Cell Death and Neuronal Replacement during Formation of the Avian Ciliary Ganglion

AbstractProgrammed cell death is a prominent feature of embryonic development and is essential in matching the number of neurons to the target tissues that are innervated. Although a decrease in neuronal number which coincides with peripheral synaptogenesis has been well documented in the avian ciliary ganglion, it has not been clear whether cell death also occurs earlier. We observed TUNEL-positive neurons as early as stage 24, with a large peak at stage 29. This cell death at stage 29 was followed by a statistically significant (P < 0.0001) decrease in total neuron number at stage 31. The total number of neurons was recovered by stage 33/34. This suggested that dying neurons were replaced by new neurons. This replacement process did not involve proliferation because bromodeoxyuridine applied at stages 29 and 31 was unable to label neurons harvested at stage 33/34. The peak of cell death at stage 29 was increased 2.3-fold by removal of the optic vesicle and was reduced by 50% when chCNTF was overexpressed. Taken together, these results suggest that the regulation of neuron number in the ciliary ganglion is a dynamic process involving both cell death and neural replacement from postmitotic precursors prior to differentiation and innervation of target tissues

Intracellular Bacterial Infection and Invariant NKT Cells

The invariant (i) natural killer (NK)T cells represent a unique subset of T lymphocytes which express the Vα14 chain of the T cell receptor (TCR), that recognizes glycolipid antigens presented by the nonpolymorphic major histocompatibility complex (MHC) class I-like antigen presentation molecule CD1d, and they participate in protection against some microbial pathogens. Although iNKT cells have originally been regarded as T cells co-expressing NKR-P1B/C (NK1.1: CD 161), they do not seem to consistently express this marker, since NK1.1 surface expression on iNKT cells undergoes dramatic changes following facultative intracellular bacterial infection, which is correlated with functional changes of this cell population. Accumulating evidence suggests that NK1.1 allows recognition of "missing-self", thus controling activation/inhibition of NK1.1-expressing cells. Therefore, it is tempting to suggest that iNKT cells participate in the regulation of host immune responses during facultative intracellular bacterial infection by controlling NK1.1 surface expression. These findings shed light not only on the unique role of iNKT cells in microbial infection, but also provide evidence for new aspects of the NK1.1 as a regulatory molecule on these cells

Evolutionarily Conserved Linkage between Enzyme Fold, Flexibility, and Catalysis

Proteins are intrinsically flexible molecules. The role of internal motions in a protein's designated function is widely debated. The role of protein structure in enzyme catalysis is well established, and conservation of structural features provides vital clues to their role in function. Recently, it has been proposed that the protein function may involve multiple conformations: the observed deviations are not random thermodynamic fluctuations; rather, flexibility may be closely linked to protein function, including enzyme catalysis. We hypothesize that the argument of conservation of important structural features can also be extended to identification of protein flexibility in interconnection with enzyme function. Three classes of enzymes (prolyl-peptidyl isomerase, oxidoreductase, and nuclease) that catalyze diverse chemical reactions have been examined using detailed computational modeling. For each class, the identification and characterization of the internal protein motions coupled to the chemical step in enzyme mechanisms in multiple species show identical enzyme conformational fluctuations. In addition to the active-site residues, motions of protein surface loop regions (>10 Å away) are observed to be identical across species, and networks of conserved interactions/residues connect these highly flexible surface regions to the active-site residues that make direct contact with substrates. More interestingly, examination of reaction-coupled motions in non-homologous enzyme systems (with no structural or sequence similarity) that catalyze the same biochemical reaction shows motions that induce remarkably similar changes in the enzyme–substrate interactions during catalysis. The results indicate that the reaction-coupled flexibility is a conserved aspect of the enzyme molecular architecture. Protein motions in distal areas of homologous and non-homologous enzyme systems mediate similar changes in the active-site enzyme–substrate interactions, thereby impacting the mechanism of catalyzed chemistry. These results have implications for understanding the mechanism of allostery, and for protein engineering and drug design

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Chaining Behavior in Urban Tripmaking: A Critical Review

Although there exists a sizeable body of literature involving complex travel behavior most of this literature is of a highly fragmentary nature due to the lack of a comprehensive theoretical framework. Within the last decade transportation research has addressed such issues as activity time allocation (duration), destination choice, trip linkages, activity participation, activity scheduling, spatial/temporal constraints and the structure of multi-purpose travel but few studies have attempted to incorporate more than one or two of these concepts into a methodological framework. Similarly, a full range of models, from conceptual to empirical involving a wide range of techniques (e.g., Markov processes, Monte Carlo simulation, multiple regression analysis, utility maximization, etc.) have been employed with varying results. Although a descriptive review of all the existing literature would provide substantial background, a critical analysis of the most relevant sources serves as a better means to identify potential "building blocks" (i.e., variables, constraints, interactions, etc.) for use in the design and construction of a comprehensive theoretical framework. In general, three types of research were considered relevant to this study:&nbsp;(1) studies that isolated critical variables and investigated their influence on individual's observed behavior&nbsp;(2) studies that employed multivariate frameworks to examine the interactions between sets of variables, and&nbsp;(3) studies that developed behavioral theories and empirically tested various theoretical constructs.&nbsp;The hypotheses generated and the inferences drawn have been compared and contrasted so that both similarities and differences in the studies are revealed. To facilitate multiple comparisons between the various approaches, a literature taxonomy has also been constructed and is included in the appendix to this paper.&nbsp

Correction: Impact and Cost of Scaling Up Voluntary Medical Male Circumcision for HIV Prevention in the Context of the New 90-90-90 HIV Treatment Targets.

[This corrects the article DOI: 10.1371/journal.pone.0155734.]

Can Mechanical Strain and Aspect Ratio Be Used to Determine Codominant Unions in Red Maple without Included Bark

Arborists maintain trees in landscapes where failure can cause damage to infrastructure. Codominant branch unions are considered less stable than lateral branch unions. Previous research has found that unions can be considered codominant when aspect ratio is greater than 0.70 when included bark is present, yet it remains unclear if this threshold is reasonable in the absences of included bark. We utilized digital image correlation to measure strain (deformation) and separation angle to failure to better understand how mechanical loads move through Acer rubrum L. (red maple) branch unions. Strain was found to be higher in the branch regions in limb failure and ball and socket failure modes and strain was greater in the branch protection zone regions of imbedded and flat failures. Strain at failure was found to decrease with increasing aspect ratio, plateauing beyond aspect ratios of 0.83. In the absence of included bark, red maple branch unions appear to become codominant at aspect ratio of 0.83. We recommend that arborists should proactively manage to keep aspect ratios lower than 0.60 and consider mitigation options as aspect ratios approach 0.70