Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites

Human malaria parasites proliferate in different erythroid cell types during infection. Whilst Plasmodium vivax exhibits a strong preference for immature reticulocytes, the more pathogenic P. falciparum primarily infects mature erythrocytes. In order to assess if these two cell types offer different growth conditions and relate them to parasite preference, we compared the metabolomes of human and rodent reticulocytes with those of their mature erythrocyte counterparts. Reticulocytes were found to have a more complex, enriched metabolic profile than mature erythrocytes and a higher level of metabolic overlap between reticulocyte resident parasite stages and their host cell. This redundancy was assessed by generating a panel of mutants of the rodent malaria parasite P. berghei with defects in intermediary carbon metabolism (ICM) and pyrimidine biosynthesis known to be important for P. falciparum growth and survival in vitro in mature erythrocytes. P. berghei ICM mutants (pbpepc-, phosphoenolpyruvate carboxylase and pbmdh-, malate dehydrogenase) multiplied in reticulocytes and committed to sexual development like wild type parasites. However, P. berghei pyrimidine biosynthesis mutants (pboprt-, orotate phosphoribosyltransferase and pbompdc-, orotidine 5′-monophosphate decarboxylase) were restricted to growth in the youngest forms of reticulocytes and had a severe slow growth phenotype in part resulting from reduced merozoite production. The pbpepc-, pboprt- and pbompdc- mutants retained virulence in mice implying that malaria parasites can partially salvage pyrimidines but failed to complete differentiation to various stages in mosquitoes. These findings suggest that species-specific differences in Plasmodium host cell tropism result in marked differences in the necessity for parasite intrinsic metabolism. These data have implications for drug design when targeting mature erythrocyte or reticulocyte resident parasites

The problem of globalization

There is a general consensus that the contemporary world is best under-stood through the prism of globalization. This view is shared by most social scientists, politicians, journalists, businesses, and indeed broad sectors of the general population. Opinions differ as to whether global-ization is a positive or a negative development, but there is general agreement that whatever is going on is either a symptom or a consequence of globalization. There are many good reasons for this view. The number of passengers on scheduled international flights has risen by a factor of six between 1975 and 2000. The number of international tourist arrivals rose by three and a half times during the same period. Much less happily, the number of internationally displaced refugees rose by around 50 percent in the 20 years before 2000. During the quarter of a century after 1975, the duration of international voice telephone calls rose by around 25 times. We could go on multiplying such striking figures i

Solar sail science mission applications and advancement : solar sailing: concepts, technology, missions

Solar sailing has long been envisaged as an enabling or disruptive technology. The promise of open-ended missions allows consideration of radically new trajectories and the delivery of spacecraft to previously unreachable or unsustainable observation outposts. A mission catalogue is presented of an extensive range of potential solar sail applications, allowing identification of the key features of missions which are enabled, or significantly enhance, through solar sail propulsion. Through these considerations a solar sail application-pull technology development roadmap is established, using each mission as a technology stepping-stone to the next. Having identified and developed a solar sail application-pull technology development roadmap, this is incorporated into a new vision for solar sailing. The development of new technologies, especially for space applications, is high-risk. The advancement difficulty of low technology readiness level research is typically underestimated due to a lack of recognition of the advancement degree of difficulty scale. Recognising the currently low technology readiness level of traditional solar sailing concepts, along with their high advancement degree of difficulty and a lack of near-term applications a new vision for solar sailing is presented which increases the technology readiness level and reduces the advancement degree of difficulty of solar sailing. Just as the basic principles of solar sailing are not new, they have also been long proven and utilised in spacecraft as a low-risk, high-return limited-capability propulsion system. It is therefore proposed that this significant heritage be used to enable rapid, near-term solar sail future advancement through coupling currently mature solar sail, and other, technologies with current solar sail technology developments. As such the near-term technology readiness level of traditional solar sailing is increased, while simultaneously reducing the advancement degree of difficulty along the solar sail application-pull technology development roadmap

Two populations of X-ray pulsars produced by two types of supernovae

Two types of supernova are thought to produce the overwhelming majority of neutron stars in the Universe. The first type, iron-core collapse supernovae, occurs when a high-mass star develops a degenerate iron core that exceeds the Chandrasekhar limit. The second type, electron-capture supernovae, is associated with the collapse of a lower-mass oxygen-neon-magnesium core as it loses pressure support owing to the sudden capture of electrons by neon and/or magnesium nuclei. It has hitherto been impossible to identify the two distinct families of neutron stars produced in these formation channels. Here we report that a large, well-known class of neutron-star-hosting X-ray pulsars is actually composed of two distinct sub-populations with different characteristic spin periods, orbital periods and orbital eccentricities. This class, the Be/X-ray binaries, contains neutron stars that accrete material from a more massive companion star. The two sub-populations are most probably associated with the two distinct types of neutron-star-forming supernovae, with electron-capture supernovae preferentially producing system with short spin period, short orbital periods and low eccentricity. Intriguingly, the split between the two sub-populations is clearest in the distribution of the logarithm of spin period, a result that had not been predicted and which still remains to be explaine

Outcomes of COVID-19 related hospitalization among people with HIV in the ISARIC WHO Clinical Characterization Protocol (UK):a prospective observational study

BACKGROUND:Evidence is conflicting about how HIV modulates COVID-19. We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the ISARIC WHO CCP study. METHODS:We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, ten individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy). RESULTS:Among 47,592 patients, 122 (0.26%) had confirmed HIV infection and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger (median 56 versus 74 years; p<0.001) and had fewer comorbidities, more systemic symptoms and higher lymphocyte counts and C-reactive protein levels. The cumulative day-28 mortality was similar in the HIV-positive vs. HIV-negative groups (26.7% vs. 32.1%; p=0.16), but in those under 60 years of age HIV-positive status was associated with increased mortality (21.3% vs. 9.6%; p<0.001 [log-rank test]). Mortality was higher among people with HIV after adjusting for age (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.01-2.14; p=0.05), and the association persisted after adjusting for the other variables (aHR 1.69; 95% CI 1.15-2.48; p=0.008) and when restricting the analysis to people aged <60 years (aHR 2.87; 95% CI 1.70-4.84; p<0.001). CONCLUSIONS:HIV-positive status was associated with an increased risk of day-28 mortality among patients hospitalized for COVID-19

Zum Einfluß der Dexamethason-Dosis auf Chemotherapie-induzierte akute Nausea und Emesis

20 mg Dexamethason oder eine dessen Wirkung äquivalente Dosis eines Corticosteroids- in Verbindung mit einem 5-HT3-Rezeptorantagonisten- erscheint derzeit als Goldstandardt der Prophylaxe zytostatisch induzierter Emesis. Neben der negativen Auswirkung auf die Tumorbiologie, sei es ein beschleunigtes Zellwachstum oder eine verminderte Tumorzellvernichtung durch die körpereigene Immunabwehr, besteht begründeter Verdacht, daß eine hohe Cortisol-Dosierung am Tag der Chemotherapie vermehrt Nausea und Emesis in der verzögerten Phase begünstigt. Deshalb erscheint es sinnvoll, den Stellenwert einer mittleren Steroiddosierung in der Prophylaxe der akuten Emesis zu überprüfen. In einer prospektiven, einfachblinden randomisierten Studie wurden zwei Dexamethason-Dosierungen -20 mg Dexamethason gegen 8 mg Dexamethason- jeweils in Verbindung mit dem 5-HT3-Rezeptorantagonisten Tropisetron in Cisplatin-haltigen Therapien anhand objektiver und subjektiver Parameter verglichen. Nach einer Zwischenanalyse von 121 Fällen (69 Patientinnen), in der keine signifikanten Unterschiede zwischen den beiden Behandlungsstrategien festgestellt werden konnten, wurde die Untersuchung beendet. Hohe Dexamethason-Dosierungen (20 mg) als antiemetische Prophylaxe ergeben weder in der Anzahl der Emesis-Episoden, noch bei den subjektiven Parameter der Rotterdam Symptoms Checklist Vorteile gegenüber einer mittleren (8 mg) Dosis. Dagegen wird gezeigt, daß das endogene Cortisol, vor der Chemotherapie und nach der Dexamethason- Applikation untersucht, die Ausprägung von Nausea und Emesis mitbeeinflußt. Die Patientinnen, deren Cortisol-Werte vor Therapiebeginn unterhalb des errechneten Medians von 169 [ng / ml] liegen, leiden im Vergleich mit den Patientinnen, deren Wert oberhalb dieser Schwelle liegen, verstärkt unter Übelkeit (p = 0,038). Weiterhin tritt bei den Patientinnen, deren Serum-Cortisol an Tag 2 unterhalb des Medians von 21 [ng/ml] liegt, subjektiv erheblichere Übelkeit (p = 0,020) und Emesis (p = 0,046) auf. Aufgrund dieser Ergebnisse ist die antiemetische Prophylaxe mit der Dosis 8 mg Dexamethason der Dosis 20 mg Dexamethason vorzuziehen, um in Verbindung mit einem 5-HT3 Rezeptorantagonisten in hoch emetogenen Chemotherapien von nicht-hämatologischen Tumoren Übelkeit und Erbrechen zu verhindern

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd

Challenges, solutions and research priorities for sustainable rangelands

Australia’s rangeland communities, industries, and environment are under increasing pressures from anthropogenic activities and global changes more broadly. We conducted a horizon scan to identify and prioritise key challenges facing Australian rangelands and their communities, and outline possible avenues to address these challenges, with a particular focus on research priorities. We surveyed participants of the Australian Rangeland Society 20th Biennial Conference, held in Canberra in September 2019, before the conference and in interactive workshops during the conference, in order to identify key challenges, potential solutions, and research priorities. The feedback was broadly grouped into six themes associated with supporting local communities, managing natural capital, climate variability and change, traditional knowledge, governance, and research and development. Each theme had several sub-themes and potential solutions to ensure positive, long-term outcomes for the rangelands. The survey responses made it clear that supporting ‘resilient and sustainable rangelands that provide cultural, societal, environmental and economic outcomes simultaneously’ is of great value to stakeholders. The synthesis of survey responses combined with expert knowledge highlighted that sustaining local communities in the long term will require that the inherent social, cultural and natural capital of rangelands are managed sustainably, particularly in light of current and projected variability in climate. Establishment of guidelines and approaches to address these challenges will benefit from: (i) an increased recognition of the value and contributions of traditional knowledge and practices; (ii) development of better governance that is guided by and benefits local stakeholders; and (iii) more funding to conduct and implement strong research and development activities, with research focused on addressing critical knowledge gaps as identified by the local stakeholders. This requires strong governance with legislation and policies that work for the rangelands. We provide a framework that indicates the key knowledge gaps and how innovations may be implemented and scaled out, up and deep to achieve the resilience of Australia’s rangelands. The same principles could be adapted to address challenges in rangelands on other continents, with similar beneficial outcomes