Role of the p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury.

Arterial injury induces a series of proliferative, vasoactive, and inflammatory responses that lead to vascular proliferative diseases, including atherosclerosis and restenosis. Although several factors have been defined which stimulate this process in vivo, the role of specific cellular gene products in limiting this response is not well understood. The p21 cyclin-dependent kinase inhibitor affects cell cycle progression, senescence, and differentiation in transformed cells, but its expression in injured blood vessels has not been investigated. In this study, we report that p21 protein is induced in porcine arteries following balloon catheter injury and suggest that p21 is likely to play a role in limiting arterial cell proliferation in vivo. Vascular endothelial and smooth muscle cell growth was arrested through the ability of p21 to inhibit progression through the G1 phase of the cell cycle. Following injury to porcine arteries, p21 gene product was detected in the neointima and correlated inversely with the location and kinetics of intimal cell proliferation. Direct gene transfer of p21 using an adenoviral vector into balloon injured porcine arteries inhibited the development of intimal hyperplasia. Taken together, these findings suggest that p21, and possibly related cyclin-dependent kinase inhibitors, may normally regulate cellular proliferation following arterial injury, and strategies to increase its expression may prove therapeutically beneficial in vascular diseases.

Regulation of yeast phospholipid biosynthetic gene expression in response to inositol involves two superimposed mechanisms.

Transcription of phospholipid biosynthetic genes in the yeast Saccharomyces cerevisiae is maximally derepressed when cells are grown in the absence of inositol and repressed when the cells are grown in its presence. We have previously suggested that this response to inositol may be dictated by regulating transcription of the cognate activator gene, INO2. However, it was also known that cells which harbor a mutant opi1 allele express constitutively derepressed levels of target genes (INO1 and CHO1), implicating the OPI1 negative regulatory gene in the response to inositol. These observations suggested that the response to inositol may involve both regulation of INO2 transcription as well as OPI1-mediated repression. We investigated these possibilities by examining the effect of inositol on target gene expression in a strain containing the INO2 gene under control of the GAL1 promoter. In this strain, transcription of the INO2 gene was regulated in response to galactose but was insensitive to inositol. The expression of the INO1 and CHO1 target genes was still responsive to inositol even though expression of the INO2 gene was unresponsive. However, the level of expression of the INO1 and CHO1 target genes correlated with the level of INO2 transcription. Furthermore, the effect of inositol on target gene expression was eliminated by deleting the OPI1 gene in the GAL1-INO2-containing strain. These data suggest that the OPI1 gene product is the primary target (sensor) of the inositol response and that derepression of INO2 transcription determines the degree of expression of the target genes.

Calcareous plankton response to orbital and millennial-scale climate changes from ODP Leg 161-975

The paleoenvironmental conditions through MIS 15-9 at the Mediterranean Ocean Drilling Program (ODP) Site 975 were interpreted by high resolution study of calcareous plankton assemblages compared with available d18O and d13C records and high resolution paleoclimate proxies from the Atlantic Ocean. Sea Surface Temperatures (SSTs) have been estimated from planktonic foraminiferal assemblages using the artificial neural networks method. Calcareous plankton varied dominantly on a glacial-interglacial scale as testified by the SST record, foraminiferal diversity, total coccolith abundance and changes in warm-water calcareous nannofossil taxa. A general increase in foraminiferal diversity and of total coccolith abundance is observed during interglacials. Warmest SSTs are reached during MIS 11, while MIS 12 and MIS 10 represent the coldest intervals of the studied record. During MIS 12, one of the most extreme glacials of the last million years, occurrence of Globorotalia inflata and of neogloboquadrinids indicates a shoaling of the interface between Atlantic inflowing and Mediterranean outflowing waters. Among calcareous nannofossils the distribution of Gephyrocapsa margereli-G. muellerae > 4 µm also supports a reduced Atlantic-Mediterranean exchange during MIS 12. Superimposed on glacial-interglacial variability, six short-terms coolings are recognized during MIS 12 and 10, which appear comparable in their distribution and amplitude to the Heinrich - type events documented in the Atlantic Ocean in the same interval. During these H-type events, N. pachyderma (s) and G. margereli-G. muellerae > 4 µm increase as a response to the enhanced inflow of cold Atlantic water into the Mediterranean via the Strait of Gibraltar. Mediterranean surface water hydrography appears to have been most severely affected at Termination V during the H-type event Ht4, possibly as a response to a large volume of Atlantic meltwater inflow via the Strait of Gibraltar and/or to freshwater/terrigenous input deriving from local mountain glaciers. Three additional SST coolings are recorded through MIS 14-16, but these are not well correlated with Heinrich - type events documented in the Atlantic Ocean in the same interval; during these cooling episodes only the subpolar Turborotalita quinqueloba increases. These results highlight the sensitive response of the Mediterranean basin to millennial-scale climate variations related to Northern Hemisphere ice-sheet instability and support the hypothesis that the tight connection between high latitude climate dynamics and Mediterranean sea surface water features can be traced through the Middle Pleistocene.

Automaticity in L2 learning: Correlation between vocabulary proficiency and response time in word recognition

Automaticity (in this essay defined as short response time) and fluency in language use are closely connected to each other and some research has been conducted regarding some of the aspects involved. In fact, the notion of automaticity is still debated and many definitions and opinions on what automaticity is have been suggested (Andersson,1987, 1992, 1993, Logan, 1988, Segalowitz, 2010). One aspect that still needs more research is the correlation between vocabulary proficiency (a person’s knowledge about words and ability to use them correctly) and response time in word recognition. Therefore, the aim of this study has been to investigate this correlation using two different tests; one vocabulary size test (Paul Nation) and one lexical decision task (SuperLab) that measures both response time and accuracy. 23 Swedish students partaking in the English 7 course in upper secondary Swedish school were tested. The data were analyzed using a quantitative method where the average values and correlations from the test were used to compare the results. The correlations were calculated using Pearson’s Coefficient Correlations Calculator. The empirical study indicates that vocabulary proficiency is not strongly correlated with shorter response times in word recognition. Rather, the data indicate that L2 learners instead are sensitive to the frequency levels of the vocabulary. The accuracy (number of correct recognized words) and response times correlate with the frequency level of the tested words. This indicates that factors other than vocabulary proficiency are important for the ability to recognize words quickly.

Response of B-type natriuretic pepticle to exercise in hypertensive patients with suspected diastolic heart failure: Correlation with cardiac function, hemodynamics, and workload

Background Diastolic heart failure (DHF) is characterized by dyspnea due to increased left ventricular (LV) filling pressures during stress. We sought the relationship of exercise-induced increases in B-type natriuretic peptide (BNP) to LV filling pressures and parameters of cardiovascular performance in suspected DHF. Methods Twenty-six treated hypertensive patients with suspected DHF (exertional dyspnea, LV ejection fraction >50%, and diastolic dysfunction) underwent maximal exercise echocardiography using the Bruce protocol. BNP, transmitral Doppler, and tissue Doppler for systolic (So) and early (Ea) and late (Aa) diastolic mitral annular velocities were obtained at rest and peak stress. LV filling pressures were estimated with E/Ea ratios. Results Resting BNP correlated with resting pulse pressure (r=0.45, P=0.02). Maximal exercise performance (4.6 +/- 2.5min) was limited by dyspnea. Blood pressure increased with exercise (from 143 +/- 19/88 +/- 8 to 191 +/- 22/90 +/- 10 mm Hg); 13 patients (50%) had a hypertensive response. Peak exercise BNP correlated with peak transmitral E velocity (r = 0.41, P <.05) and peak heart rate (r = -0.40, P <.05). BNP increased with exercise (from 48 57 to 74 97 pg/mL, P =.007), and the increment of BNP with exercise was associated with maximal workload and peak exercise So, Ea, and Aa (P <.01 for all). Filling pressures, approximated by lateral E/Ea ratio, increased with exercise (7.7 +/- 2.0 to 10.0 +/- 4.8, P <.01). BNP was higher in patients with possibly elevated filling pressures at peak exercise (E/Ea >10) compared to those with normal pressures (123 +/- 124 vs 45 +/- 71 pg/mL, P =.027). Conclusions Augmentation of BNP with exercise in hypertensive patients with suspected DHF is associated with better exercise capacity, LV systolic and diastolic function, and left atrial function. Peak exercise BNP levels may identify exercise-induced elevation of filling pressures in DHF.

Parasitization of Manduca sexta larvae by the parasitoid wasp Cotesia congregata induces an impaired host immune response

During oviposition, the parasitoid wasp Cotesia congregata injects polydnavirus, venom, and parasitoid eggs into larvae of its lepidopteran host.. the tobacco hornworm, Manduca sexta. Polydnaviruses (PDVs) suppress the immune system of the host and allow the juvenile parasitoids to develop without being encapsulated by host hemocytes mobilized by the immune system. Previous work identified a gene in the Cotesia rubecula PDV (CrV1) that is responsible for depolymerization of actin in hemocytes of the host Pieris rapae during a narrow temporal window from 4 to 8 h post-parasitization. Its expression appears temporally correlated with hemocyte dysfunction. After this time, the hemocytes recover, and encapsulation is then inhibited by other mechanism(s). In contrast, in parasitized tobacco hornworm larvae this type of inactivation in hemocytes of parasitized M. sexta larvae leads to irreversible cellular disruption. We have characterized the temporal pattern of expression of the CrV1-homolog from the C. congregata PDV in host fat body and hemocytes using Northern blots, and localized the protein in host hemocytes with polyclonal antibodies to CrV1 protein produced in P. rapae in response to expression of the CrV1 protein. Host hemocytes stained with FITC-labeled phalloidin, which binds to filamentous actin, were used to observe hemocyte disruption in parasitized and virus-injected hosts and a comparison was made to hemocytes of nonparasitized control larvae. At 24 h post-parasitization host hemocytes were significantly altered compared to those of nonparasitized larvae. Hemocytes front newly parasitized hosts displayed blebbing, inhibition of spreading and adhesion, and overall cell disruption. A CrV1-homolog gene product was localized in host hemocytes using polyclonal CrV1 antibodies, suggesting that CrV1-like gene products of C. congregata's bracovirus are responsible for the impaired immune response of the host. (C) 2005 Elsevier Ltd. All rights reserved.

The mismatch negativity (MMN) response to complex tones and spoken words in individuals with aphasia

Background: The mismatch negativity (MMN) is a fronto-centrally distributed event-related potential (ERP) that is elicited by any discriminable auditory change. It is an ideal neurophysiological tool for measuring the auditory processing skills of individuals with aphasia because it can be elicited even in the absence of attention. Previous MMN studies have shown that acoustic processing of tone or pitch deviance is relatively preserved in aphasia, whereas the basic acoustic processing of speech stimuli can be impaired (e.g., auditory discrimination). However, no MMN study has yet investigated the higher levels of auditory processing, such as language-specific phonological and/or lexical processing, in individuals with aphasia. Aims: The aim of the current study was to investigate the MMN response of normal and language-disordered subjects to tone stimuli and speech stimuli that incorporate the basic auditory processing (acoustic, acoustic-phonetic) levels of non-speech and speech sound processing, and also the language-specific phonological and lexical levels of spoken word processing. Furthermore, this study aimed to correlate the aphasic MMN data with language performance on a variety of tasks specifically targeted at the different levels of spoken word processing. Methods M Procedures: Six adults with aphasia (71.7 years +/- 3.0) and six healthy age-, gender-, and education-matched controls (72.2 years +/- 5.4) participated in the study. All subjects were right-handed and native speakers of English. Each subject was presented with complex harmonic tone stimuli, differing in pitch or duration, and consonant-vowel (CV) speech stimuli (non-word /de:/versus real world/deI/). The probability of the deviant for each tone or speech contrast was 10%. The subjects were also presented with the same stimuli in behavioural discrimination tasks, and were administered a language assessment battery to measure their auditory comprehension skills. Outcomes O Results: The aphasic subjects demonstrated attenuated MMN responses to complex tone duration deviance and to speech stimuli (words and non-words), and their responses to the frequency, duration, and real word deviant stimuli were found to strongly correlate with performance on the auditory comprehension section of the Western Aphasia Battery (WAB). Furthermore, deficits in attentional lexical decision skills demonstrated by the aphasic subjects correlated with a word-related enhancement demonstrated during the automatic MMN paradigm, providing evidence to support the word advantage effect, thought to reflect the activation of language-specific memory traces in the brain for words. Conclusions: These results indicate that the MMN may be used as a technique for investigating general and more specific auditory comprehension skills of individuals with aphasia, using speech and/or non-speech stimuli, independent of the individual's attention. The combined use of the objective MMN technique and current clinical language assessments may result in improved rehabilitative management of aphasic individuals.

Factors affecting the accommodative response to sustained visual tasks

In the absence of adequate visual stimulation accommodation adopts an intermediate resting position, appropriately termed tonic accommodation (TA). A period of sustained fixation can modify the tonic resting position, and indicate the adaptation properties of TA. This thesis investigates various factors contributing to the accommodative response during sustained visual tasks, in particular the adaptation of TA. Objective infra-red optometry was chosen as the most effective method of measurement of accommodation. This technique was compared with other methods of measuring TA and the results found to be well correlated. The inhibitory sympathetic input to the ciliary muscle provides the facility to attenuate the magnitude and duration of adaptive changes in TA. This facility is, however, restricted to those individuals having relatively high levels of pre-task TA. Furthermore, the facility is augmented by substantial levels of concurrent parasympathetic activity. The imposition of mental effort can induce concurrent changes in TA which are predominantly positive and largely the result of an increase in parasympathetic innervation of the ciliary muscle although there is some evidence for sympathetic attentuation at higher levels of TA. In emmetropes sympathetic inhibition can modify the effect of mental effort on the steady-state accommodative response at near. Late-onset myopes (onset after the age of 15 years) have significantlylower values of TA then emmetropes. Similarly, late-onset myopes show lower values of steady-state accommodative response for nearstimuli. The imposition of mental effort induces concurrent increases in TA and steady-state accommodative response in the myopic group which are significantly greater than those for emmetropes. Estimates of TA made under bright empty-field conditions are well correlated with those made under darkroom conditions. The method by which the accommodative loop is opened has no significant effect on the magnitude and duration of post-task shifts in TA induced by a near vision task. Significant differences in the post-task shifts in TA induced by a near vision task exist between emmetropes and late-onset myopes, the post-task shifts being more sustained for the myopic group.

Accuracy of Goldmann, ocular response analyser, Pascal and TonoPen XL tonometry in keratoconic and normal eyes

Aim: The aim of this study was to evaluate the practicality and accuracy of tonometers used in routine clinical practice for established keratoconus (KC). Methods: This was a prospective study of 118 normal and 76 keratoconic eyes where intraocular pressure (IOP) was measured in random order using the Goldman applanation tonometer (GAT), Pascal dynamic contour tonometer (DCT), Reichert ocular response analyser (ORA) and TonoPen XL tonometer. Corneal hysteresis (CH) and corneal resistance factor (CRF), as calculated by the ORA, were recorded. Central corneal thickness (CCT) was measured using an ultrasound pachymeter. Results: The difference in IOP values between instruments was highly significant in both study groups (p<0.001). All other IOP measures were significantly higher than those for GAT, except for the Goldmann-correlated IOP (average of the two applanation pressure points) (IOPg) as measured by ORA in the control group and the CH-corrected IOP (corneal-compensated IOP value) (IOPcc) measures in the KC group. CCT, CH and CRF were significantly less in the KC group (p<0.001). Apart from the DCT, all techniques tended to measure IOP higher in eyes with thicker corneas. Conclusion: The DCT and the ORA are currently the most appropriate tonometers to use in KC for the measurement of IOPcc. Corneal factors such as CH and CRT may be of more importance than CCT in causing inaccuracies in applanation tonometry techniques.

Laminar distribution of the pathological changes in sporadic frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy:a quantitative study using polynomial curve fitting

Aims: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. Results: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. Conclusions: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.

Optimal design for correlated processes with input-dependent noise

Optimal design for parameter estimation in Gaussian process regression models with input-dependent noise is examined. The motivation stems from the area of computer experiments, where computationally demanding simulators are approximated using Gaussian process emulators to act as statistical surrogates. In the case of stochastic simulators, which produce a random output for a given set of model inputs, repeated evaluations are useful, supporting the use of replicate observations in the experimental design. The findings are also applicable to the wider context of experimental design for Gaussian process regression and kriging. Designs are proposed with the aim of minimising the variance of the Gaussian process parameter estimates. A heteroscedastic Gaussian process model is presented which allows for an experimental design technique based on an extension of Fisher information to heteroscedastic models. It is empirically shown that the error of the approximation of the parameter variance by the inverse of the Fisher information is reduced as the number of replicated points is increased. Through a series of simulation experiments on both synthetic data and a systems biology stochastic simulator, optimal designs with replicate observations are shown to outperform space-filling designs both with and without replicate observations. Guidance is provided on best practice for optimal experimental design for stochastic response models. © 2013 Elsevier Inc. All rights reserved.

Phenobarbital for neonatal seizures:response rate and predictors of refractoriness

Background : Phenobarbital is the first-line choice for neonatal seizures treatment, despite a response rate of approximately 45%. Failure to respond to acute anticonvulsants is associated with poor neurodevelopmental outcome, but knowledge on predictors of refractoriness is limited. Objective : To quantify response rate to phenobarbital and to establish variables predictive of its lack of efficacy. Methods : We retrospectively evaluated newborns with electrographically confirmed neonatal seizures admitted between January 1999 and December 2012 to the neonatal intensive care unit of Parma University Hospital (Italy), excluding neonates with status epilepticus. Response was categorized as complete (cessation of clinical and electrographic seizures after phenobarbital administration), partial (reduction but not cessation of electrographic seizures with the first bolus, response to the second bolus), or absent (no response after the second bolus). Multivariate analysis was used to identify independent predictors of refractoriness. Results : Out of 91 newborns receiving phenobarbital, 57 (62.6%) responded completely, 15 (16.5%) partially, and 19 (20.9%) did not respond. Seizure type (p = 0.02), background electroencephalogram (EEG; p ≤ 0.005), and neurologic examination (p ≤ 0.005) correlated with response to phenobarbital. However, EEG (p ≤ 0.02) and seizure type (p ≤ 0.001) were the only independent predictors. Conclusion : Our results suggest a prominent role of neurophysiological variables (background EEG and electrographic-only seizure type) in predicting the absence of response to phenobarbital in high-risk newborns.

Regional climate gradients in precipitation and temperature in response to climate teleconnections in the Greater Everglades ecosystem of South Florida

Precipitation and temperature in Florida responds to climate teleconnections from both the Pacific and Atlantic regions. In this region south of Lake Okeechobee, encompassing NWS Climate Divisions 5, 6, and 7, modern movement of surface waters are managed by the South Florida Water Management District and the US Army Corps of Engineers for flood control, water supply, and Everglades restoration within the constraints of the climatic variability of precipitation and evaporation. Despite relatively narrow, low-relief, but multi-purposed land separating the Atlantic Ocean from the Gulf of Mexico, South Florida has patterns of precipitation and temperature that vary substantially on spatial scales of 101–102 km. Here we explore statistically significant linkages to precipitation and temperature that vary seasonally and over small spatial scales with El Niño-Southern Oscillation (ENSO), the Atlantic Multidecadal Oscillation (AMO), and the Pacific Decadal Oscillation (PDO). Over the period from 1952 to 2005, ENSO teleconnections exhibited the strongest influence on seasonal precipitation. The Multivariate ENSO Index was positively correlated with winter (dry season) precipitation and explained up to 34 % of dry season precipitation variability along the southwest Florida coast. The AMO was the most influential of these teleconnections during the summer (wet season), with significant positive correlations to South Florida precipitation. These relationships with modern climate parameters have implications for paleoclimatological and paleoecological reconstructions, and future climate predictions from the Greater Everglades system.

Salmeterol enhances the cardiac response to gene therapy in Pompe disease.

Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.

Nutrient availability affects the response of the calcifying chlorophyte Halimeda opuntia (L.) J.V. Lamouroux to low pH

Atmospheric carbon dioxide emissions cause a decrease in the pH and aragonite saturation state of surface ocean water. As a result, calcifying organisms are expected to suffer under future ocean conditions, but their physiological responses may depend on their nutrient status. Because many coral reefs experience high inorganic nutrient loads or seasonal changes in nutrient availability, reef organisms in localized areas will have to cope with elevated carbon dioxide and changes in inorganic nutrients. Halimeda opuntia is a dominant calcifying primary producer on coral reefs that contributes to coral reef accretion. Therefore, we investigated the carbon and nutrient balance of H. opuntia exposed to elevated carbon dioxide and inorganic nutrients. We measured tissue nitrogen, phosphorus and carbon content as well as the activity of enzymes involved in inorganic carbon uptake and nitrogen assimilation (external carbonic anhydrase and nitrate reductase, respectively). Inorganic carbon content was lower in algae exposed to high CO2, but calcification rates were not significantly affected by CO2 or inorganic nutrients. Organic carbon was positively correlated to external carbonic anhydrase activity, while inorganic carbon showed the opposite correlation. Carbon dioxide had a significant effect on tissue nitrogen and organic carbon content, while inorganic nutrients affected tissue phosphorus and N:P ratios. Nitrate reductase activity was highest in algae grown under elevated CO2 and inorganic nutrient conditions and lowest when phosphate was limiting. In general, we found that enzymatic responses were strongly influenced by nutrient availability, indicating its important role in dictating the local responses of the calcifying primary producer H. opuntia to ocean acidification.