Uncovering the Genetic Architecture of Major Depression

There have been several recent studies addressing the genetic architecture of depression. This review serves to take stock of what is known now about the genetics of depression, how it has increased our knowledge and understanding of its mechanisms, and how the information and knowledge can be leveraged to improve the care of people affected. We identify four priorities for how the field of MD genetics research may move forward in future years, namely by increasing the sample sizes available for genome-wide association studies (GWASs), greater inclusion of diverse ancestries and low-income countries, the closer integration of psychiatric genetics with electronic medical records, and the development of the neuroscience toolkit for polygenic disorders. A review by McIntosh et al. takes stock of recent rapid progress in the genetics of depression, how it has increased our mechanistic understanding, and how this information could be used to improve patient care in future

Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.

Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter.NHMRC Grants: 1045964 & 107211

Quantum spherical model with competing interactions

We analyze the phase diagram of a quantum mean spherical model in terms of the temperature $T$, a quantum parameter $g$, and the ratio $p=-J_{2}/J_{1}$, where $J_{1}>0$ refers to ferromagnetic interactions between first-neighbor sites along the $d$ directions of a hypercubic lattice, and $J_{2}<0$ is associated with competing antiferromagnetic interactions between second neighbors along $m\leq d$ directions. We regain a number of known results for the classical version of this model, including the topology of the critical line in the $g=0$ space, with a Lifshitz point at $p=1/4$, for $d>2$, and closed-form expressions for the decay of the pair correlations in one dimension. In the T=0 phase diagram, there is a critical border, $g_{c}=g_{c}(p)$ for $d\geq2$, with a singularity at the Lifshitz point if $d<(m+4)/2$. We also establish upper and lower critical dimensions, and analyze the quantum critical behavior in the neighborhood of $p=1/4$.Comment: 18 pages, 3 figures, refs added, minor modifications to match published versio

A cold-atom Ramsey clock with a low volume physics package

We demonstrate a Ramsey-type microwave clock interrogating the 6.835 GHz ground-state transition in cold 87Rb atoms loaded from a grating magneto-optical trap (GMOT) enclosed in an additively manufactured loop-gap resonator microwave cavity. A short-term stability of 1.5×10−11 τ−1/2 is demonstrated, in reasonable agreement with predictions from the signal-to-noise ratio of the measured Ramsey fringes. The cavity-grating package has a volume of ≈67 cm3, ensuring an inherently compact system while the use of a GMOT drastically simplifies the optical requirements for laser cooled atoms. This work is another step towards the realisation of highly compact portable cold-atom frequency standards

Nonlinear Realization of Chiral Symmetry on the Lattice

We formulate lattice theories in which chiral symmetry is realized nonlinearly on the fermion fields. In this framework the fermion mass term does not break chiral symmetry. This property allows us to use the Wilson term to remove the doubler fermions while maintaining exact chiral symmetry on the lattice. Our lattice formulation enables us to address non-perturbative questions in effective field theories of baryons interacting with pions and in models involving constituent quarks interacting with pions and gluons. We show that a system containing a non-zero density of static baryons interacting with pions can be studied on the lattice without encountering complex action problems. In our formulation one can also decide non-perturbatively if the chiral quark model of Georgi and Manohar provides an appropriate low-energy description of QCD. If so, one could understand why the non-relativistic quark model works.Comment: 34 pages, 2 figures, revised version to be published in J. High Energy Phys. (changes in the 1st paragraph, additional descriptions on the nature of the coordinate singularities in Sec.2, references added

Conference Report: Psychiatric Genomics Consortium Meeting: Pathways to Drugs, London, March 2017

[No abstract available

Coherent states in the quantum multiverse

In this paper, we study the role of coherent states in the realm of quantum cosmology, both in a second-quantized single universe and in a third-quantized quantum multiverse. In particular, most emphasis will be paid to the quantum description of multiverses made up of accelerated universes. We have shown that the quantum states involved at a quantum mechanical multiverse whose single universes are accelerated are given by squeezed states having no classical analogs.Comment: 7 pages, 3 figure

Quantifying Between-Cohort and Between-Sex Genetic Heterogeneity in Major Depressive Disorder

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD

Effectiveness of targeted enhanced terminal room disinfection on hospital-wide acquisition and infection with multidrug-resistant organisms and Clostridium difficile: a secondary analysis of a multicentre cluster randomised controlled trial with crossover design (BETR Disinfection)

Background: The hospital environment is a source of pathogen transmission. The effect of enhanced disinfection strategies on the hospital-wide incidence of infection has not been investigated in a multicentre, randomised controlled trial. We aimed to assess the effectiveness of four disinfection strategies on hospital-wide incidence of multidrug-resistant organisms and Clostridium difficile in the Benefits of Enhanced Terminal Room (BETR) Disinfection study. Methods: We did a prespecified secondary analysis of the results from the BETR Disinfection study, a pragmatic, multicentre, crossover cluster-randomised trial that assessed four different strategies for terminal room disinfection in nine hospitals in the southeastern USA. Rooms from which a patient with a specific infection or colonisation (due to the target organisms C difficile, meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci (VRE), or multidrug-resistant Acinetobacter spp) was discharged were terminally disinfected with one of four strategies: standard disinfection (quaternary ammonium disinfectant, except for C difficile, for which 10% hypochlorite [bleach] was used; reference); standard disinfection and disinfecting ultraviolet light (UV-C), except for C difficile, for which bleach and UV-C was used (UV strategy); 10% hypochlorite (bleach strategy); and bleach and UV-C (bleach and UV strategy). We randomly assigned the sequence of strategies for each hospital (1:1:1:1), and each strategy was used for 7 months, including a 1-month wash-in period and 6 months of data collection. The prespecified secondary outcomes were hospital-wide, hospital-acquired incidence of all target organisms (calculated as number of patients with hospital-acquired infection with a target organism per 10 000 patient days), and hospital-wide, hospital-acquired incidence of each target organism separately. BETR Disinfection is registered with ClinicalTrials.gov, number NCT01579370. Findings: Between April, 2012, and July, 2014, there were 271 740 unique patients with 375 918 admissions. 314 610 admissions met all inclusion criteria (n=73 071 in the reference study period, n=81 621 in the UV study period, n=78 760 in the bleach study period, and n=81 158 in the bleach and UV study period). 2681 incidenct cases of hospital-acquired infection or colonisation occurred during the study. There was no significant difference in the hospital-wide risk of target organism acquisition between standard disinfection and the three enhanced terminal disinfection strategies for all target multidrug-resistant organisms (UV study period relative risk [RR] 0·89, 95% CI 0·79–1·00; p=0·052; bleach study period 0·92, 0·79–1·08; p=0·32; bleach and UV study period 0·99, 0·89–1·11; p=0·89). The decrease in risk in the UV study period was driven by decreases in risk of acquisition of C difficile (RR 0·89, 95% CI 0·80–0·99; p=0·031) and VRE (0·56, 0·31–0·996; p=0·048). Interpretation: Enhanced terminal room disinfection with UV in a targeted subset of high-risk rooms led to a decrease in hospital-wide incidence of C difficile and VRE. Enhanced disinfection overcomes limitations of standard disinfection strategies and is a potential strategy to reduce the risk of acquisition of multidrug-resistant organisms and C difficile. Funding: US Centers for Disease Control and Prevention