Linking Linear Threshold Units with Quadratic Models of Motion Perception

Behavioral experiments on insects (Hassenstein and Reichardt 1956; Poggio and Reichardt 1976) as well as psychophysical evidence from human studies (Van Santen and Sperling 1985; Adelson and Bergen 1985; Watson and Ahumada 1985) support the notion that short-range motion perception is mediated by a system with a quadratic type of nonlinearity, as in correlation (Hassenstein and Reichardt 1956), multiplication (Torre and Poggio 1978), or squaring (Adelson and Bergen 1985). However, there is little physiological evidence for quadratic nonlinearities in directionally selective cells. For instance, the response of cortical simple cells to a moving sine grating is half-wave instead of full-wave rectified as it should be for a quadratic nonlinearity (Movshon ef al. 1978; Holub and Morton-Gibson 1981) and is linear for low contrast (Holub and Morton-Gibson 1981). Complex cells have full-wave rectified responses, but are also linear in contrast. Moreover, a detailed theoretical analysis of possible biophysical mechanisms underlying direction selectivity concludes that most do not have quadratic properties except under very limited conditions (Grzywacz and Koch 1987). Thus, it is presently mysterious how a system can show quadratic properties while its individual components do not. We briefly discuss here a simple population encoding scheme offering a possible solution to this problem

Modeling direction selectivity of simple cells in striate visual cortex within the framework of the canonical microcircuit

Nearly all models of direction selectivity (DS) in visual cortex are based on feedforward connection schemes, where geniculate input provides all excitatory synaptic input to both pyramidal and inhibitory neurons. Feedforward inhibition then suppresses feedforward excitation for nonoptimal stimuli. Anatomically, however, the majority of asymmetric, excitatory, synaptic contacts onto cortical cells is provided by other cortical neurons, as embodied in the Canonical Microcircuit of Douglas and Martin (1991). In this view, weak geniculate input is strongly amplified in the preferred direction by the action of intracortical excitatory connections, while in the null direction inhibition reduces geniculate-induced excitation. We investigate analytically and through biologically realistic computer simulations the functioning of a cortical network based on massive excitatory, cortico-cortical feedback. The behavior of this network is compared to physiological data as well as to the behavior of a purely feedforward model of DS based on nonlagged input. Our model explains a number of puzzling features of direction selective simple cells, including the small somatic input conductance changes that have been measured experimentally during stimulation in the null direction, and the persistence of DS while fully blocking inhibition in a single cell. Although the operation at the heart of our network is amplification, the network passes the linearity test of (Jagadeesh et al., 1993). We make specific predictions concerning the effect of selective blockade of cortical inhibition on the velocity-response curve

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Modeling motion detection in striate visual cortex using massive excitatory feedback

This thesis is a detailed description and analysis of a model of direction-selective simple cells in cat striate visual cortex. There are three main defining features of our modeling effort compared to previous ones. (1) Local excitatory intracortical connections, known to be very numerous, are taken into account. (2) The model is very detailed: compartmental models of neurons are used and spiking is modeled using Hodgkin and Huxley-like active ionic currents. (3) Model responses are analyzed through standard electrophysiological methods and are compared in detail to physiology. Two separate operating modes are described. When the model acts as a proportional amplifier, contrast-response curves are relatively linear. In the hysteretic amplifier mode, contrast-response curves are much steeper initially, including an early portion with expansivity nonlinearity, but saturate abruptly at high contrasts. These features of the second mode are very similar to cortical contrast-response curves, but very different from the thalamus'. The second mode also predicts that hysteresis is latent in cortex, but that because of resetting through inhibition, cortical neurons do not fire in the absence of stimulation. In both modes, the model achieves strong amplification of the input through the excitatory cortical feedback. Amplification results in small changes in conductance for stimuli moving in the null direction, long a puzzling experimental finding; direction selectivity also persists during blockade of all inhibition in a single cell, as observed in recent experiments. Due to the nonlinearity of this amplification, bandpass velocity-response curves of thalamic neurons can be transformed into velocity low-pass cortical curves. Direction selectivity is invariant over a wide range of contrasts and velocities, a prominent feature of direction-selective cells in cortex. The model also makes specific predictions concerning the effects of selective blockade of cortical inhibition on direction selectivity at different velocities. Finally, we address the important issue of testing experimentally the linearity of cortical neurons. The same intracellular linearity test that has been used for cortical neurons is performed on the model. Although the model has substantial nonlinearities, it appears quite linear according to the linearity test. We explain these surprising observations in detail, and conclude that such tests are much more limited in usefulness than apparent at first