Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson's disease and depression.

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson's disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or 'enhancer/suppressor' screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ∼ 1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems

Biallelic mutations in calcium release activated channel regulator 2A (CRACR2A) cause a primary immunodeficiency disorder

CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca2+-NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damaging variants in CRACR2A has been identified. In this study, we describe a patient harboring biallelic variants in CRACR2A [paternal allele c.834 gaG> gaT (p.E278D) and maternal alelle c.430 Aga > Gga (p.R144G) c.898 Gag> Tag (p.E300*)], the gene encoding CRACR2A. The 33-year-old patient of East-Asian origin exhibited late onset combined immunodeficiency characterised by recurrent chest infections, panhypogammaglobulinemia and CD4+ T cell lymphopenia. In vitro exposure of patient B cells to a T-dependent stimulus resulted in normal generation of antibody-secreting cells, however the patient’s T cells showed pronounced reduction in CRACR2A protein levels and reduced proximal TCR signaling, including dampened SOCE and reduced JNK phosphorylation, that contributed to a defect in proliferation and cytokine production. Expression of individual allelic mutants in CRACR2A-deleted T cells showed that the CRACR2AE278D mutant did not affect JNK phosphorylation, but impaired SOCE which resulted in reduced cytokine production. The truncated double mutant CRACR2AR144G/E300* showed a pronounced defect in JNK phosphorylation as well as SOCE and strong impairment in cytokine production. Thus, we have identified variants in CRACR2A that led to late-stage combined immunodeficiency characterized by loss of function in T cells

Darwinism, organizational evolution and survival: key challenges for future research

How do social organizations evolve? How do they adapt to environmental pressures? What resources and capabilities determine their survival within dynamic competition? Charles Darwin’s seminal work The Origin of Species (1859) has provided a significant impact on the development of the management and organization theory literatures on organizational evolution. This article introduces the JMG Special Issue focused on Darwinism, organizational evolution and survival. We discuss key themes in the organizational evolution research that have emerged in recent years. These include the increasing adoption of the co-evolutionary approach, with a particular focus on the definition of appropriate units of analysis, such as routines, and related challenges associated with exploring the relationship between co-evolution, re-use of knowledge, adaptation, and exaptation processes. We then introduce the three articles that we have finally accepted in this Special Issue after an extensive, multi-round, triple blind-review process. We briefly outline how each of these articles contributes to understanding among scholars, practitioners and policy makers of the continuous evolutionary processes within and among social organizations and systems

Process account of curiosity and interest: a reward-learning perspective

Previous studies suggested roles for curiosity and interest in knowledge acquisition and exploration, but there has been a long-standing debate about how to define these concepts and whether they are related or different. In this paper, we address the definition issue by arguing that there is inherent difficulty in defining curiosity and interest, because both curiosity and interest are naïve concepts, which are not supposed to have a priori scientific definitions. We present a reward-learning framework of autonomous knowledge acquisition and use this framework to illustrate the importance of process account as an alternative to advance our understanding of curiosity and interest without being troubled by their definitions. The framework centers on the role of rewarding experience associated with knowledge acquisition and learning and posits that the acquisition of new knowledge strengthens the value of further information. Critically, we argue that curiosity and interest are the concepts that they subjectively construe through this knowledge-acquisition process. Finally, we discuss the implications of the reward-learning framework for education and empirical research in educational psychology

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales

Psycholinguistic variables matter in odor naming

People from Western societies generally find it difficult to name odors. In trying to explain this, the olfactory literature has proposed several theories that focus heavily on properties of the odor itself but rarely discuss properties of the label used to describe it. However, recent studies show speakers of languages with dedicated smell lexicons can name odors with relative ease. Has the role of the lexicon been overlooked in the olfactory literature? Word production studies show properties of the label, such as word frequency and semantic context, influence naming; but this field of research focuses heavily on the visual domain. The current study combines methods from both fields to investigate word production for olfaction in two experiments. In the first experiment, participants named odors whose veridical labels were either high-frequency or low-frequency words in Dutch, and we found that odors with high-frequency labels were named correctly more often. In the second experiment, edibility was used for manipulating semantic context in search of a semantic interference effect, presenting the odors in blocks of edible and inedible odor source objects to half of the participants. While no evidence was found for a semantic interference effect, an effect of word frequency was again present. Our results demonstrate psycholinguistic variables-such as word frequency-are relevant for olfactory naming, and may, in part, explain why it is difficult to name odors in certain languages. Olfactory researchers cannot afford to ignore properties of an odor's label

Not all flavor expertise is equal : The language of wine and coffee experts

People in Western cultures are poor at naming smells and flavors. However, for wine and coffee experts, describing smells and flavors is part of their daily routine. So are experts better than lay people at conveying smells and flavors in language? If smells and flavors are more easily linguistically expressed by experts, or more "codable", then experts should be better than novices at describing smells and flavors. If experts are indeed better, we can also ask how general this advantage is: do experts show higher codability only for smells and flavors they are expert in (i.e., wine experts for wine and coffee experts for coffee) or is their linguistic dexterity more general? To address these questions, wine experts, coffee experts, and novices were asked to describe the smell and flavor of wines, coffees, everyday odors, and basic tastes. The resulting descriptions were compared on a number of measures. We found expertise endows a modest advantage in smell and flavor naming. Wine experts showed more consistency in how they described wine smells and flavors than coffee experts, and novices; but coffee experts were not more consistent for coffee descriptions. Neither expert group was any more accurate at identifying everyday smells or tastes. Interestingly, both wine and coffee experts tended to use more source-based terms (e.g., vanilla) in descriptions of their own area of expertise whereas novices tended to use more evaluative terms (e.g., nice). However, the overall linguistic strategies for both groups were en par. To conclude, experts only have a limited, domain-specific advantage when communicating about smells and flavors. The ability to communicate about smells and flavors is a matter not only of perceptual training, but specific linguistic training too