Dementia and hearing loss: A narrative review

Dementia and hearing loss are highly prevalent in older people. Both these conditions together increase complexities in all aspects of an individual’s care and management plan. There has been increasing research interest about the relationship between dementia and hearing loss in recent years. In this review we discuss the relationship between hearing loss and dementia, including hearing loss as a risk factor for dementia; the effects of dementia with hearing loss on affected persons’ quality of life and the care they receive; screening and available interventions; and opportunities for prevention. We also discuss dementia and hearing loss in the care home setting, as the majority of residents have either, or indeed both, dementia and/or hearing loss. Several mechanisms have been suggested for how hearing loss and dementia may be related but the evidence for how these may operate together is still unclear. Similarly, although it is to be hoped that the active identification and management of hearing problems may help to reduce the future development of cognitive impairment, evidence for this is still lacking

Spectroscopic study of local interactions of platinum in small [CexOy]Ptx ′ − clusters

Cerium oxide is a good ionic conductor, and the conductivity can be enhanced with oxygen vacancies and doping. This conductivity may play an important role in the enhancement of noble or coinage metal toward the water-gas shift reaction when supported by cerium oxide. The ceria-supported platinum catalyst in particular has received much attention because of higher activity at lower temperatures (LT) compared to the most common commercial LT-WGS catalyst. We have used a combination of anion photoelectron spectroscopy and density functional theory calculations to study the interesting molecular and electronic structures and properties of cluster models of ceria-supported platinum. [Ce$_{x}$O$_{y}$]Pt$_{x'}$ $^{-}$ (x,x$^{'}$=1,2y$\leq$2x$^{'}$) clusters exhibit evidence of ionic bonding possible because of the high electron affinity of Pt and the low ionization potential of cerium oxide clusters. In addition, Pt$^{-}$ is a common daughter ion resulting from photodissociation of [Ce$_{x}$O$_{y}$]Pt$_{x'}$ $^{-}$ clusters. Finally, several of the anion and neutral clusters have profoundly different structures. These features may play a role in the enhancement of catalytic activity toward the water-gas shift reaction

Strategic synthesis of [Cu2], [Cu4] and [Cu5] complexes: inhibition and triggering of ligand arm hydrolysis and self-aggregation by chosen ancillary bridges

The Schiff base ligand HL1 ({2,6-bis(allylimino)methyl}-4-methylphenol) having no coordinating donor arm has been examined for its reaction medium and ancillary bridge dependent reactivity for hierarchical family of CuII complexes. The ligand showed unique reactivity pattern toward CuII in solution. The bridging nature of in situ generated HO− ions in absence and presence of externally added carboxylates (RCOO−; R= CF3, C6H5 and CH3) has been utilized to produce complexes {[Cu2(µ–L2)2(H2O)]2[Cu2(µ–L2)2(H2O)2](ClO4)6} (1) (HL2 = 3-{(allylimino)methyl}-2-hydroxy-5-methylbenzaldehyde), [Cu4(µ4–O)(µ–L1)2(µ1,3–O2CCF3)4] (2), [Cu4(µ4–O)(µ–L1)2(µ1,3–O2CC6H5)4]∙H2O (3), [Cu5(µ3–OH)2(µ–L1)2(µ1,3–OAc)2(OAc)2(H2O)4][Cu5(µ3–OH)2(µ–L1)2(µ1,3–OAc)2(OAc)3(H2O)](ClO4)3∙2C2H5OH (4). Absence of carboxylate anions did not yield HO− ions in situ and triggered single ligand arm hydrolysis. The formation of tetra- and pentanuclear aggregates as well as ligand hydrolyzed dinulcear products has been rationalized to identify the possible roles of carboxylate anions in solution. Detailed characterization of the complexes in the solid state and in solution have been carried out using spectroscopic measurements, X-ray crystallography, variable temperature magnetic measurements and functional behavior. In MeOH solutions at 298 K, the complexes 1-4 showed catalytic oxidation of 3,5-di-tert-butyl catechol (3,5-DTBCH2) saturated with O2 of air

Lysophospholipid (LPA) receptors in GtoPdb v.2023.1

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [62, 23, 91, 144]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [46], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [91] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA1 [17, 80, 2] and LPA6 [128] are solved and indicate that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [17]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [92, 115]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [143]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding* assay [54]. LPA has been proposed to be a ligand for GPR35 [103], supported by a study revealing that LPA modulates macrophage function through GPR35 [60]. However chemokine (C-X-C motif) ligand 17 (CXCL17) is reported to be a ligand for GPR35/CXCR8 [85]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [96] and TRPA1 [65]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors

Lysophospholipid (LPA) receptors in GtoPdb v.2021.2

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [55, 19, 82, 129]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [40], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [82] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA1 is solved and indicates that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [13]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [83, 104]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [128]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding* assay [48]. LPA LPA has been proposed to be a ligand for GPCR35 [94], supported by a recent study revealing that LPA modulates macrophage function through GPR35 [54]. However chemokine (C-X-C motif) ligand 17 (CXCL17) is reported to be a ligand for GPR35/CXCR8 [76]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [87] and TRPA1 [58]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors

Lysophospholipid (LPA) receptors in GtoPdb v.2021.3

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [55, 19, 82, 129]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [40], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [82] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA1 is solved and indicates that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [13]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [83, 104]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [128]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding* assay [48]. LPA has been proposed to be a ligand for GPR35 [94], supported by a study revealing that LPA modulates macrophage function through GPR35 [54]. However chemokine (C-X-C motif) ligand 17 (CXCL17) is reported to be a ligand for GPR35/CXCR8 [76]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [87] and TRPA1 [58]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors

Lysophospholipid (LPA) receptors (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [54, 18, 80, 125]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [39], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA1 was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin [12]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA1 were measured using backscattering interferometry (pKd = 9) [81, 102]. Binding affinities were 77-fold lower than than values obtained using radioactivity [124]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα "shedding" assay [47]. LPA LPA has been proposed to be a ligand for GPCR35 [92], supported by a recent study revealing that LPA modulates macrophage function through GPR35 [53]. However CXCL17 is reported to be a ligand for GPR35/CXCR8 [74]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [85] and TRPA1 [57]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors

A family of [Cu2], [Cu4] and [Cu5] aggregates : alteration of reaction conditions, ancillary bridges and capping anions

The phenoxido-bridged [Cu2] complex [Cu2(μ-H4L1)(μ-OH)(μ1,3-NO3)(NO3)(OH2)]·H2O (1) and its hierarchical [Cu4] and [Cu5] assemblies [Cu4(μ-H4L1)2(μ-OH)2(μ1,3-ClO4)(OH2)2](ClO4)3·2H2O (2) and [Cu5(μ-H4L1)2(μ3-OH)2(μ1,3-O2CCF3)2(O2CCF3)2](CF3COO)2 (3) were obtained from the reactions of H5L1 (2,6-bis-{(1,3-dihydroxy-2-methylpropan-2-ylimino)methyl}-4-methylphenol) with three copper(ii) salts. The available NO3−, ClO4− and CF3COO− ions have been trapped for ‘spontaneous’ anion-directed ‘self-assembly’ reactions. All the synthesized complexes contain the [Cu2(μ-H4L1)(μ-OH)]2+ fragment, prone to assemble and crystallize [Cu4] and [Cu5] complexes under varying reaction conditions. They were characterized by UV-vis and IR spectroscopy, X-ray diffraction analysis and magnetic studies. A change from NO3− to ClO4− and CF3COO− results in different courses of reactions based on Cu2(μ-H4L1) fragments. Binding of NO3− provided 1 as an isolated [Cu2] complex by trapping the reactive fragment. In 2 a perchlorate ligand, in the μ1,3-binding mode, has been realized as a solitary support for the condensation of two Cu2(μ-H4L1) fragments. The {Cu5(μ3-OH)2(μ1,3-O2CCF3)2}6+ constellation in 3 contains five CuII centers with a unique Z-in distorted octahedral one at the central position. Binding of different anions to the copper(ii) centers controls the nuclearity of the reaction products and tuning of the self-aggregation process within the same ligand environment (μ-H4L1−). The magnetic properties of the compounds have been studied both experimentally and using DFT calculations, revealing moderate to strong antiferromagnetic coupling in all aggregates

Investigation of the Proteolytic Functions of an Expanded Cercarial Elastase Gene Family in Schistosoma mansoni

Schistosome parasites are a major cause of disease in the developing world. The larval stage of the parasite transitions between an intermediate snail host and a definitive human host in a dramatic fashion, burrowing out of the snail and subsequently penetrating human skin. This process is facilitated by secreted proteases. In Schistosoma mansoni, cercarial elastase is the predominant secreted protease and essential for host skin invasion. Genomic analysis reveals a greatly expanded cercarial elastase gene family in S. mansoni. Despite sequence divergence, SmCE isoforms show similar expression profiles throughout the S. mansoni life cycle and have largely similar substrate specificities, suggesting that the majority of protease isoforms are functionally redundant and therefore their expansion is an example of gene dosage. However, activity-based profiling also indicates that a subset of SmCE isoforms are activated prior to the parasite's exit from its intermediate snail host, suggesting that the protease may also have a role in this process

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice

Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCIassociated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 μM, KD = 1.3 nM; inactive at LPA1,3−6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI