Dopamine D4 receptor activation counteracts nigrostriatal pathway activation by morphine: relevance in drug addiction.

Morphine induces dopamine release in the caudate putamen (CPu), which promotes stereotyped behavior and habit learning for drug-seeking and –taking. Nigrostriatal pathway stimulation by morphine is due to a removal of tonic inhibition arising from SNr GABA interneurons on SNc dopaminergic neurons through the mu opioid receptor (MOR). Long-term morphine exposure produces a series of adaptations in SNc dopamine neurons, which affect neuron excitability and dopamine output to CPu. We have previously shown that dopamine D4 receptor (D4R) stimulation counteracts acute and chronic morphine-induced accumulation of several transcription factors in the CPu (Gago et al., 2011 Brain Res.). Since D4R is expressed in the SNr (Rivera et al., Brain Res. 2003), we postulate that a functional D4R-MOR interaction at the midbrain level could exists. We have investigated the role of D4R in the morphine-induced nigroestriatal dopamine metabolism in the rat brain using biochemical and immunohistochemical techniques. We also have studied the influence of D4R on morphine-induced morphological changes in SNc dopamine neurons using both immunohistochemical and image analysis techniques. Finally, we examined a possible underlying mechanism of the D4R-MOR interaction at the SN level using in vitro quantitative receptor autoradiography. We have found that D4R activation restores dopamine metabolism in the nigroestriatal pathway after acute morphine treatment and prevents morphine-induced rise of tyroxine hydroxylase and dopamine transporter. Rats receiving a continuous treatment of morphine (6 days) showed SNc dopamine neurons with smaller size and higher circularity index compared with the controls animals. These morphine-induced morphological adaptatives changes were prevented when a D4R agonist (PD168,077) was administered at the same time with morphine. Autoradiographic studies demonstrated that the D4R agonist reduce the affinity of MOR. The present study provides evidence for the existence of a fully blocking effect of the D4R on the activation of dopaminergic nigroestriatal pathway by morphine.Financiación: P09-CVI- 4702 (Proyecto de Excelencia de la Junta de Andalucía

Population History and Gene Divergence in Native Mexicans Inferred from 76 Human Exomes.

Native American genetic variation remains underrepresented in most catalogs of human genome sequencing data. Previous genotyping efforts have revealed that Mexico's Indigenous population is highly differentiated and substructured, thus potentially harboring higher proportions of private genetic variants of functional and biomedical relevance. Here we have targeted the coding fraction of the genome and characterized its full site frequency spectrum by sequencing 76 exomes from five Indigenous populations across Mexico. Using diffusion approximations, we modeled the demographic history of Indigenous populations from Mexico with northern and southern ethnic groups splitting 7.2 KYA and subsequently diverging locally 6.5 and 5.7 KYA, respectively. Selection scans for positive selection revealed BCL2L13 and KBTBD8 genes as potential candidates for adaptive evolution in Rarámuris and Triquis, respectively. BCL2L13 is highly expressed in skeletal muscle and could be related to physical endurance, a well-known phenotype of the northern Mexico Rarámuri. The KBTBD8 gene has been associated with idiopathic short stature and we found it to be highly differentiated in Triqui, a southern Indigenous group from Oaxaca whose height is extremely low compared to other Native populations

Epiparasitic plants specialized on arbuscular mycorrhizal fungi

Over 400 non-photosynthetic species from 10 families of vascular plants obtain their carbon from fungi and are thus defined as myco-heterotrophs. Many of these plants are epiparasitic on green plants from which they obtain carbon by 'cheating' shared mycorrhizal fungi. Epiparasitic plants examined to date depend on ectomycorrhizal fungi for carbon transfer and exhibit exceptional specificity for these fungi, but for most myco-heterotrophs neither the identity of the fungi nor the sources of their carbon are known. Because many myco-heterotrophs grow in forests dominated by plants associated with arbuscular mycorrhizal fungi (AMF; phylum Glomeromycota), we proposed that epiparasitism would occur also between plants linked by AMF. On a global scale AMF form the most widespread mycorrhizae, thus the ability of plants to cheat this symbiosis would be highly significant. We analysed mycorrhizae from three populations of Arachnitis uniflora (Corsiaceae, Monocotyledonae), five Voyria species and one Voyriella species (Gentianaceae, Dicotyledonae), and neighbouring green plants. Here we show that non-photosynthetic plants associate with AMF and can display the characteristic specificity of epiparasites. This suggests that AMF mediate significant inter-plant carbon transfer in nature

When is forgetting not forgetting? A discursive analysis of differences in forgetting talk between adults with cystic fibrosis with different levels of adherence to nebulizer treatments

Forgetting is often cited as a reason why people struggle to adhere to treatments for chronic conditions. Interventions have tried to improve forgetting behavior using reminders. We used a discursive psychological approach to explore differences in how high and low adherers constructed forgetting their nebulizer treatments for cystic fibrosis. Interviews were conducted with 18 adults from a cystic fibrosis center in the United Kingdom. High adherers constructed forgetting treatments as occasional lapses in automaticity and temporary lapses in memory that they found easy to repair. Low adherers utilized forgetting to normalize more consistent nonadherence to treatments. However, it is important to contextualize forgetting as a discursive resource that helped these participants to negotiate moral discourses around adherence to treatment that reminder interventions cannot address; we therefore recommend a more behavioral, patient-focused, theory-driven approach to intervention development

Laboratory-Based Prospective Surveillance for Community Outbreaks of Shigella spp. in Argentina

Background: To implement effective control measures, timely outbreak detection is essential. Shigella is the most common cause of bacterial diarrhea in Argentina. Highly resistant clones of Shigella have emerged, and outbreaks have been recognized in closed settings and in whole communities. We hereby report our experience with an evolving, integrated, laboratory-based, near real-time surveillance system operating in six contiguous provinces of Argentina during April 2009 to March 2012. Methodology To detect localized shigellosis outbreaks timely, we used the prospective space-time permutation scan statistic algorithm of SaTScan, embedded in WHONET software. Twenty three laboratories sent updated Shigella data on a weekly basis to the National Reference Laboratory. Cluster detection analysis was performed at several taxonomic levels: for all Shigella spp., for serotypes within species and for antimicrobial resistance phenotypes within species. Shigella isolates associated with statistically significant signals (clusters in time/space with recurrence interval ≥365 days) were subtyped by pulsed field gel electrophoresis (PFGE) using PulseNet protocols. Principal Findings In three years of active surveillance, our system detected 32 statistically significant events, 26 of them identified before hospital staff was aware of any unexpected increase in the number of Shigella isolates. Twenty-six signals were investigated by PFGE, which confirmed a close relationship among the isolates for 22 events (84.6%). Seven events were investigated epidemiologically, which revealed links among the patients. Seventeen events were found at the resistance profile level. The system detected events of public health importance: infrequent resistance profiles, long-lasting and/or re-emergent clusters and events important for their duration or size, which were reported to local public health authorities. Conclusions/Significance: The WHONET-SaTScan system may serve as a model for surveillance and can be applied to other pathogens, implemented by other networks, and scaled up to national and international levels for early detection and control of outbreaks

A Bacterial Shortcut to Amyloidosis

21 p.-10 fig.The synthetic bacterial prionoid RepA-WH1 causes a vertically transmissible amyloid proteinopathy in Escherichia coli that inhibits growth and eventually kills the cells. Recent in vitro studies show that RepA-WH1 builds pores through model lipid membranes, suggesting a possible mechanism for bacterial cell death. By comparing acutely (A31V) and mildly (ΔN37) cytotoxic mutant variants of the protein, we report here that RepA-WH1(A31V) expression decreases the intracellular osmotic pressure and compromise bacterial viability under either aerobic or anaerobic conditions. Both are effects expected from threatening membrane integrity and are in agreement with findings on the impairment by RepA-WH1(A31V) of the proton motive force (PMF)-dependent transport of ions (Fe3+) and ATP1 synthesis. Systems approaches reveal that, in aerobiosis, the PMF-independent respiratory dehydrogenase NdhII is induced in response to the reduction in intracellular levels of iron. While NdhII is known to generate H2O2 as a by-product of the autoxidation of its FAD cofactor, key proteins in the defense against oxidative stress (OxyR, KatE), together with other stress-resistance factors, are sequestered by co-aggregation with the RepA-WH1(A31V) amyloid. Our findings suggest a route for RepA-WH1 toxicity in bacteria: a primary hit of damage to the membrane, compromising bionergetics, triggers a stroke of oxidative stress, which is exacerbated due to the aggregation-dependent inactivation of enzymes and transcription factors that enable the cellular response to such injury. The proteinopathy caused by the prion-like protein RepA-WH1 in bacteria recapitulates some of the core hallmarks of human amyloid diseases.This work has been supported by grants from Spanish AEI / EU-FEDER (BIO2012-30852, BIO2015- 68730-R and CSD2009-00088) and CSIC (i-LINK0889) to R.G. We acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Mapping ultrafast dynamics of highly excited D2 + by ultrashort XUV pump-IR probe radiation

An ultrashort XUV laser pulse ionizes the D2 molecule creating an electronic and nuclear wave packet, with the dominant contributions from the 2sσg and 2pπu ionic states. A delayed interaction with a 780 nm IR field ejects the second electron, leading to the Coulomb explosion of the molecule, whose nuclear fragments, recorded in coincidence, map the dynamics associated to those two ionic excited states. By varying the orientation of the light polarization, one can control the molecular dynamics by modifying the ratio between the ionic states. Experimental and ab initio theoretical data are jointly reporte

UBVRI Light Curves of 44 Type Ia Supernovae

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U-B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ~40% intrinsic scatter compared to B-band.Comment: 84 authors, 71 pages, 51 tables, 10 figures. Accepted for publication in the Astronomical Journal. Version with high-res figures and electronic data at http://astron.berkeley.edu/~saurabh/cfa2snIa

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit