attributable to COVID-19 in England is one of the highest in Europe, second only to Spain. While critiqued from a public health perspective, much less attention is given to the implications of the pandemic outbreak for the right to health as defined under international human rights law and ratified by member states. Using the UK as a case study, we examine critically the extent to which the government's response to COVID-19 complied with the legal framework of the right to health. We review further key states' obligations on the right to health and assess its suitability in times of pandemic. Finally, we offer some recommendations for an update of the right to health. This paper adds to the body of literature on the right to health and human rights based-approaches to health.

ObjectivesAccess to reproductive information and contraception (RIC) continues to be a critical unmet need in Tanzania and impedes the realisation of reproductive health rights. This study examined key sources of RIC and the factors influencing their uptake by women in Mbeya region of Tanzania.SettingThis qualitative study was undertaken in a rural ward in a district in the south of the Mbeya regionParticipantsIn-depth interviews were undertaken with 48 women users and 2 nurses working in a public health facility, and focus group discussions with 16 home-based care workers in the district. Participants were recruited through a local non-governmental organisation (NGO) in the region, and via snowball sampling. All interactions were recorded, translated and transcribed and sought to identify the available resources and barriers in using them.ResultsParticipants reported six main sources of reproductive information and contraceptives: public health facilities, NGO mobile clinics, other women, Mganga wa Asili (witchdoctors/traditional doctors) and Duka la Dawa (pharmacy). Women users and healthcare workers identified a range of individual (age, marital status and geography) and health system-wide factors shaping women’s reproductive choices and preventing uptake of contraceptives. The study also revealed structural factors such as gender, ethnicity, indigeneity as key determinants of access and health seeking, placing women from Sukuma and Maasai communities is the most disadvantageous position. Historical social disadvantage, patriarchal social controls and the pressure to preserve sociocultural traditions that women experience in the Maasai and Sukuma tribes underpin their disconnect from mainstream services.ConclusionWomen’s reproductive choices and their uptake of contraceptives are shaped by the interaction of a range of individual, household, institutional and structural factors. An intersectional lens enables examination of the ways in which these factors interact and mutually constitute disadvantage and privilege.

Activin receptor-like kinase 2 (ALK2) has been implicated as a key target in multiple rare diseases. Herein, we describe the design of a novel bicyclic lactam series of potent and selective ALK2 inhibitors. This manuscript details an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor. Furthermore, we provide a detailed strategy for progressing this project in the future.

With the growing salience of ideas and reforms concerning women’s human rights and gender equality, violence against women (VAW) has received heightened policy attention. Recent global calls for ending VAW identify health care systems as having a crucial role in a multisector response to tackle this social injustice. Scholars emphasize the transformative potential of such response in its ability to not only address the varied health consequences but also prevent future recurrence by enabling wider access to support and justice. This wider consensus on the role of health systems, however, demands stronger empirical basis. This article reports findings from an exploratory research developed around the core question: What are the perceived strengths and challenges confronting health systems in offering a comprehensive response to VAW in India? Drawing on site visits, observations, and interviews with front-line staff and program managers of an integrated intervention to tackle violence in Kerala and nongovernment organisation staff in Delhi and Mumbai, the article presents its historical context and key barriers to effective implementation. While promising in terms of outreach and incremental changes in attitudes, barriers include deficits in infrastructure and institutional practices that reinforce inequities in gender–power relations, hostile attitudes, and limited capacities of health workforce to tackle the complex and diverse needs of women experiencing abuse. Locating these experiences in relation to other models rooted in feminist approach, I argue how conventional intervention models of provisioning fail to challenge institutional contexts and structural inequalities that underpin violence and compound vulnerabilities experienced by women, thereby serving a functional response. Health systems are social institutions embedded in prevailing gender norms and power relations that must be tackled alongside addressing imminent needs of women victims of abuse. To this end, feminist approaches to counselling and relational perspectives to social justice can strengthen responsiveness (and transformative potential) of integrated sector-wide interventions.

The identification of lattice multiphases in TiO2 nanocrystals is studied by high resolution transmission electron microscope and electron diffraction patterns. Based on the spectroscopic analysis using soft x-ray absorption and resonant inelastic soft x-ray scattering, it is believed that the oxygen vacancies at the interface exhibit structural distortion of the TiO68− cluster around the defect site as for the multiphase lattice. We elucidate that the extra 3d electrons nearby induce the inelastic scattering features with the excitation energy dependence owing to different energy relaxation processes, a characteristic of the electron-phonon coupling or the nature of the electron-hole pair at the intermediate state. The manifold dd excitations driven by the strong interaction between Ti-3d and O-2p electrons are noticeably rich, coexisting on both Ti and O sites. This sophisticated experiment can advance the perspective of nanocomposite TiO2 for various interactions of surface Ti3+ in applications of future devices.

BackgroundBlocking the PD-L1 immune checkpoint axis with therapeutic antibodies against either the ligand or PD-1 has proven to be an effective treatment modality for multiple cancer histologies. Small molecules targeting the PD-L1/PD-1 axis represent an alternate modality of blocking this pathway. INCB090244 is a small molecule that blocks the PD-L1/PD-1 interaction and restores T cell function similar to the clinical stage PD-L1 inhibitor INCB086550.MethodsMDA-MB-231 or CHO cells overexpressing PD-L1 were used to investigate effects of INCB090244 on PD-L1 dimerization, and intracellular trafficking. In vivo, CD34+ humanized mice harboring MDA-MB-231 tumors or C57Bl/6 mice bearing GL261 subcutaneous or orthotopic tumors were used to investigate the efficacy, biodistribution, and pharmacodynamic effects of INCB090244. Human specific gene expression changes in tumors from MDA-MB-231 bearing humanized mice were analyzed by RNA sequencing.ResultsIn vitro, INCB090244 potently disrupted the PD-L1:PD-1 interaction, induced PD-L1 dimerization, and inhibited PD-1-mediated negative signaling, resulting in enhanced IFN gamma and IL-2 production in primary human immune cells. Following dimerization, INCB090244 induced internalization of PD-L1 resulting in co-localization with the Golgi apparatus and partial localization in the nucleus. After cell treatment and washing, full restoration of PD-L1 at the cell surface was observed after 5 days of culture in vitro. In vivo, INCB090244 reduced tumor growth in CD34+ humanized mice bearing MDA-MB-231 tumors, to similar levels as atezolizumab. Antitumor activity was completely abrogated in immunodeficient mice, confirming the pharmacologic dependency on a competent immune system. RNA sequencing analysis on tumors from these mice demonstrated similar T cell activation gene signatures as clinical checkpoint blockade antibodies. Biodistribution studies in mice bearing both subcutaneous and orthotopically implanted GL261 glioma tumors demonstrated higher accumulation of INCB090244 in tumor tissue compared to PD-L1 antibodies.ConclusionsINCB090244 effectively disrupted the PD-L1/PD-1 interaction, induced dimerization and internalization of PD-L1, restored immunity in in vitro and in vivo tumor models, and is a suitable surrogate for the clinical candidate INCB086550. RNA sequencing demonstrated T cell activation signatures similar to those observed in patients receiving checkpoint blockade antibodies. Biodistribution studies demonstrated higher subcutaneous and brain tumor penetration by INCB090244 compared to PD-L1 antibodies, suggesting a potential advantage of small molecule PD-L1 inhibitors in accessing intratumoral regions. These data further support the clinical evaluation of small molecule PD-L1 inhibitors as an alternative approach to immune therapy.

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.

Transition state stabilization is essential for rate acceleration of enzymatic reactions. Despite extensive studies on various transition state structures of enzymes, an intriguing puzzle is whether an enzyme can accommodate multiple transition states (TS) to catalyze a chemical reaction. It is experimentally challenging to interrogate this proposition in terms of the choices of suitable enzymes and the feasibility to distinguish multiple TS. As a paradigm with the protein lysine methyltransferase (PKMT) SET7/9 paired with its physiological substrates H3 and p53, their TS were solved with experimental kinetic isotope effects as computational constraints. Remarkably, SET7/9 adopts two structurally distinct TS---a nearly symmetric S(N)2 and an extremely early S(N)2---for H3K4 and p53K372 methylation, respectively. The two TS are also different from those previously revealed for other PKMTs. The setting of multiple TS is expected to be essential for SET7/9 and likely other PKMTs to act on broad substrates with high efficiency.

Global Health Security and Universal Health Coverage have been frequently considered as “two sides of the same coin”. Yet, greater analysis is required as to whether and where these two ideals converge and what important differences exist. A consequence of ignoring their individual characteristics is to distort global and local health priorities in an effort to streamline policymaking and funding activities. This paper examines the areas of convergence and divergence between global health security and universal health coverage, both conceptually and empirically. We consider analytical concepts of risk and human rights as fundamental to both goals, but also identify differences in priorities between the two ideals. We support the argument that the process of Health System Strengthening provides the most promising mechanism of benefiting both goals.

The Fourth Global Symposium on Health Systems Research was themed around 'Resilient and responsive health systems for a changing world.' This commentary is the outcome of a panel discussion at the symposium in which the resilience discourse and its use in health systems development was critically interrogated. The 2014-15 Ebola outbreak in West-Africa added momentum for the wider adoption of resilient health systems as a crucial element to prepare for and effectively respond to crisis. The growing salience of resilience in development and health systems debates can be attributed in part to development actors and philanthropies such as the Rockefeller Foundation. Three concerns regarding the application of resilience to health systems development are discussed: (1) the resilience narrative overrules certain democratic procedures and priority setting in public health agendas by 'claiming' an exceptional policy space; (2) resilience compels accepting and maintaining the status quo and excludes alternative imaginations of just and equitable health systems including the socio-political struggles required to attain those; and (3) an empirical case study from Gaza makes the case that resilience and vulnerability are symbiotic with each other rather than providing a solution for developing a strong health system. In conclusion, if the normative aim of health policies is to build sustainable, universally accessible, health systems then resilience is not the answer. The current threats that health systems face demand us to imagine beyond and explore possibilities for global solidarity and justice in health. [Abstract copyright: © The Author 2017; all rights reserved. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.]

The observation of a spontaneous electron enrichment at the apexes of bismuth vanadate (BiVO4) nanopyramidal arrays is achieved by performing synchrotron-based angular dependent X-ray absorption spectroscopy. In accordance with density function theory calculations, the formation of (112) facets enriched apexes is proposed. Such intrinsically electron-enriched (112) facets at the apexes produce a potential facilitating the diffusion of photoexcited holes, which not only mitigates the recombination with the photoexcited electrons, but also provide an active reaction site for the photoassisted selective growth of cobalt phosphate (CoPi), a well known and highly active co-catalyst for water oxidation at the apex of BiVO4 nanopyramids. Benefiting from the element-resolved properties of synchrotron-based X-ray spectroscopy, 3d electrons on the vanadium site are directly resolved by resonant inelastic X-ray scattering measurements. Due to this unique morphology, the charge at the apex is expected to induce a strong interaction with CoPi, as a result of the metal-to-ligand charge transfer spectroscopy feature observed from the cobalt site. Substantial evidences are collected by means of comprehensive soft X-ray spectroscopy techniques with high spectral resolution revealing the atomic-scale origin and the nature of the synergy as well as the strong correlation between its unique structural properties and the electronic structure of this novel highly-ordered hybrid photocatalyst and its significantly improved photoelectrochemical performance.

© 2018 Elsevier Ltd The observation of a spontaneous electron enrichment at the apexes of bismuth vanadate (BiVO4) nanopyramidal arrays is achieved by performing synchrotron-based angular dependent X-ray absorption spectroscopy. In accordance with density function theory calculations, the formation of (112) facets enriched apexes is proposed. Such intrinsically electron-enriched (112) facets at the apexes produce a potential facilitating the diffusion of photoexcited holes, which not only mitigates the recombination with the photoexcited electrons, but also provide an active reaction site for the photoassisted selective growth of cobalt phosphate (CoPi), a well known and highly active co-catalyst for water oxidation at the apex of BiVO4nanopyramids. Benefiting from the element-resolved properties of synchrotron-based X-ray spectroscopy, 3d electrons on the vanadium site are directly resolved by resonant inelastic X-ray scattering measurements. Due to this unique morphology, the charge at the apex is expected to induce a strong interaction with CoPi, as a result of the metal-to-ligand charge transfer spectroscopy feature observed from the cobalt site. Substantial evidences are collected by means of comprehensive soft X-ray spectroscopy techniques with high spectral resolution revealing the atomic-scale origin and the nature of the synergy as well as the strong correlation between its unique structural properties and the electronic structure of this novel highly-ordered hybrid photocatalyst and its significantly improved photoelectrochemical performance.

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.