238 research outputs found
A Pixel Read-Out Front-End in 28 nm CMOS with Time and Space Resolution
Future high luminosity colliders will require front-end electronics with unprecedented performance, both in space and time resolution (tens of micrometers and tens of picoseconds) and in radiation hardness (tens of megagray). Moreover, the high number of events will generate an enormous quantity of data (some terabits per second), and the limited bandwidth requires to perform data selection as close as possible to the front-end stage, to reduce the amount of data transmitted and stored for off-line analysis.The TimeSpOT (TIME and SPace real-time Operating Tracker) project, funded by INFN, is developing a complete demonstrator of a tracking device including all the features needed for future high luminosity experiments.In this presentation, we describe the first prototype of the readout electronics in 28 nm CMOS technology. The modules of the front-end circuitry have been designed and integrated in a test chip, which will allow us to characterize each block separately, and to connect them in a processing chain to evaluate the overall performance
Retrograde movements determine effective stem cell numbers in the intestine
The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts(1-3). Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.Peer reviewe
Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity.
Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell-type-specific deletion of Gpr35 in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota
Does the cognitive reflection test measure cognitive reflection? A mathematical modeling approach
We used a mathematical modeling approach, based on a sample of 2,019 participants, to better understand what the cognitive reflection test (CRT; Frederick In Journal of Economic Perspectives, 19, 25–42, 2005) measures. This test, which is typically completed in less than 10 min, contains three problems and aims to measure the ability or disposition to resist reporting the response that first comes to mind. However, since the test contains three mathematically based problems, it is possible that the test only measures mathematical abilities, and not cognitive reflection. We found that the models that included an inhibition parameter (i.e., the probability of inhibiting an intuitive response), as well as a mathematical parameter (i.e., the probability of using an adequate mathematical procedure), fitted the data better than a model that only included a mathematical parameter. We also found that the inhibition parameter in males is best explained by both rational thinking ability and the disposition toward actively open-minded thinking, whereas in females this parameter was better explained by rational thinking only. With these findings, this study contributes to the understanding of the processes involved in solving the CRT, and will be particularly useful for researchers who are considering using this test in their research
The time course of conflict on the Cognitive Reflection Test
Reasoning that is deliberative and reflective often requires the inhibition of intuitive responses. The Cognitive Reflection Test (CRT) is designed to assess people's ability to suppress incorrect heuristic responses in favour of deliberation. Correct responding on the CRT predicts performance on a range of tasks in which intuitive processes lead to incorrect responses, suggesting indirectly that CRT performance is related to cognitive control. Yet little is known about the cognitive processes underlying performance on the CRT. In the current research, we employed a novel mouse tracking methodology to capture the time-course of reasoning on the CRT. Analysis of mouse cursor trajectories revealed that participants were initially drawn towards the incorrect (i.e., intuitive) option even when the correct (deliberative) option was ultimately chosen. Conversely, participants were not attracted to the correct option when they ultimately chose the incorrect intuitive one. We conclude that intuitive processes are activated automatically on the CRT and must be inhibited in order to respond correctly. When participants responded intuitively, there was no evidence that deliberative reasoning had become engaged
Virus Movements on the Plasma Membrane Support Infection and Transmission between Cells
How viruses are transmitted across the mucosal epithelia of the respiratory, digestive, or excretory tracts, and how they spread from cell to cell and cause systemic infections, is incompletely understood. Recent advances from single virus tracking experiments have revealed conserved patterns of virus movements on the plasma membrane, including diffusive motions, drifting motions depending on retrograde flow of actin filaments or actin tail formation by polymerization, and confinement to submicrometer areas. Here, we discuss how viruses take advantage of cellular mechanisms that normally drive the movements of proteins and lipids on the cell surface. A concept emerges where short periods of fast diffusive motions allow viruses to rapidly move over several micrometers. Coupling to actin flow supports directional transport of virus particles during entry and cell-cell transmission, and local confinement coincides with either nonproductive stalling or infectious endocytic uptake. These conserved features of virus–host interactions upstream of infectious entry offer new perspectives for anti-viral interference
Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes
Zaire ebolavirus (ZEBOV), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. Currently no specific therapy or vaccine is available. Virus entry is an attractive target for therapeutic intervention. However, current knowledge of the ZEBOV entry mechanism is limited. While it is known that ZEBOV enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. Previous studies have produced differing outcomes, indicating potential involvement of multiple routes but many of these studies were performed using noninfectious surrogate systems such as pseudotyped retroviral particles, which may not accurately recapitulate the entry characteristics of the morphologically distinct wild type virus. Here we used replication-competent infectious ZEBOV as well as morphologically similar virus-like particles in specific infection and entry assays to demonstrate that in HEK293T and Vero cells internalization of ZEBOV is independent of clathrin, caveolae, and dynamin. Instead the uptake mechanism has features of macropinocytosis. The binding of virus to cells appears to directly stimulate fluid phase uptake as well as localized actin polymerization. Inhibition of key regulators of macropinocytosis including Pak1 and CtBP/BARS as well as treatment with the drug EIPA, which affects macropinosome formation, resulted in significant reduction in ZEBOV entry and infection. It is also shown that following internalization, the virus enters the endolysosomal pathway and is trafficked through early and late endosomes, but the exact site of membrane fusion and nucleocapsid penetration in the cytoplasm remains unclear. This study identifies the route for ZEBOV entry and identifies the key cellular factors required for the uptake of this filamentous virus. The findings greatly expand our understanding of the ZEBOV entry mechanism that can be applied to development of new therapeutics as well as provide potential insight into the trafficking and entry mechanism of other filoviruses
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