Sometime in the next 20 to 30 years, developing countries in Asia and Africa are likely to cross a historic threshold, joining Latin America in having a majority of urban residents. The urban ...demographic transformation is described here, with an emphasis on estimates and forecasts of urban population aggregates. To provide policy-makers with useful scientific guidance in the upcoming urban era, demographic researchers will need to refine their data sets to include spatial factors as well as urban vital rates and to make improvements to forecasting methods currently in use.
Most of future population growth will take place in the world's cities and towns. Yet, there is no well-established, consistent way to measure either urban land or people. Even census-based urban ...concepts and measures undergo frequent revision, impeding rigorous comparisons over time and place. This study presents a new spatial approach to derive consistent urban proxies for the US. It compares census-designated urban blocks with proxies for land-based classifications of built-up areas derived from time-series of the Global Human Settlement Layer (GHSL) for 1990-2010. This comparison provides a new way to understand urban structure and its changes: Most land that is more than 50% built-up, and people living on such land, are officially classified as urban. However, 30% of the census-designated urban population and land is located in less built-up areas that can be characterized as mainly suburban and peri-urban in nature. Such insights are important starting points for a new urban research program: creating globally and temporally consistent proxies to guide modelling of urban change.
Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries ...since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.
Fungal skin infections are a common condition affecting 20-25 percent of the world population. While these conditions are treatable with regular application of an antifungal medication, we sought to ...develop a more convenient, longer-lasting topical antifungal platform that could increase patient adherence to treatment regimens by using Bacillus subtilis, a naturally antifungal bacteria found on the skin, for drug production and delivery. In this study, we engineered B. subtilis for increased production of the antifungal lipopeptide iturin A by overexpression of the pleiotropic regulator DegQ. The engineered strain had an over 200% increase in iturin A production as detected by HPLC, accompanied by slower growth but the same terminal cell density as determined by absorbance measurements of liquid culture. In an in vitro antifungal assay, we found that despite its higher iturin A production, the engineered strain was less effective at reducing the growth of a plug of the pathogenic fungus Trichophyton mentagrophytes on an agar plate compared to the parent strain. The reduced efficacy of the engineered strain may be explained by its reduced growth rate, which highlights the need to address trade-offs between titers (e.g. measured drug production) and other figures of merit (e.g. growth rate) during metabolic engineering.
Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show ...that the ribonucleoside analog β-d-N
-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N
-hydroxycytidine-5'-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.
Virtually all of the growth in the worlds population for the foreseeable future will take place in the cities and towns of the developing world. Over the next twenty years, most developing countries ...will for the first time become more urban than rural. The benefits from urbanization cannot be overlooked, but the speed and sheer scale of this transformation present many challenges. A new cast of policy makers is emerging to take up the many responsibilities of urban governance"as many national governments decentralize and devolve their functions, programs in poverty, health, education, and public services are increasingly being deposited in the hands of untested municipal and regional governments. Demographers have been surprisingly slow to devote attention to the implications of the urban transformation.Drawing from a wide variety of data sources, many of them previously inaccessible, Cities Transformed explores the implications of various urban contexts for marriage, fertility, health, schooling, and childrens lives. It should be of interest to all involved in city-level research, policy, planning, and investment decisions.
By 2050, two-thirds of the world's population is expected to be living in cities and towns, a marked increase from today's level of 55 percent. If the general trend is unmistakable, efforts to ...measure it precisely have been beset with difficulties: the criteria defining urban areas, cities and towns differ from one country to the next and can also change over time for any given country. The past decade has seen great progress toward the long-awaited goal of scientifically comparable urbanization measures, thanks to the combined efforts of multiple disciplines. These efforts have been organized around what is termed the "statistical urbanization" concept, whereby urban areas are defined by population density, contiguity and total population size. Data derived from remote-sensing methods can now supply a variety of spatial proxies for urban areas defined in this way. However, it remains to be understood how such proxies complement, or depart from, meaningful country-specific alternatives. In this paper, we investigate finely resolved population census and satellite-derived data for the United States, Mexico and India, three countries with widely varying conceptions of urban places and long histories of debate and refinement of their national criteria. At the extremes of the urban-rural continuum, we find evidence of generally good agreement between the national and remote sensing-derived measures (albeit with variation by country), but identify significant disagreements in the middle ranges where today's urban policies are often focused.
The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, ...underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. In addition, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East respiratory syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral that has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19.
Group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. Here, we evaluate the mechanisms of cross-sarbecovirus protective immunity, currently less clear ...yet important for pan-sarbecovirus vaccine development, using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination does not prevent virus replication, it protects against lethal heterologous disease outcomes in both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clade 2 bat sarbecovirus challenge models. The spike vaccines tested primarily elicit a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. Rather, non-neutralizing antibody functions, mechanistically linked to FcgR4 and spike S2, mediate cross-protection in wild-type mice. Protection is lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.
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•Non-neutralizing antibodies mediate pan-sarbecovirus protection•Antibody-mediated cross-protection is lost in absence of FcR function•S2-specific antibodies are a strong correlate of protective FcR effector function•Full-length spike elicits the broadest pan-sarbecovirus protection
Using a lethal model for β-coronavirus infection, Adams et al. described heterologous protection from disease that was driven by non-neutralizing antibodies through Fc-receptor-dependent mechanisms. These results reveal important protective correlates for inclusion into the design and testing of future pan-coronavirus vaccines.
In the United States and other high-income countries, there is intense scholarly and programmatic interest in the effects of household and neighborhood living standards on health. Yet few studies of ...developing-country cities have explored these issues. We investigated whether the health of urban women and children in poor countries is influenced by both household and neighborhood standards of living. Using data from the urban samples of 85 Demographic and Health Surveys and modeling living standards using factor-analytic MIMIC methods, we found that the neighborhoods of relatively poor households are more heterogeneous than is often asserted. Our results indicated that poor urban households do not tend to live in uniformly poor neighborhoods: about 1 in 10 of a poor household's neighbors is relatively affluent, belonging to the upper quartile of the urban distribution of living standards. Do household and neighborhood living standards influence health? Using multivariate models, we found that household living standards are closely associated with three health measures: unmet need for modern contraception, attendance of a trained health care provider at childbirth, and young children's height for age. Neighborhood living standards exert a significant additional influence in many of the surveys we examined, especially for birth attendance.
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