The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.

Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

Evolution of threat response-related polymorphisms at the SLC6A4 locus in callitrichid primates.

Variation in an upstream repetitive region at the SLC6A4 locus, which encodes the serotonin transporter, is associated with anxiety-related behaviour in a few primate species, including humans and rhesus macaques, and has been suggested to be related to ecological adaptability among macaques. In this study, we investigate evolution of SLC6A4 polymorphisms associated with anxiety-related behaviour in common marmosets (Callithrix jacchus). Assaying variation in the SLC6A4 repeat region across 14 species in eight genera of callitrichid primates (marmosets and tamarins), we find large interspecific variation in the number of repeats present (24-43). The black tufted-ear marmoset (C. penicillata) has sequence polymorphisms similar to those found in the common marmoset, which is its sister species, and no other species has intraspecific variation at these sites. We conclude that, similar to humans and macaques, the functional polymorphism at SLC6A4 in common marmosets has a recent evolutionary origin, and that the anxiety-related allele is evolutionarily derived. Common/black tufted-ear marmosets and rhesus/bonnet macaques share high ecological adaptability and behavioural flexibility that we propose may be related to the maintenance of the polymorphism.

Spontaneous object recognition in capuchin monkeys: assessing the effects of sex, familiarization phase and retention delay.

The spontaneous object recognition (SOR) task is a versatile and widely used memory test that was only recently established in nonhuman primates (marmosets). Here, we extended these initial findings by assessing the performance of adult capuchin monkeys on the SOR task and three potentially intervening task parameters-object familiarization phase, retention delay and sex. In Experiment 1, after an initial 10-min familiarization period with two identical objects and a pre-established retention delay (0.5, 6 or 24 h), the capuchins preferentially explored a new rather than the familiar object during a 10-min test trial, regardless of delay length. In Experiment 2, the capuchins were again exposed to two identical objects (but now for 10 or 20 min), then a 30-min retention delay and a 10-min test trial. An exploratory preference for the new over the familiar item was not affected by the length of the familiarization interval, possibly because overall exploration remained the same. However, the amount of initial object exploration was not related to task performance, and both males and females performed similarly on the SOR task with a 10-min familiarization, 30-min delay and 10-min test trial. Therefore, male and female capuchins recognize objects on the SOR task after both short and long delays, whereas a twofold increase in the familiarization phase does not affect task performance. The results also provide further support for the use of incidental learning paradigms to assess recognition memory in nonhuman primates.

Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory.

Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.

A high-performance electrochemical sensor based on a mesoporous silica/titania material and cobalt(II) phthalocyanine for sensitive pentachlorophenol determination.

The synthesis and characterization of a novel titania/silica hybrid xerogel subsequently modified with 4-methylpyridine (4-Pic), named TiSi4Pic+Cl- is reported. The physicochemical, structural and thermal properties of TiSi4Pic+Cl- were characterized using several techniques. Anchoring cobalt(II) phthalocyanine (CoTsPc) in TiSi4Pic+Cl- showed greater electroanalytical sensitivity over other sensors built with these materials. A novel electroanalytical method was developed to quantify the noxious biocide pentachlorophenol (PCP) for environmental monitoring. The peak current intensity increased linearly with the analyte concentration in the range between 0.99 and 4.21 µmol L-1, based on the oxidation process (at + 0.81 V, vs. Ag/AgCl) of differential pulse voltammetry (DPV). The estimated limit of detection (LOD) was 29 nmol L-1. Recovery tests in environmental samples showed a PCP concentration of 2.05 ± 0.03 µmol L-1 (n = 3). The method was statistically validated by comparing the PCP concentrations with those obtained by molecular absorption spectrometry and high-performance liquid chromatography-diode array detection (HPLC-DAD). At a 95% confidence level, no difference between the results was found, therefore confirming the excellent accuracy of the proposed method.

Cocaine attenuates acid sphingomyelinase activity during establishment of addiction-related behavior-A translational study in rats and monkeys.

Cocaine addiction is a severe psychiatric condition for which currently no effective pharmacotherapy is available. Brain mechanisms for the establishment of addiction-related behaviors are still not fully understood, and specific biomarkers for cocaine use are not available. Sphingolipids are major membrane lipids, which shape neuronal membrane composition and dynamics in the brain. Here, we investigated how chronic cocaine exposure during establishment of addiction-related behaviors affects the activity of the sphingolipid rheostat controlling enzymes in the brain of rats. As we detected specific effects on several enzymes in the brain, we tested whether the activity of selected enzymes in the blood may serve as potential biomarker for cocaine exposure in non-human primates (Callithrix penicillata). We found that intravenous cocaine self-administration led to a reduced mRNA expression of Cers1, Degs1 and Degs2, and Smpd1 in the prefrontal cortex of rats, as well as a reduction of Cers4 expression in the striatum. These effects reversed after 10 days of abstinence. Monkeys showed a robust cocaine-induced place preference (CPP). This coincided with a reduction in blood acid sphingomyelinase (ASM) activity after CPP establishment. This effect normalized after 15 days of abstinence. Altogether, these findings suggest that the establishment of cocaine addiction-related behaviors coincides with changes in the activity of sphingolipid controlling enzymes. In particular, blood ASM levels may serve as a translational biomarker for recent cocaine exposure.

γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion.

γ-Secretase is a multisubunit complex that catalyzes intramembranous cleavage of transmembrane proteins. The lipid environment forms membrane microdomains that serve as spatio-temporal platforms for proteins to function properly. Despite substantial advances in the regulation of γ-secretase, the effect of the local membrane lipid microenvironment on the regulation of γ-secretase is poorly understood. Here, we characterized and quantified the partitioning of γ-secretase and its substrates, the amyloid precursor protein (APP) and Notch, into lipid bilayers using solid-supported model membranes. Notch substrate is preferentially localized in the liquid-disordered (Ld) lipid domains, whereas APP and γ-secretase partition as single or higher complex in both phases but highly favor the ordered phase, especially after recruiting lipids from the ordered phase, indicating that the activity and specificity of γ-secretase against these two substrates are modulated by membrane lateral organization. Moreover, time-elapse measurements reveal that γ-secretase can recruit specific membrane components from the cholesterol-rich Lo phase and thus creates a favorable lipid environment for substrate recognition and therefore activity. This work offers insight into how γ-secretase and lipid modulate each other and control its activity and specificity.

Colour vision variation in leaf-nosed bats (Phyllostomidae): Links to cave roosting and dietary specialization.

Bats are a diverse radiation of mammals of enduring interest for understanding the evolution of sensory specialization. Colour vision variation among species has previously been linked to roosting preferences and echolocation form in the suborder Yinpterochiroptera, yet questions remain about the roles of diet and habitat in shaping bat visual ecology. We sequenced OPN1SW and OPN1LW opsin genes for 20 species of leaf-nosed bats (family Phyllostomidae; suborder Yangochiroptera) with diverse roosting and dietary ecologies, along with one vespertilionid species (Myotis lavali). OPN1LW genes appear intact for all species, and predicted spectral tuning of long-wavelength opsins varied among lineages. OPN1SW genes appear intact and under purifying selection for Myotis lavali and most phyllostomid bats, with two exceptions: (a) We found evidence of ancient OPN1SW pseudogenization in the vampire bat lineage, and loss-of-function mutations in all three species of extant vampire bats; (b) we additionally found a recent, independently derived OPN1SW pseudogene in Lonchophylla mordax, a cave-roosting species. These mutations in leaf-nosed bats are independent of the OPN1SW pseudogenization events previously reported in Yinpterochiropterans. Therefore, the evolution of monochromacy (complete colour blindness) has occurred in both suborders of bats and under various evolutionary drivers; we find independent support for the hypothesis that obligate cave roosting drives colour vision loss. We additionally suggest that haematophagous dietary specialization and corresponding selection on nonvisual senses led to loss of colour vision through evolutionary sensory trade-off. Our results underscore the evolutionary plasticity of opsins among nocturnal mammals.

ATLANTIC MAMMAL TRAITS: a data set of morphological traits of mammals in the Atlantic Forest of South America.

Measures of traits are the basis of functional biological diversity. Numerous works consider mean species-level measures of traits while ignoring individual variance within species. However, there is a large amount of variation within species and it is increasingly apparent that it is important to consider trait variation not only between species, but also within species. Mammals are an interesting group for investigating trait-based approaches because they play diverse and important ecological functions (e.g., pollination, seed dispersal, predation, grazing) that are correlated with functional traits. Here we compile a data set comprising morphological and life history information of 279 mammal species from 39,850 individuals of 388 populations ranging from -5.83 to -29.75 decimal degrees of latitude and -34.82 to -56.73 decimal degrees of longitude in the Atlantic forest of South America. We present trait information from 16,840 individuals of 181 species of non-volant mammals (Rodentia, Didelphimorphia, Carnivora, Primates, Cingulata, Artiodactyla, Pilosa, Lagomorpha, Perissodactyla) and from 23,010 individuals of 98 species of volant mammals (Chiroptera). The traits reported include body mass, age, sex, reproductive stage, as well as the geographic coordinates of sampling for all taxa. Moreover, we gathered information on forearm length for bats and body length and tail length for rodents and marsupials. No copyright restrictions are associated with the use of this data set. Please cite this data paper when the data are used in publications. We also request that researchers and teachers inform us of how they are using the data.

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation.

UNLABELLED: By assembling in a protein lattice on the host's plasma membrane, the retroviral Gag polyprotein triggers formation of the viral protein/membrane shell. The MA domain of Gag employs multiple signals--electrostatic, hydrophobic, and lipid-specific-to bring the protein to the plasma membrane, thereby complementing protein-protein interactions, located in full-length Gag, in lattice formation. We report the interaction of myristoylated and unmyristoylated HIV-1 Gag MA domains with bilayers composed of purified lipid components to dissect these complex membrane signals and quantify their contributions to the overall interaction. Surface plasmon resonance on well-defined planar membrane models is used to quantify binding affinities and amounts of protein and yields free binding energy contributions, ΔG, of the various signals. Charge-charge interactions in the absence of the phosphatidylinositide PI(4,5)P2 attract the protein to acidic membrane surfaces, and myristoylation increases the affinity by a factor of 10; thus, our data do not provide evidence for a PI(4,5)P2 trigger of myristate exposure. Lipid-specific interactions with PI(4,5)P2, the major signal lipid in the inner plasma membrane, increase membrane attraction at a level similar to that of protein lipidation. While cholesterol does not directly engage in interactions, it augments protein affinity strongly by facilitating efficient myristate insertion and PI(4,5)P2 binding. We thus observe that the isolated MA protein, in the absence of protein-protein interaction conferred by the full-length Gag, binds the membrane with submicromolar affinities. IMPORTANCE: Like other retroviral species, the Gag polyprotein of HIV-1 contains three major domains: the N-terminal, myristoylated MA domain that targets the protein to the plasma membrane of the host; a central capsid-forming domain; and the C-terminal, genome-binding nucleocapsid domain. These domains act in concert to condense Gag into a membrane-bounded protein lattice that recruits genomic RNA into the virus and forms the shell of a budding immature viral capsid. In binding studies of HIV-1 Gag MA to model membranes with well-controlled lipid composition, we dissect the multiple interactions of the MA domain with its target membrane. This results in a detailed understanding of the thermodynamic aspects that determine membrane association, preferential lipid recruitment to the viral shell, and those aspects of Gag assembly into the membrane-bound protein lattice that are determined by MA.

ATLANTIC BATS: a data set of bat communities from the Atlantic Forests of South America.

Bats are the second most diverse mammal order and they provide vital ecosystem functions (e.g., pollination, seed dispersal, and nutrient flux in caves) and services (e.g., crop pest suppression). Bats are also important vectors of infectious diseases, harboring more than 100 different virus types. In the present study, we compiled information on bat communities from the Atlantic Forests of South America, a species-rich biome that is highly threatened by habitat loss and fragmentation. The ATLANTIC BATS data set comprises 135 quantitative studies carried out in 205 sites, which cover most vegetation types of the tropical and subtropical Atlantic Forest: dense ombrophilous forest, mixed ombrophilous forest, semideciduous forest, deciduous forest, savanna, steppe, and open ombrophilous forest. The data set includes information on more than 90,000 captures of 98 bat species of eight families. Species richness averaged 12.1 per site, with a median value of 10 species (ranging from 1 to 53 species). Six species occurred in more than 50% of the communities: Artibeus lituratus, Carollia perspicillata, Sturnira lilium, Artibeus fimbriatus, Glossophaga soricina, and Platyrrhinus lineatus. The number of captures divided by sampling effort, a proxy for abundance, varied from 0.000001 to 0.77 individuals·h-1 ·m-2 (0.04 ± 0.007 individuals·h-1 ·m-2 ). Our data set reveals a hyper-dominance of eight species that together that comprise 80% of all captures: Platyrrhinus lineatus (2.3%), Molossus molossus (2.8%), Artibeus obscurus (3.4%), Artibeus planirostris (5.2%), Artibeus fimbriatus (7%), Sturnira lilium (14.5%), Carollia perspicillata (15.6%), and Artibeus lituratus (29.2%).

Structural features of membrane-bound glucocerebrosidase and α-synuclein probed by neutron reflectometry and fluorescence spectroscopy.

Mutations in glucocerebrosidase (GCase), the enzyme deficient in Gaucher disease, are a common genetic risk factor for the development of Parkinson disease and related disorders, implicating the role of this lysosomal hydrolase in the disease etiology. A specific physical interaction exists between the Parkinson disease-related protein α-synuclein (α-syn) and GCase both in solution and on the lipid membrane, resulting in efficient enzyme inhibition. Here, neutron reflectometry was employed as a first direct structural characterization of GCase and α-syn·GCase complex on a sparsely-tethered lipid bilayer, revealing the orientation of the membrane-bound GCase. GCase binds to and partially inserts into the bilayer with its active site most likely lying just above the membrane-water interface. The interaction was further characterized by intrinsic Trp fluorescence, circular dichroism, and surface plasmon resonance spectroscopy. Both Trp fluorescence and neutron reflectometry results suggest a rearrangement of loops surrounding the catalytic site, where they extend into the hydrocarbon chain region of the outer leaflet. Taking advantage of contrasting neutron scattering length densities, the use of deuterated α-syn versus protiated GCase showed a large change in the membrane-bound structure of α-syn in the complex. We propose a model of α-syn·GCase on the membrane, providing structural insights into inhibition of GCase by α-syn. The interaction displaces GCase away from the membrane, possibly impeding substrate access and perturbing the active site. GCase greatly alters membrane-bound α-syn, moving helical residues away from the bilayer, which could impact the degradation of α-syn in the lysosome where these two proteins interact.

Membrane Binding of the Rous Sarcoma Virus Gag Protein Is Cooperative and Dependent on the Spacer Peptide Assembly Domain.

UNLABELLED: The principles underlying membrane binding and assembly of retroviral Gag proteins into a lattice are understood. However, little is known about how these processes are related. Using purified Rous sarcoma virus Gag and Gag truncations, we studied the interrelation of Gag-Gag interaction and Gag-membrane interaction. Both by liposome binding and by surface plasmon resonance on a supported bilayer, Gag bound to membranes much more tightly than did matrix (MA), the isolated membrane binding domain. In principle, this difference could be explained either by protein-protein interactions leading to cooperativity in membrane binding or by the simultaneous interaction of the N-terminal MA and the C-terminal nucleocapsid (NC) of Gag with the bilayer, since both are highly basic. However, we found that NC was not required for strong membrane binding. Instead, the spacer peptide assembly domain (SPA), a putative 24-residue helical sequence comprising the 12-residue SP segment of Gag and overlapping the capsid (CA) C terminus and the NC N terminus, was required. SPA is known to be critical for proper assembly of the immature Gag lattice. A single amino acid mutation in SPA that abrogates assembly in vitro dramatically reduced binding of Gag to liposomes. In vivo, plasma membrane localization was dependent on SPA. Disulfide cross-linking based on ectopic Cys residues showed that the contacts between Gag proteins on the membrane are similar to the known contacts in virus-like particles. Taken together, we interpret these results to mean that Gag membrane interaction is cooperative in that it depends on the ability of Gag to multimerize. IMPORTANCE: The retroviral structural protein Gag has three major domains. The N-terminal MA domain interacts directly with the plasma membrane (PM) of cells. The central CA domain, together with immediately adjoining sequences, facilitates the assembly of thousands of Gag molecules into a lattice. The C-terminal NC domain interacts with the genome, resulting in packaging of viral RNA. For assembly in vitro with purified Gag, in the absence of membranes, binding of NC to nucleic acid somehow facilitates further Gag-Gag interactions that lead to formation of the Gag lattice. The contributions of MA-mediated membrane binding to virus particle assembly are not well understood. Here, we report that in the absence of nucleic acid, membranes provide a platform that facilitates Gag-Gag interactions. This study demonstrates that the binding of Gag, but not of MA, to membranes is cooperative and identifies SPA as a major factor that controls this cooperativity.

Hydrodynamic and Membrane Binding Properties of Purified Rous Sarcoma Virus Gag Protein.

UNLABELLED: Previously, no retroviral Gag protein has been highly purified in milligram quantities and in a biologically relevant and active form. We have purified Rous sarcoma virus (RSV) Gag protein and in parallel several truncation mutants of Gag and have studied their biophysical properties and membrane interactions in vitro. RSV Gag is unusual in that it is not naturally myristoylated. From its ability to assemble into virus-like particles in vitro, we infer that RSV Gag is biologically active. By size exclusion chromatography and small-angle X-ray scattering, Gag in solution appears extended and flexible, in contrast to previous reports on unmyristoylated HIV-1 Gag, which is compact. However, by neutron reflectometry measurements of RSV Gag bound to a supported bilayer, the protein appears to adopt a more compact, folded-over conformation. At physiological ionic strength, purified Gag binds strongly to liposomes containing acidic lipids. This interaction is stimulated by physiological levels of phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] and by cholesterol. However, unlike HIV-1 Gag, RSV Gag shows no sensitivity to acyl chain saturation. In contrast with full-length RSV Gag, the purified MA domain of Gag binds to liposomes only weakly. Similarly, both an N-terminally truncated version of Gag that is missing the MA domain and a C-terminally truncated version that is missing the NC domain bind only weakly. These results imply that NC contributes to membrane interaction in vitro, either by directly contacting acidic lipids or by promoting Gag multimerization. IMPORTANCE: Retroviruses like HIV assemble at and bud from the plasma membrane of cells. Assembly requires the interaction between thousands of Gag molecules to form a lattice. Previous work indicated that lattice formation at the plasma membrane is influenced by the conformation of monomeric HIV. We have extended this work to the more tractable RSV Gag. Our results show that RSV Gag is highly flexible and can adopt a folded-over conformation on a lipid bilayer, implicating both the N and C termini in membrane binding. In addition, binding of Gag to membranes is diminished when either terminal domain is truncated. RSV Gag membrane association is significantly less sensitive than HIV Gag membrane association to lipid acyl chain saturation. These findings shed light on Gag assembly and membrane binding, critical steps in the viral life cycle and an untapped target for antiretroviral drugs.

Relationship between body temperature, weight, and hematological parameters of black tufted-ear marmosets (Callithrix penicillata).

BACKGROUND: Basal thermal values of captive adult black tufted-ear marmosets (Callithrix penicillata) in a thermoneutral environment were measured via different methods, along with body weight and hematological parameters. METHOD: Body temperatures were recorded with rectal (RC), subcutaneous (SC) microchip transponder and infrared (left and right) tympanic membrane (TM) thermometries. Thermal values were correlated with body mass and some hematological data. RESULTS AND CONCLUSIONS: Similar RC and SC temperatures were observed, these being significantly higher than the left and right TM values. SC temperature was positively correlated and in close agreement with RC measurements. Although body temperatures were not influenced by gender, capture time, or body weight, they were correlated with hematological parameters. Thus, body temperatures in this species seem to reflect some of the characteristics of the assessments' location, with SC microchip transponders being a less invasive method to assess body temperature in these small-bodied non-human primates.

Decreased methylation of the NK3 receptor coding gene (TACR3) after cocaine-induced place preference in marmoset monkeys.

Epigenetic processes have been implicated in neuronal plasticity following repeated cocaine application. Here we measured DNA methylation at promoter CpG sites of the dopamine transporter (DAT1) and serotonin transporter (SERT) and neurokinin3-receptor (NK3-R)-receptor (TACR3) coding genes in marmoset monkeys after repeated cocaine injections in a conditioned place preference paradigm. We found a decrease in DNA methylation at a specific CpG site in TACR3, but not DAT1 or SERT. Thus, TACR3 is a locus for DNA methylation changes in response to repeated cocaine administration and its establishment as a reinforcer, in support of other evidence implicating the NK3-R in reinforcement- and addiction-related processes.

Ranking mAb-excipient interactions in biologics formulations by NMR spectroscopy and computational approaches.

Excipients are added to biopharmaceutical formulations to enhance protein stability and enable the development of robust formulations with acceptable physicochemical properties, but the mechanism by which they confer stability is not fully understood. Here, we aimed to elucidate the mechanism through direct experimental evidence of the binding affinity of an excipient to a monoclonal antibody (mAb), using saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopic method. We ranked a series of excipients with respect to their dissociation constant (KD) and nonspecific binding constants (Ns). In parallel, molecular dynamic and site identification by ligand competitive saturation (SILCS)-Monte Carlo simulations were done to rank the excipient proximity to the proteins, thereby corroborating the ranking by STD NMR. Finally, the excipient ranking by NMR was correlated with mAb conformational and colloidal stability. Our approach can aid excipient selection in biologic formulations by providing insights into mAb-excipient affinities before conventional and time-consuming excipient screening studies are conducted.

Symptomatic fractures in systemic sclerosis: A case-control study.

This case-control study analyzed risk factors for symptomatic fractures in a group of 52 patients with systemic sclerosis compared with a group of 104 patients without fractures, matched for sex and age, who were attended at a single systemic sclerosis outpatient clinic from 2010 to 2020. Fractures affected predominantly vertebral (65.4%), rib (13.5%), and hip (7.7%) joints, while the mean age of fracture was 55.3 ± 9.5 years. Age at disease onset, age at diagnosis, disease duration, age at menarche, and age at menopause were similar in both groups, and 58.9% of the patients were menopausal at the time of the fracture. The presence of fractures had a significant association with densitometric osteoporosis (p < 0.001), lower weight (p = 0.032), and bone mineral index (p = 0.044), anti-RNA polymerase III (p = 0.040), use of corticosteroids (p = 0.019), and bisphosphonates (p < 0.001), as well as with densitometric T-scores of lumbar spine (p < 0.001), femoral neck (p = 0.025), and total hip (p = 0.013). Multivariate analysis showed that the variables significantly associated with fractures were high doses of corticosteroids (odds ratio = 4.10; 95% confidence interval = 1.290-13.090; p = 0.017), bisphosphonates (odds ratio = 3.91; 95% confidence interval = 1.699-8.984; p = 0.001), negative anti-Scl70 (OR = 0.34; 95% confidence interval = 0.124-0.943; p = 0.038), and lumbar T-score (odds ratio = 0.39; 95% confidence interval = 0.034-0.460; p = 0.010). In conclusion, symptomatic fractures were associated predominantly with lower bone mineral density of lumbar spine and use of high doses of corticosteroids and bisphosphonates in this cohort.

Diet and the evolution of ADH7 across seven orders of mammals.

Dietary variation within and across species drives the eco-evolutionary responsiveness of genes necessary to metabolize nutrients and other components. Recent evidence from humans and other mammals suggests that sugar-rich diets of floral nectar and ripe fruit have favoured mutations in, and functional preservation of, the ADH7 gene, which encodes the ADH class 4 enzyme responsible for metabolizing ethanol. Here we interrogate a large, comparative dataset of ADH7 gene sequence variation, including that underlying the amino acid residue located at the key site (294) that regulates the affinity of ADH7 for ethanol. Our analyses span 171 mammal species, including 59 newly sequenced. We report extensive variation, especially among frugivorous and nectarivorous bats, with potential for functional impact. We also report widespread variation in the retention and probable pseudogenization of ADH7. However, we find little statistical evidence of an overarching impact of dietary behaviour on putative ADH7 function or presence of derived alleles at site 294 across mammals, which suggests that the evolution of ADH7 is shaped by complex factors. Our study reports extensive new diversity in a gene of longstanding ecological interest, offers new sources of variation to be explored in functional assays in future study, and advances our understanding of the processes of molecular evolution.

The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK3-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK3-R agonists and their activating influence on ACh suggest a possible role of the NK3-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK3-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous--s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object-place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object-place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK3-R agonists is mediated by muscarinic cholinergic mechanisms.