Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.

MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4+T cells

T cell maturation and activation depend upon T cell receptor (TCR) interactions with a wide variety of antigenic peptides displayed in a given major histocompatibility complex (MHC) context. Complementarity-determining region 3 (CDR3) is the most variable part of the TCRα and -β chains, which govern interactions with peptide–MHC complexes. However, it remains unclear how the CDR3 landscape is shaped by individual MHC context during thymic selection of naïve T cells. We established two mouse strains carrying distinct allelic variants ofH2-Aand analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4+T (Tconv) and naïve regulatory CD4+T (Treg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-Ab) mice, the tuberculosis-susceptible H2-Ajmice had fewer CD4+T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for Tconvand was compensated for by peripheral reconstitution for Treg. We show that H2-Ajfavors selection of a narrower and more convergent repertoire with more hydrophobic and strongly interacting amino acid residues in the middle of CDR3α and CDR3β, suggesting more stringent selection against a narrower peptide–MHC-II context. H2-Ajand H2-Abmice have prominent reciprocal differences in CDR3α and CDR3β features, probably reflecting distinct modes of TCR fitting to MHC-II variants. These data reveal the mechanics and extent of how MHC-II shapes the naïve CD4+T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.

Endometrial Cancer

Lifestyle factors contribute appreciably to endometrial cancer risk, with obesity accounting for over one-third of incident cases in high-income societies. Unlike cervical cancer, which is a model of viral carcinogenesis, endometrial cancer is considered a model of hormonal carcinogenesis, as use of unopposed estrogens postmenopausally and obesity are the best-established risk factors. Endometrial cancer is also the only known malignancy for which cigarette smoking has been shown to confer protection. Risk reduction conferred by current smoking, past oral contraceptive use, childbearing, and physical activity is believed to be mediated by hormones. This may also apply to the increase in risk associated with obesity, which increases peripheral production of estrogens, and with diabetes mellitus. Hence, it should be possible to prevent a substantial fraction of endometrial cancers through lifestyle modification. Pathological classification of endometrial cancer is currently evolving and studies are revealing different molecular subtypes within the same histological groups.

A Socialist–Capitalist joint venture: Citroën in Romania during the 1980s

After summarising 1960s first Romanian industrial deals with the West countries, this paper explores the 1976–94 cooperation with the French automobile manufacturer Citroën to build a new automotive plant in Romania. The contract with Citroën established a joint venture in Romania to produce the Citroën Axel for Western markets (branded Oltcit in Romania, after the name of the Romanian company). The deal highlighted the importance of transport for state-building processes and for creating a modern society in socialist Romania through industrial capacity building. Citroën was instead looking for peripheral production centres to lower production costs and boost sales. Unmet production volumes and standards, and shaky supply lines, gradually undermined the project. The Oltcit–Citroën deal failed because, even with Citroën’s assistance, Romanian car manufactures proved incapable of producing flawless cars and of meeting delivery terms.

Experimental Autoimmune Encephalomyelitis Development Is Aggravated byCandida albicansInfection

Multiple sclerosis (MS) is an inflammatory/autoimmune disease of the central nervous system (CNS) mainly mediated by myelin specific T cells. It is widely believed that environmental factors, including fungal infections, contribute to disease induction or evolution. Even thoughCandidainfection among MS patients has been described, the participation of this fungus in this pathology is not clear. The purpose of this work was to evaluate the effect of aCandida albicansinfection on experimental autoimmune encephalomyelitis (EAE) that is a widely accepted model to study MS. Female C57BL/6 mice were infected withC. albicansand 3 days later, animals were submitted to EAE induction by immunization with myelin oligodendrocyte glycoprotein. Previous infection increased the clinical score and also the body weight loss. EAE aggravation was associated with expansion of peripheral CD4+T cells and production of high levels of TNF-α, IFN-γIL-6, and IL-17 by spleen and CNS cells. In addition to yeast and hyphae, fungus specific T cells were found in the CNS. These findings suggest thatC. albicansinfection before EAE induction aggravates EAE, and possibly MS, mainly by CNS dissemination and local induction of encephalitogenic cytokines. Peripheral production of encephalitogenic cytokines could also contribute to disease aggravation.

Correlation between Serum RANTES Levels and the Severity of Parkinson’s Disease

Inflammatory mediators may reflect a role of systemic inflammation in the neurodegenerative process of Parkinson’s disease (PD). Interleukin-6 (IL-6) and chemokine ligand 5 (CCL5), also known as RANTES (regulated on activation, normal T cell expressed and secreted), have been implicated in neurodegenerative diseases including PD. Serum levels of RANTES and IL-6 of 78 consecutive PD patients and age-matched 80 controls were measured. Patients with PD had higher RANTES and IL-6 levels compared with the controls. We found that serum RANTES levels strongly correlated with Hoehn-Yahr score and disease duration in PD patients. This study indicated that patients with PD have an on-going systemic inflammatory profile where the elevated peripheral production of RANTES may play a role in the neurodegenerative process.

Mercantilist origins of capitalism and its legacies: from birth to decline of Western hegemony

In this paper we trace capitalism from its origins in European expansion by commerce and conquest to the financialization of Western economies and the unraveling of Anglo–American hegemony. We emphasize continuities in the domination of metropolitan capital over peripheral production from the slave plantations to the outsourcing of manufacturing to cheap labor locations by multinational corporations. But the subordination of production to powerful agglomerations of commercial and financial capital has now penetrated the Western heartlands of capitalism, where rampant financialization is destroying productive capacity and has precipitated the most serious crisis since the 1930s. This predatory style of capitalism is more concerned with the accumulation of wealth by financial manipulation, mergers and acquisitions, privatization of public assets, and dispossession of peoples in distant lands than with investment in productive capacity. In this sense we may regard contemporary Western capitalism as a return to its mercantile commercial origins.

Cytokines in Bipolar Disorder: Recent Findings, Deleterious Effects But Promise for Future Therapeutics

An emerging body of evidence points to impairments in neuroplasticity, cell resilience, and neuronal survival as major pathophysiological mechanisms in bipolar disorder. Neuronal survival is influenced by several factors including an orchestrated action of neurotransmitters, hormones, and neurotrophins. Patients with bipolar disorder exhibit increased peripheral level of inflammatory mediators such as cytokines, mainly during acute mood episodes. These mediators interact in several pathways involved in regulation of mood and energy including hypothalamic-pituitary-adrenal axis and monoamine metabolism. Importantly, inflammatory cytokines have a potential role in controlling neuronal and glial cell loss that occurs during mood episodes, especially during mania, as they are the most powerful extracellular stimuli to apoptosis. Bipolar patients have been reported to show imbalanced peripheral production of cytokines both at the mRNA and protein levels, associated signal transduction machinery, as well as to have specific functional polymorphisms in the genes that encode these cytokines. Interestingly, lithium, valproate, and several antidepressants have demonstrated to have immunomodulatory properties. Growing evidence supports the involvement of inflammatory mechanisms in bipolar disorder, opening new paths of investigation using immunomodulatory medications. These findings can offer not only an opportunity of treating mood symptoms but also understanding and reverting neurobiological changes associated with the disorder.