High Resolution Maps of the Vasculature of An Entire Organ

The structure of vascular networks represents a great, unsolved problem in anatomy. Network geometry and topology differ dramatically from left to right and person to person as evidenced by the superficial venation of the hands and the vasculature of the retinae. Mathematically, we may state that there is no conserved topology in vascular networks. Efficiency demands that these networks be regular on a statistical level and perhaps optimal. We have taken the first steps towards elucidating the principles underlying vascular organization, creating the rst map of the hierarchical vasculature (above the capillaries) of an entire organ. Using serial blockface microscopy and fluorescence imaging, we are able to identify vasculature at 5 μm resolution. We have designed image analysis software to segment, align, and skeletonize the resulting data, yielding a map of the individual vessels. We transformed these data into a mathematical graph, allowing computationally efficient storage and the calculation of geometric and topological statistics for the network. Our data revealed a complexity of structure unexpected by theory. We observe loops at all scales that complicate the assignment of hierarchy within the network and the existence of set length scales, implying a distinctly non-fractal structure of components within

Semantic Decomposition Improves Learning of Large Language Models on EHR Data

Electronic health records (EHR) are widely believed to hold a profusion of actionable insights, encrypted in an irregular, semi-structured format, amidst a loud noise background. To simplify learning patterns of health and disease, medical codes in EHR can be decomposed into semantic units connected by hierarchical graphs. Building on earlier synergy between Bidirectional Encoder Representations from Transformers (BERT) and Graph Attention Networks (GAT), we present H-BERT, which ingests complete graph tree expansions of hierarchical medical codes as opposed to only ingesting the leaves and pushes patient-level labels down to each visit. This methodology significantly improves prediction of patient membership in over 500 medical diagnosis classes as measured by aggregated AUC and APS, and creates distinct representations of patients in closely related but clinically distinct phenotypes.Comment: Extended Abstract presented at Machine Learning for Health (ML4H) symposium 2022, November 28th, 2022, New Orleans, United States & Virtual, http://www.ml4h.cc, 9 page

Human Time-Frequency Acuity Beats the Fourier Uncertainty Principle

The time-frequency uncertainty principle states that the product of the temporal and frequency extents of a signal cannot be smaller than $1/(4\pi)$. We study human ability to simultaneously judge the frequency and the timing of a sound. Our subjects often exceeded the uncertainty limit, sometimes by more than tenfold, mostly through remarkable timing acuity. Our results establish a lower bound for the nonlinearity and complexity of the algorithms employed by our brains in parsing transient sounds, rule out simple "linear filter" models of early auditory processing, and highlight timing acuity as a central feature in auditory object processing.Comment: 4 pages, 2 figures; Accepted at PR

Transfer pricing: strategies, practices, and tax minimization

Using a survey of tax executives from multinational corporations, we document that some firms set their transfer pricing strategy to minimize tax payments, but more firms focus on tax compliance. We estimate that a firm focusing on minimizing taxes has a GAAP effective tax rate that is 6.6 percentage points lower and generates about $43 million more in tax savings, on average, than a firm focusing on tax compliance. Available COMPUSTAT data on sample firms confirm our survey‐based inferences. We also find that transfer pricing‐related tax savings are greater when higher foreign income, tax haven use, and R&D activities are combined with a tax minimization strategy. Finally, compliance‐focused firms report lower FIN 48 tax reserves than tax‐minimizing firms, consistent with the former group using less uncertain transfer pricing arrangements. Collectively, our study provides direct evidence that multinational firms have differing internal priorities for transfer pricing, and that these differences are strongly related to the taxes reported by these firms.First author draf

Molecular Distributions in Gene Regulatory Dynamics

We show how one may analytically compute the stationary density of the distribution of molecular constituents in populations of cells in the presence of noise arising from either bursting transcription or translation, or noise in degradation rates arising from low numbers of molecules. We have compared our results with an analysis of the same model systems (either inducible or repressible operons) in the absence of any stochastic effects, and shown the correspondence between behaviour in the deterministic system and the stochastic analogs. We have identified key dimensionless parameters that control the appearance of one or two steady states in the deterministic case, or unimodal and bimodal densities in the stochastic systems, and detailed the analytic requirements for the occurrence of different behaviours. This approach provides, in some situations, an alternative to computationally intensive stochastic simulations. Our results indicate that, within the context of the simple models we have examined, bursting and degradation noise cannot be distinguished analytically when present alone.Comment: 14 pages, 12 figures. Conferences: "2010 Annual Meeting of The Society of Mathematical Biology", Rio de Janeiro (Brazil), 24-29/07/2010. "First International workshop on Differential and Integral Equations with Applications in Biology and Medicine", Aegean University, Karlovassi, Samos island (Greece), 6-10/09/201

Drosophila Neurotrophins Reveal a Common Mechanism for Nervous System Formation

Neurotrophic interactions occur in Drosophila, but to date, no neurotrophic factor had been found. Neurotrophins are the main vertebrate secreted signalling molecules that link nervous system structure and function: they regulate neuronal survival, targeting, synaptic plasticity, memory and cognition. We have identified a neurotrophic factor in flies, Drosophila Neurotrophin (DNT1), structurally related to all known neurotrophins and highly conserved in insects.By investigating with genetics the consequences of removing DNT1 or adding it in excess, we show that DNT1 maintains neuronal survival, as more neurons die in DNT1 mutants and expression of DNT1 rescues naturally occurring cell death, and it enables targeting by motor neurons. We show that Spa¨ tzle and a further fly neurotrophin superfamily member, DNT2, also have neurotrophic functions in flies. Our findings imply that most likely a neurotrophin was present in the common ancestor of all bilateral organisms, giving rise to invertebrate and vertebrate neurotrophins through gene or whole-genome duplications. This work provides a missing link between aspects of neuronal function in flies and vertebrates, and it opens the opportunity to use Drosophila to investigate further aspects of neurotrophin function and to model related diseases

Operon mRNAs are organized into ORF-centric structures that predict translation efficiency

Bacterial mRNAs are organized into operons consisting of discrete open reading frames (ORFs) in a single polycistronic mRNA. Individual ORFs on the mRNA are differentially translated, with rates varying as much as 100-fold. The signals controlling differential translation are poorly understood. Our genome-wide mRNA secondary structure analysis indicated that operonic mRNAs are comprised of ORF-wide units of secondary structure that vary across ORF boundaries such that adjacent ORFs on the same mRNA molecule are structurally distinct. ORF translation rate is strongly correlated with its mRNA structure in vivo, and correlation persists, albeit in a reduced form, with its structure when translation is inhibited and with that of in vitro refolded mRNA. These data suggest that intrinsic ORF mRNA structure encodes a rough blueprint for translation efficiency. This structure is then amplified by translation, in a self-reinforcing loop, to provide the structure that ultimately specifies the translation of each ORF

Patient empowerment within a coronary care unit: insights for health professionals drawn from a patient satisfaction survey

The aim of this exploratory study was to investigate coronary care patients’ perceptions of their care and interventions related to empowerment and strengthening patient choice. The study, conducted in one acute National Health Service (NHS) Trust in Cambridgeshire, England, and completed in 2002, employed a prospective survey design. The research used a self-completion, pilot, postal questionnaire, including closed, open and scaled questions as the main method of data collection. From a total of 200 eligible patients, an unselected, consecutive sample of 142 in-patients consented to participate, of whom 103 returned the questionnaire—–a response rate of 73%. In contrast to much published literature, this study demonstrated that empowerment issues involving the rights of coronary care patients to be primary decision makers, managers of their illnesses and ultimate arbiters of their treatment and care were of minimal concern to all but a few. Almost 90% of patients were content to entrust their care exclusively to health professionals based on their confidence in the clinical expertise of the medical and nursing staff. Findings suggested that, while respondents were well-satisfied with their care, the ethos of patient empowerment was of peripheral concern and readily abdicated in the face of acute illness

Cell death delineates axon pathways in the hindlimb and does so independently of neurite outgrowth

We wished to know whether the cell death and phagocytosis seen near the outgrowing nerve front in the hindlimb delineate axon pathways and, if so, whether the cells died only in the presence of growth cones. We unilaterally deleted the lumbosacral neural tube and reconstructed the patterns of neurite outgrowth and phagocytes during the stage when neurites first begin to colonize the thigh. In the control limbs, sensory and motor nerve pathways coincided with sites of phagocytosis, including those pathways that had yet to be colonized by growth cones. For instance, phagocytes were clustered at foci within the muscle masses where muscle nerves form a day later. However, they were not seen in adjacent, nonpathway regions such as posterior sclerotome or dorsal and ventral to the region of the plexus in which axons extend only posteriorly. Phagocytes were also seen in defined regions that are probably inaccessible to growth cones because they are too distant from pathways (i.e., subjacent to the apical ectodermal ridge) or express substances that are typical of precartilagenous tissues which may prohibit axon advance. In the experimental limbs, we conservatively estimated that neurite outgrowth was reduced to less than one-tenth (neurites were visible only with electron microscopy) or less than one-third of normal. Outgrowth extended less far distally and, in half the cases, motor innervation was completely abolished. Despite the extensive reduction in neurite outgrowth, the distribution of phagocytes was indistinguishable from that of the control side. Furthermore, the number of phagocytes did not differ significantly. We conclude that cell death delineates axon pathways remarkably well and does so without an interaction with growth cones; it is an independent characteristic of the axonal pathways and may be directly or indirectly important to axonal pathfinding. This is the first identification of a feature that characterizes prospective nerve pathways in the hindlimb.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27050/1/0000040.pd