A new and flexible method for constructing designs for computer experiments

We develop a new method for constructing "good" designs for computer experiments. The method derives its power from its basic structure that builds large designs using small designs. We specialize the method for the construction of orthogonal Latin hypercubes and obtain many results along the way. In terms of run sizes, the existence problem of orthogonal Latin hypercubes is completely solved. We also present an explicit result showing how large orthogonal Latin hypercubes can be constructed using small orthogonal Latin hypercubes. Another appealing feature of our method is that it can easily be adapted to construct other designs; we examine how to make use of the method to construct nearly orthogonal and cascading Latin hypercubes.Comment: Published in at http://dx.doi.org/10.1214/09-AOS757 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Calcium-independent inhibitory G-protein signaling induces persistent presynaptic muting of hippocampal synapses

Adaptive forms of synaptic plasticity that reduce excitatory synaptic transmission in response to prolonged increases in neuronal activity may prevent runaway positive feedback in neuronal circuits. In hippocampal neurons, for example, glutamatergic presynaptic terminals are selectively silenced, creating mute synapses, after periods of increased neuronal activity or sustained depolarization. Previous work suggests that cAMP-dependent and proteasome-dependent mechanisms participate in silencing induction by depolarization, but upstream activators are unknown. We, therefore, tested the role of calcium and G-protein signaling in silencing induction in cultured hippocampal neurons. We found that silencing induction by depolarization was not dependent on rises in intracellular calcium, from either extracellular or intracellular sources. Silencing was, however, pertussis toxin sensitive, which suggests that inhibitory G-proteins are recruited. Surprisingly, blocking four common inhibitory G-protein-coupled receptors (GPCRs) (adenosine A(1) receptors, GABA(B) receptors, metabotropic glutamate receptors, and CB(1) cannabinoid receptors) and one ionotropic receptor with metabotropic properties (kainate receptors) failed to prevent depolarization-induced silencing. Activating a subset of these GPCRs (A(1) and GABA(B)) with agonist application induced silencing, however, which supports the hypothesis that G-protein activation is a critical step in silencing. Overall, our results suggest that depolarization activates silencing through an atypical GPCR or through receptor-independent G-protein activation. GPCR agonist-induced silencing exhibited dependence on the ubiquitin-proteasome system, as was shown previously for depolarization-induced silencing, implicating the degradation of vital synaptic proteins in silencing by GPCR activation. These data suggest that presynaptic muting in hippocampal neurons uses a G-protein-dependent but calcium-independent mechanism to depress presynaptic vesicle release

Measuring the impact of the Capital Card®, a novel form of contingency management, on substance misuse treatment outcomes:A retrospective evaluation

Background The Capital Card, developed by WDP, is a digital innovation which acts as a form of contingency management, and aims to significantly improve service user outcomes. WDP is a substance misuse treatment provider commissioned by local authorities across the UK to support service users and their families affected by addiction. The Capital Card, much like commercial loyalty cards, uses a simple earn-spend points system which incentivises and rewards service users for engaging with services e.g. by attending key work sessions, Blood Borne Virus appointments or group-work sessions. The Spend activities available to service users are designed to improve overall wellbeing and build social and recovery capital, and include activities such as educational classes, fitness classes, driving lessons, and cinema tickets. Methods and findings We compared successful completion rates of 1,545 service users accessing one of WDP’s London based community services over a two-year period; before and after the Capital Card was introduced. Client demographics (age, sex and primary substance) were controlled for during the analysis. Once client demographics were controlled for, analysis showed that clients with a Capital Card were 1.5 times more likely to successfully complete treatment than those who had not had the Capital Card (OR = 1.507, 95% CI = 1.194 to 1.902). Conclusions The results of this initial evaluation are of particular interest to commissioners and policy makers as it indicates that the Capital Card can be used effectively as a form of contingency management to enhance recovery outcomes for service users engaging in community-based substance misuse services

Understanding sports hernia (athletic pubalgia) - The anatomic and pathophysiologic basis for abdominal and groin pain in athletes

Recent publicity and some scientific reports suggest increasing success in treating an entity called “sports hernia” - more accurately named athletic pubalgia. The primary purpose of this article is to portray what we believe to be the key concept for understanding this wide variety of abdominal and groin injuries that afflict high performance athletes. These injuries have been plaguing athletes for a long time, and past treatments, based on concepts of occult hernia or simple strains, have generally failed. The former concepts do not take into account the likely mechanisms of injury or various patterns of pain that these athletes exhibit. The authors believe that the concept of a pubic joint or pubic dynamic complex is fundamental to understanding the anatomy and pertinent pathophysiology in these patients. Many injuries can now be treated successfully. Some of the injuries require surgery and others do not. In most cases, decisions regarding treatment and timing for return to full play require proper identification of the problems and consideration of a wide variety of medical, social, and business factors

Soot formation and radiation in turbulent jet diffusion flames under normal and reduced gravity conditions

Most practical combustion processes, as well as fires and explosions, exhibit some characteristics of turbulent diffusion flames. For hydrocarbon fuels, the presence of soot particles significantly increases the level of radiative heat transfer from flames. In some cases, flame radiation can reach up to 75 percent of the heat release by combustion. Laminar diffusion flame results show that radiation becomes stronger under reduced gravity conditions. Therefore, detailed soot formation and radiation must be included in the flame structure analysis. A study of sooting turbulent diffusion flames under reduced-gravity conditions will not only provide necessary information for such practical issues as spacecraft fire safety, but also develop better understanding of fundamentals for diffusion combustion. In this paper, a summary of the work to date and of future plans is reported

Loss of local astrocyte support disrupts action potential propagation and glutamate release synchrony from unmyelinated hippocampal axon terminals in vitro

Neuron–astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (−astrocyte) within the same culture dish. −Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. SIGNIFICANCE STATEMENT Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform and arrival time of axonal action potentials to synaptic terminals. GABA transmission was not disrupted. The disruption did not involve detectable morphological changes to axons of glutamate neurons. Our work identifies a developmental role for astrocytes in the temporal precision of excitatory signals

Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro

Astrocytes contribute to many neuronal functions, including synaptogenesis, but their role in the development of synaptic plasticity remains unclear. Presynaptic muting of hippocampal glutamatergic terminals defends against excitotoxicity. Here we studied the role of astrocytes in the development of presynaptic muting at glutamatergic synapses in rat hippocampal neurons. We found that astrocytes were critical for the development of depolarization-dependent and G(i/o)-dependent presynaptic muting. The ability of cAMP analogues to modulate presynaptic function was also impaired by astrocyte deficiency. Although astrocyte deprivation resulted in postsynaptic glutamate receptor deficits, this effect appeared independent of astrocytes’ role in presynaptic muting. Muting was restored with chronic, but not acute, treatment with astrocyte-conditioned medium, indicating that a soluble factor is permissive for muting. Astrocyte-derived thrombospondins (TSPs) are likely responsible because TSP1 mimicked the effect of conditioned medium, and gabapentin, a high-affinity antagonist of TSP binding to the α2δ-1 calcium channel subunit, mimicked astrocyte deprivation. We found evidence that protein kinase A activity is abnormal in astrocyte-deprived neurons but restored by TSP1, so protein kinase A dysfunction may provide a mechanism by which muting is disrupted during astrocyte deficiency. In summary our results suggest an important role for astrocyte-derived TSPs, acting through α2δ-1, in maturation of a potentially important form of presynaptic plasticity