Dopamine D-3 receptors regulate GABA(A) receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens

The dopamine D-3 receptor, which is highly enriched in nucleus accumbens (NAc), has been suggested to play an important role in reinforcement and reward. To understand the potential cellular mechanism underlying D-3 receptor functions, we examined the effect of D-3 receptor activation on GABA(A) receptor (GABA(A)R)-mediated current and inhibitory synaptic transmission in medium spiny neurons of NAc. Application of PD128907 [(4aR, 10bR)-3,4a, 4,10b-tetrahydro-4-propyl-2H, 5H-[1] benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a specific D-3 receptor agonist, caused a significant reduction of GABAAR current in acutely dissociated NAc neurons and miniature IPSC amplitude in NAc slices. This effect was blocked by dialysis with a dynamin inhibitory peptide, which prevents the clathrin/activator protein 2 (AP2)-mediated GABA(A) receptor endocytosis. In addition, the D-3 effect on GABA(A)R current was prevented by agents that manipulate protein kinase A (PKA) activity. Infusion of a peptide derived from GABA(A) beta subunits, which contains an atypical binding motif for the clathrin AP2 adaptor complex and the major PKA phosphorylation sites and binds with high affinity to AP2 only when dephosphorylated, diminished the D-3 regulation of IPSC amplitude. The phosphorylated equivalent of the peptide was without effect. Moreover, PD128907 increased GABAAR internalization and reduced the surface expression of GABA(A) receptor beta subunits in NAc slices, which was prevented by dynamin inhibitory peptide or cAMP treatment. Together, our results suggest that D-3 receptor activation suppresses the efficacy of inhibitory synaptic transmission in NAc by increasing the phospho-dependent endocytosis of GABA(A) receptors

Class reconstruction driven adversarial domain adaptation for hyperspectral image classification

We address the problem of cross-domain classification of hyperspectral image (HSI) pairs under the notion of unsupervised domain adaptation (UDA). The UDA problem aims at classifying the test samples of a target domain by exploiting the labeled training samples from a related but different source domain. In this respect, the use of adversarial training driven domain classifiers is popular which seeks to learn a shared feature space for both the domains. However, such a formalism apparently fails to ensure the (i) discriminativeness, and (ii) non-redundancy of the learned space. In general, the feature space learned by domain classifier does not convey any meaningful insight regarding the data. On the other hand, we are interested in constraining the space which is deemed to be simultaneously discriminative and reconstructive at the class-scale. In particular, the reconstructive constraint enables the learning of category-specific meaningful feature abstractions and UDA in such a latent space is expected to better associate the domains. On the other hand, we consider an orthogonality constraint to ensure non-redundancy of the learned space. Experimental results obtained on benchmark HSI datasets (Botswana and Pavia) confirm the efficacy of the proposal approach

A novel tool for individual haplotype inference using mixed data

© 2009 Lin and Fann; licensee BioMed Central Ltd

Biomass smoke exposure enhances rhinovirus-induced inflammation in primary lung fibroblasts

© 2016 by the authors; licensee MDPI, Basel, Switzerland. Biomass smoke is one of the majorair pollutants and contributors of household air pollution worldwide. More than 3 billion people use biomass fuels for cooking and heating, while other sources of exposure are from the occurrence of bushfires and occupational conditions. Persistent biomass smoke exposure has been associated with acute lower respiratory infection (ALRI) as a major environmental risk factor. Children under the age of five years are the most susceptible in developing severe ALRI, which accounts for 940,000 deaths globally. Around 90% of cases are attributed to viral infections, such as influenza, adenovirus, and rhinovirus. Although several epidemiological studies have generated substantial evidence of the association of biomass smoke and respiratory infections, the underlying mechanism is still unknown. Using an in vitro model, primary human lung fibroblasts were stimulated with biomass smoke extract (BME), specifically investigating hardwood and softwood types, and human rhinovirus-16 for 24 h. Production of pro-inflammatory mediators, such as IL-6 and IL-8, were measured via ELISA. Firstly, we found that hardwood and softwood smoke extract (1%) up-regulate IL-6 and IL-8 release (p ≤ 0.05). In addition, human rhinovirus-16 further increased biomass smoke-induced IL-8 in fibroblasts, in comparison to the two stimulatory agents alone. We also investigated the effect of biomass smoke on viral susceptibility by measuring viral load, and found no significant changes between BME exposed and non-exposed infected fibroblasts. Activated signaling pathways for IL-6 and IL-8 production by BME stimulation were examined using signaling pathway inhibitors. p38 MAPK inhibitor SB239063 significantly attenuated IL-6 and IL-8 release the most (p ≤ 0.05). This study demonstrated that biomass smoke can modulate rhinovirus-induced inflammation during infection, which can alter the severity of the disease. The mechanism by which biomass smoke exposure increases inflammation in the lungs can be targeted and inhibited via p38 MAP kinase pathway

Comprehension of Subject and Object Relative Clauses in a Trilingual Acquisition Context

Chinese relative clauses (RCs) have word order properties that are distinctly rare across languages of the world; such properties provide a good testing ground to tease apart predictions regarding the relative complexity of subject and object RCs in acquisition and processing. This study considers these special word order properties in a multilingual acquisition context, examining how Cantonese(L1)-English(L2)-Mandarin(L3) trilingual children process RCs in two Chinese languages differing in exposure conditions. Studying in an English immersion international school, these trilinguals are also under intensive exposure to English. Comparisons of the trilinguals with their monolingual counterparts are made with a focus on the directionality of cross-linguistic influence. The study considers how various factors such as language exposure, structural overlaps in the target languages, typological distance, and language dominance can account for the linguistic abilities and vulnerabilities exhibited by a group of children in a trilingual acquisition context. Twenty-one trilingual 5- to 6-year-olds completed tests of subject- and object- RC comprehension in all three languages. Twenty-four age-matched Cantonese monolinguals and 24 age-matched Mandarin monolinguals served as comparison groups. Despite limited exposure to Mandarin, the trilinguals performed comparable to the monolinguals. Their Cantonese performance uniquely predicts their Mandarin performance, suggesting positive transfer from L1 Cantonese to L3 Mandarin. In Cantonese, however, despite extensive exposure from birth, the trilinguals comprehended object RCs significantly worse than the monolinguals. Error analyses suggested an English-based head-initial analysis, implying negative transfer from L2 English to L1 Cantonese. Overall, we identified a specific case of bi-directional influence between the first and second/third languages. The trilinguals experience facilitation in processing Mandarin RCs, because parallels and overlaps in both form and function provide a transparent basis for positive transfer from L1 Cantonese to L3 Mandarin. On the other hand, they experience more difficulty in processing object RCs in Cantonese compared to their monolingual peers, because structural overlaps with competing structures from English plus intensive exposure to English lead to negative transfer from L2 English to L1 Cantonese. The findings provide further evidence that head noun assignment in object RCs is especially vulnerable in multilingual Cantonese children when they are under intensive exposure to English.published_or_final_versio

Transcranial magnetic stimulation for the treatment of epilepsy

© 2016 The Cochrane Collaboration.Background: Epilepsy is a highly prevalent neurological condition characterized by repeated unprovoked seizures with various etiologies. Although antiepileptic medications produce clinical improvement in most individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. Objectives: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side-effects. Search methods: We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 10 March 2016), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) up to March 2016. We also searched SCOPUS (1823 to June 2014) as a substitute for Embase (but it is no longer necessary to search SCOPUS, because randomized controlled trials (RCTs) and quasi-RCTs in EMBASE are now included in CENTRAL). Selection criteria: Eligible studies were RCTs that were double-blinded, single-blinded or unblinded, and placebo, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, duration, intensity, or setup (focal or vertex treatment) on patients with drug-resistant epilepsy. The search revealed 274 records from the databases, that after selection provided seven full-text relevant studies for inclusion. Of the seven studies included, five were completed studies with published data and included randomized, blinded trials. The total number of participants in the seven trials was 230. Data collection and analysis: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. Main results: Two of the seven studies analyzed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively). The other five studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls. We were not able to combine the results of the trials in analysis due to differences in the designs of the studies. Four studies evaluated our secondary endpoint of mean number of epileptic discharges, and three of the four showed a statistically significant reduction in discharges. Quality of life was not assessed in any of the studies. Adverse effects were uncommon among the studies and typically involved headache, dizziness, and tinnitus. No significant changes in medication use were found in the trials. Authors' conclusions: Overall, we judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges

Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring

© 2018 The Author(s). Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed

238U/235U in calcite is more susceptible to carbonate diagenesis

The uranium isotopic composition (δ238U) of bulk marine calcium carbonates has been extensively explored as a promising paleoredox proxy to track the extent of global oceanic anoxia in deep time. Multiple studies have examined whether primary calcium carbonates can directly capture seawater δ238U and whether bulk measurements of recent and ancient carbonates preserve seawater U isotope signatures. Here we assess the role of diagenesis in altering δ238U signatures in carbonates sediments that have a primary calcitic mineralogy at the Paleocene-Eocene Thermal Maximum (PETM), an interval with rapid global warming and oceanic deoxygenation at ∼56 million years ago. Although primary abiotic and biogenic calcium carbonates (aragonite and calcite) can directly capture seawater δ238U with small offsets (1 ppm vs. <0.1 ppm), δ238U in calcite should be even more susceptible to diagenesis than that in aragonite. We find strong evidence of this effect in analysis of δ238U in PETM shallow-water carbonate sediments from Drilling Project (ODP) Hole 871C (Limalok Guyot, Pacific Ocean). Our results reveal large fluctuations in bulk carbonate δ238U from −0.69 to +0.71‰ around the PETM boundary but consistently heavier δ238U (between −0.14 and +0.47‰) than modern seawater outside of this interval. The significantly lighter δ238U values than modern seawater were interpreted to result from the operation of a Mn oxide shuttle. The heavier δ238U values are most likely caused by authigenic reductive accumulation of U(IV) in pore waters below the sediment-water interface. We found that carbonate δ238U values higher than modern seawater tend to increase with increasing U/Ca. This relationship is well-explained by an authigenic reductive accumulation model that simply assumes addition to primary calcite during diagenesis of calcitic cements containing isotopically heavier U(IV). Our work confirms expectations that δ238U in primary calcite is more susceptible to the amount of diagenetic cementation compared to primary aragonite, and that variations of δ238U in carbonate sediments with a primary calcitic mineralogy would more dominantly reflect the local redox state of depositional and early diagenetic environments. It is essential to identify the original carbonate mineralogy, the diagenetic history, and constrain the redox state of local deposition environments of sedimentary carbonate rocks when applying bulk carbonate δ238U as a global proxy for oceanic anoxia in deep time

Questioning Classic Patient Classification Techniques in Gait Rehabilitation: Insights from Wearable Haptic Technology

Classifying stroke survivors based on their walking abilities is an important part of the gait rehabilitation process. It can act as powerful indicator of function and prognosis in both the early days after a stroke and long after a survivor receives rehabilitation. This classification often relies solely on walking speed; a quick and easy measure, with only a stopwatch needed. However, walking speed may not be the most accurate way of judging individual’s walking ability. Advances in technology mean we are now in a position where ubiquitous and wearable technologies can be used to elicit much richer measures to characterise gait. In this paper we present a case study from one of our studies, where within a homogenous group of stroke survivors (based on walking speed classification) important differences in individual results and the way they responded to rhythmic haptic cueing were identified during the piloting of a novel gait rehabilitation technique

Modelling the binding mode of macrocycles: Docking and conformational sampling

Drug discovery is increasingly tackling challenging protein binding sites regarding molecular recognition and druggability, including shallow and solvent-exposed protein-protein interaction interfaces. Macrocycles are emerging as promising chemotypes to modulate such sites. Despite their chemical complexity, macrocycles comprise important drugs and offer advantages compared to non-cyclic analogs, hence the recent impetus in the medicinal chemistry of macrocycles. Elaboration of macrocycles, or constituent fragments, can strongly benefit from knowledge of their binding mode to a target. When such information from X-ray crystallography is elusive, computational docking can provide working models. However, few studies have explored docking protocols for macrocycles, since conventional docking methods struggle with the conformational complexity of macrocycles, and also potentially with the shallower topology of their binding sites. Indeed, macrocycle binding mode prediction with the mainstream docking software GOLD has hardly been explored. Here, we present an in-depth study of macrocycle docking with GOLD and the ChemPLP scores. First, we summarize the thorough curation of a test set of 41 protein-macrocycle X-ray structures, raising the issue of lattice contacts with such systems. Rigid docking of the known bioactive conformers was successful (three top ranked poses) for 92.7% of the systems, in absence of crystallographic waters. Thus, without conformational search issues, scoring performed well. However, docking success dropped to 29.3% with the GOLD built-in conformational search. Yet, the success rate doubled to 58.5% when GOLD was supplied with extensive conformer ensembles docked rigidly. The reasons for failure, sampling or scoring, were analyzed, exemplified with particular cases. Overall, binding mode prediction of macrocycles remains challenging, but can be much improved with tailored protocols. The analysis of the interplay between conformational sampling and docking will be relevant to the prospective modelling of macrocycles in general