Cystic fibrosis (CF) patients undergo progressive airway destruction caused in part by chronic neutrophilic inflammation. While opportunistic pathogens infecting CF airways can cause inflammation, we hypothesized that host-derived metabolic and stress signals would also play a role in this process. We show that neutrophils that have entered CF airways have increased phosphorylation of the eukaryotic initiation factor 4E and its partner the 4E-binding protein 1; 2 key effectors in the growth factor-and amino acid-regulated mammalian target of rapamycin (mTOR) pathway. Furthermore CF airway neutrophils display increased phosphorylation of the cAMP response element binding protein (CREB), a major transcriptional coactivator in stress signaling cascades. These active intracellular pathways are associated with increased surface expression of critical adaptor molecules, including the growth factor receptor CD114 and the receptor for advanced glycation end-products (RAGE), a CREB inducer and sensor for host-derived damage-associated molecular patterns (DAMPs). Most CF airway fluids lack any detectable soluble RAGE, an inhibitory decoy receptor for DAMPs. Concomitantly, CF airway fluids displayed high and consequently unopposed levels of S100A12; a potent mucosa-and neutrophil-derived DAMP. CF airway neutrophils also show increased surface levels of 2 critical CREB targets, the purine-recycling enzyme CD39 and the multifunctional, mTORinducing CXCR4 receptor. This coordinated set of events occurs in all patients, even in the context of minimal airway inflammation and well-preserved lung function. Taken together, our data demonstrate an early and sustained activation of host-responsive metabolic and stress pathways upon neutrophil entry into CF airways, suggesting potential targets for therapeutic modulation.CFTR ͉ EN-RAGE ͉ flow cytometry ͉ S6 ribosomal protein ͉ stromal derived factor-1

Memories are consolidated and strengthened during sleep. Here we show that memories can also be weakened during sleep. We used a fear-conditioning paradigm in mice to condition footshock to an odor (conditioned stimulus (CS)). Twenty-four hours later, presentation of the CS odor during sleep resulted in an enhanced fear response when tested during subsequent wake. However, if the re-exposure of the CS odor during sleep was preceded by bilateral microinjections of a protein synthesis inhibitor into the basolateral amygdala, the subsequent fear response was attenuated. These findings demonstrate that specific fear memories can be selectively reactivated and either strengthened or attenuated during sleep, suggesting the potential for developing sleep therapies for emotional disorders.

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The use of personal protective equipment (PPE) increases the risk of heat related maladies. A means to enhance heat dissipation capacity of individuals clad in PPE would be of benefit. The glabrous skin regions of the hands, face, and feet are portals for direct heat transfer between the body core and the external environment. The effects of PPE outerwear and palmar glabrous skin cooling on heat storage were assessed. Subjects engaged in fixed load treadmill exercise in a thermoneutral environment (T = 20-24°C) or rested in a hot environment (45 ± 0.5°C). The use of PPE outerwear increased the rate of core temperature rise by five-fold during vigorous exercise. Palm cooling using a stationary water circulation system attenuated the rate of core temperature rise by 30-60% during rest and light, moderate, and vigorous exercise while wearing PPE outerwear. However, the subjects were tethered to the system. A wearable cooling system was devised that allowed free range of motion and unrestricted mobility. The wearable system provided thermal benefits equivalent to the use of the tethering cooling system. With optimization, this wearable cooling technique could neutralize the negative thermoregulatory effects of wearing PPE while engaged in light workload activities such as those encountered by healthcare professionals working in infectious disease treatment centers. For individuals working at higher workloads, such as firefighters, a wearable glabrous skin-based cooling system could extend work bout duration as well as enhance heat loss during episodic recovery periods.

The circadian system organizes sleep and wake through imposing a daily cycle of sleep propensity on the organism. Sleep has been shown to play an important role in learning and memory. Apart from the daily cycle of sleep propensity, however, direct effects of the circadian system on learning and memory also have been well documented. Many mechanistic components of the memory consolidation process ranging from the molecular to the systems level have been identified and studied. The question that remains is how do these various processes and components work together to produce cycles of increased and decreased learning abilities, and why should there be times of day when neural plasticity appears to be restricted? Insights into this complex problem can be gained through investigations of the learning disabilities caused by circadian disruption in Siberian hamsters and by aneuploidy in Down syndrome mice. A simple working hypothesis that has been explored in this work is that the observed learning disabilities are due to an altered excitation/inhibition balance in the CNS. Excessive inhibition is the suspected cause of deficits in memory consolidation. In this paper we present the evidence that excessive inhibition in these cases of learning disability involves GABAergic neurotransmission, that treatment with GABA receptor inhibitors can reverse the learning disability, and that the efficacy of the treatment is time sensitive coincident with the major daily sleep phase, and that it depends on sleep. The evidence we present leads us to hypothesize that a function of the circadian system is to reduce neuroplasticity during the daily sleep phase when processes of memory consolidation are taking place.

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