Sitting Down with Dr. John Weg: Pulmonary Medicine Pioneer

Recently, the Quill & Scope’s Jenny Lam and Edward Hurley spoke with pulmonary medicine pioneer Dr. John Weg, Class of 1959, about his career, medicine in general and his time at New York Medical College

Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure

Air pollution is linked to increased emergency department visits for headache and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that chronic environmental irritant exposure sensitizes the trigeminovascular system response to nasal administration of environmental irritants. Here, we examine whether chronic environmental irritant exposure induces migraine behavioral phenotypes. Male rats were exposed to acrolein, a transient receptor potential channel ankyrin-1 (TRPA1) agonist, or room air by inhalation for 4 days before meningeal blood flow measurements, periorbital cutaneous sensory testing, or other behavioral testing. Touch-induced c-Fos expression in trigeminal nucleus caudalis was compared in animals exposed to room air or acrolein. Spontaneous behavior and olfactory discrimination was examined in open-field testing. Acrolein inhalation exposure produced long-lasting potentiation of blood flow responses to a subsequent TRPA1 agonist and sensitized cutaneous responses to mechanical stimulation. C-Fos expression in response to touch was increased in trigeminal nucleus caudalis in animals exposed to acrolein compared with room air. Spontaneous activity in an open-field and scent preference behavior was different in acrolein-exposed compared with room air-exposed animals. Sumatriptan, an acute migraine treatment blocked acute blood flow changes in response to TRPA1 or transient receptor potential vanilloid receptor-1 agonists. Pretreatment with valproic acid, a prophylactic migraine treatment, attenuated the enhanced blood flow responses observed after acrolein inhalation exposures. Environmental irritant exposure yields an animal model of chronic migraine in which to study mechanisms for enhanced headache susceptibility after chemical exposure

A Possible Cepheid-Like Luminosity Estimator for the Long Gamma-Ray Bursts

We present a possible Cepheid-like luminosity estimator for the long gamma-ray bursts based on the variability of their light curves. To construct the luminosity estimator, we use CGRO/BATSE data for 13 bursts, Wind/KONUS data for 5 bursts, Ulysses/GRB data for 1 burst, and NEAR/XGRS data for 1 burst. Spectroscopic redshifts, peak fluxes, and high resolution light curves are available for 11 of these bursts; partial information is available for the remaining 9 bursts. We find that the isotropic-equivalent luminosities L of these bursts positively correlate with a rigorously-constructed measure V of the variability of their light curves. We fit a model to these data that accommodates both intrinsic scatter (statistical variance) and extrinsic scatter (sample variance). If one excludes GRB 980425 from the fit on the grounds that its association with SN 1998bw at a redshift of z = 0.0085 is not secure, the luminosity estimator spans approx. 2.5 orders of magnitude in L, and the slope of the correlation between L and V is positive with a probability of 1 - 1.4 x 10^-4 (3.8 sigma). Although GRB 980425 is excluded from this fit, its L and V values are consistent with the fitted model, which suggests that GRB 980425 may well be associated with SN 1998bw, and that GRB 980425 and the cosmological bursts may share a common physical origin. If one includes GRB 980425 in the fit, the luminosity estimator spans approx. 6.3 orders of magnitude in L, and the slope of the correlation is positive with a probability of 1 - 9.3 x 10^-7 (4.9 sigma). Independently of whether or not GRB 980425 should be included in the fit, its light curve is unique in that it is much less variable than the other approx. 17 light curves in our sample for which the signal-to-noise is reasonably good.Comment: Accepted to The Astrophysical Journal, 31 pages, 13 figures, LaTe

Streaming Graph Challenge: Stochastic Block Partition

An important objective for analyzing real-world graphs is to achieve scalable performance on large, streaming graphs. A challenging and relevant example is the graph partition problem. As a combinatorial problem, graph partition is NP-hard, but existing relaxation methods provide reasonable approximate solutions that can be scaled for large graphs. Competitive benchmarks and challenges have proven to be an effective means to advance state-of-the-art performance and foster community collaboration. This paper describes a graph partition challenge with a baseline partition algorithm of sub-quadratic complexity. The algorithm employs rigorous Bayesian inferential methods based on a statistical model that captures characteristics of the real-world graphs. This strong foundation enables the algorithm to address limitations of well-known graph partition approaches such as modularity maximization. This paper describes various aspects of the challenge including: (1) the data sets and streaming graph generator, (2) the baseline partition algorithm with pseudocode, (3) an argument for the correctness of parallelizing the Bayesian inference, (4) different parallel computation strategies such as node-based parallelism and matrix-based parallelism, (5) evaluation metrics for partition correctness and computational requirements, (6) preliminary timing of a Python-based demonstration code and the open source C++ code, and (7) considerations for partitioning the graph in streaming fashion. Data sets and source code for the algorithm as well as metrics, with detailed documentation are available at GraphChallenge.org.Comment: To be published in 2017 IEEE High Performance Extreme Computing Conference (HPEC

Game Theoretic Modelling of a Ransom and Extortion Attack on Ethereum Validators

Consensus algorithms facilitate agreement on and resolution of blockchain functions, such as smart contracts and transactions. Ethereum uses a Proof-of-Stake (PoS) consensus mechanism, which depends on financial incentives to ensure that validators perform certain duties and do not act maliciously. Should a validator attempt to defraud the system, legitimate validators will identify this and then staked cryptocurrency is ‘burned’ through a process of slashing. In this paper, we show that an attacker who has compromised a set of validators could threaten to perform malicious actions that would result in slashing and thus, hold those validators to ransom. We use game theory to study how an attacker can coerce payment from a victim, for example by deploying a smart contract to provide a root of trust shared between attacker and victim during the extortion process. Our game theoretic model finds that it is in the interests of the validators to fully pay the ransom due to a lack of systemic protections for validators. Financial risk is solely placed on the victim during such an attack, with no mitigations available to them aside from capitulation (payment of ransom) in many scenarios. Such attacks could be disruptive to Ethereum and, likely, to many other PoS networks, if public trust in the validator system is eroded. We also discuss and evaluate potential mitigation measures arising from our analysis of the game theoretic model

Role of intraganglionic transmission in the trigeminovascular pathway

Migraine is triggered by poor air quality and odors through unknown mechanisms. Activation of the trigeminovascular pathway by environmental irritants may occur via activation of transient receptor potential ankyrin 1 (TRPA1) receptors on nasal trigeminal neurons, but how that results in peripheral and central sensitization is unclear. The anatomy of the trigeminal ganglion suggests that noxious nasal stimuli are not being transduced to the meninges by axon reflex but likely through intraganglionic transmission. Consistent with this concept, we injected calcitonin gene-related peptide, adenosine triphosphate, or glutamate receptor antagonists or a gap junction channel blocker directly and exclusively into the trigeminal ganglion and blocked meningeal blood flow changes in response to acute nasal TRP agonists. Previously, we observed chronic sensitization of the trigeminovascular pathway after acrolein exposure, a known TRPA1 receptor agonist. To explore the mechanism of this sensitization, we utilized laser dissection microscopy to separately harvest nasal and meningeal trigeminal neuron populations in the absence or presence of acrolein exposure. mRNA levels of neurotransmitters important in migraine were then determined by reverse transcription polymerase chain reaction. TRPA1 message levels were significantly increased in meningeal cell populations following acrolein exposure compared to room air exposure. This was specific to TRPA1 message in meningeal cell populations as changes were not observed in either nasal trigeminal cell populations or dorsal root ganglion populations. Taken together, these data suggest an important role for intraganglionic transmission in acute activation of the trigeminovascular pathway. It also supports a role for upregulation of TRPA1 receptors in peripheral sensitization and a possible mechanism for chronification of migraine after environmental irritant exposure

Sensitization of the Trigeminovascular System following Environmental Irritant Exposure

Background Air pollution is linked to increased emergency room visits for headache, and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that nasal administration of environmental irritants acutely increases meningeal blood flow via a TRPA1-dependent mechanism involving the trigeminovascular system. Here, we examine whether chronic environmental irritant exposure sensitizes the trigeminovascular system. Methods Male rats were exposed to acrolein, a TRPA1 agonist, or room air by inhalation for four days prior to meningeal blood flow measurements. Some animals were injected daily with a TRPA1 antagonist, AP-18, or vehicle prior to inhalation exposure. Trigeminal ganglia were isolated following blood flow measurements for immunocytochemistry and/or qPCR determination of TRPV1, TRPA1 and CGRP levels. Results Acrolein inhalation exposure potentiated blood flow responses both to TRPA1 and TRPV1 agonists compared to room air. Acrolein exposure did not alter TRPV1 or TRPA1 mRNA levels or TRPV1 or CGRP immunoreactive cell counts in the trigeminal ganglion. Acrolein sensitization of trigeminovascular responses to a TRPA1 agonist was attenuated by pre-treatment with AP-18. Interpretation These results suggest trigeminovascular sensitization as a mechanism for enhanced headache susceptibility after chemical exposure

Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria