Search

Abstract

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50= 0.29 nM). The evaluation of 17in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

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.

•Fe-doped MgO thin films are ‘in-situ’ prepared by inkjet printing technology.•The Fe doping increases the ferromagnetism by 5 times comparing with MgO film.•The ferromagnetism can be tuned by the crystallinity and defects of the films.

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 (TSs) to catalyze a chemical reaction. It is experimentally challenging to study this proposition in terms of the choices of suitable enzymes and the feasibility to distinguish multiple TSs. As a paradigm with the protein lysine methyltransferase (PKMT) SET7/9 paired with its physiological substrates H3 and p53, their TSs were solved with experimental kinetic isotope effects as computational constraints. Remarkably, SET7/9 adopts two structurally distinct TSs, a nearly symmetric SN2 and an extremely early SN2, for H3K4 and p53K372 methylation, respectively. The two TSs are also different from those previously revealed for other PKMTs. The setting of multiple TSs is expected to be essential for SET7/9 and likely other PKMTs to act on broad substrates with high efficiency.

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.

– Research on potential differences in walking between men and women have mixed and inconclusive results, and no study has examined differences in walking between men and women across multiple countries and generations (i.e., young-old, old-old, and oldest-old). This study aimed to compare older men and women with respect to their walking for transportation across three generations and among six countries (i.e., China, Mexico, Russia, South Africa, Ghana, and India).

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.

Asparagine deprivation causes inhibition of T cell activation characterized by the suppression of mTOR signaling, autophagy, Myc expression, and lactate secretion. Salmonellaeare pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l‐asparaginase produced by SalmonellaTyphimurium 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 SalmonellaTyphimurium 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 SalmonellaTyphimurium 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 SalmonellaTyphimurium 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 SalmonellaTyphimurium 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.

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.

Selected IMPHOS heats,12have 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 events. Skull build-up on the scrap pile is at a maximum when the bulk bath temperature is ~1460°C. At this time, the solid scrap and skull component of the bulk bath makes-up just over 60% of all the metal charged to the converter. All scrap and skull is melted out at a bulk bath temperature of ~1610°C. 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.

A unique in blow sampling system has been applied to a blowing converter to retrieve simultaneously representative bulk metal bath and slag/metal emulsion samples from seven specified positions and every 2 min from start of blow. Full sample datasets from 20 heats have been grouped according to differences in the bulk bath phosphorus removal profiles and analysed with respect to relative refining ability of the slag/metal emulsion and the bulk metal bath. The complexity of the thermokinetic relationships behind the removal of carbon and the transfer of silicon, phosphorus, manganese and sulphur between the metal and slag is highlighted and the metal circulation rate in the emulsion is derived.

Abstract: Slag foaming under dynamic conditions has been studied in laboratory scale to examine the influence of properties commonly used to describe the foaminess and foam stability of slags under steady-state conditions. Synthetically produced slags with compositions relevant to tool steel and stainless steel production were studied through X-ray equipment in measurements simulating the dynamic conditions found in real processes. It is found that the dynamic systems display a more complex behavior than systems under steady state. Traditional theories for foaming do not seem to be valid for slag foaming under dynamic conditions. The foam displays a fluctuating behavior, which the presently available models are not able to take into account. The concept of a foaming index does not seem to be applicable, resulting in the need for alternative models.

Abstract: In the present article, slag foaming phenomenon under dynamic conditions is critically analyzed on the basis of the results of high-temperature X-ray image analysis experiments. The results indicate that the mismatch between the gas generation rate and gas escape rate has a serious impact on the foam height. This mismatch is attributed to the chemical reaction rate, which has to be considered in modeling slag foaming under dynamic conditions. The results further imply that a critical ratio of bubble size/crucible size exists, where wall effects are likely to become prominent.

Slag foaming is an important phenomenon in steelmaking processes with both beneficial as well as negative effects. The present work is part of the wider project on the modelling of slag foaming, with special reference to dynamic conditions. Since bubble formation is the first step to foam formation, the present work was carried out in an attempt to simulate the bubble formation in slag/metal reactions in steelmaking processes by water‐modelling experiments. The bubble formation due to the gas produced through chemical reaction at the interface between oleic acid and sodium bicarbonate solution was systematically monitored. The chemical reaction rate was varied by varying the concentration of sodium bicarbonate. The bubbles were observed to be generated in the heavier aqueous phase just below the water‐oil interface. The bubbles penetrated the interface and escaped through the oil phase. The rate of the reaction was estimated from the volume of the gas that passed the water/oil interface. It was observed that the bubble formation and bubble growth mechanism were influenced by the reaction rate while the bubble size seemed to be unaffected by the reaction rate.

Abstract: The X-ray sessile-drop method was employed in the present investigation to measure the contact angle between liquid iron and a silica substrate under argon as well as CO-CO2-Ar atmospheres in the temperature range of 1823 to 1833 K. In the latter case, the measurements were carried out in the dynamic mode, and the contact-angle changes were followed as a function of time as oxygen in the gas dissolved in the metal. The static measurements in argon showed that the contact angles in the experimental temperature range are of the order of 135 deg, similar to those observed in the case of the alumina substrate. In the dynamic mode, oxygen partial pressures varying between 9.910−4 and 1.510−2 Pa were imposed on the system. In these experiments, the contact angle decreased in two stages, with an intermediate steady-state region. Fayalite slag, formed due to the reaction between the metallic phase and the substrate, was found to accumulate around the drop. The results are of relevance in understanding the mechanism of corrosion of silica-containing refractories by molten iron.

Abstract: In the present work, the reaction between a molten iron drop and dense alumina was studied using the X-ray sessile-drop method under different oxygen partial pressures in the gas atmosphere. The changes in contact angles between the iron drop and the alumina substrate were followed as functions of temperature and varying partial pressures of oxygen in the temperature range 1823 to 1873 K both in static and dynamic modes. The results of the contact angle measurements with pure iron in contact with dense alumina in extremely well-purified argon as well as under different oxygen partial pressures in the gas atmosphere showed good agreement with earlier measurements reported in the literature. In the dynamic mode, when argon was replaced by a CO-CO2-Ar mixture with a well-defined $$P_{O_2 } $$ in the gas, the contact angle showed an initial decrease followed by a period of nearly constant contact angle. At the end of this period, the length of which was a function of the $$P_{O_2 } $$ imposed, a further steep decrease in the contact angle was noticed. An intermediate layer of FeAl2O4 was detected in the scanning electron microscope (SEM) analysis of the reacted substrates. An interesting observation in the present experiments is that the iron drop moved away from the site of the reaction once the product layer covered the interface. The results are analyzed on the basis of the various forces acting on the drop.

Low birth weight (LBW) is responsible for a significant proportion of child morbidity and mortality apart from its possible role in the occurrence of chronic disease in adult life. This study highlights the overall low incidence of LBWs at 13.6% among the Armed Forces families. The Other Ranks had a proportionally higher incidence of LBW at 24.14%. 82.14% of the LBWs occurred in the age group of 20-29 yrs, with only 6.93% of the births being teenage pregnancies. Primiparous women accounted for 54.95% of births but 75% of the LBWs. Smoking was not a significant factor. The findings underscore the need for special attention to other rank families and primiparas. A continued effort at updating the health care facilities provided to the Armed Forces families, and a concerted health and dietary advice by the authorised medical attendants, directed at the primiparous women, will further help lower the incidence of LBWs. The National LBW target of less than 10% by 2000 AD is definitely achievable by the Armed Forces.

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 vivorodent 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.

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.