Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function ...of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells
. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies
. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD
, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.
Simplified limits on resonances at the LHC Chivukula, R. Sekhar; Ittisamai, Pawin; Mohan, Kirtimaan ...
Physical review. D,
11/2016, Letnik:
94, Številka:
9
Journal Article
Recenzirano
Odprti dostop
In the earliest stages of evaluating new collider data, especially if a small excess may be present, it would be useful to have a method for comparing the data with entire classes of models, to get ...an immediate sense of which classes could conceivably be relevant. In this paper, we propose a method that applies when the new physics invoked to explain the excess corresponds to the production and decay of a single, relatively narrow, s-channel resonance. A simplifed model of the resonance allows us to convert an estimated signal cross section into general bounds on the product of the branching ratios corresponding to the dominant production and decay modes. This quickly reveals whether a given class of models could possibly produce a signal of the required size at the LHC. Our work sets up a general framework, outlines how it operates for resonances with different numbers of production and decay modes, and analyzes cases of current experimental interest, including resonances decaying to dibosons, diphotons, dileptons, or dijets. If the LHC experiments were to report their searches for new resonances beyond the standard model in the simplified limits variable ζ defined in this paper, that would make it far easier to avoid blind alleys and home in on the most likely candidate models to explain any observed excesses.
Objective
Poorer executive function (EF) has been linked to disinhibited eating in youth, suggesting poor EF predisposes toward obesity, yet the specific nature and extent of interconnections between ...facets of these domains is unclear. Network analysis provides a promising framework for elucidating the relationship between poor EF and disinhibited eating, and offers insights into potential maintenance processes.
Method
Among youth ages 8–17 years, a regularized partial correlation network of EF and disinhibited eating facets was estimated to examine expected influence centrality and bridge expected influence. Computerized neurocognitive tasks assessed EF variables, including decision‐making, general and food‐related inhibitory control, delayed gratification, cognitive flexibility, and working memory. Disinhibited eating variables included total carbohydrate–fat intake at a laboratory test meal and self‐reported eating in the absence of hunger, emotional eating, and loss‐of‐control eating severity.
Results
In the current sample (N = 248; Mage = 12.5; 54.8% female; 43.5% non‐Hispanic White; 25.8% non‐Hispanic Black; BMI %ile = 65.8 ± 27.8), emotional eating in response to depressive symptoms emerged as a central symptom in the network. Carbohydrate–fat intake had the highest bridge expected influence and was most strongly connected to general inhibitory control (part r = .14).
Discussion
The link between general inhibitory control and objective palatable food intake may be particularly salient in maintaining maladaptive eating behavior. Interventions targeting behavioral disinhibition may disrupt associations among a network of disinhibited eating facets in youth and should be targets for longitudinal research.
Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. ...PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype
an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (
., JAK-STAT, Smad, Wnt signaling, Hedgehog
.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.
The flow in a spherical cavity on a curved round pipe is a canonical flow that describes well the flow inside a sidewall aneurysm on an intracranial artery. Intracranial aneurysms are often treated ...with a flow-diverting stent (FDS), a low-porosity metal mesh that covers the entrance to the cavity, to reduce blood flow into the aneurysm sac and exclude it from mechanical stresses imposed by the blood flow. Successful treatment is highly dependent on the degree of reduction of flow inside the cavity, and the resulting altered fluid mechanics inside the aneurysm following treatment. Using stereoscopic particle image velocimetry, we characterize the fluid mechanics in a canonical configuration representative of an intracranial aneurysm treated with a FDS: a spherical cavity on the side of a curved round pipe covered with a metal mesh formed by an actual medical FDS. This porous mesh coverage is the focus of Part 2 of the paper, characterizing the effects of parent vessel $Re$, $De$ and pulsatility, $Wo$, on the fluid dynamics, compared with the canonical configuration with no impediments to flow into the cavity that is described in Part 1 (Chassagne et al., J. Fluid Mech., vol. 915, 2021, A123). Coverage with a FDS markedly reduces the flow $Re$ in the aneurysmal cavity, creating a viscous-dominated flow environment despite the parent vessel $Re>100$. Under steady flow conditions, the topology that forms inside the cavity is shown to be a function of the parent vessel $De$. At low values of $De$, flow enters the cavity at the leading edge and remains attached to the wall before exiting at the trailing edge, a novel behaviour that was not found under any conditions of the high-$Re$, unimpeded cavity flow described in Part 1. Under these conditions, flow in the cavity co-rotates with the direction of the free-stream flow, similar to Stokes flow in a cavity. As $De$ increases, the flow along the leading edge begins to separate, and the recirculation zone grows with increasing $De$, until, above $De \approx 180$, the flow inside the cavity is fully recirculating, counter-rotating with respect to the free-stream flow. Under pulsatile flow conditions, the vortex inside the cavity progresses through the same cycle – switching from attached and co-rotating with the free-stream flow at the beginning of the cycle (low velocity and positive acceleration) to separated and counter-rotating as $De$ reaches a critical value. The location of separation within the harmonic cycle is shown to be a function of both $De$ and $Wo$. The values of aneurysmal cavity $Re$ based on both the average velocity and the circulation inside the cavity are shown to increase with increasing values of $De$, while $Wo$ is shown to have little influence on the time-averaged metrics. As $De$ increases, the strength of the secondary flow in the parent vessel grows, due to the inertial instability in the curved pipe, and the flow rate entering the cavity increases. Thus, the effectiveness of FDS treatment to exclude the aneurysmal cavity from the haemodynamic stresses is compromised for aneurysms located on high-curvature arteries, i.e. vessels with high $De$, and this can be a fluid mechanics criterion to guide treatment selection.
Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two ...cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsy specimens showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages. This novel constellation was termed diffuse alveolar injury with delayed epithelization. In addition, mirroring data from murine models of lung injury/regeneration, peribronchiolar basaloid pods (previously described as squamous metaplasia) and ciliated bronchiolarization were identified in these patients and in 39% of 57 historical cases with diffuse alveolar damage. These findings demonstrate a common and clinically relevant human disease correlate for murine models of severe acute lung injury. Evidence suggests that peribronchiolar basaloid pods and bronchiolarization are related spatially and temporally and likely represent overlapping sequential stages of the response to severe distal airway injury.
PDF
