Background: One of the major challenges for malaria control and elimination is the phenomenally efficient spread of malaria through sexual stage malaria parasites (gametocytes). The epidemiology and dynamics of gametocytes are poorly understood: it is presently unknown when commitment to gametocytes first occurs during infections and what intrinsic or extrinsic factors influence gametocyte production and infectivity to mosquitoes. I hypothesize that continuous early commitment to gametocyte production and the preferential sequestration of mature gametocytes in the subdermal vasculature are key to explaining the high efficiency of malaria transmission. Aim: This proposal has three main aims: i) to determine when commitment to gametocyte production first occurs during experimental and natural infections; ii) to delineate environmental triggers that stimulate gametocyte production in the absence and presence of treatment; iii) to quantify the differential distribution of parasite developmental stages in different compartments of the human bloodstream. Approach: We will use novel parasite stage composition assays in combination with epidemiological methods to determine the dynamics of gametocyte commitment and maturation during controlled malaria infections in malaria-naive volunteers and during naturally acquired malaria infections in cohorts exposed to malaria in Burkina Faso. A stage-specific immunohistochemistry assay will, for the first time, directly quantify malaria stage composition in the subdermal vasculature and mosquito bloodmeals and allow comparison with other compartments of the circulation. Importance and Innovation: This is the first study to comprehensively characterize gametocyte commitment, maturation and infectivity in experimental and natural infections. This proposal will provide insight in one of the most important questions for malaria elimination: what processes are responsible for the phenomenally efficient transmission of malaria.

A central problem of understanding the Earth system is quantifying climate-solid Earth feedback that requires time-series studies. One important time series is the climate (sea level) record that shows transitions between ice ages and warm periods for the last millions of years, involving vast mass transfer between continents (ice load) and oceans. Volcanism is sensitive to such pressure changes, but its response to glacial cycles is largely unknown for the global mid-ocean-ridge (MOR) system, where 80% of Earth’s volcanism occurs. Models of MOR response to sealevel fluctuations predict changes in crustal thickness, chemistry of lavas and hydrothermal activity. Establishing high-resolution time series on MORs, however, has previously not been possible, because the sea floor is rapidly covered by sediment as it moves away from the MOR and thus cannot be directly sampled. Recent studies, however, show MOR eruptions deposit samples of lava as glass on nearby sediments for up to 100 ka. These carbonate-rich sediments can be precisely dated by oxygen isotope stratigraphy and provide an archive of ridge eruptions (glasses) and hydrothermal activity (trace metals) in the sediments that can be sampled by gravity coring. Through closely spaced new cores to be retrieved during multiple research cruises, a high-resolution time series of volcanism and hydrothermal activity can be achieved and directly linked to the climate record, whereas seismic techniques can be used to determine variations in crustal thickness over time. We propose to obtain integrated data sets for all these processes from slow, intermediate and fast spreading ridge segments over the past 1.5 Ma in unprecedented detail. The results of these glass, sediment and crustal thickness time series will allow us to unequivocally test the influence of glacial cycles on MOR processes and will provide the first high-resolution time series of ocean ridge magmatism, opening up a new frontier of scientific exploration.

In the historical tradition, Venice is a city without walls and gates, and hence lacking suburbs. VeNiss reverses this trope by examining the urban, political, and cultural patterns connecting the capital with the chain of over sixty islands forming its lagoon fringes. Investigation of their integral role in Venice's spatial practices establishes a ground-breaking approach for the study of historic cities' margins as connective tissues, a subject seldom tackled by urban scholars. Reframing Venice within its archipelago, this project addresses that gap and explores the impact of urban edges on city planning, economic dependence, social responsiveness, and artistic production. From the 16th century, Venice became critically conscious of the granular nature of its hinterland, constructing a governance that involved the islands. Lagoon sites were systematically included in the network of capillary infrastructures for the city's supply, defence, and healthcare as well as civic rituals. Cultural entanglements sometimes bypassed the city, as novel lagoon architectural solutions permeated the Italian Peninsula through the agency of religious communities. Maps, atlases, and books of islands published on and in Venice helped consolidate the capital's archipelagic thinking into a coherent framework. VeNiss sheds light on this physical and theoretical construct –abruptly interrupted by the fall of the Venetian Republic (1797)– through a holistic project which combines social history, architecture, art and literary studies with advanced digital technologies. Coupling close archival readings with modelling systems, it proposes a pioneering methodology to reconstruct the islands' transformations alongside their interwoven relationships in a geographically- and temporally-based digital environment. VeNiss will constitute a crucial contribution to Venetian history while providing a valuable model for future urban studies seeking to visualise dispersed places through time and space.

The interactions between tumor and its microenvironment are often critical to uncovering the mechanisms of tumor survival. A striking example is the recent success of immunotherapy approaches that expose tumor cells to immune attack by disrupting a specific interaction between the tumor and infiltrating lymphocytes. The tumor can also repress immune response by inducing complex interactions among dozens of immune and stromal cell types that typically make up tumor microenvironment, however those remain largely uncharacterized as we currently lack systematic approaches to uncover relevant cell-cell interactions. The alternative to killing tumor cells, either directly or through immune system, is to force them to differentiate. Such strategy is particularly promising for tumors arising due to failure of progenitor populations to follow proper differentiation cascade. Here as well, the progress has been limited by lack of understanding of specific intercellular signals that that are disrupted in tumorigenesis. We propose a systematic approach for characterizing cell-cell interactions in complex microenvironments through joint analysis of spatially-resolved and disassociated single-cell transcriptomics. We will apply it to identify inter-cellular signals and pathways that can push tumors of neural crest origin, including as pheochromocytoma (PCC), paraganglioma (PGL) and neuroblastoma (NB), towards terminal differentiation. Building on our expertise with neural crest development, we will use single-cell profiling to map individual tumor cells onto developmental trajectory of neural crest differentiation. Spatial transcriptomics analysis will then be used to identify the sources and nature of microenvironment signals that channel neural crest differentiation during normal development. Contrasting interactions in normal and tumor tissues we will then aim to identify factors, pathways or signals that would push that PCC, PGL and NB tumors towards benign state.

Cells continuously sense and interpret the external signals coming from their time-varying environments to generate context-dependent responses. This is true for the entire tree of life, ranging from bacteria and unicellular eukaryotes to neurons forming networks in the developing brain. Identifying the fundamental principles and underlying mechanisms that enable cells to interpret their complex natural surroundings and adequately respond remains one of the fundamental questions in biology. Conceptual views so far have been mainly guided by molecular biology descriptions, suggesting that cells are controlled by a genomic program executing a pre-scripted plan. Our goal is to develop an alternative conceptual framework: cells generate internal representations of their external ‘world’, which they utilise to actively infer information about it and predict changes, in order to determine their response. We will formalise this concept in a theory of single-cell learning, by combining information theory concepts to quantify the predictive information from the internal cell representations, with dynamical systems theory to explain how these encodings are realised. We will interrogate experimentally systems across all scales of biological organization: bacteria (B. subtilis), single-cell organisms (Paramecium, Tetrahymena) and neuronal cell culture models. By studying them in a comparative manner, we aim at identifying generic molecular mechanisms through which single-cell learning is realised. The acquired understanding will enable us to address in vivo how single neurons during D. melanogaster development learn to form, stabilize or eliminate axonal branches, to generate stereotyped synaptic patterning under highly-variable conditions. We argue that providing a broader and generic definition of learning will serve as a unifying framework, linking disparate areas and scales of biology, and offering a basis for addressing fundamental biological questions.