Modeling the partially coherent behavior of few-mode far-infrared grating spectrometers.

Modeling ultra-low-noise far-infrared grating spectrometers has become crucial for the next generation of far-infrared space observatories. Conventional techniques are awkward to apply because of the partially coherent form of the incident spectral field, and the few-mode response of the optics and detectors. We present a modal technique for modeling the behavior of spectrometers that allows for the propagation and detection of partially coherent fields, and the inclusion of straylight radiated by warm internal surfaces. We illustrate the technique by modeling the behavior of the long wavelength band of the proposed SAFARI instrument on the well-studied SPICA mission.

Endotoxin-induced cytokine, chemokine and white blood cell profiles of variable stress-responding sheep.

Individual variation of the hypothalamic-pituitary-adrenal (HPA) axis response to stress could contribute to variable stress resiliency of livestock. During stress events, the innate immune system can also become activated and work in concert with the neuroendocrine system to restore homeostasis, while minimizing tissue damage. The purpose of this study was to assess immune function in variable stress-responding sheep in response to bacterial lipopolysaccharide (LPS) endotoxin immune-challenge. High (HSR, n = 12), middle (MSR, n = 12), and low-stress responders (LSR, n = 12) were selected from a population of 112 female lambs and classified based on serum cortisol concentration after receiving an intravenous bolus of LPS (400 ng/kg). Blood was collected from the jugular vein at 0 and 4 hrs post-LPS challenge to monitor changes in serum pro- and anti-inflammatory cytokines and chemokines, and white blood cell populations. Rectal temperature was recorded hourly to monitor fever. HSR had the greatest increase in rectal temperature and strongest pro-inflammatory IL-6 and IFN-γ cytokine responses compared to MSR and LSR. HSR and MSR had stronger anti-inflammatory IL-10 cytokine and CCL2 chemokine responses than LSR. White blood cell counts changed between 0 and 4 h; however, no differences were detected among the variable stress response groups. The distinct inflammatory response in variable stress responding sheep could contribute to individual differences in stress resiliency and this warrants investigation in the context of other types of stress.

LAY SUMMARYAcute inflammation was studied in sheep stress-phenotyped using bacterial lipopolysaccharide. Sheep selected based on stress responsiveness (i.e. serum cortisol concentration) have different immune responses to bacterial stress. Specifically, high-stress responders have a more pronounced inflammatory response than low-stress responders.

Short communication: Characterizing ovine serum stress biomarkers during endotoxemia.

Breeding stress-resilient livestock is a potential strategy to help mitigate the negative effect of environmental and pathogenic stressors. The hypothalamic-pituitary-adrenal axis and immune system are activated during stress events and release mediators into the circulation that help restore physiological homeostasis. The purpose of this study was to assess a comprehensive set of circulatory mediators released in response to an acute immune stress challenge to identify candidate biomarkers that can be used for the selection of stress-resilient animals. Fifteen female lambs were stress challenged with an intravenous bolus of lipopolysaccharide (LPS; 400 ng/kg), and blood was collected from the jugular vein at 0, 2, 4, and 6 h after LPS challenge to identify and monitor candidate stress biomarkers; temperature was also recorded over time. Biomarker responses were evaluated with a repeated-measures model to compare time points with baseline values. As expected, all sheep had a monophasic febrile response to LPS challenge, and cortisol increased and returned to baseline by 6 h. The cytokines tumor necrosis factor-α, IL-6, IFN-γ (proinflammatory), and IL-10 (anti-inflammatory) increased, but only tumor necrosis factor-α returned to baseline during the monitoring period. The cytokines IL-1α, IL-1ß, IL-17α (proinflammatory), and IL-4 (anti-inflammatory) did not respond to LPS challenge. All chemokines (CCL2, CCL3, CCL4, CXCL10, and IL-8) responded to LPS challenge; however, only CCL2, CCL3, CCL4, and CXCL10 increased over time, and only CCL3, CCL4, and CXCL10 returned to baseline during the monitoring period. MicroRNA (miR-145, miR-233, and miR-1246) also increased and remained elevated during the study. In summary, the LPS challenge induced a strong stress response in Rideau-Dorset sheep that could be monitored with a distinct profile of circulatory biomarkers.

Data from subjects receiving intrathecal laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I.

Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4-month pilot study and/or a 12-month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects.

Multiply charged thorium crystals for nuclear laser spectroscopy.

We have produced laser-cooled crystals of 232Th3+ in a linear rf Paul trap. This is the first time that a multiply charged ion has been laser cooled. Our work opens an avenue for excitation of the nuclear transition in a trapped, cold 229Th3+ ion. Laser excitation of nuclear states would establish a new bridge between atomic and nuclear physics, with the promise of new levels of metrological precision.

Advances in the pathophysiology of status epilepticus.

Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABAA (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABAA receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, 'spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed.

Advances in the pathophysiology of status epilepticus.

Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABA(A) (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABA(A) receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, 'spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed.

Dual function of protein confinement in chaperonin-assisted protein folding.

The GroEL/GroES chaperonin system mediates the folding of a range of newly synthesized polypeptides in the bacterial cytosol. Using a rapid biotin-streptavidin-based inhibition of chaperonin function, we show that the cage formed by GroEL and its cofactor GroES can have a dual role in promoting folding. First, enclosure of nonnative protein in the GroEL:GroES complex is essential for folding to proceed unimpaired by aggregation. Second, folding inside the cage can be significantly faster than folding in free solution, independently of ATP-driven cycles of GroES binding and release. This suggests that confinement of unfolded protein in the narrow hydrophilic space of the chaperonin cage smoothes the energy landscape for the folding of some proteins, increasing the flux of folding intermediates toward the native state.

Contribution of molecular chaperones to protein folding in the cytoplasm of prokaryotic and eukaryotic cells.

While it is clear that many unfolded proteins can attain their native state spontaneously in vitro, the efficiency of such folding is usually limited to conditions far removed from those encountered within cells. Two properties of the cellular environment are expected to enhance strongly the propensity of incompletely folded polypeptides to misfold and aggregate: the crowding effect caused by the high concentration of macromolecules, and the close proximity of nascent polypeptide chains emerging from polyribosomes. However, in the living cell, non-productive protein folding is in many, if not most, cases prevented by the action of a highly conserved set of proteins termed molecular chaperones. In the cytoplasm, the Hsp70 (heat-shock protein of 70 kDa) and chaperonin families of molecular chaperones appear to be the major contributors to efficient protein folding during both normal conditions and adverse conditions such as heat stress. Hsp70 chaperones recognize and shield short, hydrophobic peptide segments in the context of non-native polypeptides and probably promote folding by decreasing the concentration of aggregation-prone intermediates. In contrast, the chaperonins interact with and globally enclose collapsed folding intermediates in a central cavity where efficient folding can proceed in a protected environment. For a number of proteins, folding requires the co-ordinated action of both of these molecular chaperones.

Hepatic ischemia/reperfusion injury in P-selectin and intercellular adhesion molecule-1 double-mutant mice.

Neutrophil adhesion and recruitment represents one of the early cellular events that occur during hepatic ischemia/reperfusion (IR) injury and plays a critical role in determining the extent of tissue damage. The adhesion molecules, such as selectins and intercellular adhesion molecules (ICAM), are important in mediating neutrophil-endothelial cell interactions and neutrophil emigration. The goal of this study was to evaluate the role of P-selectin and ICAM-1 in hepatic IR injury. Male wild-type and P-selectin/ICAM-1-deficient (P/I null) mice underwent 90 minutes of partial hepatic ischemia followed by reperfusion at various time points (0, 1.5, 3, and 6 hours). Reperfusion caused a time-dependent hepatocellular injury in both wild-type and P/I null mice as judged by plasma alanine aminotransferase (ALT) levels and liver histopathology examination. Although ALT levels were slightly lower in the P/I null mice compared with the wild-type mice the differences were not statistically significant. Neutrophil infiltration to the ischemic liver was observed in both mouse groups after 6 hours of reperfusion; however, the infiltration to the midzonal region of the ischemic liver was more pronounced in the wild-type group. This study suggests that hepatocellular injury induced after hepatic IR was independent of P-selectin and ICAM-1 in this model of acute inflammatory tissue injury.

Synapse-specific contribution of the variation of transmitter concentration to the decay of inhibitory postsynaptic currents.

Synaptic transmission is characterized by a remarkable trial-to-trial variability in the postsynaptic response, influencing the way in which information is processed in neuronal networks. This variability may originate from the probabilistic nature of quantal transmitter release, from the stochastic behavior of the receptors, or from the fluctuation of the transmitter concentration in the cleft. We combined nonstationary noise analysis and modeling techniques to estimate the contribution of transmitter fluctuation to miniature inhibitory postsynaptic current (mIPSC) variability. A substantial variability (approximately 30%) in mIPSC decay was found in all cell types studied (neocortical layer2/3 pyramidal cells, granule cells of the olfactory bulb, and interneurons of the cerebellar molecular layer). This large variability was not solely the consequence of the expression of multiple types of GABA(A) receptors, as a similar mIPSC decay variability was observed in cerebellar interneurons that express only a single type (alpha(1)beta(2)gamma(2)) of GABA(A) receptor. At large synapses on these cells, all variance in mIPSC decay could be accounted for by the stochastic behavior of approximately 36 pS channels, consistent with the conductance of alpha(1)beta(2)gamma(2) GABA(A) receptors at physiological temperatures. In contrast, at small synapses, a significant amount of variability in the synaptic cleft GABA transient had to be present to account for the additional variance in IPSC decay over that produced by stochastic channel openings. Thus, our results suggest a synapse-specific contribution of the variation of the spatiotemporal profile of GABA to the decay of IPSCs.

In the queue for coronary artery bypass grafting: patients' perceptions of risk and 'maximal acceptable waiting time'.

OBJECTIVES: To elicit patients' maximal acceptable waiting times (MAWT) for non-urgent coronary artery bypass grafting (CABG), and to determine if MAWT is related to prior expectations of waiting times, symptom burden, expected relief, or perceived risks of myocardial infarction while waiting. METHODS: Seventy-two patients on an elective CABG waiting list chose between two hypothetical but plausible options: a 1-month wait with 2% risk of surgical mortality, and a 6-month wait with 1% risk of surgical mortality. Waiting time in the 6-month option was varied up if respondents chose the 6-month/lower risk option, and down if they chose the 1-month/higher risk option, until the MAWT switch point was reached. Patients also reported their expected waiting time, perceived risks of myocardial infarction while waiting, current function, expected functional improvement and the value of that improvement. RESULTS: Only 17 (24%) patients chose the 6-month/1% risk option, while 55 (76%) chose the 1-month/2% risk option. The median MAWT was 2 months; scores ranged from 1 to 12 months (with two outliers). Many perceived high cumulative risks of myocardial infarction if waiting for 1 (upper quartile, > or = 1.45%) or 6 (upper quartile, > or = 10%) months. However, MAWT scores were related only to expected waiting time (r = 0.47; P < 0.0001). CONCLUSIONS: Most patients reject waiting 6 months for elective CABG, even if offered along with a halving in surgical mortality (from 2% to 1%). Intolerance for further delay seems to be determined primarily by patients' attachment to their scheduled surgical dates. Many also have severely inflated perceptions of their risk of myocardial infarction in the queue. These results suggest a need for interventions to modify patients' inaccurate risk perceptions, particularly if a scheduled surgical date must be deferred.

Proline accumulation in developing grapevine fruit occurs independently of changes in the levels of delta1-pyrroline-5-carboxylate synthetase mRNA or protein.

Mature fruit of grapevine (Vitis vinifera) contains unusually high levels of free proline (Pro; up to 24 micromol or 2.8 mg/g fresh weight). Pro accumulation does not occur uniformly throughout berry development but only during the last 4 to 6 weeks of ripening when both berry growth and net protein accumulation have ceased. In contrast, the steady-state levels of both the mRNA encoding V. vinifera Delta1-pyrroline-5-carboxylate synthetase (VVP5CS), a key regulatory enzyme in Pro biosynthesis, and its protein product remain relatively uniform throughout fruit development. In addition, the steady-state protein levels of Pro dehydrogenase, the first enzyme in Pro degradation, increased throughout early fruit development but thereafter remained relatively constant. The developmental accumulation of free Pro late in grape berry ripening is thus clearly distinct from the osmotic stress-induced accumulation of Pro in plants. It is not associated with either sustained increases in steady-state levels of P5CS mRNA or protein or a decrease in steady-state levels of Pro dehydrogenase protein, suggesting that other physiological factors are important for its regulation.