Mapping the contribution of single muscles to facial movements in the rhesus macaque

The rhesus macaque (Macaca mulatta) is the most utilized primate model in the biomedical and psychological sciences. Expressive behavior is of interest to scientists studying these animals, both as a direct variable (modeling neuropsychiatric disease, where expressivity is a primary deficit), as an indirect measure of health and welfare, and also in order to understand the evolution of communication. Here, intramuscular electrical stimulation of facial muscles was conducted in the rhesus macaque in order to document the relative contribution of each muscle to the range of facial movements and to compare the expressive function of homologous muscles in humans, chimpanzees and macaques. Despite published accounts that monkeys possess less differentiated and less complex facial musculature, the majority of muscles previously identified in humans and chimpanzees were stimulated successfully in the rhesus macaque and caused similar appearance changes. These observations suggest that the facial muscular apparatus of the monkey has extensive homology to the human face. The muscles of the human face, therefore, do not represent a significant evolutionary departure from those of a monkey species. Thus, facial expressions can be compared between humans and rhesus macaques at the level of the facial musculature, facilitating the systematic investigation of comparative facial communication

Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex

Neuroinflammation has a major role in several brain disorders including Alzheimer’s disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecularweight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone–pyridylhydrazone copper(II) complex (CuL5 ), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer’s disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.Xin Yi Choo, Lachlan E. McInnes, Alexandra Grubman, Joanna M. Wasielewska, Irina Belaya, Emma Burrows, Hazel Quek, Jorge Cañas Martín, Sanna Loppi, Annika Sorvari, Dzhessi Rait, Andrew Powell, Clare Duncan, Jeffrey R. Liddell, Heikki Tanila, Jose M. Polo, Tarja Malm, Katja M. Kanninen, Paul S. Donnelly, and Anthony R. Whit

Planck early results XV : Spectral energy distributions and radio continuum spectra of northern extragalactic radio sources

Peer reviewe

STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): An international consortium of randomised placebo-controlled trials

Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.  Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.  Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis

Planck early results. XV. Spectral energy distributions and radio continuum spectra of northern extragalactic radio sources

Spectral energy distributions (SEDs) and radio continuum spectra are presented for a northern sample of 104 extragalactic radio sources, based on the Planck Early Release Compact Source Catalogue (ERCSC) and simultaneous multifrequency data. The nine Planck frequencies, from 30 to 857 GHz, are complemented by a set of simultaneous observations ranging from radio to gamma-rays. This is the first extensive frequency coverage in the radio and millimetre domains for an essentially complete sample of extragalactic radio sources, and it shows how the individual shocks, each in their own phase of development, shape the radio spectra as they move in the relativistic jet. The SEDs presented in this paper were fitted with second and third degree polynomials to estimate the frequencies of the synchrotron and inverse Compton (IC) peaks, and the spectral indices of low and high frequency radio data, including the Planck ERCSC data, were calculated. SED modelling methods are discussed, with an emphasis on proper, physical modelling of the synchrotron bump using multiple components. Planck ERCSC data also suggest that the original accelerated electron energy spectrum could be much harder than commonly thought, with power-law index around 1.5 instead of the canonical 2.5. The implications of this are discussed for the acceleration mechanisms effective in blazar shocks. Furthermore in many cases the Planck data indicate that gamma-ray emission must originate in the same shocks that produce the radio emission

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Modelling mosquito infection at natural parasite densities identifies drugs targeting EF2, PI4K or ATP4 as key candidates for interrupting malaria transmission

Eradication of malaria requires a novel type of drug that blocks transmission from the human to the mosquito host, but selection of such a drug is hampered by a lack of translational models. Experimental mosquito infections yield infection intensities that are substantially higher than observed in natural infections and, as a consequence, underestimate the drug effect on the proportion of mosquitoes that become infected. Here we introduce a novel experimental and computational method to adequately describe drug efficacy at natural parasite densities. Parameters of a beta-binomial infection model were established and validated using a large number of experimental mosquito infections at different parasite densities. Analyses of 15 experimental and marketed drugs revealed a class-specific ability to block parasite transmission. Our results highlight the parasite's elongation factor EF2, PI4 kinase and the ATP4 sodium channel as key targets for interruption of transmission, and compounds DDD107498 and KAE609 as most advanced drug candidates