In vivo imaging of the nucleus of the solitary tract with Magnetization Transfer at 7 Tesla

The nucleus of the solitary tract (NTS) is a nuclei complex with, among others, a high concentration of noradrenergic neurons (including the noradrenergic subnuclei named A1 and A2) in the medulla. The NTS regulates several cognitive, neuroendocrine and autonomic functions. No method currently exists to anatomically visualize the NTS in vivo. Several noradrenergic and dopaminergic nuclei have been successfully imaged using Magnetization Transfer (MT) contrast manipulation. We therefore hypothesized that an efficient, high-resolution MT-weighted sequence at 7 T might successfully image the NTS. In this study, we found a hyperintensity, similar to hyperintensities found in other noradrenergic and dopaminergic nuclei, consistent with the expected NTS location, and specific to the MT-weighted images. The localization of the hyperintensity was found to be consistent between individuals and slices and in good correspondence to a histological atlas and a meta-analytic map of fMRI-based NTS activation. We conclude that the method may, for the first time, achieve NTS imaging in vivo and within a clinically-feasible acquisition time. To facilitate NTS research at lower field strengths, an NTS template was created and made publicly available

Generating collection transformations from proofs

Nested relations, built up from atomic types via product and set types, form a rich data model. Over the last decades the nested relational calculus, NRC, has emerged as a standard language for defining transformations on nested collections. NRC is a strongly-typed functional language which allows building up transformations using tupling and projections, a singleton-former, and a map operation that lifts transformations on tuples to transformations on sets.In this work we describe an alternative declarative method of describing transformations in logic. A formula with distinguished inputs and outputs gives an implicit definition if one can prove that for each input there is only one output that satisfies it. Our main result shows that one can synthesize transformations from proofs that a formula provides an implicit definition, where the proof is in an intuitionistic calculus that captures a natural style of reasoning about nested collections. Our polynomial time synthesis procedure is based on an analog of Craig’s interpolation lemma, starting with a provable containment between terms representing nested collections and generating an NRC expression that interpolates between them.We further show that NRC expressions that implement an implicit definition can be found when there is a classical proof of functionality, not just when there is an intuitionistic one. That is, whenever a formula implicitly defines a transformation, there is an NRC expression that implements it

Compensation methods to support cooperative applications: A case study in automated verification of schema requirements for an advanced transaction model

Compensation plays an important role in advanced transaction models, cooperative work and workflow systems. A schema designer is typically required to supply for each transaction another transaction to semantically undo the effects of . Little attention has been paid to the verification of the desirable properties of such operations, however. This paper demonstrates the use of a higher-order logic theorem prover for verifying that compensating transactions return a database to its original state. It is shown how an OODB schema is translated to the language of the theorem prover so that proofs can be performed on the compensating transactions

Systemic and Intra-Nodal Activation of NK Cells After Rituximab Monotherapy for Follicular Lymphoma

Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity

Learning nominal automata

We present an Angluin-style algorithm to learn nominal automata, which are acceptors of languages over infinite (structured) alphabets. The abstract approach we take allows us to seamlessly extend known variations of the algorithm to this new setting. In particular we can learn a subclass of nominal non-deterministic automata. An implementation using a recently developed Haskell library for nominal computation is provided for preliminary experiments

Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form

Bisimulation as path type for guarded recursive types

In type theory, coinductive types are used to represent processes, and are thus crucial for the formal verification of non-terminating reactive programs in proof assistants based on type theory, such as Coq and Agda. Currently, programming and reasoning about coinductive types is difficult for two reasons: The need for recursive definitions to be productive, and the lack of coincidence of the built-in identity types and the important notion of bisimilarity. Guarded recursion in the sense of Nakano has recently been suggested as a possible approach to dealing with the problem of productivity, allowing this to be encoded in types. Indeed, coinductive types can be encoded using a combination of guarded recursion and universal quantification over clocks. This paper studies the notion of bisimilarity for guarded recursive types in Ticked Cubical Type Theory, an extension of Cubical Type Theory with guarded recursion. We prove that, for any functor, an abstract, category theoretic notion of bisimilarity for the final guarded coalgebra is equivalent (in the sense of homotopy type theory) to path equality (the primitive notion of equality in cubical type theory). As a worked example we study a guarded notion of labelled transition systems, and show that, as a special case of the general theorem, path equality coincides with an adaptation of the usual notion of bisimulation for processes. In particular, this implies that guarded recursion can be used to give simple equational reasoning proofs of bisimilarity. This work should be seen as a step towards obtaining bisimilarity as path equality for coinductive types using the encodings mentioned above

Switching on the Lights for Gene Therapy

Strategies for non-invasive and quantitative imaging of gene expression in vivo have been developed over the past decade. Non-invasive assessment of the dynamics of gene regulation is of interest for the detection of endogenous disease-specific biological alterations (e.g., signal transduction) and for monitoring the induction and regulation of therapeutic genes (e.g., gene therapy). To demonstrate that non-invasive imaging of regulated expression of any type of gene after in vivo transduction by versatile vectors is feasible, we generated regulatable herpes simplex virus type 1 (HSV-1) amplicon vectors carrying hormone (mifepristone) or antibiotic (tetracycline) regulated promoters driving the proportional co-expression of two marker genes. Regulated gene expression was monitored by fluorescence microscopy in culture and by positron emission tomography (PET) or bioluminescence (BLI) in vivo. The induction levels evaluated in glioma models varied depending on the dose of inductor. With fluorescence microscopy and BLI being the tools for assessing gene expression in culture and animal models, and with PET being the technology for possible application in humans, the generated vectors may serve to non-invasively monitor the dynamics of any gene of interest which is proportionally co-expressed with the respective imaging marker gene in research applications aiming towards translation into clinical application