Cigarette smoke-exposed neutrophils die unconventionally but are rapidly phagocytosed by macrophages

Pulmonary accumulation of neutrophils is typical for active smokers who are also predisposed to multiple inflammatory and infectious lung diseases. We show that human neutrophil exposure to cigarette smoke extract (CSE) leads to an atypical cell death sharing features of apoptosis, autophagy and necrosis. Accumulation of tar-like substances in autophagosomes is also apparent. Before detection of established cell death markers, CSE-treated neutrophils are effectively recognized and non-phlogistically phagocytosed by monocyte-derived macrophages. Blockade of LOX-1 and scavenger receptor A, but not MARCO or CD36, as well as pre-incubation with oxLDL, inhibited phagocytosis, suggesting that oxLDL-like structures are major phagocytosis signals. Specific lipid (β-carotene and quercetin), but not aqueous, antioxidants increased the pro-phagocytic effects of CSE. In contrast to non-phlogistic phagocytosis, degranulation of secondary granules, as monitored by lactoferrin release, was apparent on CSE exposure, which is likely to promote pulmonary inflammation and tissue degradation. Furthermore, CSE-exposed neutrophils exhibited a compromised ability to ingest the respiratory pathogen, Staphylococcus aureus, which likely contributes to bacterial persistence in the lungs of smokers and is likely to promote further pulmonary recruitment of neutrophils. These data provide mechanistic insight into the lack of accumulation of apoptotic neutrophil populations in the lungs of smokers and their increased susceptibility to degradative pulmonary diseases and bacterial infections.     

A Connectionist Model of Left-Right Sound Discrimination by the Mauthner System

Artificial neural networks were used to explore the auditory function of the Mauthner system, the brainstem circuit in teleost fishes that initiates fast-start escape responses. The artificial neural networks were trained with backpropagation to assign connectivity and receptive fields in an architecture consistent with the known anatomy of the Mauthner system. Our first goal was to develop neurally specific hypotheses for how the Mauthner system discriminates right from left in the onset of a sound. Our model was consistent with the phase model for directional hearing underwater, the prevalent theory for sound source localization by fishes. Our second goal was to demonstrate how the neural mechanisms that permit sound localization according to the phase model can coexist with the mechanisms that permit the Mauthner system to discriminate between stimuli based on amplitude. Our results indicate possible computational roles for elements of the Mauthner system, which has provided us a theoretical context within which to consider past and future experiments on the cellular physiology. Thus, these findings demonstrate the potential significance of this approach in generating experimentally testable hypotheses for small systems of identified cells.     

Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests

Background  

Fabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.