Classical Flt3L-dependent dendritic cells control immunity to protein vaccine

DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin+ DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3Ldependent, LN-resident cDCs

Global Trends in Space Access and Utilization

In the not-so-distant past, space access and air/space technology superiority were within the purview of the U.S. and former Soviet Union's respective space agencies, both vying for global leadership in space exploitation. In more recent years, with the emergence of the European Space Agency (ESA) member countries and Asian countries joining the family of space-faring nations, it is truer now more than ever that space access and utilization has become a truly global enterprise. In fact, according to the Space Report 2007, this enterprise is a $251-billion economy. It is possible to gauge the vitality of worldwide efforts from open sources in today's transparent, media-based society. In particular, print and web broadcasters regularly report and catalog global space activities for defense and civil purposes. For the purposes of this paper, a representative catalog of missions is used to illustrate the nature of the emerging "globalization." This paper highlights global trends in terms of not only the providers of space access, but also the end-users for the various recently accomplished missions. With well over 50 launches per year, in recent years, the launch-log reveals a surprising percentage of "cooperative or co-dependent missions" where different agencies, countries, and/or commercial entities are so engaged presumably to the benefit of all who participate. Statistics are cited and used to show that recently over d0% of the 50-plus missions involved multiple nations working collectively to deliver payloads to orbit. Observers, space policy professionals, and space agency leaders have eloquently proposed that it might require the combined resources and talents of multiple nations to advance human exploration goals beyond low earth orbit. This paper does not intend to offer new information with respect to whether international collaboration is necessary but to observe that, in continuing to monitor global trends, the results seem to support the thesis that a global interdependent effort with all its likely complexities is an increasingly viable and pragmatic option. The discussion includes a breakdown of space missions into those of civil (scientific), military, and strictly commercial nature. It concludes that all three are robust components of a globally diversified portfolio of activities relying, essentially, on a common space industrial base and space infrastructure. As in other industries, the distribution of space industry assets and knowledge across countries and continents enables a diverse suite of options and arrangements, particularly in the areas of civil and commercial space utilization. A survey of several ongoing bilateral and multilateral space collaboration examples are provided to augment the observations regarding multinational work in space

Erratum: Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

[No abstract available

Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the skin-draining lymph nodes (LNs). In mice, Langerin-CD11b- dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b- migDCs). Here, we build on the observation that Langerin-CD11b- migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b- Flt3L-responsive DCs are largely CD24(+) and CX 3 CR1 low and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b- migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8α cDCs and Langerin+CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin- CD11b- dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment

Developing a model of short-term integrated palliative and supportive care for frail older people in community settings: perspectives of older people, carers and other key stakeholders

Background: Understanding how best to provide palliative care for frail older people with non-malignant conditions is an international priority. We aimed to develop a community-based episodic model of short-term integrated palliative and supportive care (SIPS) based on the views of service users and other key stakeholders in the United Kingdom. Method: Transparent expert consultations with health professionals, voluntary sector and carer representatives including a consensus survey; and focus groups with older people and carers were used to generate recommendations for the SIPS model. Discussions focused on three key components of the model: potential benefit of SIPS; timing of delivery; and processes of integrated working between specialist palliative care and generalist practitioners. Content and descriptive analysis was employed and findings integrated across the data sources. Findings: We conducted two expert consultations (n=63), a consensus survey (n=42) and three focus groups (n=17). Potential benefits of SIPS included holistic assessment, opportunity for end of life discussion, symptom management, and carer reassurance. Older people and carers advocated early access to SIPS, while other stakeholders proposed delivery based on complex symptom burden. A priority for integrated working was the assignment of a key worker to coordinate care, but the assignment criteria remain uncertain. Interpretation: Key stakeholders agree that a model of SIPS for frail older people with non-malignant conditions has potential benefits within community settings, but differ in opinion on the optimal timing and indications for this service. Our findings highlight the importance of consulting all key stakeholders in model development prior to feasibility evaluation

Treatment of neonatal infections: a multi-country analysis of health system bottlenecks and potential solutions.

BACKGROUND: Around one-third of the world's 2.8 million neonatal deaths are caused by infections. Most of these deaths are preventable, but occur due to delays in care-seeking, and access to effective antibiotic treatment with supportive care. Understanding variation in health system bottlenecks to scale-up of case management of neonatal infections and identifying solutions is essential to reduce mortality, and also morbidity. METHODS: A standardised bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the development of the Every Newborn Action Plan. Country workshops involved technical experts to complete a survey tool, to grade health system "bottlenecks" hindering scale up of maternal-newborn intervention packages. Quantitative and qualitative methods were used to analyse the data, combined with literature review, to present priority bottlenecks and synthesise actions to improve case management of newborn infections. RESULTS: For neonatal infections, the health system building blocks most frequently graded as major or significant bottlenecks, irrespective of mortality context and geographical region, were health workforce (11 out of 12 countries), and community ownership and partnership (11 out of 12 countries). Lack of data to inform decision making, and limited funding to increase access to quality neonatal care were also major challenges. CONCLUSIONS: Rapid recognition of possible serious bacterial infection and access to care is essential. Inpatient hospital care remains the first line of treatment for neonatal infections. In situations where referral is not possible, the use of simplified antibiotic regimens for outpatient management for non-critically ill young infants has recently been reported in large clinical trials; WHO is developing a guideline to treat this group of young infants. Improving quality of care through more investment in the health workforce at all levels of care is critical, in addition to ensuring development and dissemination of national guidelines. Improved information systems are needed to track coverage and adequately manage drug supply logistics for improved health outcomes. It is important to increase community ownership and partnership, for example through involvement of community groups