ABSTRACT. Interactions between distant places are increasingly widespread and influential, often leading to unexpected outcomes with profound implications for sustainability. Numerous sustainability studies have been conducted within a particular place with little attention to the impacts of distant interactions on sustainability in multiple places. Although distant forces have been studied, they are usually treated as exogenous variables and feedbacks have rarely been considered. To understand and integrate various distant interactions better, we propose an integrated framework based on telecoupling, an umbrella concept that refers to socioeconomic and environmental interactions over distances. The concept of telecoupling is a logical extension of research on coupled human and natural systems, in which interactions occur within particular geographic locations. The telecoupling framework contains five major interrelated components, i.e., coupled human and natural systems, flows, agents, causes, and effects. We illustrate the framework using two examples of distant interactions associated with trade of agricultural commodities and invasive species, highlight the implications of the framework, and discuss research needs and approaches to move research on telecouplings forward. The framework can help to analyze system components and their interrelationships, identify research gaps, detect hidden costs and untapped benefits, provide a useful means to incorporate feedbacks as well as trade-offs and synergies across multiple systems (sending, receiving, and spillover systems), and improve the understanding of distant interactions and the effectiveness of policies for socioeconomic and environmental sustainability from local to global levels.

SUMMARY Germinal center (GC) B cells evolve towards increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten-specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens – Bacillus anthracis protective antigen and influenza hemagglutinin – in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naïve B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early “winners” were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection.

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IntroductionCD4 ϩ T cells are essential components of the adaptive immune system that regulate immune responses against foreign pathogens and tumors. Upon antigen recognition, naive CD4 ϩ T cells undergo activation and expansion, and then contract via programmed cell death. 1 Specific antigen challenges also induce CD4 ϩ T cells to differentiate into distinct Th cell lineages characterized by unique cytokine production profiles. 2 Among these lineages, Th1 cells, the differentiation of which is controlled by the master transcription factor T-bet, 3 are specialized for the clearance of intracellular infections and are implicated as the major effectors against tumors. 4 In addition, the conversion of effector T cells to Foxp3 ϩ inducible regulatory T cells (iTregs) is an important mechanism used to balance immune responses 5 that is exploited by tumors as a strategy for immune evasion. 6 Whereas the protein-based regulatory machinery that operates during the T-cell response has been vigorously explored, we have recently become aware of a novel and crucial element modulating T-cell function: miRNA. 7,8 miRNAs are 18-to 24-nucleotide noncoding RNAs that regulate gene expression by destabilizing target mRNAs, leading to mRNA degradation and/or translational repression. 9 Recent studies suggest that miRNA-mediated gene regulation represents a fundamental layer of posttranscriptional regulatory programs in metazoan genomes. 10 Global disruption of miRNAs caused by defective biogenesis had profound effects on the development of B cells, 11 Th1/Th2 differentiation, 12,13 and Treg function. 14,15 In addition to these demonstrations of the importance of miRNA biogenesis in general, accumulating evidence shows that many specific miRNAs are differentially regulated in hematopoietic lineages and play important roles in controlling the development and function of immune cells. 7,8,[16][17][18] One such regulator is the miR-17-92 cluster.This cluster of miRNAs is encoded by a polycistronic miRNA gene and generates a single transcript that yields 6 individual mature miRNAs. These miRNAs are categorized into 3 families based on sequence homology: the miR-17 family (miR-17, miR-20, and miR-18a), the miR-19 family (miR-19a and miR-19b), and the miR-25 family (miR-92a; supplemental Figure 1A, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). miR-17-92 is well recognized as an "onco-miR" because of its genomic amplification in certain tumor tissues and its potent acceleration of c-My-induced B-cell lymphoma. 19 Genetic ablation has clearly established the critical roles of miR-17-92 in embryonic development. 20 In immune cells, miR-17-92 plays an integral part in the development of myeloid cells and B cells. 20,21 Mice with germline deletion of miR-17-92 exhibit a severe defect in adult B-cell development with an augmentation of apoptosis in the pro-B-cell fraction and consequently a blockade at the pro-B to pre-B transition. 20 In addition, transgenic mice overexpressing the miR-...