Single Cell Proteomics in Biomedicine: High-dimensional Data Acquisition, Visualization and Analysis

New insights on cellular heterogeneity in the last decade provoke the development of a variety of single cell omics tools at a lightning pace. The resultant high-dimensional single cell data generated by these tools require new theoretical approaches and analytical algorithms for effective visualization and interpretation. In this review, we briefly survey the state-of-the-art single cell proteomic tools with a particular focus on data acquisition and quantification, followed by an elaboration of a number of statistical and computational approaches developed to date for dissecting the high-dimensional single cell data. The underlying assumptions, unique features, and limitations of the analytical methods with the designated biological questions they seek to answer will be discussed. Particular attention will be given to those information theoretical approaches that are anchored in a set of first principles of physics and can yield detailed (and often surprising) predictions

Mapping complex cell morphology in the grey matter with double diffusion encoding MR: A simulation study

This paper investigates the impact of cell body (namely soma) size and branching of cellular projections on diffusion MR imaging (dMRI) and spectroscopy (dMRS) signals for both standard single diffusion encoding (SDE) and more advanced double diffusion encoding (DDE) measurements using numerical simulations. The aim is to investigate the ability of dMRI/dMRS to characterize the complex morphology of brain cells focusing on these two distinctive features of brain grey matter. To this end, we employ a recently developed computational framework to create three dimensional meshes of neuron-like structures for Monte Carlo simulations, using diffusion coefficients typical of water and brain metabolites. Modelling the cellular structure as realistically connected spherical soma and cylindrical cellular projections, we cover a wide range of combinations of sphere radii and branching order of cellular projections, characteristic of various grey matter cells. We assess the impact of spherical soma size and branching order on the b-value dependence of the SDE signal as well as the time dependence of the mean diffusivity (MD) and mean kurtosis (MK). Moreover, we also assess the impact of spherical soma size and branching order on the angular modulation of DDE signal at different mixing times, together with the mixing time dependence of the apparent microscopic anisotropy (μA), a promising contrast derived from DDE measurements. The SDE results show that spherical soma size has a measurable impact on both the b-value dependence of the SDE signal and the MD and MK diffusion time dependence for both water and metabolites. On the other hand, we show that branching order has little impact on either, especially for water. In contrast, the DDE results show that spherical soma size has a measurable impact on the DDE signal's angular modulation at short mixing times and the branching order of cellular projections significantly impacts the mixing time dependence of the DDE signal's angular modulation as well as of the derived μA, for both water and metabolites. Our results confirm that SDE based techniques may be sensitive to spherical soma size, and most importantly, show for the first time that DDE measurements may be more sensitive to the dendritic tree complexity (as parametrized by the branching order of cellular projections), paving the way for new ways of characterizing grey matter morphology, non-invasively using dMRS and potentially dMRI

Double diffusion encoding and applications for biomedical imaging

Diffusion Magnetic Resonance Imaging (dMRI) is one of the most important contemporary non-invasive modalities for probing tissue structure at the microscopic scale. The majority of dMRI techniques employ standard single diffusion encoding (SDE) measurements, covering different sequence parameter ranges depending on the complexity of the method. Although many signal representations and biophysical models have been proposed for SDE data, they are intrinsically limited by a lack of specificity. Advanced dMRI methods have been proposed to provide additional microstructural information beyond what can be inferred from SDE. These enhanced contrasts can play important roles in characterizing biological tissues, for instance upon diseases (e.g. neurodegenerative, cancer, stroke), aging, learning, and development. In this review we focus on double diffusion encoding (DDE), which stands out among other advanced acquisitions for its versatility, ability to probe more specific diffusion correlations, and feasibility for preclinical and clinical applications. Various DDE methodologies have been employed to probe compartment sizes (Section 3), decouple the effects of microscopic diffusion anisotropy from orientation dispersion (Section 4), probe displacement correlations, study exchange, or suppress fast diffusing compartments (Section 6). DDE measurements can also be used to improve the robustness of biophysical models (Section 5) and study intra-cellular diffusion via magnetic resonance spectroscopy of metabolites (Section 7). This review discusses all these topics as well as important practical aspects related to the implementation and contrast in preclinical and clinical settings (Section 9) and aims to provide the readers a guide for deciding on the right DDE acquisition for their specific application

Probing brain microstructure with multidimensional diffusion MRI: Encoding, interpretation, and the role of exchange

Diffusion MRI (dMRI) is a non-invasive probe of human brain microstructure. It is a long-standing promise to use dMRI for ‘in vivo histology’ and estimate tissue quantities. However, this faces several challenges. First, the microstructure models used for dMRI data are based on assumptions that may cause erroneous interpretations. Also, probing neurites in gray matter assumes high microscopic diffusion anisotropy in both axons and dendrites, which is not supported by evidence. Furthermore, dMRI data analysis typically ignores diffusional exchange between microscopic environments. This thesis investigates and addresses these challenges using ‘multidimensional’ dMRI techniques that vary additional sequence encoding parameters to obtain new information on the tissue. In Paper I, we optimized an acquisition protocol for filter exchange imaging (FEXI). We found slow rates of diffusional exchange in normal brain tissue. In patients with gliomas and meningiomas, faster exchange was tentatively associated with higher tumor grade. In Paper II, we used tensor-valued diffusion encoding to test the NODDI microstructure model. The NODDI assumptions were contradicted by independent data and parameter estimates were found to be biased in normal brain and in gliomas. The CODIVIDE model combined data acquired with different b-tensor shapes to remove NODDI assumptions and reduce the susceptibility to bias. In Paper III, we used tensor-valued diffusion encoding with multiple echo times to investigate challenges in estimating neurite density. We found that microscopic anisotropy in the brain reflected axons but not dendrites. We could not separate the densities and T2 values of a two-component model in normal brain, but we did detect different component T2 values in white matter lesions. Microstructure models ranked regions from normal brain and white matter lesions inconsistently with respect to neurite density. In Paper IV, we optimized an acquisition protocol for tensor-valued diffusion encoding with multiple echo times. The data allowed removing all assumptions on diffusion and T2 relaxation from a two-component model. This increased the measurable parameters from two to six and reduced their susceptibility to bias. Data from the normal brain showed different component T2 values and contradicted common model assumptions. In Paper V, we used tensor-valued diffusion encoding in malformations of cortical development. Lesions that appeared gray matter-like in T1- and T2-weighted contrasts featured white matter-like regions with high microscopic diffusion anisotropy. We interpreted these regions as myelin-poor white matter with a high axonal content. By primarily reflecting axons and not dendrites or myelin, microscopic anisotropy may differentiate tissue where alterations to myelin confound conventional MRI contrasts. In Paper VI, we used SDE with multiple diffusion times in patients with acute ischemic stroke. Subacute lesions exhibited elevated diffusional exchange that predicted later infarction. MD reduction was partially reversible and did not predict infarction. Diffusional exchange may improve definition of ischemic core and identify additional patients for late revascularization

Mechanosensory structures in the beaks of probe-foraging birds in relation to their foraging ecology

Some taxa of probe-foraging birds (ibises, kiwi and scolopacid shorebirds) possess the sensory of capability of “remote-touch”, allowing them to detect mechanical vibrations in their foraging substrates using a specialised bill-tip organ in their beaks. This enables them to remotely detect the location of prey submerged in opaque substrates in the absence of all other sensory cues. The bill-tip organ that facilitates remote-touch is made up of mechanoreceptors housed in dense clusters of foramina in the distal portions of the beak bones (each unit of foramen and associated receptors is referred to as a “sensory pit”). Previous research showed that in ibises (Family: Threskiornithidae), species which live in more aquatic habitats tend to have more extensively pitted beak bones (i.e., the relative size of the bill-tip organ increases with increasing aquatic habitat usage of the species) than species living in drier habitats. The first three data chapters of this thesis investigate this trend, using three species of southern African ibises. These three species represent a spectrum of habitat usage, ranging from mainly terrestrial (Hadeda Ibises) to mainly aquatic (Glossy Ibises), with African Sacred Ibises a generalist species. My main hypothesis is that the interspecific differences in bill-tip organ morphology are related to differences in the moisture content of the birds' foraging substrates, as this affects how well these substrates transmit vibrations that the birds are sensing using remote-touch. The morphology of the bill-tip organs of the three species (Chapter 2) and their foraging behaviour in the wild (Chapter 3) indicate that species which forage in less saturated substrates have higher densities of mechanoreceptors in their bill-tip organs, suggesting that they are more sensitive to vibratory cues. This follows logically from the fact that drier substrates transmit vibrations more poorly than wetter ones, thus I hypothesize that species which forage frequently in dry substrates may have faced evolutionary pressure selecting for more sensitive bill-tip organs. My data on foraging behaviour of all three species of ibis in the wild suggests that bill-tip organ pitting extent on the beak bones is linked to depth of probing, which is in turn related to the penetrability of their probing substrates. As substrate penetrability is strongly affected by moisture content, the extent of pitting on the bill-tip organ is a good osteological correlate for the water content of the foraging substrate in the absence of soft tissue histology in ibises. Experiments using captive Hadeda Ibises (Chapter 4) provide further support for the hypothesis that species foraging in drier substrates require more sensitive bill-tip organs as their success rate using remote-touch was positively affected by substrate moisture content. Additionally, as this species' recent range expansion across southern Africa has been closely tied to increased soil irrigation in urban and agricultural habitats, I suggest that this in part due to Hadeda Ibises being better able to detect prey in more saturated substrates. The final data chapter of this thesis concerns the evolution of the remote-touch bill-tip organ in modern birds: the three families which possess remote-touch capability are widely phylogenetically separated, indicating that it evolved convergently. Kiwi (order: Apterygiformes) present an interesting case, as they are part of the palaeognath clade of Neornithes and are the only members of this clade which use remote-touch probeforaging. However, various other palaeognathous birds (ostriches & emu) possess a bill-tip organ, though its function in these taxa is unknown. I show that all species of modern palaeognathous birds (including the extinct moa and elephant birds) have the same beak morphology (bony pits containing numerous mechanoreceptors). This is at odds with the fact that none use the organ or possess the neuroanatomical correlates that would allow them to do so, indicating that the organ is vestigial in most palaeognaths. I thus hypothesized that the trait is plesiomorphic in palaeognathous birds, inherited from a common ancestor that used remote-touch probe-foraging. As the bill-tip organ is characterized by pitting in the beak bones, I was able to study the fossilized beaks of the oldest known palaeognaths, the lithornithids (which evolved during the Cretaceous period). By comparing them to an extensive sample of extant birds' beak bones, I showed that these ancient palaeognaths had bill-tip organs which were probably capable of remote-touch. Aside from supporting the hypothesis that the remote-touch bill-tip organ in palaeognaths is plesiomorphic, this indicates that remote-touch is one of the oldest documented foraging specialisations in modern birds

Commons in Design

The scarcity of resources, climate change, and the digitalization of everyday life are fuelling the economy of swapping, sharing, and lending—all of which are in some way linked to a culture of commoning. In this context, we understand commons as community-based processes that use, collectively manage, and organize generally accessible resources—referring to both goods and knowledge. Commons in Design explores the meaning and impact of commons—especially knowledge-based peer commons—and acts of commoning in design. It discusses networked, participatory, and open procedures based on the commons and commoning, testing models that negotiate the use of commons within design processes. In doing so, it critically engages with questions regarding designers’ positionings, everyday practices, self-understandings, ways of working, and approaches to education

Science Impacts of the SPHEREx All-Sky Optical to Near-Infrared Spectral Survey II: Report of a Community Workshop on the Scientific Synergies Between the SPHEREx Survey and Other Astronomy Observatories

SPHEREx is a proposed NASA MIDEX mission selected for Phase A study. SPHEREx would carry out the first all-sky spectral survey in the near infrared. At the end of its two-year mission, SPHEREx would obtain 0.75-to-5μm spectra of every 6.2 arcsec pixel on the sky, with spectral resolution R>35 and a 5-σ sensitivity AB>19 per spectral/spatial resolution element. More details concerning SPHEREx are available at http://spherex.caltech.edu. The SPHEREx team has proposed three specific science investigations to be carried out with this unique data set: cosmic inflation, interstellar and circumstellar ices, and the extra-galactic background light. Though these three themes are undoubtedly compelling, they are far from exhausting the scientific output of SPHEREx. Indeed, SPHEREx would create a unique all-sky spectral database including spectra of very large numbers of astronomical and solar system targets, including both extended and diffuse sources. These spectra would enable a wide variety of investigations, and the SPHEREx team is dedicated to making the data available to the community to enable these investigations, which we refer to as Legacy Science. To that end, we have sponsored two workshops for the general scientific community to identify the most interesting Legacy Science themes and to ensure that the SPHEREx data products are responsive to their needs. In February of 2016, some 50 scientists from all fields met in Pasadena to develop these themes and to understand their implications for the SPHEREx mission. The 2016 workshop highlighted many synergies between SPHEREx and other contemporaneous astronomical missions, facilities, and databases. Consequently, in January 2018 we convened a second workshop at the Center for Astrophysics in Cambridge to focus specifically on these synergies. This white paper reports on the results of the 2018 SPHEREx workshop