Civil Rights - Americans with Disabilities Act of 1990 - Prohibition of Public Entity Discrimination against Qualified Individual with a Disability - Application to Inmates in State Prisons

The United States Supreme Court held that Title II of the Americans with Disabilities Act of 1990, which prohibits a public entity from discriminating against a qualified individual with a disability on account of that individual\u27s disability, applies to inmates in state prisons. Pa. Dep\u27t of Corrections v. Yeskey, 118 S.Ct. 1952 (1998)

The Dopamine D3 Receptor Antagonist VK4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity in Mice

In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of OUD. More specifically, D3R antagonists have been shown by us and others to attenuate the abuse-related behavioral effects of opioids without producing adverse side effects associated with nonselective D2-like receptor antagonists. We previously examined the effects of the selective D3R antagonist PG01037 (133-fold selectivity for D3R vs. D2R) using drug-induced hyperactivity as a behavioral proxy for DA release within the nucleus accumbens. Interestingly, we found that PG01037 enhances cocaine-induced hyperlocomotion while it attenuates morphine-induced hyperlocomotion in mice. The potentiation of psychostimulant effects could confound the potential use of D3R antagonists for the treatment of OUD, since many opioid users co-abuse stimulants such as cocaine. However, recent studies with more selective D3R antagonists found that they do not enhance certain effects of cocaine while still reducing opioid effects. It is currently unknown what impact these highly-selective D3R antagonists will have on cocaine-induced hyperactivity and/or dopamine neurotransmission. The purpose of this study was to examine the impact of pretreatment with the novel and highly selective D3R antagonist VK4-40 (250-fold selectivity for D3R vs. D2R) on cocaine- and morphine-induced hyperlocomotion in mice

Characterization of the cofactor-binding site in the SPOUT-fold methyltransferases by computational docking of S-adenosylmethionine to three crystal structures

BACKGROUND: There are several evolutionarily unrelated and structurally dissimilar superfamilies of S-adenosylmethionine (AdoMet)-dependent methyltransferases (MTases). A new superfamily (SPOUT) has been recently characterized on a sequence level and three structures of its members (1gz0, 1ipa, and 1k3r) have been solved. However, none of these structures include the cofactor or the substrate. Due to the strong evolutionary divergence and the paucity of experimental information, no confident predictions of protein-ligand and protein-substrate interactions could be made, which hampered the study of sequence-structure-function relationships in the SPOUT superfamily. RESULTS: We used the computational docking program AutoDock to identify the AdoMet-binding site on the surface of three MTase structures. We analyzed the sequence divergence in two distinct lineages of the SPOUT superfamily in the context of surface features and preferred cofactor binding mode to propose specific function for the conserved residues. CONCLUSION: Our docking analysis has confidently predicted the common AdoMet-binding site in three remotely related proteins structures. In the vicinity of the cofactor-binding site, subfamily-conserved grooves were identified on the protein surface, suggesting location of the target-binding/catalytic site. Functionally important residues were inferred and a general reaction mechanism, involving conformational change of a glycine-rich loop, was proposed

Signatures of the disk-jet coupling in the Broad-line Radio Quasar 4C+74.26

Here we explore the disk-jet connection in the broad-line radio quasar 4C+74.26, utilizing the results of the multiwavelength monitoring of the source. The target is unique in that its radiative output at radio wavelengths is dominated by a moderately-beamed nuclear jet, at optical frequencies by the accretion disk, and in the hard X-ray range by the disk corona. Our analysis reveals a correlation (local and global significance of 96\% and 98\%, respectively) between the optical and radio bands, with the disk lagging behind the jet by $250 \pm 42$ days. We discuss the possible explanation for this, speculating that the observed disk and the jet flux changes are generated by magnetic fluctuations originating within the innermost parts of a truncated disk, and that the lag is related to a delayed radiative response of the disk when compared with the propagation timescale of magnetic perturbations along relativistic outflow. This scenario is supported by the re-analysis of the NuSTAR data, modelled in terms of a relativistic reflection from the disk illuminated by the coronal emission, which returns the inner disk radius $R_{\rm in}/R_{\rm ISCO} =35^{+40}_{-16}$. We discuss the global energetics in the system, arguing that while the accretion proceeds at the Eddington rate, with the accretion-related bolometric luminosity $L_{\rm bol} \sim 9 \times 10^{46}$ erg s$^{-1}$ $\sim 0.2 L_{\rm Edd}$, the jet total kinetic energy $L_\textrm{j} \sim 4 \times 10^{44}$ erg s$^{-1}$, inferred from the dynamical modelling of the giant radio lobes in the source, constitutes only a small fraction of the available accretion power.Comment: 9 pages and 6 figures, ApJ accepte

Two-step phosphorylation of Ana2 by Plk4 is required for the sequential loading of Ana2 and Sas6 to initiate procentriole formation.

The conserved process of centriole duplication requires Plk4 kinase to recruit and promote interactions between Sas6 and Sas5/Ana2/STIL (respective nomenclature of worms/flies/humans). Plk4-mediated phosphorylation of Ana2/STIL in its conserved STAN motif has been shown to promote its interaction with Sas6. However, STAN motif phosphorylation is not required for recruitment of Ana2 to the centriole. Here we show that in Drosophila, Ana2 loads onto the site of procentriole formation ahead of Sas6 in a process that also requires Plk4. However, whereas Plk4 is first recruited to multiple sites around the ring of zone II at the periphery of the centriole, Ana2 is recruited to a single site in telophase before Plk4 becomes finally restricted to this same single site. When we over-ride the auto-destruction of Plk4, it remains localized to multiple sites in the outer ring of the centriole and, if catalytically active, recruits Ana2 to these sites. Thus, it is the active form of Plk4 that promotes Ana2's recruitment to the centriole. We now show that Plk4 phosphorylates Ana2 at a site other than the STAN motif, which lies in a conserved region we term the ANST (ANa2-STil) motif. Mutation of this site, S38, to a non-phosphorylatable residue prevents the procentriole loading of Ana2 and blocks centriole duplication. Thus the initiation of procentriole formation requires Plk4 to first phosphorylate a single serine residue in the ANST motif to promote Ana2's recruitment and, secondly, to phosphorylate four residues in the STAN motif enabling Ana2 to recruit Sas6. We discuss these findings in light of the multiple Plk4 phosphorylation sites on Ana2

Chl a fluorescence and proteomics reveal protection of the photosynthetic apparatus to dehydration in tolerant but not in susceptible wheat cultivars

Seedlings of spring wheat (Triticum aestivum L.) cultivars, Ethos and Zebra, differing in drought tolerance were dehydrated to reach a water saturation deficit (WSD) in leaves ~15, 30, and 50 %. Ethos, the drought tolerant cultivar, dried slower in comparison with Zebra and regrew in 70 % upon rehydration. The effect of dehydration on photosystem Seedlings of spring wheat (Triticum aestivum L.) cultivars, Ethos and Zebra, differing in drought tolerance were dehydrated to reach a water saturation deficit (WSD) in leaves ~15, 30, and 50 %. Ethos, the drought tolerant cultivar, dried slower in comparison with Zebra and regrew in 70 % upon rehydration. The effect of dehydration on photosystem II was evaluated by Chl a fluorescence (OJIP transients). The inflection point of double normalized curves (ΔWOJ) calculated for Ethos was negative for seedlings with 15 % WSD, nearly zero for those with 30 % WSD, and about +0.05 for those with 50 % WSD. In case of Zebra, the 15 % WSD already induced a positive ΔWOJ (+0.05) and 50 % WSD maximized it to +0.10, which is a sign of drought susceptibility. The proteomic studies revealed, that among identified 850 spots, 80 protein spots were differentially expressed during dehydration. The differentially expressed proteins of the drought tolerant cultivar indicated the protection of the photosynthetic apparatus and proteome rebuilding in response to drought. In the drought susceptible cultivar, protection of proteins and membranes and partial scavenging reactive oxygen species appeared.Bio-organic Synthesi

Neuroactivational and Behavioral Correlates of Psychosocial Stress-Induced Cocaine Seeking in Rats

A prominent feature of cocaine abuse is a high risk of relapse even despite prolonged periods of abstinence. Psychosocial stress is thought to be a major contributor to the onset of cocaine craving and relapse in human substance abusers, yet most preclinical models of stress-induced relapse employ physical stressors (e.g., unpredictable footshock) or pharmacological stressors (e.g., yohimbine to elicit a drug seeking response) and do not rely upon psychosocial stress per se. Importantly, social stressors are well known to activate distinct neural circuits within the brain as compared to other stressors. It is therefore possible that currently available animal models of stress-induced drug relapse do not fully engage the neuroanatomical, neurochemical, and/or molecular substrates that are recruited specifically by psychosocial stressors to produce drug-seeking behavior. Social defeat stress has been proposed as an ethologically valid psychosocial stressor in rodents that more closely models the forms of psychosocial stress that precede relapse episodes in drug abusers. We previously developed a model of psychosocial stress-induced reinstatement in rats in which cocaine seeking is elicited via exposure to a cue signaling impending social defeat stress. Using this model, we discovered that predilection towards displaying active coping behaviors during prior social defeat stress exposures was positively correlated with levels of psychosocial stress-induced cocaine seeking. The present study aimed to expand upon these initial findings by assessing and comparing patterns of neural activation in key brain areas during stress induced cocaine seeking that is triggered by psychosocial or footshock stress predictive cues

Suppression of Scant Identifies Endos as a Substrate of Greatwall Kinase and a Negative Regulator of Protein Phosphatase 2A in Mitosis

Protein phosphatase 2A (PP2A) plays a major role in dephosphorylating the targets of the major mitotic kinase Cdk1 at mitotic exit, yet how it is regulated in mitotic progression is poorly understood. Here we show that mutations in either the catalytic or regulatory twins/B55 subunit of PP2A act as enhancers of gwl^(Scant), a gain-of-function allele of the Greatwall kinase gene that leads to embryonic lethality in Drosophila when the maternal dosage of the mitotic kinase Polo is reduced. We also show that heterozygous mutant endos alleles suppress heterozygous gwl^(Scant); many more embryos survive. Furthermore, heterozygous PP2A mutations make females heterozygous for the strong mutation polo¹¹ partially sterile, even in the absence of gwl^(Scant). Heterozygosity for an endos mutation suppresses this PP2A/polo¹¹ sterility. Homozygous mutation or knockdown of endos leads to phenotypes suggestive of defects in maintaining the mitotic state. In accord with the genetic interactions shown by the gwl^(Scant) dominant mutant, the mitotic defects of Endos knockdown in cultured cells can be suppressed by knockdown of either the catalytic or the Twins/B55 regulatory subunits of PP2A but not by the other three regulatory B subunits of Drosophila PP2A. Greatwall phosphorylates Endos at a single site, Ser68, and this is essential for Endos function. Together these interactions suggest that Greatwall and Endos act to promote the inactivation of PP2A-Twins/B55 in Drosophila. We discuss the involvement of Polo kinase in such a regulatory loop