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In this paper, we design a hybrid controller that globally exponentially stabilizes a system evolving on the n-dimensional sphere, denoted by Sn. This hybrid controller is induced by a “synergistic” collection of potential functions on Sn. We propose a particular construction of this class of functions that generates flows along geodesics of the sphere, providing convergence to the desired reference with minimal path length. We show that the proposed strategy is suitable to the exponential stabilization of a quadrotor vehicle.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Ultra-high dose-rate 'FLASH' radiotherapy may be a pivotal step forward for cancer treatment, widening the therapeutic window between radiation tumour killing and damage to neighbouring normal tissues. The extent of normal tissue sparing reported in pre-clinical FLASH studies typically corresponds to an increase in isotoxic dose-levels of 5-20%, though gains are larger at higher doses. Conditions currently thought necessary for FLASH normal tissue sparing are a dose-rate =40 Gy s-1, dose-per-fraction =5-10 Gy and irradiation duration =0.2-0.5 s. Cyclotron proton accelerators are the first clinical systems to be adapted to irradiate deepseated tumours at FLASH dose-rates, but even using these machines it is challenging to meet the FLASH conditions. In this review we describe the challenges for delivering FLASH proton beam therapy, the compromises that ensue if these challenges are not addressed, and resulting dosimetric losses. Some of these losses are on the same scale as the gains from FLASH found preclinically. We therefore conclude that for FLASH to succeed clinically the challenges must be systematically overcome rather than accommodated, and we survey physical and pre-clinical routes for achieving this. [ABSTRACT FROM AUTHOR]

In this paper, we design a hybrid controller based on the concept of centrally synergistic potential functions on the n-dimensional sphere to achieve global tracking of an attitude reference as well as exponential stabilization of the position and velocity of a vectored-thrust vehicle. The proposed hybrid attitude controller renders a partial attitude reference globally exponentially stable, and the full attitude reference globally attractive and locally exponentially stable. This controller is then combined with a position controller for the quadrotor vehicle for tracking of a given reference. Simulation results are provided so as to demonstrate the performance of the proposed controller.

Nasal epithelial cells (NECs) are the part of the airways that respond to air pollutants and are the first cells infected with respiratory viruses. They are also involved in many airway diseases through their innate immune response and interaction with immune and airway stromal cells. NECs are of particular interest for studies in children due to their accessibility during clinical visits. Human induced pluripotent stem cells (iPSCs) have been generated from multiple cell types and are a powerful tool for modeling human development and disease, as well as for their potential applications in regenerative medicine. This is the first protocol to lay out methods for successful generation of iPSCs from NECs derived from pediatric participants for research purposes. It describes how to obtain nasal epithelial cells from children, how to generate primary NEC cultures from these samples, and how to reprogram primary NECs into well-characterized iPSCs. Nasal mucosa samples are useful in epidemiological studies related to the effects of air pollution in children, and provide an important tool for studying airway disease. Primary nasal cells and iPSCs derived from them can be a tool for providing unlimited material for patient-specific research in diverse areas of airway epithelial biology, including asthma and COPD research.

In this paper, we show that the existence of centrally synergistic potential functions on the n-dimensional sphere, denoted by Sn, is a sufficient condition for the global asymptotic stabilization of a point in Sn. Additionally, if these functions decrease exponentially fast during flows and are bounded from above and from below by some polynomial function of the tracking error, then the reference point can be globally exponentially stabilized. We construct two kinds of centrally synergistic functions: the first kind consists of a finite family of potential functions on Sn while the second kind consists of an uncountable number of potential functions on Sn. While the former generates a simpler jump logic, the latter is optimal in the sense that it generates flows with minimal length.

BackgroundInduced pluripotent stem cells (iPSCs) hold tremendous potential, both as a biological tool to uncover the pathophysiology of disease by creating relevant human cell models and as a source of cells for cell-based therapeutic applications. Studying the reprogramming process will also provide significant insight into tissue development.ObjectiveWe sought to characterize the derivation of iPSC lines from nasal epithelial cells (NECs) isolated from nasal mucosa samples of children, a highly relevant and easily accessible tissue for pediatric populations.MethodsWe performed detailed comparative analysis on the transcriptomes and methylomes of NECs, iPSCs derived from NECs (NEC-iPSCs), and embryonic stem cells (ESCs).ResultsNEC-iPSCs express pluripotent cell markers, can differentiate into all 3 germ layers in vivo and in vitro, and have a transcriptome and methylome remarkably similar to those of ESCs. However, residual DNA methylation marks exist, which are differentially methylated between NEC-iPSCs and ESCs. A subset of these methylation markers related to epithelium development and asthma and specific to NEC-iPSCs persisted after several passages in vitro, suggesting the retention of an epigenetic memory of their tissue of origin. Our analysis also identified novel candidate genes with dynamic gene expression and DNA methylation changes during reprogramming, which are indicative of possible roles in airway epithelium development.ConclusionNECs are an excellent tissue source to generate iPSCs in pediatric asthmatic patients, and detailed characterization of the resulting iPSC lines would help us better understand the reprogramming process and retention of epigenetic memory.

The unit quaternion is a pervasive representation of rigid-body attitude used for the design and analysis of feedback control laws. Because the space of unit quaternions constitutes a double cover of the rigid - body - attitude space, quaternion-based control laws are often - by design - inconsistent, i.e., they do not have a unique value for each rigid-body attitude. Inconsistent quaternion-based control laws require an additional mechanism that uniquely converts an attitude estimate into its quaternion representation; however, conversion mechanisms that are memoryless - e.g., selecting the quaternion having positive scalar component- have a limited domain where they remain injective and, when used globally, introduce discontinuities into the closed-loop system. We show-through an explicit construction and Lyapunov analysis-that such discontinuities can be hijacked by arbitrarily small measurement disturbances to stabilize attitudes far from the desired attitude. To remedy this limitation, we propose a hybrid-dynamic algorithm for smoothly lifting an attitude path to the unit-quaternion space. We show that this hybrid-dynamic mechanism allows us to directly translate quaternion-based controllers and their asymptotic stability properties (obtained in the unit-quaternion space) to the actual rigid-body-attitude space.We also show that when quaternion-based controllers are not designed to account for the double covering of the rigid-body-attitude space by a unit-quaternion parameterization, they can give rise to the unwinding phenomenon, which we characterize in terms of the projection of asymptotically stable sets. Finally, we employ the main results to show that certain hybrid feedbacks can globally asymptotically stabilize the attitude of a rigid body.

Differentiation of human pluripotent stem cells (hPSCs) into organ-specific subtypes offers an exciting avenue for the study of embryonic development and disease processes, for pharmacologic studies and as a potential resource for therapeutic transplant (1,2). To date, limited in vivo models exist for human intestine, all of which are dependent upon primary epithelial cultures or digested tissue from surgical biopsies that include mesenchymal cells transplanted on biodegradable scaffolds (3,4). Here, we generated human intestinal organoids (HIOs) produced in vitro from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) (5,6) that can engraft in vivo. These HIOs form mature human intestinal epithelium with intestinal stem cells contributing to the cryptvillus architecture and a laminated human mesenchyme, both supported by mouse vasculature ingrowth. In vivo transplantation resulted in marked expansion and maturation of the epithelium and mesenchyme, as demonstrated by differentiated intestinal cell lineages (enterocytes, goblet cells, Paneth cells, tuft cells and enteroendocrine cells), presence of functional brush-border enzymes (lactase, sucrase-isomaltase and dipeptidyl peptidase 4) and visible subepithelial and smooth muscle layers when compared with HIOs in vitro. Transplanted intestinal tissues demonstrated digestive functions as shown by permeability and peptide uptake studies. Furthermore, transplanted HIO-derived tissue was responsive to systemic signals from the host mouse following ileocecal resection, suggesting a role for circulating factors in the intestinal adaptive response (7-9). This model of the human small intestine may pave the way for studies of intestinal physiology, disease and translational studies., Because of the complexity of a vascularized hollow organ such as the intestine, the development of an adequate human model for its study and replacement following surgery or pathological processes [...]

Studies in embryonic development have guided successful efforts to direct the differentiation of human embryonic and induced pluripotent stem cells (PSCs) into specific organ cell types in vitro (1,2). For example, human PSCs have been differentiated into monolayer cultures of liver hepatocytes and pancreatic endocrine cells (3-6) that have therapeutic efficacy in animal models of liver disease (7,8) and diabetes (9), respectively. However, the generation of complex three-dimensional organ tissues in vitro remains a major challenge for translational studies. Here we establish a robust and efficient process to direct the differentiation of human PSCs into intestinal tissue in vitro using a temporal series of growth factor manipulations to mimic embryonic intestinal development (10). This involved activin-induced definitive endoderm formation (11), FGF/Wnt-induced posterior endoderm pattering, hindgut specification and morphogenesis (12-14), and a pro-intestinal culture system (15,16) to promote intestinal growth, morphogenesis and cytodifferentiation. The resulting three-dimensional intestinal 'organoids' consisted of a polarized, columnar epithelium that was patterned into villus-like structures and crypt-like proliferative zones that expressed intestinal stem cell markers (17). The epithelium contained functional enterocytes, as well as goblet, Paneth and enteroendocrine cells. Using this culture system as a model to study human intestinal development, we identified that the combined activity of WNT3A and FGF4 is required for hindgut specification whereas FGF4 alone is sufficient to promote hindgut morphogenesis. Our data indicate that human intestinal stem cells form denovoduring development. We also determined that NEUROG3, a pro-endocrine transcription factor that is mutated in enteric anendocrinosis (18), is both necessary and sufficient for human enteroendocrine cell development invitro. PSC-derived human intestinal tissue should allow for unprecedented studies of human intestinal development and disease., The epithelium of the intestine is derived from a simple sheet of cells called the definitive endoderm (17). As a first step to generating intestinal tissue from PSCs (summarized in [...]