Modeling driver cells in developing neuronal networks.

Spontaneous emergence of synchronized population activity is a characteristic feature of developing brain circuits. Recent experiments in the developing neo-cortex showed the existence of driver cells able to impact the synchronization dynamics when single-handedly stimulated. We have developed a spiking network model capable to reproduce the experimental results, thus identifying two classes of driver cells: functional hubs and low functionally connected (LC) neurons. The functional hubs arranged in a clique orchestrated the synchronization build-up, while the LC drivers were lately or not at all recruited in the synchronization process. Notwithstanding, they were able to alter the network state when stimulated by modifying the temporal activation of the functional clique or even its composition. LC drivers can lead either to higher population synchrony or even to the arrest of population dynamics, upon stimulation. Noticeably, some LC driver can display both effects depending on the received stimulus. We show that in the model the presence of inhibitory neurons together with the assumption that younger cells are more excitable and less connected is crucial for the emergence of LC drivers. These results provide a further understanding of the structural-functional mechanisms underlying synchronized firings in developing circuits possibly related to the coordinated activity of cell assemblies in the adult brain.

A 28-year-old woman with fever, rash, and pancytopenia.

A 28-year-old Hispanic woman was admitted to the hospital with fever, sore throat, arthralgia, and a generalized rash of 2 weeks' duration. Her medical history was significant for various food and medication allergies. Multiple antibiotics were given for suspected infection, and she subsequently developed a new skin rash, acute liver injury, eosinophilia, and pancytopenia. Additional studies showed hypertriglyceridemia; elevated interleukin-2 receptor levels; absent natural killer cell activity; and hemophagocytosis in skin, liver, and bone marrow biopsy specimens. Treatment with intravenous immunoglobulin and steroids resulted in complete remission.

Clique of functional hubs orchestrates population bursts in developmentally regulated neural networks.

It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrate population activity.

Prevalence of self-reported food allergy in U.S. adults: 2001, 2006, and 2010.

BACKGROUND: Epidemiologic evidence indicates that food allergies are increasing in the population. Information on a change in self-reported food allergy (srFA) in adults over time is lacking. OBJECTIVE: To report the prevalence of srFA and compare differences at three time points over a decade. METHODS: We analyzed srFA and reported physician-diagnosed food allergy in >4000 U.S. adults who participated in the 2010 U.S. Food and Drug Administration Food Safety Survey. Information on causative food(s), reaction severity characteristics, and various diagnostic factors was also analyzed. We compared 2010 Food Safety Survey data with 2006 and 2001 data, and highlighted relevant differences. RESULTS: SrFA prevalence increased significantly, to 13% in 2010 and 14.9% in 2006 compared with 9.1% in 2001 (p < 0.001). Physician diagnosed food allergy was 6.5% in 2010, which was not significantly different compared with 7.6% in 2006 and 5.3% in 2001. SrFA increased in both men and women, non-Hispanic white and black adults, 50-59 year olds, and in adults with a high school or lower education. In 2010, milk, shellfish, and fruits were the most commonly reported food allergens, similar to 2001. Also, in 2010, 15% of reactions reportedly required a hospital visit and 8.4% were treated with epinephrine. Minor differences in reaction severity characteristics were noted among the surveys. CONCLUSIONS: Analysis of survey results indicates that the prevalence of srFA increased among U.S. adults from 2001 to 2010 and that adults are increasingly self-reporting FAs without obtaining medical diagnosis. Improved education about food allergies is needed for this risk group.

Recalls Associated with Food Allergens and Gluten in FDA-Regulated Foods from Fiscal Years 2013 to 2019.

Allergens are one of the leading causes of food recalls in the US. The Food and Drug Administration (FDA) enforces requirements relating to major food allergens (MFAs) and gluten-free labeling to ensure food safety for allergic and celiac patients, respectively. Violative foods are subject to recalls. In this study, recall data for FDA-regulated foods were analyzed for fiscal years (FYs) 2013-2019 to identify trends and root causes associated with 1471 food allergen and gluten recalls. Of the 1471 recalls, 1415 recalls were due to MFAs, 34 recalls were due to gluten-free labeling violation and 23 recalls involved other allergens. Recalls due to MFAs overall increased during the study period with a peak incidence in FY 2017. MFA recall health hazard classifications were assessed as Class I (51.2%), Class II (45.5%), and Class III (3.3%). A majority of MFA recalls involved one allergen (78.8%). Milk was the most common MFA involved in MFA recalls (37.5%), followed by soy (22.5%) and tree nuts (21.6%). Almond, anchovy, and shrimp were the most common allergens recalled within the MFA groups of tree nuts, fish, and Crustacean shellfish, respectively. About 97% of MFA recalls involved one product category and among them, the category of 'bakery products, dough, bakery mixes and icings' ranked first (367 recalls), followed by the category of 'chocolate and cocoa products' (120 recalls). Labeling-associated errors accounted for 71.1% of MFA recalls with known root causes (914 out of 1286). It is important for the industry to develop and implement appropriate allergen controls to reduce the number of MFA recalls.

Collective dynamics in sparse networks.

The microscopic and macroscopic dynamics of random networks is investigated in the strong-dilution limit (i.e., for sparse networks). By simulating chaotic maps, Stuart-Landau oscillators, and leaky integrate-and-fire neurons, we show that a finite connectivity (of the order of a few tens) is able to sustain a nontrivial collective dynamics even in the thermodynamic limit. Although the network structure implies a nonadditive dynamics, the microscopic evolution is extensive (i.e., the number of active degrees of freedom is proportional to the number of network elements).

Discrete breathers in a realistic coarse-grained model of proteins.

We report the results of molecular dynamics simulations of an off-lattice protein model featuring a physical force-field and amino-acid sequence. We show that localized modes of nonlinear origin, discrete breathers (DBs), emerge naturally as continuations of a subset of high-frequency normal modes residing at specific sites dictated by the native fold. DBs are time-periodic, space-localized vibrational modes that exist generically in nonlinear discrete systems and are known for their resilience and ability to concentrate energy for long times. In the case of the small ß-barrel structure that we consider, DB-mediated localization occurs on the turns connecting the strands. At high energies, DBs stabilize the structure by concentrating energy on a few sites, while their collapse marks the onset of large-amplitude fluctuations of the protein. Furthermore, we show how breathers develop as energy-accumulating centres following perturbations even at distant locations, thus mediating efficient and irreversible energy transfers. Remarkably, due to the presence of angular potentials, the breather induces a local static distortion of the native fold. Altogether, the combination of these two nonlinear effects may provide a ready means for remotely controlling local conformational changes in proteins.

F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins.

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.

Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.

Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.

Irregular collective behavior of heterogeneous neural networks.

We investigate a network of integrate-and-fire neurons characterized by a distribution of spiking frequencies. Upon increasing the coupling strength, the model exhibits a transition from an asynchronous regime to a nontrivial collective behavior. Numerical simulations of large systems indicate that, at variance with the Kuramoto model, (i) the macroscopic dynamics stays irregular and (ii) the microscopic (single-neuron) evolution is linearly stable.

Effects of diet on skin sensitization by nickel, poison ivy, and sesquiterpene lactones.

Skin contact or exposure to sensitizers often occurs as a consequence of occupational exposures (e.g. poison ivy in forestry), wearing jewelry (e.g. nickel), or use of cosmetics (e.g. fragrances). However, many of the known skin sensitizers or their chemical variants are also consumed orally through foods or other sources. Since oral exposure to antigenic substances can lead to tolerance, consumption of sensitizers may impact the development and potency of skin sensitization, especially if the sensitizer is consumed early in life, prior to the first skin contact. To address this issue, we have reviewed human clinical and epidemiological literature relevant to this subject and evaluated whether early oral exposures to relevant sensitizers, or their chemical variants, are associated with reduced prevalence of skin sensitization to three main allergic sensitizers - nickel, urushiols of poison ivy, and sesquiterpene lactones of chrysanthemum and other plants.

Changing the mechanical unfolding pathway of FnIII10 by tuning the pulling strength.

We investigate the mechanical unfolding of the tenth type III domain from fibronectin (FnIII(10)) both at constant force and at constant pulling velocity, by all-atom Monte Carlo simulations. We observe both apparent two-state unfolding and several unfolding pathways involving one of three major, mutually exclusive intermediate states. All three major intermediates lack two of seven native beta-strands, and share a quite similar extension. The unfolding behavior is found to depend strongly on the pulling conditions. In particular, we observe large variations in the relative frequencies of occurrence for the intermediates. At low constant force or low constant velocity, all three major intermediates occur with a significant frequency. At high constant force or high constant velocity, one of them, with the N- and C-terminal beta-strands detached, dominates over the other two. Using the extended Jarzynski equality, we also estimate the equilibrium free-energy landscape, calculated as a function of chain extension. The application of a constant pulling force leads to a free-energy profile with three major local minima. Two of these correspond to the native and fully unfolded states, respectively, whereas the third one can be associated with the major unfolding intermediates.

Clinical reactivity to ingestion challenge with mixed mold extract may be enhanced in subjects sensitized to molds.

Manifestations of mold allergy are classically associated with inhalation of mold spores leading to symptoms of asthma and other respiratory illnesses. It is largely unknown, however, whether ingestion of aeroallergenic molds, mold spores, or other fungi found in food can also elicit hypersensitivity reactions in mold-sensitive individuals. The aim of this study was to evaluate the association between exposure to molds by oral challenge and elicitation of symptoms in mold- versus nonmold-sensitive individuals. Thirty-four adult atopic subjects were randomized into mold-sensitive groups based on skin test reactivity by skin percutaneous testing (SPT) and/or intradermal (ID) testing to a mixed mold (MM) extract preparation. All subjects underwent a single-blinded, placebo-controlled food challenge to the MM preparation. A modified scoring system was used to grade the clinical severity of symptoms elicited by challenge. All subjects tolerated challenges to the maximal oral mold dose concentration. However, higher symptom scores after challenge were found in mold-sensitive subjects compared with nonmold-sensitive subjects (p = 0.01). When mold-sensitive subjects were compared based on SPT and/or ID reactivity, higher symptom scores and lower symptom-eliciting concentrations of mold were associated with the SPT reactive subgroup compared with the subgroup with ID reactivity alone. In summary, based on our challenge results and scoring model, mold-sensitive subjects compared with nonmold-sensitive subjects experienced cumulatively higher symptom scores after oral challenge to an MM extract preparation. Future studies are warranted to confirm whether ingestion of aeroallergenic molds in food may be another contributor to symptoms in mold-sensitive individuals.

Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System.

BACKGROUND: The National Electronic Injury Surveillance System (NEISS) captures a nationally representative probability sample from hospital emergency departments (EDs) in the United States. OBJECTIVE: Emergency department data from NEISS were analyzed to assess the magnitude and severity of adverse events attributable to food allergies. METHODS: Emergency department events describing food-related allergic symptomatology were identified from 34 participating EDs from August 1 to September 30, 2003. RESULTS: Extrapolation of NEISS event data predicts a total of 20,821 hospital ED visits, 2333 visits for anaphylaxis, and 520 hospitalizations caused by food allergy in the United States during the 2-month study period. The median age was 26 years; 24% of visits involved children < or =5 years old. Shellfish was the most frequently implicated food in persons > or =6 years old, whereas children < or =5 years old experienced more events from eggs, fruit, peanuts, and tree nuts. There were no reported deaths. Review of medical records found that only 19% of patients received epinephrine, and, using criteria established by a 2005 anaphylaxis symposium, 57% of likely anaphylactic events did not have an ED diagnosis of anaphylaxis. CONCLUSION: Analysis of NEISS data may be a useful tool for assessing the magnitude and severity of food-allergic events. A criteria-based review of medical records suggests underdiagnosis of anaphylactic events in EDs.

Neural activity of heterogeneous inhibitory spiking networks with delay.

We study a network of spiking neurons with heterogeneous excitabilities connected via inhibitory delayed pulses. For globally coupled systems the increase of the inhibitory coupling reduces the number of firing neurons by following a winner-takes-all mechanism. For sufficiently large transmission delay we observe the emergence of collective oscillations in the system beyond a critical coupling value. Heterogeneity promotes neural inactivation and asynchronous dynamics and its effect can be counteracted by considering longer time delays. In sparse networks, inhibition has the counterintuitive effect of promoting neural reactivation of silent neurons for sufficiently large coupling. In this regime, current fluctuations are on one side responsible for neural firing of subthreshold neurons and on the other side for their desynchronization. Therefore, collective oscillations are present only in a limited range of coupling values, which remains finite in the thermodynamic limit. Out of this range the dynamics is asynchronous and for very large inhibition neurons display a bursting behavior alternating periods of silence with periods where they fire freely in absence of any inhibition.

Free-energy landscape of mechanically unfolded model proteins: extended Jarzinsky versus inherent structure reconstruction.

The equilibrium free-energy landscape of off-lattice model heteropolymers as a function of an internal coordinate, namely the end-to-end distance, is reconstructed from out-of-equilibrium steered molecular dynamics data. This task is accomplished via two independent methods: By employing an extended version of the Jarzynski equality and the inherent structure formalism. A comparison of the free energies estimated with these two schemes with equilibrium results obtained via the umbrella sampling technique reveals a good quantitative agreement among all the approaches in a range of temperatures around the "folding transition" for the two examined sequences. In particular, for the sequence with good foldability properties, the mechanically induced structural transitions can be related to thermodynamical aspects of folding. Moreover, for the same sequence the knowledge of the landscape profile allows for a good estimation of the lifetimes of the native configuration for temperatures ranging from the folding to the collapse temperature. For the random sequence, mechanical and thermal unfolding appear to follow different paths along the landscape.

Dynamical response of the Hodgkin-Huxley model in the high-input regime.

The response of the Hodgkin-Huxley neuronal model subjected to stochastic uncorrelated spike trains originating from a large number of inhibitory and excitatory post-synaptic potentials is analyzed in detail. The model is examined in its three fundamental dynamical regimes: silence, bistability, and repetitive firing. Its response is characterized in terms of statistical indicators (interspike-interval distributions and their first moments) as well as of dynamical indicators (autocorrelation functions and conditional entropies). In the silent regime, the coexistence of two different coherence resonances is revealed: one occurs at quite low noise and is related to the stimulation of subthreshold oscillations around the rest state; the second one (at intermediate noise variance) is associated with the regularization of the sequence of spikes emitted by the neuron. Bistability in the low noise limit can be interpreted in terms of jumping processes across barriers activated by stochastic fluctuations. In the repetitive firing regime a maximization of incoherence is observed at finite noise variance. Finally, the mechanisms responsible for the different features appearing in the interspike-interval distributions (like multimodality and exponential tails) are clearly identified in the various regimes.