SPX-101 is stable in and retains function after exposure to cystic fibrosis sputum

Background: In healthy lungs, epithelial sodium channel (ENaC) is regulated by short, palate, lung, and nasal clone 1 (SPLUNC1). In cystic fibrosis (CF), ENaC is hyperactivated in part due to a loss of SPLUNC1 function. We have developed SPX-101 to replace the lost function of SPLUNC1 in the CF lung. Methods: Expression of SPLUNC1 was determined in sputum from healthy and CF donors. Stability of SPLUNC1, S18 (the ENaC regulatory domain of SPLUNC1), and SPX-101 was determined in sputum from CF donors and towards neutrophil elastase. Activity of SPX-101 after exposure to CF sputum was determined in airway epithelial cells from CF donors and in the βENaC transgenic mouse model. Results: SPLUNC1 protein expression is significantly reduced in CF as compared to healthy sputum. SPLUNC1 is rapidly degraded in CF sputum as well as by a number of individual proteases known to be found in the sputum. SPX-101, but not S18, is stable in CF sputum. Finally, SPX-101 retains its ability to internalize ENaC, regulate airway surface liquid height, and increase survival of βENaC mice after exposure to CF sputum. Conclusions: Our results demonstrate that SPX-101, but not SPLUNC1 or S18, is stable in CF sputum. These results support the therapeutic development of SPX-101 for the treatment of cystic fibrosis.Fil: Sesma, Juliana. Spyryx Biosciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wu, Bryant. Spyryx Biosciences; Estados UnidosFil: Stuhlmiller, Timothy J.. Spyryx Biosciences; Estados UnidosFil: Scott, David W.. Spyryx Biosciences; Estados Unido

Properties of hydrophobically modified polyacrylamide with low molecular weight and interaction with surfactant in aqueous solution

Hydrophobically modified polyacrylamide (HMPAM), with a molecular weight of 104 g/mol, was studied using a range of rheological methods and dynamic light scattering (DLS). DLS measurements indicate that the association of the modified polymer begins at low concentration. The modified polymer with high substitution forms transient networks below the critical concentration, but the networks are disrupted by the micelles formed by the polymer itself, and the networks do not contribute to viscosity enhancement. The modified polymers exhibited surface activity, and so they may be regarded as nonionic polymeric surfactants rather than thickeners. On the other hand, HMPAM is shown to interact with the surfactant SDS while PAM is inert to SDS. In the hydrophobic domains, it undergoes a surfactant-induced association process; in the hydro-phobe-surfactant transition regions, the surfactant binds to the polymer in a noncooperative way and forms a polymer-surfactant complex. Contracted polymer chains begin to extend because of electrostatic repulsion, which can overcome the association at surfactant domains. The conformation of HMPAM polymer chains could be controlled by adding a specific amount of surfactant

Filters, Random Fields and Maximum Entropy (FRAME): Towards a Unified Theory for Texture Modeling

This article presents a statistical theory for texture modeling. This theory combines filtering theory and Markov random field modeling through the maximum entropy principle, and interprets and clarifies many previous concepts and methods for texture analysis and synthesis from a unified point of view. Our theory characterizes the ensemble of images $I$ with the same texture appearance by a probability distribution $f(I)$ on a random field, and the objective of texture modeling is to make inference about $f(I)$, given a set of observed texture examples. In our theory, texture modeling consists of two steps. (1) A set of filters is selected from a general filter bank to capture features of the texture, these filters are applied to observed texture images, and the histograms of the filtered images are extracted. These histograms are estimates of the marginal distributions of $f(I)$. This step is called feature extraction. (2) The maximum entropy principle is employed to derive a distribution $p(I)$, which is restricted to have the same marginal distributions as those in (1). This $p(I)$ is considered as an estimate of $f(I)$ . This step is called feature fusion. A stepwise algorithm is proposed to choose filters from a general filter bank. The resulting model, called FRAME (Filters, Random fields And Maximum Entropy), is a Markov random field (MRF) model, but with a much enriched vocabulary and hence much stronger descriptive ability than the previous MRF models used for texture modeling. Gibbs sampler is adopted to synthesize texture images by drawing typical samples from $p(I)$ , thus the model is verified by seeing whether the synthesized texture images have similar visual appearances to the texture images being modeled. Experiments on a variety of 1D and 2D textures are described to illustrate our theory and to show the performance of our algorithms. These experiments demonstrate that many textures which are previously considered as from different categories can be modeled and synthesized in a common framework.Mathematic

Industrially Scalable Human Liver Organoids

Tissue engineering research is a multidisciplinary effort that incorporates the use of resources from various fields to address specific problems. Biomatrix scaffolds have recently been more widely used to improve the culture of cells by supporting their differentiated functions more than any known matrix extract or purified matrix component. However, they are not readily converted to industrial scale usage. Additionally, improved imaging techniques using ultrasound have been developed and are being used to characterize the biomatrix scaffolds in more detail to assess which preparation might be best for industrially scaled studies. The primary objective of this thesis was to identify methods that would most optimally use the biomatrix scaffold extracts while preserving the critical components of the matrix but in a way that was scalable for use in industry. We also demonstrate the use of novel ultrasound technologies that are non-invasive and non-destructive in the evaluation of biomatrix scaffolds.Master of Scienc

A parsimony-based metric for phylogenetic trees

In evolutionary biology various metrics have been defined and studied for comparing phylogenetic trees. Such metrics are used, for example, to compare competing evolutionary hypotheses or to help organize algorithms that search for optimal trees. Here we introduce a new metric dpdp on the collection of binary phylogenetic trees each labeled by the same set of species. The metric is based on the so-called parsimony score, an important concept in phylogenetics that is commonly used to construct phylogenetic trees. Our main results include a characterization of the unit neighborhood of a tree in the dpdp metric, and an explicit formula for its diameter, that is, a formula for the maximum possible value of dpdp over all possible pairs of trees labeled by the same set of species. We also show that dpdp is closely related to the well-known tree bisection and reconnection (tbr) and subtree prune and regraft (spr) distances, a connection which will hopefully provide a useful new approach to understanding properties of these and related metrics

Neighborhoods of trees in circular orderings

In phylogenetics, a common strategy used to construct an evolutionary tree for a set of species X is to search in the space of all such trees for one that optimizes some given score function (such as the minimum evolution, parsimony or likelihood score). As this can be computationally intensive, it was recently proposed to restrict such searches to the set of all those trees that are compatible with some circular ordering of the set X. To inform the design of efficient algorithms to perform such searches, it is therefore of interest to find bounds for the number of trees compatible with a fixed ordering in the neighborhood of a tree that is determined by certain tree operations commonly used to search for trees: the nearest neighbor interchange (nni), the subtree prune and regraft (spr) and the tree bisection and reconnection (tbr) operations. We show that the size of such a neighborhood of a binary tree associated with the nni operation is independent of the tree’s topology, but that this is not the case for the spr and tbr operations. We also give tight upper and lower bounds for the size of the neighborhood of a binary tree for the spr and tbr operations and characterize those trees for which these bounds are attained

Holonomy algebras of pseudo-quaternionic-K\"ahlerian manifolds of signature (4,4)(4,4)

Possible holonomy algebras of pseudo-quaternionic-K\"ahlerian manifolds of signature $(4,4)$ are classified. Using this, a new proof of the classification of simply connected pseudo-quaternionic-K\"ahlerian symmetric spaces of signature $(4,4)$ is obtained.Comment: 16 page

Modeling and Decoding Motor Cortical Activity Using a Switching Kalman Filter

We present a switching Kalman filter model for the real-time inference of hand kinematics from a population of motor cortical neurons. Firing rates are modeled as a Gaussian mixture where the mean of each Gaussian component is a linear function of hand kinematics. A "hidden state" models the probability of each mixture component and evolves over time in a Markov chain. The model generalizes previous encoding and decoding methods, addresses the non-Gaussian nature of firing rates, and can cope with crudely sorted neural data common in on-line prosthetic applications.Mathematic

Species, Clusters and the 'Tree of Life': A graph-theoretic perspective

A hierarchical structure describing the inter-relationships of species has long been a fundamental concept in systematic biology, from Linnean classification through to the more recent quest for a 'Tree of Life.' In this paper we use an approach based on discrete mathematics to address a basic question: Could one delineate this hierarchical structure in nature purely by reference to the 'genealogy' of present-day individuals, which describes how they are related with one another by ancestry through a continuous line of descent? We describe several mathematically precise ways by which one can naturally define collections of subsets of present day individuals so that these subsets are nested (and so form a tree) based purely on the directed graph that describes the ancestry of these individuals. We also explore the relationship between these and related clustering constructions.Comment: 19 pages, 4 figure

The effects of sildenafil on ciliary beat frequency in patients with pulmonary non-tuberculous mycobacteria disease: phase I/II trial.

RATIONALE:Pulmonary non-tuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Abnormal mucociliary clearance and abnormal nasal nitric oxide (nNO) have been associated with PNTM disease in other patient cohorts. Mucociliary clearance can be affected by NO-cyclic guanosine monophosphate signalling and, therefore, modulation of the pathway may be possible with phosphodiesterase inhibitors such as sildenafil as a novel therapeutic approach. OBJECTIVE:To define ex vivo characteristics of PNTM disease affected by sildenafil. METHODS:Subjects with PNTM infections were recruited into an open-label dose-escalation trial of sildenafil. Laboratory measurements and mucociliary measurements-ciliary beat frequency, nNO and 24-hour sputum production-were collected throughout the study period. Patients received sildenafil daily during the study period, with escalation from 20 to 40 mg three times per day. MEASUREMENTS AND MAIN RESULTS:Increased ciliary beat frequency occurred after a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil. The increase ciliary beat frequency was not seen with 20 mg sildenafil dosing. There were no changes in sputum production, nNO production, Quality of Life-Bronchiectasis-NTM module (QOL-B-NTM) questionnaire or the St George's Respiratory Questionnaire during the study period. CONCLUSION:Sildenafil, 40 mg, increased ciliary beat frequency acutely as well as with extended administration