Center for Advanced Studies
Center for Advanced Studies
News Article | May 11, 2017
How do T cells, the beat cops of the immune system, detect signs of disease without the benefit of eyes? Like most cells, they explore their surroundings through direct physical contact, but how T cells feel out intruders rapidly and reliably enough to nip infections and other threats in the bud has remained a mystery to researchers. In a new study, published online May 11, 2017 in Science, UC San Francisco researchers began to address this question by using cutting-edge techniques to capture videos of the surface of living T cells in more detail than ever before. Researchers had previously observed tentacle-like protrusions called microvilli covering the surface of T cells, but the new research revealed that these tentacles are in constant motion: they crawl across the cell surface, each independently searching for signs of danger or infection in a fractal-like pattern that allows T cells to spend the minimum time necessary feeling for a potential threat before moving on. "Previous techniques had allowed us to take snapshots of the surface of T cells, but that's like trying to understand a basketball game by studying a black-and-white photo," said Matthew Krummel, PhD, associate professor of pathology at UCSF and senior author of the new study. "Now we can watch these amazing little fingers of membrane move around in real-time - and it turns out they're incredibly efficient." Among other potential benefits, Krummel says, understanding how T cells efficiently sample their environment to search for invasive pathogens opens up new questions about what countermeasures infectious organisms or even cancer cells may have evolved as a way of avoiding detection, and could suggest new ways for researchers to help T cells see through such a ruse. Efficient search by T cells is key to an effective immune response As they make their rounds through the body, T cells make contact with a network of informants -- other immune cells that scour the body for potential signs of danger and display the protein fragments they find (called "antigens") on their surface for inspection by the T cells. If a T cell meets one of these so-called antigen-presenting cells and recognizes a protein fragment it carries as evidence of danger, the T cell sounds the alarm and triggers a more global immune response to fight off the invaders. Scientists estimate that you have only about 100 T cells in your body at any given moment that can recognize and responding to a specific antigen, such a protein from this year's flu virus, and these few cells each take days to patrol your entire body, Krummel said. "This means the immune system really needs to get ahead of whatever is attacking the body at the very first evidence that there's an intruder on board. If one T cell misses the signs of a virus, the next time a cell that can recognize the threat might come through that tissue, the virus has had hours to make tens of thousands of copies of itself." New imaging techniques reveal how immune cells "talk" using touch In the Science study, Krummel's team was able to study how T cells efficiently interrogate antigen-presenting cells in real time, thanks to a high-resolution cellular imaging technique called lattice light-sheet microscopy, which the team set up at UCSF in collaboration with its inventor, 2014 Nobel prize winner and study co-author Eric Betzig, PhD, of the Howard Hughes Medical Institute's Janelia Research Campus in Virginia. Using this technology, the team studied mouse T cells exploring simulated patches of antigen-presenting cell membrane in laboratory dishes, and found that the T cell microvilli move independently of one another in a fractal-like geometry, such as is often seen in nature as a way of optimizing efficient use of space, such as by plant roots or foraging animals. The researchers calculated that, thanks to this efficient search pattern, in an average minute-long encounter win an antigen-presenting cell, T cell microvilli can thoroughly explore 98 percent of the contact surface between the two cells -- called an "immunological synapse" after the neuronal synapses of the nervous system. This suggests that T cells are tuned to spend the minimum time necessary to get a clear read on the information available at each antigen-presenting cell before moving on, the authors say. To study the details of threat detection by microvilli, the authors devised a new approach that allowed them to simultaneously track microvilli as well as the T cell receptor (TCR) proteins T cells use to detect their target antigens. To do this, the team covered simulated patches of antigen-presenting cell membrane with tiny fluorescent particles called quantum dots, which questing T cell microvilli had to push out of the way to reach the membrane surface. This technique, dubbed synaptic contact mapping, allowed the researchers to visualize the microvilli as holes of negative space in the quantum dot fluorescence, while at the same time visualizing TCRs with a different-colored fluorescent marker. They found that normally, individual microvilli poke and prod at the antigen-presenting cell membrane for an average of about four seconds at a time. But when the microvilli found the antigen they were searching for, they stayed in contact with the antigen-presenting cell membrane for 20 seconds or more and accumulated large rafts of TCRs, suggesting that they were likely signaling the T cell to trigger its immune response. "These videos give me a much more visceral understanding of what's happening when T cells and antigen-presenting cells come into contact," Krummel said. "T cells have these anemone-like sensory organs, and when they want to get information from another cell, their only chance appears to be during this short period of intimate contact. If they don't detect a strong signal during that contact, they move on." Real-time imaging technology opens new opportunities to study immunity and disease Krummel's team also briefly studied the surfaces of other types of immune cells, such as dendritic cells and B cells, which play different roles in pathogen detection and immune response. They found that each cell type appears to use distinct patterns of surface protrusions -- such as tentacles, waves, or curtain-like ripples -- to probe and communicate with their environments, though more research is needed to understand these diverse patterns and how they interact with one another. (See video.) "Understanding how the immune system reliably detects and responds to the huge range of potential threats it has to deal with is one of the key questions we still face as immunologists," Krummel said. "Of course, the immune system also makes mistakes -- like when it attacks the body's own cells in autoimmune disease or fails to recognize cancerous cells as a threat. Understanding the mechanics and constraints of how the immune system recognizes threats in the first place could potentially help us correct those errors." En Cai, PhD, Kyle Marchuk, PhD, Peter Beemiller, PhD, and Casey Beppler, BS, of UCSF, were co-first authors of the new study. Other authors were Matthew G. Rubashkin, PhD, Valerie M. Weaver, PhD, and Audrey Gérard, PhD, of UCSF; Tsung-Li Liu, PhD, and Bi-Chang Chen, PhD, of Janelia; and Frederic Bartumeus, PhD, of the Center for Advanced Studies of Blanes in Girona, Spain and Institut Català de Recerca i Estudis Avançats (ICREA) in Barcelona. Funding for this research was provided by the National Institutes of Health (AI052116), National Cancer Institute (U01CA202241), a US Department of Defense National Defense Science and Engineering Graduate Fellowship, and a National Science Foundation Graduate Research Fellowship (1650113). Betzig is an inventor on patent application US 20130286181 A1, submitted by Howard Hughes Medical Institute (HHMI), which covers LLS imaging. The authors declare no competing financial interests. About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www. .
Massidda L.,Center for Advanced Studies |
Marrocu M.,Center for Advanced Studies
Solar Energy | Year: 2017
The development of accurate forecasting methods for renewable energy sources can act as an important tool to integrate renewable power systems in the electricity grid. This paper proposes a technique that can forecast the power production of a photovoltaic plant one day in advance. The procedure is based on a regression model that considers the weather forecasts of the US Global Forecasting Service (GFS) as inputs, and it is trained and tested on a year of power production data of a 1.3 MW plant located in Borkum, Germany. The Multilinear Adaptive Regression Splines method was used to automatically define a reasonably simple model for the system with regression coefficients that could be easily interpreted. The results indicated that the forecasted power obtained by the model exhibited a high correlation with the measured data and relatively low errors despite the limited number of features that were included in the model and a low number of training samples. © 2017 Elsevier Ltd
News Article | December 2, 2016
Leading education company Manhattan Prep has made it through the penultimate stage of judging to be shortlisted for the Reimagine Education Awards 2016 Digital Content Award. In response to the evolving needs of higher education, the Reimagine Education Conference & Awards has recognized Interact™, Manhattan Prep’s interactive, proprietary e-learning platform that uses intuitive technology to guide the student on a customized study path tailored to their learning needs. The Reimagine Education Conference & Awards 2016, organized by career and education network QS in collaboration with the esteemed Wharton School of the University of Pennsylvania’s SEI Center for Advanced Studies in Management, will take place in Philadelphia from December 5-6 at the Inn at Penn, a Hilton Hotel. The concept behind the Awards is that traditional education is both insufficient and overly expensive for the needs of modern students, and therefore must be “reimagined.” An international panel of 40 distinguished judges has been selected to honor “innovative education pedagogies enhancing learning and employability.” By shortlisting Interact™, the panel has deemed the product to be one of the 120 most innovative educational projects among over 500 submissions. Created to immerse students in an engaging, on-demand, self-paced learning experience, Interact™ offers full GMAT and LSAT prep courses in which students can determine their own paths to success. Guided entirely by 99th percentile Manhattan Prep instructors, the program aims to connect students to comprehensive, interactive instruction that will benefit them before, during, and after the test. “It’s our deep belief at Manhattan Prep that exceptional teachers are the centerpiece of a transformational learning experience, but featuring teachers in self-study products is a challenge.” said Noah Teitelbaum, the company’s VP of Instruction & Customer Experience. “Interact™ is our answer to the challenge of creating a self-study product that harnesses the power of great teaching. Being shortlisted for this award is proof that what we’re doing is stretching ed tech’s boundaries.” Rey Fernández, the company’s VP & General Manager, added that “the product is authentic in aiming to create a student-teacher connection in a usually sterile and staid delivery mode. What makes Interact™ great is what makes our classrooms great too.” If Interact™ is selected as the 2016 Digital Content Award winner, it will have been deemed “the project that...creates the most compelling, detailed, informative digital content, with an interface or medium designed to support learners everywhere.”
News Article | December 1, 2016
PHILADELPHIA--(BUSINESS WIRE)--LiquidHub, a customer engagement company, today announced its research sponsorship of a 12-part series with Knowledge@Wharton, an online business analysis journal for the Wharton School of the University of Pennsylvania. The series, titled The Network Revolution, is authored by Barry Libert, Megan Beck, and Jerry (Yoram) Wind, professor of marketing at the Wharton School and director of Wharton’s SEI Center for Advanced Studies in Management. The authors explore w
Pisani L.,Center for Advanced Studies
Transport in Porous Media | Year: 2011
In this article, we derive a simple expression for the tortuosity of porous media as a function of porosity and of a single parameter characterizing the shape of the porous medium components. Following its value, a very large range of porous materials is described, from non-tortuous to high tortuosity ones with percolation limits. The proposed relation is compared with a widely used expression derived from percolation theory, and its predictive power is demonstrated through comparison with numerical simulations of diffusion phenomena. Application to the tortuosity of hydrated polymeric membranes is shown. © 2011 Springer Science+Business Media B.V.
Leonardi E.,Center for Advanced Studies |
D'Aguanno B.,Center for Advanced Studies
Energy | Year: 2011
The analysis of the solar power collected at the receiver in solar tower systems requires the use of efficient and accurate numerical codes. This paper presents a new Fortran computer program, CRS4-2 (an acronym for Crs4 Research Software for Central Receiver Solar System SimulationS), for the simulation of the optical performance of a central receiver solar plant. The implemented mathematical algorithm allows for the calculation of cosine, shading and blocking effects for heliostats arbitrarily arranged in the solar field. Special attention has been given to ensure the maximum flexibility concerning the number, dimension, shape, and position of the heliostats. In the present implementation, the solar field can be composed of both square and circular heliostats possibly mixed together, each one of them characterized by the size and height from the ground. The modular design of CRS4-2 allows the extension to heliostats of arbitrary shape with only minor modifications of the code. Shading and blocking effects are computed by a tessellation of the heliostats: therefore, the numerical accuracy depends only on the refinement of the tessellation. The application to actual systems has shown that the approach is stable and general. © 2011 Elsevier Ltd.
Pinna A.,Center for Advanced Studies |
Soranzo N.,Center for Advanced Studies |
de la Fuente A.,Center for Advanced Studies
PLoS ONE | Year: 2010
Background: Reverse-engineering gene networks from expression profiles is a difficult problem for which a multitude of techniques have been developed over the last decade. The yearly organized DREAM challenges allow for a fair evaluation and unbiased comparison of these methods. Results: We propose an inference algorithm that combines confidence matrices, computed as the standard scores from single-gene knockout data, with the down-ranking of feed-forward edges. Substantial improvements on the predictions can be obtained after the execution of this second step. Conclusions: Our algorithm was awarded the best overall performance at the DREAM4 In Silico 100-gene network sub-challenge, proving to be effective in inferring medium-size gene regulatory networks. This success demonstrates once again the decisive importance of gene expression data obtained after systematic gene perturbations and highlights the usefulness of graph analysis to increase the reliability of inference. © 2010 Pinna et al.
Pisani L.,Center for Advanced Studies
Transport in Porous Media | Year: 2016
In this article, the dependence of tortuosity on the geometrical structure of a porous medium is studied. In particular, the considered porous media have anisotropic structures, being composed by a collection of object of similar shape, with a well-defined orientation. Geometrical expressions for the tortuosity as a function of the porosity, of shape factors characterizing the geometry of the solid objects and of the orientation of the flow with respect to the object axes are derived. Besides the general case, two simpler expressions are derived for 2D porous media and for media composed by axisymmetric objects. The expressions for the two particular cases are validated through a series of numerical simulations of diffusion phenomena, finding a good agreement. The model is also compared with experimental data from literature, showing its possible use in the prediction of the transport properties of a porous medium made by assembling similar solid particles, by a simple geometrical characterization of its components. Finally, a parametric analysis is performed, showing a strong dependence of the tortuosity on the objects shape and on their orientation with respect to the flow. The capability of the presented model to predict such effects can be used to design materials with particular non-isotropic transport characteristics. © 2016 Springer Science+Business Media Dordrecht
Palomo A.M.,Center for Advanced Studies
Journal of Public Health Policy | Year: 2015
The Ebola epidemic exemplifies the importance of social determinants of health: poverty and illiteracy, among others. © 2015 Macmillan Publishers Ltd.
Leonardi E.,Center for Advanced Studies
Solar Energy | Year: 2012
The design of a beam-down solar power plant represents a very complex problem, being its performance dependent on many interrelated parameters. A systematic analysis of these parameters is proposed in the present study. The effect of the hyperboloid eccentricity on both the sunshape and the size of the heliostats is analyzed. Optimal values of the characteristic parameters of the compound parabolic concentrator are also proposed and on the basis of these considerations, extensive calculations are presented to evaluate yearly solar power collection. © 2011 Elsevier Ltd.