Common Neural Mechanisms Underlying Reversal Learning by Reward and Punishment

Impairments in flexible goal-directed decisions, often examined by reversal learning, are associated with behavioral abnormalities characterized by impulsiveness and disinhibition. Although the lateral orbital frontal cortex (OFC) has been consistently implicated in reversal learning, it is still unclear whether this region is involved in negative feedback processing, behavioral control, or both, and whether reward and punishment might have different effects on lateral OFC involvement. Using a relatively large sample (N = 47), and a categorical learning task with either monetary reward or moderate electric shock as feedback, we found overlapping activations in the right lateral OFC (and adjacent insula) for reward and punishment reversal learning when comparing correct reversal trials with correct acquisition trials, whereas we found overlapping activations in the right dorsolateral prefrontal cortex (DLPFC) when negative feedback signaled contingency change. The right lateral OFC and DLPFC also showed greater sensitivity to punishment than did their left homologues, indicating an asymmetry in how punishment is processed. We propose that the right lateral OFC and anterior insula are important for transforming affective feedback to behavioral adjustment, whereas the right DLPFC is involved in higher level attention control. These results provide insight into the neural mechanisms of reversal learning and behavioral flexibility, which can be leveraged to understand risky behaviors among vulnerable populations.     

The Minichromosome Maintenance Replicative Helicase

The eukaryotic replicative helicase, the minichromosome maintenance (MCM) complex, is composed of six distinct, but related, subunits MCM(2–7). The relationship between the sequences of the subunits indicates that they are derived from a common ancestor and indeed, present-day archaea possess a homohexameric MCM. Recent progress in the biochemical and structural studies of both eukaryal and archaeal MCM complexes are beginning to shed light on the mechanisms of action of this key component of the replisome.The minichromosome maintenance (MCM) complex subunits are members of the AAA⁺ superfamily of ATPases and thus use energy derived from cycles of ATP binding and hydrolysis to move or reorganize bound substrates. In the case of the MCM complex, the energy is harnessed to effect DNA unwinding. The AAA⁺ proteins can be classified into seven distinct clades, based on the topography of their active sites. MCMs are members of clade 7, being characterized by the presence of an additional α-helix when compared with the classical AAA⁺ fold (Iyer et al. 2004; Erzberger and Berger 2006). In addition to the AAA⁺ domain, MCMs also have an amino-terminal domain (NTD) that plays a role in higher-order structure assembly. Finally, following the AAA⁺ domain is a degenerate winged helix (wH) structure (Fig. 1). Although the archaeal MCMs possess this simple NTD–AAA⁺–wH domain architecture, many of the eukaryal MCM(2–7) subunits are embellished with amino- or carboxy-terminal extensions that play roles in the regulation or recruitment of MCM(2–7). The eukaryal MCM complex is an important target for regulatory posttranslational modifications; the nature and consequences of these modifications are dealt with in Bell and Kaguni (2013), Tanaka and Araki (2013), and Siddiqui et al. (2013). Much of what we know regarding the inner workings of the MCM helicase has been learned from structural and mechanistic studies of the simple archaeal model (Sakakibara et al. 2009). Additionally, the crystal structures of distantly related superfamily three helicases, SV40 LTAg, and the E1 helicase of bovine papilloma virus, have provided important structural frameworks for understanding the mode of action of hexameric helicases (Gai et al. 2004; Enemark and Joshua-Tor 2006, 2008). In the following, we shall describe structural and mechanistic insights derived from studies of the simpler archaeal MCMs before extending our discussion to the eukaryotic assembly.Open in a separate windowFigure 1.(A) Linear representation of a monomer of the archaeal MCM. (Gray) The central AAA⁺ domain; (white) the flanking amino-terminal domains and winged helix (wH). The position of key secondary structural elements—(Zn) zinc-binding; (ACL) allosteric communication loop; (NBH) amino-terminal β-hairpin; (EXT-HP) external β-hairpin; (H2I) helix 2 insert; and (PS1BH) pre-sensor 1 β-hairpin—are indicated above the figure and shown by colored blocks, the colors corresponding to those used in panels B and C. Key residues involved in the ATPase active site are indicated below the figure. (Orange lines) A, B, and S1, shown as orange lines are the Walker A lysine (K346), Walker B glutamate (E404), and Sensor 1 asparagine (N448), respectively, and constitute “cis”-acting residues. (Black lines) “Trans”-acting residues T1 (R331), T2 (Q423), arginine finger (R473), and Sensor 2 (R560). Numbering is from SsoMCM.(B) Structure of a monomer of SsoMCM (lacking detail of the wH domain). Secondary structure elements are labeled and colored in cartoon format, using the color scheme in panel A. (Purple spheres) The atoms of the zinc-coordinating residues; (orange spheres) the cis-acting residues; (black spheres) the trans-residues.(C) Model of a symmetric hexamer of SsoMCM. (Left) View down the central cavity of SsoMCM, looking from the carboxy-terminal face. (Right) The same hexamer rotated 90° to show a side view. The two tiers corresponding to the amino-terminal and AAA⁺ domains are indicated. The color scheme is as in panels A and B. Panels B and C were generated from PDB entry 3F9V using PyMOL (http://www.pymol.org).     

Mitochondrial Regulation of Cell Death

Although required for life, paradoxically, mitochondria are often essential for initiating apoptotic cell death. Mitochondria regulate caspase activation and cell death through an event termed mitochondrial outer membrane permeabilization (MOMP); this leads to the release of various mitochondrial intermembrane space proteins that activate caspases, resulting in apoptosis. MOMP is often considered a point of no return because it typically leads to cell death, even in the absence of caspase activity. Because of this pivotal role in deciding cell fate, deregulation of MOMP impacts on many diseases and represents a fruitful site for therapeutic intervention. Here we discuss the mechanisms underlying mitochondrial permeabilization and how this key event leads to cell death through caspase-dependent and -independent means. We then proceed to explore how the release of mitochondrial proteins may be regulated following MOMP. Finally, we discuss mechanisms that enable cells sometimes to survive MOMP, allowing them, in essence, to return from the point of no return.In most organisms, mitochondria play an essential role in activating caspase proteases through a pathway termed the mitochondrial or intrinsic pathway of apoptosis. Mitochondria regulate caspase activation by a process called mitochondrial outer membrane permeabilization (MOMP). Selective permeabilization of the mitochondrial outer membrane releases intermembrane space (IMS) proteins that drive robust caspase activity leading to rapid cell death. However, even in the absence of caspase activity, MOMP typically commits a cell to death and is therefore considered a point of no return (Fig. 1). Because of this pivotal role in dictating cell fate, MOMP is highly regulated, mainly through interactions between pro- and antiapoptotic members of the Bcl-2 family. In this article, we begin by discussing how mitochondria may have evolved to become central players in apoptotic cell death. We then provide an overview of current models addressing the mechanics of MOMP, outlining how this crucial event leads to cell death through both caspase-dependent or -independent mechanisms. Finally, we discuss how caspase activity may be regulated post-MOMP and define other processes that allow cells to survive MOMP and, in effect, return from the point of no return.Open in a separate windowFigure 1.Mitochondrial regulation of cell death. Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP) can lead to caspase-dependent apoptosis (left) or caspase-independent cell death (right). Following MOMP, soluble proteins are released from the mitochondrial intermembrane space into the cytoplasm. Cytochrome c binds to monomeric Apaf-1 leading to its conformational change and oligomerization. Procaspase-9 is recruited to heptameric Apaf-1 complexes forming the apoptosome. This leads to activation of caspase-9 and, through caspase-9-mediated cleavage, activation of the executioner caspases-3 and -7. Release of Smac and Omi from the mitochondrial intermembrane space facilitates caspase activation by neutralizing the caspase inhibitor XIAP. MOMP can also lead to nonapoptotic cell death through a gradual loss of mitochondrial function and/or release of mitochondrial proteins that kill the cell in a caspase-independent manner.     

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development.     

Long-term population size of the North Atlantic humpback whale within the context of worldwide population structure

Once hunted to the brink of extinction, humpback whales (Megaptera novaeangliae) in the North Atlantic have recently been increasing in numbers. However, uncertain information on past abundance makes it difficult to assess the extent of the recovery in this species. While estimates of pre-exploitation abundance based upon catch data suggest the population might be approaching pre-whaling numbers, estimates based on mtDNA genetic diversity suggest they are still only a fraction of their past abundance levels. The difference between the two estimates could be accounted for by inaccuracies in the catch record, by uncertainties surrounding the genetic estimate, or by differences in the timescale to which the two estimates apply. Here we report an estimate of long-term population size based on nuclear gene diversity. We increase the reliability of our genetic estimate by increasing the number of loci, incorporating uncertainty in each parameter and increasing sampling across the geographic range. We report an estimate of long-term population size in the North Atlantic humpback of ~112,000 individuals (95 % CI 45,000–235,000). This value is 2–3 fold higher than estimates based upon catch data. This persistent difference between estimates parallels difficulties encountered by population models in explaining the historical crash of North Atlantic humpback whales. The remaining discrepancy between genetic and catch-record values, and the failure of population models, highlights a need for continued evaluation of whale population growth and shifts over time, and continued caution about changing the conservation status of this population.     

Classification of mitocans,anti-cancer drugs acting on mitochondria

Mitochondria have emerged as an intriguing target for anti-cancer drugs, inherent to vast majority if not all types of tumours. Drugs that target mitochondria and exert anti-cancer activity have become a focus of recent research due to their great clinical potential (which has not been harnessed thus far). The exceptional potential of mitochondria as a target for anti-cancer agents has been reinforced by the discouraging finding that even tumours of the same type from individual patients differ in a number of mutations. This is consistent with the idea of personalised therapy, an elusive goal at this stage, in line with the notion that tumours are unlikely to be treated by agents that target only a single gene or a single pathway. This endows mitochondria, an invariant target present in all tumours, with an exceptional momentum. This train of thoughts inspired us to define a class of anti-cancer drugs acting by way of mitochondrial ‘destabilisation’, termed ‘mitocans’. In this communication, we define mitocans (many of which have been known for a long time) and classify them into several classes based on their molecular mode of action. We chose the targets that are of major importance from the point of view of their role in mitochondrial destabilisation by small compounds, some of which are now trialled as anti-cancer agents. The classification starts with targets at the surface of mitochondria and ending up with those in the mitochondrial matrix. The purpose of this review is to present in a concise manner the classification of compounds that hold a considerable promise as potential anti-cancer drugs.     

Young Children's Probability of Dying Before and After Their Mother's Death: A Rural South African Population-Based Surveillance Study

Background

There is evidence that a young child''s risk of dying increases following the mother''s death, but little is known about the risk when the mother becomes very ill prior to her death. We hypothesized that children would be more likely to die during the period several months before their mother''s death, as well as for several months after her death. Therefore we investigated the relationship between young children''s likelihood of dying and the timing of their mother''s death and, in particular, the existence of a critical period of increased risk.

Methods and Findings

Data from a health and socio-demographic surveillance system in rural South Africa were collected on children 0–5 y of age from 1 January 1994 to 31 December 2008. Discrete time survival analysis was used to estimate children''s probability of dying before and after their mother''s death, accounting for moderators. 1,244 children (3% of sample) died from 1994 to 2008. The probability of child death began to rise 6–11 mo prior to the mother''s death and increased markedly during the 2 mo immediately before the month of her death (odds ratio [OR] 7.1 [95% CI 3.9–12.7]), in the month of her death (OR 12.6 [6.2–25.3]), and during the 2 mo following her death (OR 7.0 [3.2–15.6]). This increase in the probability of dying was more pronounced for children whose mothers died of AIDS or tuberculosis compared to other causes of death, but the pattern remained for causes unrelated to AIDS/tuberculosis. Infants aged 0–6 mo at the time of their mother''s death were nine times more likely to die than children aged 2–5 y. The limitations of the study included the lack of knowledge about precisely when a very ill mother will die, a lack of information about child nutrition and care, and the diagnosis of AIDS deaths by verbal autopsy rather than serostatus.

Conclusions

Young children in lower income settings are more likely to die not only after their mother''s death but also in the months before, when she is seriously ill. Interventions are urgently needed to support families both when the mother becomes very ill and after her death. Please see later in the article for the Editors'' Summary     

Evidence for Finely-Regulated Asynchronous Growth of Toxoplasma gondii Cysts Based on Data-Driven Model Selection

Toxoplasma gondii establishes a chronic infection by forming cysts preferentially in the brain. This chronic infection is one of the most common parasitic infections in humans and can be reactivated to develop life-threatening toxoplasmic encephalitis in immunocompromised patients. Host-pathogen interactions during the chronic infection include growth of the cysts and their removal by both natural rupture and elimination by the immune system. Analyzing these interactions is important for understanding the pathogenesis of this common infection. We developed a differential equation framework of cyst growth and employed Akaike Information Criteria (AIC) to determine the growth and removal functions that best describe the distribution of cyst sizes measured from the brains of chronically infected mice. The AIC strongly support models in which T. gondii cysts grow at a constant rate such that the per capita growth rate of the parasite is inversely proportional to the number of parasites within a cyst, suggesting finely-regulated asynchronous replication of the parasites. Our analyses were also able to reject the models where cyst removal rate increases linearly or quadratically in association with increase in cyst size. The modeling and analysis framework may provide a useful tool for understanding the pathogenesis of infections with other cyst producing parasites.