Mitochondrial Mutations in Subjects with Psychiatric Disorders

A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.     

SBOL Visual: A Graphical Language for Genetic Designs

Synthetic Biology Open Language (SBOL) Visual is a graphical standard for genetic engineering. It consists of symbols representing DNA subsequences, including regulatory elements and DNA assembly features. These symbols can be used to draw illustrations for communication and instruction, and as image assets for computer-aided design. SBOL Visual is a community standard, freely available for personal, academic, and commercial use (Creative Commons CC0 license). We provide prototypical symbol images that have been used in scientific publications and software tools. We encourage users to use and modify them freely, and to join the SBOL Visual community: http://www.sbolstandard.org/visual.     

Variability in Tuberculosis Granuloma T Cell Responses Exists,but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization

Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few “multi-functional” T cells were observed. However, granulomas were found to be “multi-functional” with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas.     

Heat shock response and autophagy—cooperation and control

Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems.     

The Role of Informative and Ambiguous Feedback in Avoidance Behavior: Empirical and Computational Findings

Avoidance behavior is a critical component of many psychiatric disorders, and as such, it is important to understand how avoidance behavior arises, and whether it can be modified. In this study, we used empirical and computational methods to assess the role of informational feedback and ambiguous outcome in avoidance behavior. We adapted a computer-based probabilistic classification learning task, which includes positive, negative and no-feedback outcomes; the latter outcome is ambiguous as it might signal either a successful outcome (missed punishment) or a failure (missed reward). Prior work with this task suggested that most healthy subjects viewed the no-feedback outcome as strongly positive. Interestingly, in a later version of the classification task, when healthy subjects were allowed to opt out of (i.e. avoid) responding, some subjects (“avoiders”) reliably avoided trials where there was a risk of punishment, but other subjects (“non-avoiders”) never made any avoidance responses at all. One possible interpretation is that the “non-avoiders” valued the no-feedback outcome so positively on punishment-based trials that they had little incentive to avoid. Another possible interpretation is that the outcome of an avoided trial is unspecified and that lack of information is aversive, decreasing subjects’ tendency to avoid. To examine these ideas, we here tested healthy young adults on versions of the task where avoidance responses either did or did not generate informational feedback about the optimal response. Results showed that provision of informational feedback decreased avoidance responses and also decreased categorization performance, without significantly affecting the percentage of subjects classified as “avoiders.” To better understand these results, we used a modified Q-learning model to fit individual subject data. Simulation results suggest that subjects in the feedback condition adjusted their behavior faster following better-than-expected outcomes, compared to subjects in the no-feedback condition. Additionally, in both task conditions, “avoiders” adjusted their behavior faster following worse-than-expected outcomes, and treated the ambiguous no-feedback outcome as less rewarding, compared to non-avoiders. Together, results shed light on the important role of ambiguous and informative feedback in avoidance behavior.     

The Nicotinic Receptor Alpha7 Impacts the Mouse Lung Response to LPS through Multiple Mechanisms

The nicotinic acetylcholine receptor alpha7 (α7) is expressed by neuronal and non-neuronal cells throughout the body. We examined the mechanisms of the lung inflammatory response to intranasal (i.n.) lipopolysaccharide (LPS) regulated by α7. This was done in mice using homologous recombination to introduce a point mutation in the α7 receptor that replaces the glutamate residue 260 that lines the pore with alanine (α7^E260A), which has been implicated in controlling the exceptional calcium ion conductance of this receptor. The α7^E260A mice exhibit normal inflammatory cell recruitment to the blood in response to i.n. LPS administration. This differs from the α7knock-out (α7^KO) in which upstream signaling to initiate the recruitment to the blood following i.n. LPS is significantly impaired. While hematopoietic cells are recruited to the bloodstream in the α7^E260A mouse, they fail to be recruited efficiently into both the interstitium and alveolar spaces of the lung. Bone marrow reconstitution experiments demonstrate that the responsiveness of both CD45⁺ and CD45^- cells of the α7^E260A mouse are impaired. The expression of several pro-inflammatory cytokine and chemokine RNAs including TNFα, IL-1α, Ccl2 and Cxcl10 are decreased in the α7^E260A mouse. However, there is a substantial increase in IL-13 expression by CD45^- lung interstitial cells in the α7^E260A mouse. Our results support the conclusion that α7 functional pleiotropy contributes to modulating the tissue response to an inflammatory insult through impacting upon a variety of mechanisms reflecting the individual cell composition of the lung.     

All around Australia and overseas: Christianity and indigenous identities in Central Australia 1988

This paper discusses the themes and practices of Christian performance at the Western Desert Aboriginal community of Warlungurru in 1988, 1 six years after the Pintupi return to their homelands (see Myers 1986 ; McMillan 1988 ; Nathan & Japanangka Leichleitner 1983 ) and the enthusiastic Christian revival—nightly Gospel singing, a ban on gambling—experienced in the first years of their return. My concern is with how a distinctively Lutheran focus in Pintupi Christianity (in opposition to competing Pentecostal orientations in Central Australia at that time) was grasped by some Pintupi as a structure organising relations between Indigenous people and others in the world, and how specialised knowledge constituted positions of prestige and authority. Thus, I explore certain convergences between prior Indigenous formulations of personhood and relatedness and the way in which Lutheran Christianity was articulated during this period.