A discrete-time Markov modulated queuing system with batched arrivals

This paper examines a discrete-time queuing system with applications to telecommunications traffic. The arrival process is a particular Markov modulated process which belongs to the class of discrete batched Markovian arrival processes. The server process is a single server deterministic queue. A closed form exact solution is given for the expected queue length and delay. A simple system of equations is given for the probability of the queue exceeding a given length.Comment: to appear Performance Evaluatio

A full free spectral range tuning of p-i-n doped Gallium Nitride microdisk cavity

Effective, permanent tuning of the whispering gallery modes (WGMs) of p-i-n doped GaN microdisk cavity with embedded InGaN quantum dots over one free spectral range is successfully demonstrated by irradiating the microdisks with a ultraviolet laser (380nm) in DI water. For incident laser powers between 150 and 960 nW, the tuning rate varies linearly. Etching of the top surface of the cavity is proposed as the driving force for the observed shift in WGMs, and is supported by experiments. The tuning for GaN/InGaN microdisk cavities is an important step for deterministically realizing novel nanophotonic devices for studying cavity quantum electrodynamics

Mas-related G-protein–coupled receptors inhibit pathological pain in mice

An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein–coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8–22 (BAM 8–22), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8–22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets

Speech and language therapy for aphasia following stroke

Background  Aphasia is an acquired language impairment following brain damage that affects some or all language modalities: expression and understanding of speech, reading, and writing. Approximately one third of people who have a stroke experience aphasia.  Objectives  To assess the effects of speech and language therapy (SLT) for aphasia following stroke.  Search methods  We searched the Cochrane Stroke Group Trials Register (last searched 9 September 2015), CENTRAL (2015, Issue 5) and other Cochrane Library Databases (CDSR, DARE, HTA, to 22 September 2015), MEDLINE (1946 to September 2015), EMBASE (1980 to September 2015), CINAHL (1982 to September 2015), AMED (1985 to September 2015), LLBA (1973 to September 2015), and SpeechBITE (2008 to September 2015). We also searched major trials registers for ongoing trials including ClinicalTrials.gov (to 21 September 2015), the Stroke Trials Registry (to 21 September 2015), Current Controlled Trials (to 22 September 2015), and WHO ICTRP (to 22 September 2015). In an effort to identify further published, unpublished, and ongoing trials we also handsearched theInternational Journal of Language and Communication Disorders(1969 to 2005) and reference lists of relevant articles, and we contacted academic institutions and other researchers. There were no language restrictions.  Selection criteria  Randomised controlled trials (RCTs) comparing SLT (a formal intervention that aims to improve language and communication abilities, activity and participation) versus no SLT; social support or stimulation (an intervention that provides social support and communication stimulation but does not include targeted therapeutic interventions); or another SLT intervention (differing in duration, intensity, frequency, intervention methodology or theoretical approach).  Data collection and analysis  We independently extracted the data and assessed the quality of included trials. We sought missing data from investigators.  Main results  We included 57 RCTs (74 randomised comparisons) involving 3002 participants in this review (some appearing in more than one comparison). Twenty-seven randomised comparisons (1620 participants) assessed SLT versus no SLT; SLT resulted in clinically and statistically significant benefits to patients' functional communication (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.49, P = 0.01), reading, writing, and expressive language, but (based on smaller numbers) benefits were not evident at follow-up. Nine randomised comparisons (447 participants) assessed SLT with social support and stimulation; meta-analyses found no evidence of a difference in functional communication, but more participants withdrew from social support interventions than SLT. Thirty-eight randomised comparisons (1242 participants) assessed two approaches to SLT. Functional communication was significantly better in people with aphasia that received therapy at a high intensity, high dose, or over a long duration compared to those that received therapy at a lower intensity, lower dose, or over a shorter period of time. The benefits of a high intensity or a high dose of SLT were confounded by a significantly higher dropout rate in these intervention groups. Generally, trials randomised small numbers of participants across a range of characteristics (age, time since stroke, and severity profiles), interventions, and outcomes.  Authors' conclusions  Our review provides evidence of the effectiveness of SLT for people with aphasia following stroke in terms of improved functional communication, reading, writing, and expressive language compared with no therapy. There is some indication that therapy at high intensity, high dose or over a longer period may be beneficial. HIgh-intensity and high dose interventions may not be acceptable to all

An essential function for the ATR-Activation-Domain (AAD) of TopBP1 in mouse development and cellular senescence

ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins – Dpb11TopBP1, Ddc1Rad9 and Dna2 - all interact with and activate Mec1ATR. Each contains an ATR activation domain (ADD) that interacts directly with the Mec1ATR:Ddc2ATRIP complex. Any of the Dpb11TopBP1, Ddc1Rad9 or Dna2 ADDs is sufficient to activate Mec1ATR in vitro. All three can also independently activate Mec1ATR in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development

Controls on Open‐Ocean North Atlantic ΔpCO2 at Seasonal and Interannual Time Scales Are Different

The North Atlantic is a substantial sink for anthropogenic CO2. Understanding the mechanisms driving the sink's variability is key to assessing its current state and predicting its potential response to global climate change. Here we apply a time series decomposition technique to satellite and in situ data to examine separately the factors (both biological and nonbiological) that affect the sea‐air CO2 difference (ΔpCO2) on seasonal and interannual time scales. We demonstrate that on seasonal time scales, the subpolar North Atlantic ΔpCO2 signal is predominantly correlated with biological processes, whereas seawater temperature dominates in the subtropics. However, the same factors do not necessarily control ΔpCO2 on interannual time scales. Our results imply that the mechanisms driving seasonal variability in ΔpCO2 cannot necessarily be extrapolated to predict how ΔpCO2, and thus the North Atlantic CO2 sink, may respond to increases in anthropogenic CO2 over longer time scales

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain

Identifying chondroprotective diet-derived bioactives and investigating their synergism

Osteoarthritis (OA) is a multifactorial disease and nutrition is a modifiable factor that may contribute to disease onset or progression. A detailed understanding of mechanisms through which diet-derived bioactive molecules function and interact in OA is needed. We profiled 96 diet-derived, mainly plant-based bioactives using an in vitro model in chondrocytes, selecting four candidates for further study. We aimed to determine synergistic interactions between bioactives that affected the expression of key genes in OA. Selected bioactives, sulforaphane, apigenin, isoliquiritigenin and luteolin, inhibited one or more interleukin-1-induced metalloproteinases implicated in OA (MMP1, MMP13, ADAMTS4, ADAMTS5). Isoliquiritigenin and luteolin showed reactive oxygen species scavenging activity in chondrocytes whereas sulforaphane had no effect and apigenin showed only a weak trend. Sulforaphane inhibited the IL-1/NFκB and Wnt3a/TCF/Lef pathways and increased TGFβ/Smad2/3 and BMP6/Smad1/5/8 signalling. Apigenin showed potent inhibition of the IL-1/NFκB and TGFβ/Smad2/3 pathways, whereas luteolin showed only weak inhibition of the IL-1/NFκB pathway. All four bioactives inhibited cytokine-induced aggrecan loss from cartilage tissue explants. The combination of sulforaphane and isoliquiritigenin was synergistic for inhibiting MMP13 gene expression in chondrocytes. We conclude that dietary-derived bioactives may be important modulators of cartilage homeostasis and synergistic relationships between bioactives may have an anti-inflammatory and chondroprotective role

Prevalence and correlates of alcohol dependence disorder among TB and HIV infected patients in Zambia.

OBJECTIVES: To determine the prevalence and correlates of alcohol dependence disorders in persons receiving treatment for HIV and Tuberculosis (TB) at 16 Primary Health Care centres (PHC) across Zambia. METHODS: 649 adult patients receiving treatment for HIV and/or TB at PHCs in Zambia (363 males, 286 females) were recruited between 1st December 2009 and 31st January 2010. Data on socio-demographic variables, clinical disease features (TB and HIV), and psychopathological status were collected. The Mini International Neuropsychiatric Interview (MINI) was used to diagnose alcohol dependence disorder. Correlates of alcohol dependence were analyzed for men only, due to low prevalence in women. Univariable and multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI), using general estimating equations to allow for within-PHC clustering. RESULTS: The prevalence of alcohol dependence was 27.2% (95%CI: 17.7-39.5%) for men and 3.9% (95%CI: 1.4-0.1%) for women. Factors associated with alcohol dependence disorder in men included being single, divorced or widowed compared with married (adjusted OR = 1.47, 95%CI: 1.00-2.14) and being unemployed (adjusted OR=1.30, 95%CI: 1.01-1.67). The highest prevalence of alcohol dependence was among HIV-test unknown TB patients (34.7%), and lowest was among HIV positive patients on treatment but without TB (14.1%), although the difference was not statistically significant (p=0.38). CONCLUSIONS: Male TB/HIV patients in this population have high prevalence of alcohol dependence disorder, and prevalence differs by HIV/TB status. Further work is needed to explore interventions to reduce harmful drinking in this population

Photochemical activation of TRPA1 channels in neurons and animals

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in non-transgenic animals, including humans