Cancer arises from multiple genetic errors occurring in a single stem cell (clonality). Every time DNA replicates, mistakes occur. Thus, agents can increase the risk of cancer either by directly ...damaging DNA (DNA-reactive carcinogens) or increasing the number of DNA replications (increased cell proliferation). Increased cell proliferation can be achieved either by direct mitogenesis or cytotoxicity with regenerative proliferation. Human carcinogens have a mode of action of DNA reactivity, immunomodulation (mostly immunosuppression), increased estrogenic activity (mitogenesis), or cytotoxicity and regeneration. By focusing on screening for these four effects utilizing in silico , in vitro , and short-term in vivo assays, a biologically based screening for human chemical carcinogens can be accomplished with greater predictivity than the traditional 2-year bioassay with considerably less cost, less time, and the use of fewer animals.
Abstract
SARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults are unclear. Here, we report SARS-CoV-2 specific T cell responses in infected adults ...and children and find that the acute and memory CD4
+
T cell responses to structural SARS-CoV-2 proteins increase with age, whereas CD8
+
T cell responses increase with time post-infection. Infected children have lower CD4
+
and CD8
+
T cell responses to SARS-CoV-2 structural and ORF1ab proteins when compared with infected adults, comparable T cell polyfunctionality and reduced CD4
+
T cell effector memory. Compared with adults, children have lower levels of antibodies to β-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses are increased, whilst monocyte numbers are reduced, indicating rapid adaptive co-ordination of the T and B cell responses and differing levels of inflammation. Therefore, reduced prior β-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis.
Abstract While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in ...schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl- d -aspartate receptor (NMDAR) function. By highlighting postmortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Many large and small decisions we make in our daily lives-which ice cream to choose, what research projects to pursue, which partner to marry-require an exploration of alternatives before committing ...to and exploiting the benefits of a particular choice. Furthermore, many decisions require re-evaluation, and further exploration of alternatives, in the face of changing needs or circumstances. That is, often our decisions depend on a higher level choice: whether to exploit well known but possibly suboptimal alternatives or to explore risky but potentially more profitable ones. How adaptive agents choose between exploitation and exploration remains an important and open question that has received relatively limited attention in the behavioural and brain sciences. The choice could depend on a number of factors, including the familiarity of the environment, how quickly the environment is likely to change and the relative value of exploiting known sources of reward versus the cost of reducing uncertainty through exploration. There is no known generally optimal solution to the exploration versus exploitation problem, and a solution to the general case may indeed not be possible. However, there have been formal analyses of the optimal policy under constrained circumstances. There have also been specific suggestions of how humans and animals may respond to this problem under particular experimental conditions as well as proposals about the brain mechanisms involved. Here, we provide a brief review of this work, discuss how exploration and exploitation may be mediated in the brain and highlight some promising future directions for research.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Time Discounting for Primary Rewards McClure, Samuel M; Ericson, Keith M; Laibson, David I ...
The Journal of neuroscience,
05/2007, Volume:
27, Issue:
21
Journal Article
Peer reviewed
Open access
Previous research, involving monetary rewards, found that limbic reward-related areas show greater activity when an intertemporal choice includes an immediate reward than when the options include ...only delayed rewards. In contrast, the lateral prefrontal and parietal cortex (areas commonly associated with deliberative cognitive processes, including future planning) respond to intertemporal choices in general but do not exhibit sensitivity to immediacy (McClure et al., 2004). The current experiments extend these findings to primary rewards (fruit juice or water) and time delays of minutes instead of weeks. Thirsty subjects choose between small volumes of drinks delivered at precise times during the experiment (e.g., 2 ml now vs 3 ml in 5 min). Consistent with previous findings, limbic activation was greater for choices between an immediate reward and a delayed reward than for choices between two delayed rewards, whereas the lateral prefrontal cortex and posterior parietal cortex responded similarly whether choices were between an immediate and a delayed reward or between two delayed rewards. Moreover, relative activation of the two sets of brain regions predicts actual choice behavior. A second experiment finds that when the delivery of all rewards is offset by 10 min (so that the earliest available juice reward in any choice is 10 min), no differential activity is observed in limbic reward-related areas for choices involving the earliest versus only more delayed rewards. We discuss implications of this finding for differences between primary and secondary rewards.
Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory ...coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.
•Voltage-gated Ca2+ influx triggers nuclear translocation of CaM in PV+ interneurons•CaMK signaling promotes CREB phosphorylation and activates key genes in PV+ cells•γCaMKI, not γCaMKII, operates to shuttle CaM to the nucleus in PV+ cells•Low CaMKIV levels rate-limit CREB phosphorylation in PV+ cells
Activity-dependent gene regulation is critical for long-term plasticity. Cohen et al. demonstrate that PV+ cortical interneurons rely on a CaM kinase-dependent signaling pathway, hinging on γCaMKI and rate-limited by CaMKIV, to trigger CREB phosphorylation and gene expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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