G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory. GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α-helices spanning the cell membrane, and forming the majority of the known ortho- or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently marketed drugs. GPCRs activate one or more of the four G protein families (Gq/11 , Gi/o , Gs and G12/13 ) and/or ß-arrestin. About a third of the non-olfactory GPCRs are referred to as orphan receptors which means that their endogenous agonist(s) have not yet been found or firmly established. In this MiniReview, we focus on the orphan GPR139 receptor, for which the aromatic amino acids L-Trp and L-Phe as well as ACTH/α-MSH-related peptides have been proposed as endogenous agonists. GPR139 has been reported to activate several G protein pathways of which Gq/11 is the primary one. The receptor shows the highest expression in the striatum, thalamus, hypothalamus, pituitary and habenula of the human, rat and mouse CNS. We review the surrogate agonists and antagonists that have been published as well as the agonist pharmacophore and binding site. Finally, the putative physiological functions and therapeutic potential are outlined.

An increasing body of evidence suggests that aggregation-prone proteins associated with various neurodegenerative diseases synergistically promote their mutual aggregation, leading to the co-occurrence of multiple neurodegenerative diseases in the same patient. Here we investigated teh molecular basis of synergistic interactions between the two pathological proteins, tau and α-synuclein, using various biophysical techniques including transmission electron microscopy (TEM), circular dichroism (CD), and solution and solid-state NMR. Our biophysical analyses of α-synuclein aggregation in the absence and presence of tau reveal that tau monomers promote the formation of α-synuclein oligomers and subsequently fibril formation. Solution NMR results also indicate that monomeric forms of tau selectively interact with the C-terminal region of the α-synuclein monomer, accelerating α-synuclein aggregation. In addition, a combined use of TEM and solid-state NMR spectroscopy reveals that the synergistic interactions lead to the formation of toxic α-synuclein aggregates with a distinct morphology and molecular conformation. The filamentous α-synuclein aggregates as well as α-synuclein monomers were also able to induce tau aggregation.

We evaluate fine particulate matter (PM2.5) exposure-response models to propose a consistent set of global effect factors for product and policy assessments across spatial scales and across urban and rural environments. Relationships among exposure concentrations and PM2.5-attributable health effects largely depend on location, population density, and mortality rates. Existing effect factors build mostly on an essentially linear exposure-response function with coefficients from the American Cancer Society study. In contrast, the Global Burden of Disease analysis offers a nonlinear integrated exposure-response (IER) model with coefficients derived from numerous epidemiological studies covering a wide range of exposure concentrations. We explore the IER, additionally provide a simplified regression as a function of PM2.5 level, mortality rates, and severity, and compare results with effect factors derived from the recently published global exposure mortality model (GEMM). Uncertainty in effect factors is dominated by the exposure-response shape, background mortality, and geographic variability. Our central IER-based effect factor estimates for different regions do not differ substantially from previous estimates. However, IER estimates exhibit significant variability between locations as well as between urban and rural environments, driven primarily by variability in PM2.5 concentrations and mortality rates. Using the IER as the basis for effect factors presents a consistent picture of global PM2.5-related effects for use in product and policy assessment frameworks.

This study was aimed at evaluating the regional changes in the cerebral metabolic rate of oxygen (CMRO2) in relation to the cerebral blood flow (CBF) in the bilateral common carotid artery occlusion (BCAO) rat model. Ligation of the bilateral common carotid arteries (or a sham operation in control animals) was performed in 10-week-old male Wistar rats. O-15 PET images were acquired in the subacute phase (1 week after the surgery) and chronic phase (6 weeks after the surgery) with the animals under anesthesia, using a small-animal PET system and the O-15 gas steady-state inhalation method with arterial blood sampling developed in our previous study. Histopathological staining by Klüver-Barrera method and immunocytochemistry staining by glial fibrillary acidic protein were performed. Cognitive function was tested by using the apparatus of Y-maze. Significantly lower CBF and higher oxygen extraction fraction were observed in broad areas of the cerebrum in the subacute phase in the BCAO rats, with recovery in the chronic phase. A stable decrease of the CMRO2 in the subacute phase of arterial occlusion and later was observed in the BCAO rat model, mainly in the anterior cerebral artery territory. Atrophy and rarefaction of corpus callosum were found in the BCAO in the chronic phase. Activity of astrocytes in the BCAO was prominent in the both phases. Working memory was impaired in the BCAO in the chronic phase. Regional changes in cerebral perfusion and oxygen metabolism in the subacute and chronic phases of arterial occlusion were clarified in a rat model of BCAO by quantitative O-15 PET based on the steady-state method.

Aniseikonia has demonstrated to deteriorate the binocular function, however its impact on the accommodative response remains unknown. The present study aimed to analyze the effects of artificially-induced aniseikonia, using afocal magnifiers, on the dynamics of the accommodative response. The magnitude and variability of the accommodative response were objectively measured in 20 young healthy subjects by a binocular open-field autorefractometer. Participants observed a static stimulus for 90 s, under seven degrees of aniseikonia (0%, 1%, 3%, 5%, 8%, 10% and 12%), and at three distances (500 cm, 40 cm and 20 cm). Complementarily, near stereoacuity, and perceived levels of fatigue and visual discomfort were assessed. The degree of induced aniseikonia was associated with the magnitude of the accommodative response (p < 0.001, ηp2 = 0.329), obtaining a statistically significant reduced accommodative lag for the induced aniseikonia conditions of 8%, 10% and 12% in comparison to the control condition at 40 cm (p-corrected = 0.019, <0.001 and 0.013, respectively) and at 20 cm (p-corrected < 0.001, <0.001 and 0.003, respectively). However, the degree of induced aniseikonia did not reveal any effect on the variability of accommodation (p > 0.05). We also found a decline in near stereoacuity and an increment of visual symptomatology when inducing aniseikonia (p < 0.05). Our data evidenced that greater degrees of induced aniseikonia cause a heightened accommodative response. These preliminary findings may be of relevance for patients undergoing cataract or refractive surgery procedures in which aniseikonia can be induced.

Listeria monocytogenes is riboflavin auxotrophic, but it has two genes envisaged to transform riboflavin into FMN and FAD after its uptaked by specialized transporters. One encodes a bifunctional type I FAD synthase (FADS, herein LmFADS-1), while the other produces a protein similar to type I at the FMN:ATP adenylyltransferase (FMNAT) site but with a shorter C-terminal that lacks any riboflavin kinase (RFK) motif. This second protein is rare among bacteria and has been named FADS type II (LmFADS-2). Here we present a biochemical and biophysical study of LmFADS-1 and LmFADS-2 by integrating kinetic and thermodynamic data together with sequence and structural prediction methods to evaluate their occurrence in Listeria, as well as their function and molecular properties. Despite LmFADS-1 similarities to other type I FADSs, (i) its RFK activity has not riboflavin substrate inhibition and occurs under reducing and oxidizing conditions, (ii) its FMNAT activity requires strong reducing environment, and (iii) binding of reaction products, but not substrates, favors binding of the second ligand. LmFADS-2 produces FAD under oxidizing and reducing environments, but its C-terminus module function remains unknown. Listeria species conserve both FADSs, being sequence identity high within L. monocytogenes strains. Our data exemplify alternative strategies for FMN and FAD biosynthesis and homeostasis, envisaging that in Listeria two FADSs might be required to fulfill the supply of flavin cofactors under niches that can go from saprophytism to virulence. As FADSs are attractive antimicrobial targets, understanding of FADSs traits in different species is essential to help in the discovery of specific antimicrobials.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and authors. The authors reported that the paper had been submitted without permission of all authors (specifically Professor Wu). When asked to respond to alleged image manipulation by ‘Hoya camphorifolia’ in Fig. 8B and western blots, they responded that they regret the mistakes in figure 8B and that their technical collaborators could not provide the original images of the Western blots in this paper. The authors apologise for any misconceptions that this paper may have resulted in.

The acute toxicity of organophosphorus-based compounds is primarily a result of acetylcholinesterase inhibition in the central and peripheral nervous systems. The resulting cholinergic crisis manifests as seizure, paralysis, respiratory failure and neurotoxicity. Though overstimulation of muscarinic receptors is the mechanistic basis of central organophosphorus (OP) toxicities, short-term changes in synapse physiology that precede OP-induced seizures have not been investigated in detail. To study acute effects of OP exposure on synaptic function, field excitatory postsynaptic potentials (fEPSPs) were recorded from Schaffer collateral synapses in the mouse hippocampus CA1 stratum radiatum during perfusion with various OP compounds. Administration of the OPs paraoxon, soman or VX rapidly and stably depressed fEPSPs via a presynaptic mechanism, while the non-OP proconvulsant tetramethylenedisulfotetramine had no effect on fEPSP amplitudes. OP-induced presynaptic long-term depression manifested prior to interictal spiking, occurred independent of recurrent firing, and did not require NMDA receptor currents, suggesting that it was not mediated by activity-dependent calcium uptake. Pharmacological dissection revealed that the presynaptic endocannabinoid type 1 receptor (CB1R) as well as postsynaptic M1 and M3 muscarinic acetylcholine receptors were necessary for OP-LTD. Administration of CB1R antagonists significantly reduced survival in mice after a soman challenge, revealing an acute protective role for endogenous CB1R signaling during OP exposure. Collectively these data demonstrate that the endocannabinoid system alters glutamatergic synaptic function during the acute response to OP acetylcholinesterase inhibitors.

Immobilization of protein, compared to the use of free protein, offers improved stability, easy separation and continuous reusability. However, the classic routes for protein immobilization, based on non-specific adsorption, often negatively affect protein functionality. In this study, EctP1 peptide was explored as a novel short fusion tag for non-covalent adsorption on unmodified solid surfaces, silica and titania. A fusion of EctP1 with bovine carbonic anhydrase (BCA) was employed to investigate the optimal binding conditions that could diminish the nonspecific adsorption of Escherichia coli proteins. The stable binding of BCA-EctP1 on titania was observed in the pH range of 2-9, while the stable binding on silica was in the pH range 6-9. Moreover, the immobilized BCA-EctP1 on silica and titania particles showed enhanced thermal and storage stability and retained 95% of its residual activity after 5 uses. We further demonstrated the merits of the noncovalent immobilization of EctP1 fusion proteins to silica and titania in the recovery of the bound proteins. Interestingly, monomeric arginine showed better recovery yield of EctP1 fusion proteins (about 78-84%), compared to the recovery yield by the salts, NaCl and MgCl2 (about 30-51%). Using BCA and monomeric red fluorescent protein (mRFP) as model proteins, the EctP1 fusion proteins were released in a biologically active form with approximately 80% recovery and 93% purity. Our approach is a simple and reproducible technique for direct immobilization of recombinant proteins from E. coli lysates on solid supports, with the potential high-purity recovery of recombinant proteins.

One of the key behavioral phenotypes in infancy are different temperament traits, and certain early life temperament traits have been shown to precede later mental health problems. Differences in the gut microbiota composition (GMC) have been suggested to link with neurodevelopment. For example, toddler temperament traits have been found to associate with differences in GMC; however, studies in infants are lacking although infancy is a rapid period of neurodevelopment as well as GM development. Thus, we aimed to investigate association between infant GMC and temperament.

Traditional Chinese medicine Celastrus orbiculatus Thunb (C. orbiculatus) with peel and seeds is mainly composed of flavonoids, sesquiterpenes and tripenes. According to the Traditional Chinese medicine standard of Liaoning province (2009), it has been long used to invigorate blood circulation.

Inflammation plays a crucial role in the progression of atherosclerotic plaques. The aim of the study was to investigate serum levels and expression of Interleukin-33 (IL-33) and ST2 receptor in atherosclerotic plaques and to analyze correlation with the type of the carotid plaques in patients with carotid disease.

This study aims to investigate the apoptotic effect of Doxorubicin and its nano-formulated form (Doxil) on oral squamous cell carcinoma CAL-27 cells.

Hypoxia is one of the critical features in solid tumors, and hypoxia-targeting contrast agents (CAs) could greatly enhance the magnetic resonance imaging (MRI) of tumors by increasing its specificity and providing more diagnosis information. In this article, an internally hydroxy dendrimer of high molecular weight was facilely synthesized by "epoxy-amine" and "thiol-ene" reactions with a β-cyclodextrin (β-CD) as the core, and a hypoxia-targeting dendritic contrast agent (DCA) was synthesized through conjugating Gd chelates onto the internal hydroxyl groups and grafting the hypoxia-targeting groups sulfonamides and zwitterionic groups onto the exterior groups of the dendrimer. The zwitterionic surface without disturbance from internally conjugated CAs could reduce unspecific cellular uptake by normal cells, while the hypoxia-targeting group mediate the cellular uptake by hypoxic tumor cells. The in vitro and in vivo study showed that the hypoxia-targeting DCA could be selectively uptake by hypoxic cancer cells and greatly enhance the MRI of orthotopic breast tumor in a mouse model.

Male genitals have repeatedly evolved left-right asymmetries, and the causes of such evolution remain unclear. The Drosophila nannoptera group contains four species, among which three exhibit left-right asymmetries of distinct genital organs. In the most studied species, Drosophila pachea, males display asymmetric genital lobes and they mate right-sided on top of the female. Copulation position of the other species is unknown.

An eukaryotic translation elongation factor-2 (eEF-2) plays an important role in protein synthesis, however, investigation on its role in abiotic stress responses is limited. A cold responsive eEF2 named as MfEF2 was isolated from yellow-flowered alfalfa [Medicago sativa subsp. falcata (L.) Arcang, thereafter M. falcata], a forage legume with great cold tolerance, and transgenic tobacco (Nicotiana tabacum L.) plants overexpressing MfEF2 were analyzed in cold tolerance and proteomic profiling was conducted under low temperature in this study.

To determine whether magnetic resonance imaging (MRI)-detected extramural vascular invasion (mrEMVI) status is associated with quantitative perfusion parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) in rectal cancer.

Obesity has been associated with gene methylation regulation. Recent studies have shown that epigenetic signature plays a role in metabolic homeostasis after Roux-en Y gastric bypass (RYGB). To conduct a genome-wide epigenetic analysis in peripheral blood to investigate whether epigenetic changes following RYGB stem from weight loss or the surgical procedure per se.

Despite growing evidence of a critical link between neuromodulation technologies and neuroplastic recovery, the underlying mechanisms of these technologies remain elusive.

The immune system is likely involved in the pathophysiology of Meniere's disease (MD). However, its role of patients with MD has not been well studied. Given that histamine H4 receptors are highly expressed in immune system, we tested the hypothesis that histamine H4 receptor gene polymorphisms are a potential contributor to the risk of MD.