General anesthesia, sleep and coma

In the United States, nearly 60,000 patients per day receive general anesthesia for surgery.1 General anesthesia is a drug-induced, reversible condition that includes specific behavioral and physiological traits — unconsciousness, amnesia, analgesia, and akinesia — with concomitant stability of the autonomic, cardiovascular, respiratory, and thermoregulatory systems.2 General anesthesia produces distinct patterns on the electroencephalogram (EEG), the most common of which is a progressive increase in low-frequency, high-amplitude activity as the level of general anesthesia deepens3,4 (Figure 1Figure 1Electroencephalographic (EEG) Patterns during the Awake State, General Anesthesia, and Sleep.). How anesthetic drugs induce and maintain the behavioral states of general anesthesia is an important question in medicine and neuroscience.6 Substantial insights can be gained by considering the relationship of general anesthesia to sleep and to coma. Humans spend approximately one third of their lives asleep. Sleep, a state of decreased arousal that is actively generated by nuclei in the hypothalamus, brain stem, and basal forebrain, is crucial for the maintenance of health.7,8 Normal human sleep cycles between two states — rapid-eye-movement (REM) sleep and non-REM sleep — at approximately 90-minute intervals. REM sleep is characterized by rapid eye movements, dreaming, irregularities of respiration and heart rate, penile and clitoral erection, and airway and skeletal-muscle hypotonia.7 In REM sleep, the EEG shows active high-frequency, low-amplitude rhythms (Figure 1). Non-REM sleep has three distinct EEG stages, with higher-amplitude, lower-frequency rhythms accompanied by waxing and waning muscle tone, decreased body temperature, and decreased heart rate. Coma is a state of profound unresponsiveness, usually the result of a severe brain injury.9 Comatose patients typically lie with eyes closed and cannot be roused to respond appropriately to vigorous stimulation. A comatose patient may grimace, move limbs, and have stereotypical withdrawal responses to painful stimuli yet make no localizing responses or discrete defensive movements. As the coma deepens, the patient's responsiveness even to painful stimuli may diminish or disappear. Although the patterns of EEG activity observed in comatose patients depend on the extent of the brain injury, they frequently resemble the high–amplitude, low-frequency activity seen in patients under general anesthesia10 (Figure 1). General anesthesia is, in fact, a reversible drug-induced coma. Nevertheless, anesthesiologists refer to it as “sleep” to avoid disquieting patients. Unfortunately, anesthesiologists also use the word “sleep” in technical descriptions to refer to unconsciousness induced by anesthetic drugs.11 (For a glossary of terms commonly used in the field of anesthesiology, see the Supplementary Appendix, available with the full text of this article at NEJM.org.) This review discusses the clinical and neurophysiological features of general anesthesia and their relationships to sleep and coma, focusing on the neural mechanisms of unconsciousness induced by selected intravenous anesthetic drugs.Massachusetts General Hospital. Dept. of Anesthesia and Critical Care, and Pain MedicineNational Institutes of Health (NIH) (Director’s Pioneer Award DP1OD003646)University of Michigan. Dept. of AnesthesiologyNational Institutes of Health (U.S.) (grant HL40881)National Institutes of Health (U.S.) (grant HL65272)James S. McDonnell FoundationNational Institutes of Health (U.S.) (grant HD51912

Orexin receptors exert a neuroprotective effect in Alzheimer's disease (AD) via heterodimerization with GPR103

Orexins are neuropeptides that regulate the sleep-wake cycle and feeding behaviour. QRFP is a newly discovered neuropeptide which exerts similar orexigenic activity, thus playing an important role in energy homeostasis and regulation of appetite. The exact expression and signalling characteristics and physiological actions of QRFP and its receptor GPR103 are poorly understood. Alzheimerâ €™ s disease (AD) patients experience increased nocturnal activity, excessive daytime sleepiness, and weight loss. We hypothesised therefore that orexins and QRFP might be implicated in the pathophysiology of AD. We report that the down-regulation of hippocampal orexin receptors (OXRs) and GPR103 particularly in the cornu ammonis (CA) subfield from AD patients suffering from early onset familial AD (EOFAD) and late onset familial AD (LOAD). Using an in vitro model we demonstrate that this downregulation is due to to Aβ-plaque formation and tau hyper-phosphorylation. Transcriptomics revealed a neuroprotective role for both orexins and QRFP. Finally we provide conclusive evidence using BRET and FRET that OXRs and GPR103 form functional hetero-dimers to exert their effects involving activation of ERK 1/2. Pharmacological intervention directed at the orexigenic system may prove to be an attractive avenue towards the discovery of novel therapeutics for diseases such as AD and improving neuroprotective signalling pathways

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Searches for Long Lived Neutral Particles

An intriguing possibility for TeV scale physics is the existence of neutral long lived particles (LOLIPs) that subsequently decay into SM states. Such particles are many cases indistinguishable from missing transverse energy (MET) at colliders. We propose new methods to search for these particles using neutrino telescopes. We study their detection prospects, assuming production either at the LHC or through dark matter (DM) annihilations in the Sun and the Earth. We find that the sensitivity for LOLIPs produced at the LHC is limited by luminosity and detection energy thresholds. On the other hand, in the case of DM annihilation into LOLIPs, the sensitivity of neutrino telescopes is promising and may extend beyond the reach of upcoming direct detection experiments. In the context of low scale hidden sectors weakly coupled to the SM, such indirect searches allow to probe couplings as small as 10^-15.Comment: 22 pages, 6 figure

Non-global logarithms and jet algorithms in high-pT jet shapes

We consider jet-shape observables of the type proposed recently, where the shapes of one or more high-pT jets, produced in a multi-jet event with definite jet multiplicity, may be measured leaving other jets in the event unmeasured. We point out the structure of the full next-to-leading logarithmic resummation specifically including resummation of non-global logarithms in the leading-Nc limit and emphasising their properties. We also point out differences between jet algorithms in the context of soft gluon resummation for such observables.Comment: 22 pages, 4 figures. Title and a few words changed. Several typos corrected. Version accepted by JHE

Diboson-Jets and the Search for Resonant Zh Production

New particles at the TeV-scale may have sizeable decay rates into boosted Higgs bosons or other heavy scalars. Here, we investigate the possibility of identifying such processes when the Higgs/scalar subsequently decays into a pair of W bosons, constituting a highly distinctive "diboson-jet." These can appear as a simple dilepton (plus MET) configuration, as a two-prong jet with an embedded lepton, or as a four-prong jet. We study jet substructure methods to discriminate these objects from their dominant backgrounds. We then demonstrate the use of these techniques in the search for a heavy spin-one Z' boson, such as may arise from strong dynamics or an extended gauge sector, utilizing the decay chain Z' -> Zh -> Z(WW^(*)). We find that modes with multiple boosted hadronic Zs and Ws tend to offer the best prospects for the highest accessible masses. For 100/fb luminosity at the 14 TeV LHC, Z' decays into a standard 125 GeV Higgs can be observed with 5-sigma significance for masses of 1.5-2.5 TeV for a range of models. For a 200 GeV Higgs (requiring nonstandard couplings, such as fermiophobic), the reach may improve to up to 2.5-3.0 TeV.Comment: 23 pages plus appendices, 9 figure

Non-Global Logarithms in Filtered Jet Algorithms

We analytically and numerically study the effect of perturbative gluons emission on the "Filtering analysis", which is part of a subjet analysis procedure proposed two years ago to possibly identify a low-mass Higgs boson decaying into b\bar{b} at the LHC. This leads us to examine the non-global structure of the resulting perturbative series in the leading single-log large-N_c approximation, including all-orders numerical results, simple analytical approximations to them and comments on the structure of their series expansion. We then use these results to semi-analytically optimize the parameters of the Filtering analysis so as to suppress as much as possible the effect of underlying event and pile-up on the Higgs mass peak reconstruction while keeping the major part of the perturbative radiation from the b\bar{b} dipole.Comment: 47 pages, 25 figures, 1 figure and a few comments added, version accepted for publication in JHE

Sarcomere Formation Occurs by the Assembly of Multiple Latent Protein Complexes

The stereotyped striation of myofibrils is a conserved feature of muscle organization that is critical to its function. Although most components that constitute the basic myofibrils are well-characterized biochemically and are conserved across the animal kingdom, the mechanisms leading to the precise assembly of sarcomeres, the basic units of myofibrils, are poorly understood. To gain insights into this process, we investigated the functional relationships of sarcomeric protein complexes. Specifically, we systematically analyzed, using either RNAi in primary muscle cells or available genetic mutations, the organization of myofibrils in Drosophila muscles that lack one or more sarcomeric proteins. Our study reveals that the thin and thick filaments are mutually dependent on each other for striation. Further, the tension sensor complex comprised of zipper/Zasp/α-actinin is involved in stabilizing the sarcomere but not in its initial formation. Finally, integrins appear essential for the interdigitation of thin and thick filaments that occurs prior to striation. Thus, sarcomere formation occurs by the coordinated assembly of multiple latent protein complexes, as opposed to sequential assembly

QTL mapping of yield components and kernel traits in wheat cultivars TAM 112 and Duster

In the Southern Great Plains, wheat cultivars have been selected for a combination of outstanding yield and drought tolerance as a long-term breeding goal. To understand the underlying genetic mechanisms, this study aimed to dissect the quantitative trait loci (QTL) associated with yield components and kernel traits in two wheat cultivars `TAM 112' and `Duster' under both irrigated and dryland environments. A set of 182 recombined inbred lines (RIL) derived from the cross of TAM 112/Duster were planted in 13 diverse environments for evaluation of 18 yield and kernel related traits. High-density genetic linkage map was constructed using 5,081 single nucleotide polymorphisms (SNPs) from genotyping-by-sequencing (GBS). QTL mapping analysis detected 134 QTL regions on all 21 wheat chromosomes, including 30 pleiotropic QTL regions and 21 consistent QTL regions, with 10 QTL regions in common. Three major pleiotropic QTL on the short arms of chromosomes 2B (57.5 - 61.6 Mbps), 2D (37.1 - 38.7 Mbps), and 7D (66.0 - 69.2 Mbps) colocalized with genes Ppd-B1, Ppd-D1, and FT-D1, respectively. And four consistent QTL associated with kernel length (KLEN), thousand kernel weight (TKW), plot grain yield (YLD), and kernel spike-1 (KPS) (Qklen.tamu.1A.325, Qtkw.tamu.2B.137, Qyld.tamu.2D.3, and Qkps.tamu.6A.113) explained more than 5% of the phenotypic variation. QTL Qklen.tamu.1A.325 is a novel QTL with consistent effects under all tested environments. Marker haplotype analysis indicated the QTL combinations significantly increased yield and kernel traits. QTL and the linked markers identified in this study will facilitate future marker-assisted selection (MAS) for pyramiding the favorable alleles and QTL map-based cloning.Horticulture and Landscape Architectur

Anxiety is not enough to drive me away: A latent profile analysis on math anxiety and math motivation

Mathematics anxiety (MA) and mathematics motivation (MM) are important multi-dimensional non-cognitive factors in mathematics learning. While the negative relation between global MA and MM is well replicated, the relations between specific dimensions of MA and MM are largely unexplored. The present study utilized latent profile analysis to explore profiles of various aspects of MA (including learning MA and exam MA) and MM (including importance, self-perceived ability, and interest), to provide a more holistic understanding of the math-specific emotion and motivation experiences. In a sample of 927 high school students (13–21 years old), we found 8 distinct profiles characterized by various combinations of dimensions of MA and MM, revealing the complexity in the math-specific emotion-motivation relation beyond a single negative correlation. Further, these profiles differed on mathematics learning behaviors and mathematics achievement. For example, the highest achieving students reported modest exam MA and high MM, whereas the most engaged students were characterized by a combination of high exam MA and high MM. These results call for the need to move beyond linear relations among global constructs to address the complexity in the emotion-motivation-cognition interplay in mathematics learning, and highlight the importance of customized intervention for these heterogeneous groups