Epidemiologic studies, including prospective birth cohort investigations, have implicated maternal immune activation in the etiology of neuropsychiatric disorders. Maternal infectious pathogens and ...inflammation are plausible risk factors for these outcomes and have been associated with schizophrenia, autism spectrum disorder, and bipolar disorder. Concurrent with epidemiologic research are animal models of prenatal immune activation, which have documented behavioral, neurochemical, neuroanatomic, and neurophysiologic disruptions that mirror phenotypes observed in these neuropsychiatric disorders. Epidemiologic studies of maternal immune activation offer the advantage of directly evaluating human populations but are limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between maternal immune activation and neuropsychiatric phenotypes. Incorporating these risk factors in reverse translational animal models of maternal immune activation has yielded a wealth of data supporting the predictive potential of epidemiologic studies. To further enhance the translatability between epidemiology and basic science, the authors propose a complementary approach that includes deconstructing neuropsychiatric outcomes of maternal immune activation into key pathophysiologically defined phenotypes that are identifiable in humans and animals and that evaluate the interspecies concordance regarding interactions between maternal immune activation and genetic and epigenetic factors, including processes involving intergenerational disease transmission. AJP AT 175: Remembering Our Past As We Envision Our Future October 1857: The Pathology of Insanity J.C. Bucknill: "In the brain the state of inflammation itself either very quickly ceases or very soon causes death; but when it does cease it leaves behind it consequences which are frequently the causes of insanity, and the conditions of cerebral atrophy." (Am J Psychiatry 1857; 14:172-193 ).
In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may ...play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. This paper is divided into four sections. In the first, the descriptive epidemiology of schizophrenia is reviewed. This includes general studies on incidence, prevalence, and differences in these measures by urban-rural, neighborhood, migrant, and season of birth status, as well as time trends. In the second section, we discuss the contribution of environmental risk factors acting during fetal and perinatal life; these include infections e.g. rubella, influenza, Toxoplasma gondii (T. gondii), herpes simplex virus type 2 (HSV-2), nutritional deficiencies (e.g., famine, folic acid, iron, vitamin D), paternal age, fetal/neonatal hypoxic and other obstetric insults and complications, maternal stress and other exposures e.g. lead, rhesus (Rh) incompatibility, maternal stress. Other putative neurodevelopmental determinants, including cannabis, socioeconomic status, trauma, and infections during childhood and adolescence are also covered. In the third section, these findings are synthesized and their implications for prevention and uncovering biological mechanisms, including oxidative stress, apoptosis, and inflammation, are discussed. Animal models, including maternal immune activation, have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. In the final section, future studies including new, larger, and more rigorous epidemiologic investigations, and research on translational and clinical neuroscience, gene-environment interactions, epigenetics, developmental trajectories and windows of vulnerability, are elaborated upon. These studies are aimed at confirming observed risk factors, identifying new environmental exposures, elucidating developmental mechanisms, and shedding further light on genes and exposures that may not be identified in the absence of these integrated approaches. The study of environmental factors in schizophrenia may have important implications for the identification of causes and prevention of this disorder, and offers the potential to complement, and refine, existing efforts on explanatory neurodevelopmental models.
Epidemiologic studies have provided evidence that prenatal exposure to maternal infection is associated with an increased risk of developing schizophrenia in the offspring. Research over the past ...decade has added further to our understanding of the role of prenatal infection in schizophrenia risk. These investigations include several well-powered designs, and like some earlier studies, measured maternal antibodies to specific infectious agents in stored serum samples and large registers to identify clinically diagnosed infections during pregnancy. Convergent findings from antibody studies suggest that prenatal maternal infection with Toxoplasma gondii is associated with increased schizophrenia risk in the offspring, while associations with HSV-2 infection are likely attributable to confounding. Maternal influenza infection remains a viable candidate for schizophrenia, based on an early serological study, though there has been only one attempt to replicate this finding, with a differing methodology. A prior association between maternal serologically confirmed cytomegalovirus infections require further study. Clinically diagnosed maternal infection, particularly bacterial infection, also appears to be associated with increased risk of offspring schizophrenia, and heterogeneity in these findings is likely due to methodological differences between studies. Further clarification may be provided by future studies that address the timing, type, and clinical features of infections. Important insight may be gained by examining the long-term offspring outcomes in emerging epidemics such as Zika virus and COVID-19, and by investigating the interaction between exposure to prenatal infection and other risk or protective factors.
An emerging literature from epidemiologic, clinical, and preclinical investigations has provided evidence that gestational exposure to infection contributes to the etiology of schizophrenia. In ...recent years, these studies have moved from ecologic designs, which ascertain infection based on epidemics in populations, to investigations that have capitalized on reliable biomarkers in individual pregnancies. These studies have documented specific candidate infections that appear to be associated with an elevated risk of schizophrenia. Animal models of maternal immune activation inspired by this work have revealed intriguing findings indicating behavioral, neurochemical, and neurophysiologic abnormalities consistent with observations in schizophrenia. In parallel studies in humans and animals, investigators are working to uncover the cellular and molecular mechanisms by which in utero exposure to infection contributes to schizophrenia risk. In this review, the authors discuss and critically evaluate the epidemiologic literature on in utero exposure to infection and schizophrenia, summarize emerging animal models of maternal immune activation, and discuss putative unique and common mechanisms by which in utero exposure to infection alters neurodevelopment, potentially increasing susceptibility to schizophrenia. The promise of this work for facilitating the identification of susceptibility loci in genetic studies of schizophrenia is illustrated by examples of interaction between in utero exposure to infection and genetic variants. The authors then elaborate on possible implications of this work, including the use of preventive measures for reducing the incidence of schizophrenia. Finally, they discuss new approaches aimed at addressing current challenges in this area of research.
Cooperative binding pervades Nature. This review discusses the use of isothermal titration calorimetry (ITC) in the identification and characterisation of cooperativity in biological interactions. ...ITC has broad scope in the analysis of cooperativity as it determines binding stiochiometries, affinities and thermodynamic parameters, including enthalpy and entropy in a single experiment. Examples from the literature are used to demonstrate the applicability of ITC in the characterisation of cooperative systems.
In R (McConnell and YY) v Registrar General for England and Wales 2020 EWCA Civ 559, the Court of Appeal held the Registrar General was correct to register a trans man, who had given birth after the ...issuing of his gender recognition certificate, as ‘mother’ on his son’s birth certificate. In their judgement, the court rejected the appellants’ contention that the Gender Recognition Act 2004 should be construed to allow registration as either ‘father’ or ‘parent’. The court further held that the interference with the appellants’ Article 8 rights which resulted from the registration as ‘mother’ was proportionate and justified.
This paper describes a systematic review (1980-2014) of evidence on effects of transport noise interventions on human health. The sources are road traffic, railways, and air traffic. Health outcomes ...include sleep disturbance, annoyance, cognitive impairment of children and cardiovascular diseases. A conceptual framework to classify noise interventions and health effects was developed. Evidence was thinly spread across source types, outcomes, and intervention types. Further, diverse intervention study designs, methods of analyses, exposure levels, and changes in exposure do not allow a meta-analysis of the association between changes in noise level and health outcomes, and risk of bias in most studies was high. However, 43 individual transport noise intervention studies were examined (33 road traffic; 7 air traffic; 3 rail) as to whether the intervention was associated with a change in health outcome. Results showed that many of the interventions were associated with changes in health outcomes irrespective of the source type, the outcome or intervention type (source, path or infrastructure). For road traffic sources and the annoyance outcome, the expected effect-size can be estimated from an appropriate exposure-response function, though the change in annoyance in most studies was larger than could be expected based on noise level change.
Mitochondria are essential organelles of endosymbiotic origin that are responsible for oxidative phosphorylation within eukaryotic cells. Independent evolution between species has generated ...mitochondrial genomes that are extremely diverse, with the composition of the vestigial genome determining their translational requirements. Typically, translation within mitochondria is restricted to a few key subunits of the oxidative phosphorylation complexes that are synthesized by dedicated ribosomes (mitoribosomes). The dramatically rearranged mitochondrial genomes, the limited set of transcripts, and the need for the synthesized proteins to coassemble with nuclear-encoded subunits have had substantial consequences for the translation machinery. Recent high-resolution cryo-electron microscopy has revealed the effect of coevolution on the mitoribosome with the mitochondrial genome. In this review, we place the new structural information in the context of the molecular mechanisms of mitochondrial translation and focus on the novel ways protein synthesis is organized and regulated in mitochondria.
Axonemal dyneins are tethered to doublet microtubules inside cilia to drive ciliary beating, a process critical for cellular motility and extracellular fluid flow. Axonemal dyneins are evolutionarily ...and biochemically distinct from cytoplasmic dyneins that transport cargo, and the mechanisms regulating their localization and function are poorly understood. Here, we report a single-particle cryo-EM reconstruction of a three-headed axonemal dynein natively bound to doublet microtubules isolated from cilia. The slanted conformation of the axonemal dynein causes interaction of its motor domains with the neighboring dynein complex. Our structure shows how a heterotrimeric docking complex specifically localizes the linear array of axonemal dyneins to the doublet microtubule by directly interacting with the heavy chains. Our structural analysis establishes the arrangement of conserved heavy, intermediate and light chain subunits, and provides a framework to understand the roles of individual subunits and the interactions between dyneins during ciliary waveform generation.
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