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This article uses ethnographic and qualitative research to explore the health implications and social responses of a low-income neighborhood in Southeast England, to more than a decade of austerity policies and declining institutional and welfare support. Findings examine how cuts to public services and welfare programs alongside changes to the area's social structure shape resident's perceptions of health risks and threats. Residents pointed to poor levels of mental health that were exacerbated by financial insecurity, the closure of community facilities and difficulties accessing support and professional help. An increase in social disorder and sense of danger within the vicinity were attributed to changes in the area's social composition and a reduction of policing in the neighborhood, which were an additional cause of anxiety for residents. Many people felt their neighborhood was treated inequitably with regard to law-and-order, health provision and other services designed to address health problems and risks and dangers in their social environment. This institutional vacuum generates unmet health needs facilitating informal practices and methods for managing health, such as through self-provision or using alternative, and more readily available, sources of medical advice and treatment. The demise of older forms of social control and surveillance that ran parallel with closure of the area's communal spaces had been partly compensated by social media usage, while informal methods of policing were a growing presence in the neighborhood in reaction to rising lawlessness and the ineffectiveness of police and local authorities. [ABSTRACT FROM AUTHOR]

Proteasome activator 28γ (PA28γ/REGγ) is a member of the 11S family of proteasomal regulators that is constitutively expressed in the nucleus and implicated in various diseases, including certain cancers and systemic lupus erythematosus. Despite years of investigation, how PA28γ functions to stimulate proteasomal protein degradation remains unclear. Alternative hypotheses have been proposed for the molecular mechanism of PA28γ, including the following: (1) substrate selection, (2) allosteric upregulation of the trypsin-like (T-L) site, (3) allosteric inhibition of the chymotrypsin-like (CT-L) and caspase-like (C-L) sites, (4) conversion of the CT-L or C-L sites to new T-L sites, and (5) gate opening alone or in combination with a previous hypothesis. Here, by mechanistically decoupling gating effects from active site effects, we unambiguously demonstrate that WT PA28γ allosterically activates the T-L site. We show PA28γ binding increases the Kcat/Km by 13-fold for T-L peptide substrates while having little-to-no effect on hydrolysis kinetics for CT-L or C-L substrates. Furthermore, mutagenesis and domain swaps of PA28γ reveal that it does not select for T-L peptide substrates through either the substrate entry pore or the distal intrinsically disordered region. We also show that a previously reported point mutation can functionally switch PA28γ from a T-L activating to a gateopening activator in a mutually exclusive fashion. Finally, using cryogenic electron microscopy, we visualized the PA28γ-proteasome complex at 4.3 Å and confirmed its expected quaternary structure. The results of this study provide unambiguous evidence that PA28γ can function by binding the 20S proteasome to allosterically activate the T-L proteolytic site. [ABSTRACT FROM AUTHOR]

The hippocampus (HPC) and retrosplenial cortex (RSC) are key components of the brain's memory and navigation systems. Lesions of either region produce profound deficits in spatial cognition and HPC neurons exhibit well‐known spatial firing patterns (place fields). Recent studies have also identified an array of navigation‐related firing patterns in the RSC. However, there has been little work comparing the response properties and information coding mechanisms of these two brain regions. In the present study, we examined the firing patterns of HPC and RSC neurons in two tasks which are commonly used to study spatial cognition in rodents, open field foraging with an environmental context manipulation and continuous T‐maze alternation. We found striking similarities in the kinds of spatial and contextual information encoded by these two brain regions. Neurons in both regions carried information about the rat's current spatial location, trajectories and goal locations, and both regions reliably differentiated the contexts. However, we also found several key differences. For example, information about head direction was a prominent component of RSC representations but was only weakly encoded in the HPC. The two regions also used different coding schemes, even when they encoded the same kind of information. As expected, the HPC employed a sparse coding scheme characterized by compact, high contrast place fields, and information about spatial location was the dominant component of HPC representations. RSC firing patterns were more consistent with a distributed coding scheme. Instead of compact place fields, RSC neurons exhibited broad, but reliable, spatial and directional tuning, and they typically carried information about multiple navigational variables. The observed similarities highlight the closely related functions of the HPC and RSC, whereas the differences in information types and coding schemes suggest that these two regions likely make somewhat different contributions to spatial cognition. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) plays a key role in behavioral flexibility, and the ability to resolve conflict from shifting strategies, task rules or attentional demands seems to be a hallmark of PFC function. Conflict also occurs in the domain of memory and the PFC plays an important role in the ability to cope with interference between competing retrieval targets. Previous studies often involved both interference and changes in task demands, which makes it difficult to determine the degree to which mnemonic interference per se engages PFC processing. We trained rats on a continuous matching to sample task in two conditions that varied in terms of the amount of interference present but not the task demands and found that temporary inactivation of the medial PFC caused a greater impairment in the high-interference condition. This result suggests that the PFC plays an important role in resolving interference which can be distinguished from its role in shifting task demands. [ABSTRACT FROM AUTHOR]

The conventional vibration-rotation Hamiltonian for an asymmetric-top molecule is rewritten by expanding the elements of the inverse inertial tensor about the equilibrium molecular geometry. The approach allows the identification of terms in the Hamiltonian that couple states differing by two, three, or four vibrational quanta and hence the calculation of dimensioned Coriolis ξ coupling coefficients for interacting fundamental, overtone, and combination levels. The matrix elements that result from the application of the expanded Hamiltonian depend upon the harmonic vibrational wave numbers, equilibrium moments of inertia, Coriolis ζ parameters, and the derivatives of the elements of the inertial tensor matrix with respect to each of the normal coordinates. The Coriolis coupling coefficients may be calculated through evaluation of the summations that result from the appropriate terms. The validity of the approach is demonstrated through the calculation of coupling coefficients for interacting levels in formaldehyde and ketene. The uncertainty in the calculated values of the coupling coefficients is typically better than ±6%, although the values calculated for interactions that involve low-frequency vibrational modes are less reliable. Comparisons are made between the calculated values and experimental results. © 2005 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The effect of replacing the standard single-determinant reference wave functions in variants of G2 and G3 theory by multireference (MR) wave functions based on a full-valence complete active space has been investigated. Twelve methods of this type have been introduced and comparisons, based on a slightly reduced G2-1 test set, are made both internally and with the equivalent single-reference methods. We use CASPT2 as the standard MR-MP2 method and MRCl+Q as the higher correlation procedure in these calculations. We find that MR-G2(MP2,SVP), MR-G2(MP2), and MR-G3(MP2) perform comparably with their single-reference analogs, G2(MP2,SVP), G2(MP2), and G3(MP2), with mean absolute deviations (MADs) from the experimental data of 1.41, 1.54, and 1.23 kcal mol&sup-1;, compared with 1.60, 1.59, and 1.19 kcal mol&sup-1;, respectively. The additivity assumptions in the MR-Gn methods have been tested by carrying out MR-G2/MRCI+Q and MR-G3/MRCI+Q calculations, which correspond to large-basis-set MRCI + Q + ZPVE + HLC calculations. These give MADs of 1.84 and 1.58 kcal mol&sup-1;, respectively, i.e., the agreement with experiment is somewhat worse than that obtained with the MR-G2(MP2) and MR-G3(MP2) methods. In a third series of calculations, we have examined pure MP2 and MR-MP2 analogs of the G2 and G3 procedures by carrying out large-basis-set MP2 and CASPT2(+ZPVE+HLC) calculations. The resultant methods, which we denote G2/MP2, G3/MP2, MR-G2/MP2, and MR-G3/MP2, give MADs of 4.19, 3.36, 2.01, and 1.66 kcal mol&sup-1;, respectively. Finally, we have examined the effect of using MCQDPT2 in place of CASPT2 in five of our MR-Gn procedures, and find that there is a small but consistent deterioration in performance. Our calculations suggest that the MR-G3(MP2) and MR-G3/MP2 procedures may be useful in situations where a multireference approach is desirable. [ABSTRACT FROM AUTHOR]

The retrosplenial cortex (RSC) has recently begun to gain widespread interest because of its anatomical connectivity with other well-known memory structures, such as the hippocampus and anterior thalamus, and its role in spatial, contextual, and episodic memory. Although much of the current work on the RSC is focused on spatial cognition, there is also an extensive literature that shows that the RSC plays a critical role in a variety of conditioning tasks that have no obvious spatial component. Many of these studies suggest that the RSC is involved in identifying and encoding behaviorally significant cues, particularly those cues that predict reinforcement or the need for a behavioral response. Consistent with this idea, recent studies have shown that RSC neurons also encode cues in spatial navigation tasks. In this article, we review these findings and suggest that the encoding of cues is an important component of the RSC contribution to many forms of learning. [ABSTRACT FROM AUTHOR]

The presence of multiple paramagnetic species can lead to overlapping electron paramagnetic resonance (EPR) signals. This complication can be a critical obstacle for the use of EPR to unravel mechanisms and aid the understanding of earth abundant metal catalysis. Furthermore, redox or spin-crossover processes can result in the simultaneous presence of metal centres in different oxidation or spin states. In this contribution, pulse EPR experiments on model systems containing discrete mixtures of Cr(i) and Cr(iii) or Cu(ii) and Mn(ii) complexes demonstrate the feasibility of the separation of the EPR spectra of these species by inversion recovery filters and the identification of the relevant spin states by transient nutation experiments. We demonstrate the isolation of component spectra and identification of spin states in a mixture of catalyst precursors. The usefulness of the approach is emphasised by monitoring the fate of the chromium species upon activation of an industrially used precatalyst system. [ABSTRACT FROM AUTHOR]

The proteasome, a complex multi-catalytic protease machinery, orchestrates the protein degradation essential for maintaining cellular homeostasis, and its dysregulation also underlies many different types of diseases. Its function is regulated by many different mechanisms that encompass various factors such as proteasome activators (PAs), adaptor proteins, and post-translational modifications. This review highlights the unique characteristics of proteasomal regulation through the lens of a distinct family of regulators, the 11S, REGs, or PA26/PA28. This ATP-independent family, spanning from amoebas to mammals, exhibits a common architectural structure; yet, their cellular biology and criteria for protein degradation remain mostly elusive. We delve into their evolution and cellular biology, and contrast their structure and function comprehensively, emphasizing the unanswered questions regarding their regulatory mechanisms and broader roles in proteostasis. A deeper understanding of these processes will illuminate the roles of this regulatory family in biology and disease, thus contributing to the advancement of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Considering the link between neurodegenerative diseases and impaired proteasome function, and the neuro-protective impact of enhanced proteasome activity in animal models, it's crucial to understand proteasome activation mechanisms. A hydrophobic-tyrosine-any residue (HbYX) motif on the C-termini of proteasome-activating complexes independently triggers gate-opening of the 20S core particle for protein degradation; however, the causal allosteric mechanism remains unclear. Our study employs a structurally irreducible dipeptide HbYX mimetic to investigate the allosteric mechanism of gate-opening in the archaeal proteasome. High-resolution cryo-EM structures pinpoint vital residues and conformational changes in the proteasome α-subunit implicated in HbYX-dependent activation. Using point mutations, we simulated the HbYX-bound state, providing support for our mechanistic model. We discerned four main mechanistic elements triggering gate-opening: 1) back-loop rearrangement adjacent to K66, 2) intra- and inter- α subunit conformational changes, 3) occupancy of the hydrophobic pocket, and 4) a highly conserved isoleucine-threonine pair in the 20S channel stabilizing the open and closed states, termed the "IT switch." Comparison of different complexes unveiled convergent and divergent mechanism of 20S gate-opening among HbYX-dependent and independent activators. This study delivers a detailed molecular model for HbYX-dependent 20S gate-opening, enabling the development of small molecule proteasome activators that hold promise to treat neurodegenerative diseases. Cryo-EM structures and mutagenesis of the archaeal 20S proteasome with a small molecular activator mimicking the HbYX motif reveal new details of a conserved gating switch mechanism and mechanistic differences between HbYX-dependent and -independent gate-opening [ABSTRACT FROM AUTHOR]

The implication of reduced proteasomal function in neurodegenerative diseases combined with studies showing the protective effects of increasing proteasome activity in animal models highlight the need to understand the capacity for proteasome activation by small molecules. The C-terminal HbYX motif is present on many proteasome binding proteins and functions to tether activators to the 20S core particle. Previous studies have shown that peptides with a HbYX motif can autonomously activate 20S gate-opening to allow protein degradation. In this study, through an iterative process of peptide synthesis, we design a HbYX-like dipeptide mimetic that represents only the fundamental components of the HbYX motif. The mimetic robustly induces gate-opening in archaeal, yeast, and mammalian proteasomes. We identify multiple proteasome α subunit residues in the archaeal proteasome involved in HbYX-dependent activation. When stimulated by the mimetic, the mammalian 20S can degrade unfolded proteins such as tau. Findings using our peptide mimetic suggest the HbYX-dependent mechanism requires cooperative binding in at least two intersubunit pockets of the α ring. Most significantly, our peptide mimetic reverses proteasome impairment by neurodegenerative disease-associated oligomers. Collectively, these results validate HbYX-like molecules as having robust potential to stimulate proteasome function, which are potentially useful for treating neurodegenerative diseases. An HbYX-like dipeptide induces gate-opening in archaeal, yeast, and mammalian 20S proteasomes, stimulates proteasome activity, and reverses inhibition of the proteasome by toxic protein oligomers that are implicated in various neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The reactions catalyzed by coenzyme B12 dependent enzymes are formally initiated by the homolytic cleavage of a carbon-cobalt bond and a subsequent or concerted H-atom-transfer reaction. A reasonable model chemistry for describing those reactions should, therefore, account for an accurate description of both reactions. The inherent limitation due to the necessary system size renders the coenzyme B12 system a suitable candidate for DFT or hybrid QM/MM methods; however, the accurate description of both homolytic Co-C cleavage and H-atom-transfer reactions within this framework is challenging and can lead to controversial results with varying accuracy. We present an assessment study of 16 common density functionals applied to prototypical model systems for both reactions. H-abstraction reactions were modeled on the basis of four reference reactions designed to resemble a broad range of coenzyme B12 reactions. The Co-C cleavage reaction is treated by an ONIOM(QM/MM) setup that is in excellent agreement with solution-phase experimental data and is as accurate as full DFT calculations on the complete model system. We find that the meta-GGAs TPSS-D3 and M06L-D3 and the meta-hybrid M06-D3 give the best overall performance with MUEs for both types of reactions below 10 kJ mol-1. Our recommended model chemistry allows for a fast and accurate description of coenzyme B12 chemistry that is readily applicable to study the reactions in an enzymatic framework. [ABSTRACT FROM AUTHOR]

Background and Purpose: Free fatty acid receptors FFA1 and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation causes the release of glucagon-like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic β cells. As these receptors are modulators of nutrient-stimulated glucose regulation, the aim of this study was to compare the pharmacology of commercially available agonists (TUG424, TUG891, GW9508) with proven selective agonists (JTT, TAK-875, AZ423, Metabolex-36) in mice.Experimental Approach: Mouse mucosa was mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (Isc ) was recorded continuously. Pretreatments included antagonists of FFA1, Y1  or Y2 receptors. Glucose sensitivity was investigated by mannitol replacement apically, and colonic and upper GI transit was assessed in vitro and in vivo.Key Results: FFA1 and FFA4 agonism required glucose and reduced Isc in a PYY-Y1 receptor-dependent manner. The novel compounds were more potent than GW9508. The FFA1 antagonists (GW1100 and ANT825) blocked FFA1 activity only and revealed FFA1 tonic activity. The FFA4 agonist, Metabolex-36, slowed colonic transit in vitro but increased small intestinal transit in vivo.Conclusions and Implications: The selective FFA1 and FFA4 agonists were more potent at reducing Isc than GW9508, a dual FFA1 and FFA4 agonist. A paracrine epithelial mechanism involving PYY-stimulated Y1 receptors mediated their responses, which were glucose sensitive, potentially limiting hypoglycaemia. ANT825 revealed tonic activity and the possibility of endogenous FFA1 ligands causing PYY release. Finally, FFA4 agonism induced regional differences in transit. [ABSTRACT FROM AUTHOR]

We present a procedure for localization of deuterium uptake from overlapping proteolytic peptides to contiguous protein parts called segments. A system of linear equations expressing experimental peptide uptakes in segments cannot be solved by ordinary methods because of insufficient rank and/or linearly dependent peptides. Solvable segments are identified, and their uptakes and associated variances are evaluated by using the Moore-Penrose pseudoinverse. The method also allows consistency check of experimental data and detection of outliers. The conditions for segment solvability are formulated in a peptide graph. From the peptide graph, it is easy to find more useful information hidden in the experimental data, like sums or differences of unsolvable segment uptakes. Expected localization gain was estimated from simulations with random peptide arrangements. The recently proposed averaging method (Keppel TR, Weis DD. J. Am. Soc. Mass Spectrom. 2015; 26: 547) for resolution of exchange halftimes was extended to resolution of uptakes and combined with the present approach to achieve maximum uptake localization, which is also consistent with experimental data. [ABSTRACT FROM AUTHOR]

Virtually all age-related neurodegenerative diseases (NDs) can be characterized by the accumulation of proteins inside and outside the cell that are thought to significantly contribute to disease pathogenesis. One of the cell's primary systems for the degradation of misfolded/damaged proteins is the ubiquitin proteasome system (UPS), and its impairment is implicated in essentially all NDs. Thus, upregulating this system to combat NDs has garnered a great deal of interest in recent years. Various animal models have focused on stimulating 26S activity and increasing 20S proteasome levels, but thus far, none have targeted intrinsic activation of the 20S proteasome itself. Therefore, we constructed an animal model that endogenously expresses a hyperactive, open gate proteasome in Caenorhabditis elegans. The gate-destabilizing mutation that we introduced into the nematode germline yielded a viable nematode population with enhanced proteasomal activity, including peptide, unstructured protein, and ubiquitin-dependent degradation activities. We determined these nematodes showed a significantly increased lifespan and substantial resistance to oxidative and proteotoxic stress but a significant decrease in fecundity. Our results show that introducing a constitutively active proteasome into a multicellular organism is feasible and suggests targeting the proteasome gating mechanism as a valid approach for future age-related disease research efforts in mammals. [ABSTRACT FROM AUTHOR]

The hippocampus, retrosplenial cortex and anterior thalamus are key components of a neural circuit known to be involved in a variety of memory functions, including spatial, contextual and episodic memory. In this review, we focus on the role of this circuit in contextual memory processes. The background environment, or context, is a powerful cue for memory retrieval, and neural representations of the context provide a mechanism for efficiently retrieving relevant memories while avoiding interference from memories that belong to other contexts. Data from experimental lesions and neural manipulation techniques indicate that each of these regions is critical for contextual memory. Neurophysiological evidence from the hippocampus and retrosplenial cortex suggest that contextual information is represented within this circuit by population-level neural firing patterns that reliably differentiate each context a subject encounters. These findings indicate that encoding contextual information to support context-dependent memory retrieval is a key function of this circuit. [ABSTRACT FROM AUTHOR]

Highlights: [•] Contextual information plays a critical role in memory. [•] Contexts are represented by coherent ensembles of hippocampal neurons. [•] Activity in these ensembles primes the retrieval of context appropriate memories. [•] Priming the relevant memories prevents interference by other, irrelevant memories. [ABSTRACT FROM AUTHOR]

Explaining variability observed in the accretion flows of black hole X-ray binary systems remains challenging, especially concerning timescales less than, or comparable to, the viscous timescale but much larger than the inner orbital period despite decades of research identifying numerous relevant physical mechanisms. We take a simplified but broad approach to study several mechanisms likely relevant to patterns of variability observed in the persistently high-soft Roche-lobe overflow system LMC X-3. Based on simple estimates and upper bounds, we find that physics beyond varying disk/corona bifurcation at the disk edge, Compton-heated winds, modulation of total supply rate via irradiation of the companion, and the likely extent of the partial hydrogen ionization instability is needed to explain the degree, and especially the pattern, of variability in LMC X-3 largely due to viscous dampening. We then show how evaporation-condensation may resolve or compound the problem given the uncertainties associated with this complex mechanism and our current implementation. We briefly mention our plans to resolve the question, refine and extend our model, and alternatives we have not yet explored. [ABSTRACT FROM AUTHOR]

The anterior thalamus (AT) is anatomically interconnected with the hippocampus and other structures known to be involved in memory, and the AT is involved in many of the same learning and memory functions as the hippocampus. For example, like the hippocampus, the AT is involved in spatial cognition and episodic memory. The hippocampus also has a well-documented role in contextual memory processes, but it is not known whether the AT is similarly involved in contextual memory. In the present study, we assessed the role of the AT in contextual memory processes by temporarily inactivating the AT and training rats on a recently developed context-based olfactory list learning task, which was designed to assess the use of contextual information to resolve interference. Rats were trained on one list of odor discrimination problems, followed by training on a second list in either the same context or a different context. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. Control rats that learned the two lists in different contexts performed significantly better than rats that learned the two lists in the same context. However, AT lesions completely abolished this contextual learning advantage, a result that is very similar to the effects of hippocampal inactivation. These findings demonstrate that the AT, like the hippocampus, is involved in contextual memory and suggest that the hippocampus and AT are part of a functional circuit involved in contextual memory. [ABSTRACT FROM AUTHOR]

In recent years, many animal models of memory have focused on one or more of the various components of episodic memory. For example, the odor sequence memory task requires subjects to remember individual items and events (the odors) and the temporal aspects of the experience (the sequence of odor presentation). The well-known spatial context coding function of the hippocampus, as exemplified by place cell firing, may reflect the "where" component of episodic memory. In the present study, we added a contextual component to the odor sequence memory task by training rats to choose the earlier odor in one context and the later odor in another context and we compared the effects of temporary hippocampal lesions on performance of the original single context task and the new dual context task. Temporary lesions significantly impaired the single context task, although performance remained significantly above chance levels. In contrast, performance dropped all the way to chance when temporary lesions were used in the dual context task. These results demonstrate that rats can learn a dual context version of the odor sequence learning task that requires the use of contextual information along with the requirement to remember the "what" and "when" components of the odor sequence. Moreover, the addition of the contextual component made the task fully dependent on die hippocampus. [ABSTRACT FROM AUTHOR]

Electrically controllable deoxyribonuclic acid (DNA) nanolevers are used to investigate the binding interaction between Influenza A/Aichi/2/1968 and the peptide called "PeB", which specifically binds the viral surface protein hemagglutinin. PeB is immobilized on gold electrodes of a "switchSENSE" biochip by conjugation to DNA‐strands that are hybridized to complementary anchors. The surface‐tethered DNA strand carries a fluorophore while the complementary strand is a multivalent arrangement carrying up to three PeB peptides. The nanolevers are kept upright (static) by applying a negative potential. Signal read‐out for this static measurement mode is the change in fluorescence intensity due to changes in the local environment of the dye upon binding. Measurements of virus‐peptide interaction show that the virus material specifically binds to the immobilized peptides and remains bound throughout the measurement time. Immobilized viruses are subsequently used as ligands to characterize oligovalent peptide binding to hemagglutinin, revealing rate constants of the interaction. Moreover, three Influenza A subtypes are compared in their binding behavior. Overall, this paper shows the ability to immobilize virus material on a sensor surface, which allows to target virus‐proteins in their native environment. The "switchSENSE" method is therefore applicable to characterize virus‐receptor interactions. [ABSTRACT FROM AUTHOR]

Complex cognitive functions, such as learning and memory, arise from the interaction of multiple brain regions that comprise functional circuits and different components of these circuits make unique contributions to learning. The hippocampus and the retrosplenial cortex (RSC) are anatomically interconnected and both regions are involved in learning and memory. Previous studies indicate that the hippocampus exhibits unique firing patterns for different contexts and that RSC neurons selectively respond to cues that predict reinforcement or the need for a behavioral response, suggesting a hippocampal role in encoding contexts and an RSC role in encoding behaviorally significant cues. To test this, we simultaneously recorded hippocampal and RSC neuronal activity as rats learned to discriminate two behavioral contexts. The rats learned to approach the east arm of a plus maze for reward during the first half of each session and to approach the west arm during the second half. The 'go east' and 'go west' conditions constitute distinct behavioral contexts, which were cued by the reward location. Neurons in both regions developed highly context-specific responses as subjects learned to discriminate the contexts, but the response patterns differed in the two brain regions. Consistent with a context processing role, hippocampal neurons developed context-specific responses to a variety of task stimuli and events. In contrast, RSC neurons only developed context-specific responses to the reward location, which served as the context identifying cue. These results suggest that the hippocampus and RSC play distinct, but complimentary roles in mediating context appropriate memories and behaviors. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This article describes a collection of Fortran-95 routines for evaluating the exponential integral function, error function, sine and cosine integrals, Fresnel integrals, Bessel functions, and related mathematical special functions using the FM multiple-precision arithmetic package. [ABSTRACT FROM AUTHOR]

We introduce Network Automata, a framework which couples the topological evolution of a network to its structure. To demonstrate its implementation we describe a simple model which exhibits behavior similar to the "Game of Life" before recasting some simple, well-known network models as Network Automata. We then introduce Functional Network Automata which are useful for dealing with networks in which the topology evolves according to some specified microscopic rules and, simultaneously, there is a dynamic process taking place on the network that both depends on its structure but is also capable of modifying it. It is a generic framework for modeling systems in which network structure, dynamics, and function are interrelated. At the practical level, this framework allows for precise, unambiguous implementation of the microscopic rules involved in such systems. To demonstrate the approach, we develop a family of simple biologically inspired models of fungal growth. [ABSTRACT FROM AUTHOR]

Summary: In the eukaryotic 26S proteasome, the 20S particle is regulated by six AAA ATPase subunits and, in archaea, by a homologous ring complex, PAN. To clarify the role of ATP in proteolysis, we studied how nucleotides bind to PAN. Although PAN has six identical subunits, it binds ATPs in pairs, and its subunits exhibit three conformational states with high, low, or no affinity for ATP. When PAN binds two ATPγS molecules or two ATPγS plus two ADP molecules, it is maximally active in binding protein substrates, associating with the 20S particle, and promoting 20S gate opening. However, binding of four ATPγS molecules reduces these functions. The 26S proteasome shows similar nucleotide dependence. These findings imply an ordered cyclical mechanism in which two ATPase subunits bind ATP simultaneously and dock into the 20S. These results can explain how these hexameric ATPases interact with and “wobble” on top of the heptameric 20S proteasome. [ABSTRACT FROM AUTHOR]

This article describes a collection of Fortran-95 routines for evaluating the exponential integral function, error function, sine and cosine integrals, Fresnel integrals, Bessel functions, and related mathematical special functions using the FM multiple-precision arithmetic package. [ABSTRACT FROM AUTHOR]

Protein degradation in the 20S proteasome is regulated in eukaryotes by the 19S ATPase complex and in archaea by the homologous PAN ATPase ring complex. Subunits of these hexameric ATPases contain on their C-termini a conserved hydrophobic-tyrosine-X (HbYX) motif that docks into pockets in the 20S to stimulate the opening of a gated substrate entry channel. Here, we report the crystal structure of the archaeal 20S proteasome in complex with the C-terminus of the archaeal proteasome regulatory ATPase, PAN. This structure defines the detailed interactions between the critical C-terminal HbYX motif and the 20S α-subunits and indicates that the intersubunit pocket in the 20S undergoes an induced-fit conformational change on binding of the HbYX motif. This structure together with related mutagenesis data suggest how in eukaryotes certain proteasomal ATPases bind to specific pockets in an asymmetrical manner to regulate gate opening. [ABSTRACT FROM AUTHOR]

High-level quantum chemistry calculations have been performed to examine the carbon-skeleton rearrangement of the tropane alkaloid littorine to hyoscyamine. Two pathways involving radical and carbocation intermediates have been investigated in this regard, namely, stepwise (or fragmentation--recombination) and concerted. The fragmentation products are calculated to be of high energy for both the radical- and carbocation-based mechanisms (136.3 and 170.9 kJ mol-1, respectively). Similarly, the rearrangement barrier for the radical-based concerted pathway is calculated to be quite high (135.6 kJ mol-1). In contrast, the carbocation-based concerted pathway is found to be associated with a relatively low barrier (47.4 kJ mol-1). The ionization energy of the substrate-derived radical 3a is calculated to be 7.01 eV, suggesting that its oxidation to generate the substrate-derived carbocation 3b ought to be facile. In an attempt to investigate how an enzyme might modulate the rearrangement barriers, the separate and combined influences of partially protonating the migrating group and partially deprotonating the spectator OH group of the substrate were investigated. Such interactions can lead to significant reductions in the rearrangement barrier for both the radical- and carbocation-based concerted pathways, although the carbocation pathway continues to have significantly lower energy requirements. Also, the relatively high (gas-phase) acidity of the OH group of the product-related carbocation 4b indicates that the direct formation of hyoscyamine aldehyde (6) is a highly exothermic process. Although we would not wish to rule out alternative possibilities, our calculations suggest that a concerted rearrangement mechanism involving carbocations constitutes a viable low-energy pathway for the carbon-skeleton rearrangement in tropane alkaloid biosynthesis. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (TTDM) is characterized by progressive loss of glucose control through multifactorial mechanisms. The search for an understanding of TTDM has relied on animal models since the realization of the importance of the pancreas in controlling plasma glucose concentration. Rodent models of TTDM are developed to express hyperglycemia and not islet degeneration per se. Degeneration of the islets of Langerhans with β-cell loss is secondary to insulin resistance and is regarded as the more important lesion. Despite this, differences between models are seen in the development and progression of islet degeneration. Assessing the differences between the models is important to appreciate the various aspects of TTDM and understand their advantages as well as their deficiencies. Relevant animal models of TTDM provide opportunities to investigate important physiological and cell biological processes that may ultimately lead to development of targeted therapies. This article reviews the importance, advantages, and limitations of rodent models of TTDM in relation to the histopathological changes that characterize islet degeneration. Pathophysiological mechanisms that contribute to islet degeneration are also discussed and are placed into the context of changes in islet histological appearances. [ABSTRACT FROM AUTHOR]

Summary: Substrates enter the cylindrical 20S proteasome through a gated channel that is regulated by the ATPases in the 19S regulatory particle in eukaryotes or the homologous PAN ATPase complex in archaea. These ATPases contain a conserved C-terminal hydrophobic-tyrosine-X (HbYX) motif that triggers gate opening upon ATP binding. Using cryo-electron microscopy, we identified the sites in the archaeal 20S where PAN''s C-terminal residues bind and determined the structures of the gate in its closed and open forms. Peptides containing the HbYX motif bind to 20S in the pockets between neighboring α subunits where they interact with conserved residues required for gate opening. This interaction induces a rotation in the α subunits and displacement of a reverse-turn loop that stabilizes the open-gate conformation. This mechanism differs from that of PA26/28, which lacks the HbYX motif and does not cause α subunit rotation. These findings demonstrated how the ATPases'' C termini function to facilitate substrate entry. [Copyright &y& Elsevier]

Summary: The 20S proteasome functions in protein degradation in eukaryotes together with the 19S ATPases or in archaea with the homologous PAN ATPase complex. These ATPases contain a conserved C-terminal hydrophobic-tyrosine-X motif (HbYX). We show that these residues are essential for PAN to associate with the 20S and open its gated channel for substrate entry. Upon ATP binding, these C-terminal residues bind to pockets between the 20S''s α subunits. Seven-residue or longer peptides from PAN''s C terminus containing the HbYX motif also bind to these sites and induce gate opening in the 20S. Gate opening could be induced by C-terminal peptides from the 19S ATPase subunits, Rpt2, and Rpt5, but not by ones from PA28/26, which lack the HbYX motif and cause gate opening by distinct mechanisms. C-terminal residues in the 19S ATPases were also shown to be critical for gating and stability of 26S proteasomes. Thus, the C termini of the proteasomal ATPases function like a “key in a lock” to induce gate opening and allow substrate entry. [Copyright &y& Elsevier]

There is substantial evidence that hippocampus plays an important role in the processing of contextual information. Its specific role, however, remains unclear. One possibility is that single hippocampal neurons represent context information so that local circuits can construct representations of the current context, and the context that is expected based on past experience. Population codes derived from input by multiple local circuits may then engage match-mismatch algorithms that compare current and expected context information to determine the extent to which an expected context has changed. The results of such match-mismatch comparisons can be used to discriminate contexts. When context changes are detected, efferent messages may be passed on to connected neocortical areas so that informed 'decisions' regarding future behavioral and cognitive strategies can be made. Here, a brief review describes evidence that a primary consequence of hippocampal processing is the discrimination of meaningful contexts. Then, the functional significance of neocortical circuits that likely receive hippocampal output messages are described in terms of their contribution to the control of ongoing behavioral and cognitive strategy, especially during active navigation. It is clear from this systems view that studies of spatial navigation continue to provide researchers with an excellent model of hippocampal-neocortical interactions during learning. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Hydroxy-substituted methyl cations , n =1–3 have been studied with the B3LYP/6-31G∗ and G3B3 levels of theory. Their relative stabilities have been estimated with isodesmic and isogyric reactions. Increased degree of substitution increases the stability of the cation, but, due to competition among the OH groups, this does not occur in a linear fashion. The π-bond energies are estimated as approximately 78, 55 and 43kcal/mol per OH group for 1, 2 and 3, respectively. [Copyright &y& Elsevier]

High-level quantum chemistry calculations have been used to examine the catalytic reactions of adenosylcobalamin-dependent glutamate mutase (GM) with the natural substrate (S)-glutamic acid. We have also examined the rearrangement of (S)-2-hydroxyglutaric acid, (S)-2-thiolglutaric acid, and 2-ketoglutaric acid, all of which have previously been shown to react as substrates or inhibitors of the enzyme. Our calculations support the notion that the 100-fold difference in kcat between glutamate and 2-hydroxyglutarate is associated with the relatively high energy of the glycolyl radical intermediate compared with the glycyl radical. More generally, calculations of radical stabilization energies for a variety of substituted glycyl radical analogues indicate that modifications at the radical center can profoundly affect the relative stability of the resulting radical, leading to important mechanistic consequences. We find that the formation of a thioglycolyl radical, derived from (S)-2-thiolglutaric acid, is highly dependent on the protonation state of sulfur. The neutral radical is found to be of stability similar to that of the glycolyl radical, whereas the S-form of the thioglycolyl radical is much more stable, thus providing a rationalization for the inhibition of the enzyme by the substrate analogue 2-thiolglutarate. Two possible rearrangement pathways have been examined for the reaction of GM with 2-ketoglutaric acid, for which previous experiments had suggested no rearrangement took place. The fragmentation-recombination pathway is associated with a fragmentation step that is very endothermic (by 102.2 kJ mol-1). In contrast, the addition-elimination pathway has significantly lower energy requirements. An alternative possibility, namely, that 2-ketoglutaric acid is bound in its hydrated form, 2,2-dihydroxyglutaric acid, also leads to a pathway with relatively low energy requirements, suggesting that some rearrangement might be expected under such circumstances. [ABSTRACT FROM AUTHOR]

Abstract: Protein degradation by 20S proteasomes in vivo requires ATP hydrolysis by associated hexameric AAA ATPase complexes such as PAN in archaea and the homologous ATPases in the eukaryotic 26S proteasome. This review discusses recent insights into their multistep mechanisms and the roles of ATP. We have focused on the PAN complex, which offers many advantages for mechanistic and structural studies over the more complex 26S proteasome. By single-particle EM, PAN resembles a “top-hat” capping the ends of the 20S proteasome and resembles densities in the base of the 19S regulatory complex. The binding of ATP promotes formation of the PAN–20S complex, which induces opening of a gate for substrate entry into the 20S. PAN’s C-termini, containing a conserved motif, docks into pockets in the 20S’s α ring and causes gate opening. Surprisingly, once substrates are unfolded, their translocation into the 20S requires ATP-binding but not hydrolysis and can occur by facilitated diffusion through the ATPase in its ATP-bound form. ATP therefore serves multiple functions in proteolysis and the only step that absolutely requires ATP hydrolysis is the unfolding of globular proteins. The 26S proteasome appears to function by similar mechanisms. [Copyright &y& Elsevier]

Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which, if combined with temporal information, could provide a means of differentiating memory episodes. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Contextual information plays a key role in learning and memory. Learned information becomes associated with the context such that the context can cue the relevant memories and behaviors. An extensive literature involving experimental brain lesions has implicated the hippocampus in context processing. However, the neurophysiological mechanisms of context coding are not known. Although "context" has typically been defined in terms of the background cues, recent studies indicate that hippocampal neurons are sensitive to subtle changes in task demands, even in an unchanging environment. Thus, the context may also include non-environmental features of a learning situation. In the present study, hippocampal neuronal activity was recorded while rats learned to approach different reward locations in two contexts. Because all of the training took place in the same environment, the contexts were defined by the task demands rather than by environmental stimuli. Learning to differentiate two such contexts was associated with the development of highly contextspecific neuronal firing patterns. These included different place fields in pyramidal neurons and different event (e.g., reward) responses in pyramidal and interneurons. The differential firing patterns did not develop in a control condition that did not involve a context manipulation. The context-specific firing patterns could modulate activity in extrahippocampal structures to prime context-appropriate behavioral responses and memories. These results provide direct support for a context processing role of the hippocampus and suggest that the hippocampus contributes contextual representations to episodic memories. [ABSTRACT FROM AUTHOR]

High-level quantum chemistry calculations have been used to examine the hydrogen-abstraction reactions of diol dehydratase (DDH) in the context of both the catalytic mechanism and the enzyme dysfunction phenomenon termed suicide inactivation. The barriers for the catalytic hydrogen-abstraction reactions of ethane-1,2-diol and propane-1,2-diol are examined in isolation, as well as in the presence of various Brønsted acids and bases. Modest changes in the magnitudes of the initial and final abstraction barriers are seen, depending on the strength of the acid or base, and on whether these effects are considered individually or together. The most significant changes (ca. 20 kJ mol-1) are found for the initial abstraction barrier when the spectator OH group is partially deprotonated. Kinetic isotope effects including Eckart tunneling corrections (KIEs) have also been calculated for these model systems. We find that contributions from tunneling are of a magnitude similar to that of the contributions from semiclassical theory alone, meaning that quantum effects serve to significantly accelerate the rate of hydrogen transfer. The calculated KIEs for the partially deprotonated system are in qualitative agreement with experimentally determined values. In complementary investigations, the ability of DDH to become deactivated by certain substrate analogues is examined. In all cases, the formation of a stable radical intermediate causes the hydrogen re-abstraction step to become an extremely endothermic process. The consequent inability of 5′-deoxyadenosyl radical to be regenerated breaks the catalytic cycle, resulting in the suicide inactivation of DDH. [ABSTRACT FROM AUTHOR]

We present analysis on two X-ray bright points observed over several hours during the recent solar minimum (2020 February 21 and 2020 September 12–13) with the Nuclear Spectroscopic Telescope Array (NuSTAR), a sensitive hard X-ray imaging spectrometer. This is so far the most detailed study of bright points in hard X-rays, emission which can be used to search for faint hot and/or non-thermal sources. We investigate the bright points' time evolution with NuSTAR, and in extreme ultraviolet (EUV) and soft X-rays with Solar Dynamic Observatory/Atmospheric Imaging Assembly (SDO/AIA) and Hinode/X-Ray Telescope. The variability in the X-ray and EUV time profiles is generally not well matched, with NuSTAR detecting spikes that do not appear in EUV. We find that, for the 2020 February bright point, the increased X-ray emission during these spikes is due to material heated to ∼ 4.2–4.4 MK (found from fitting the X-ray spectrum). The 2020 September bright point also shows spikes in the NuSTAR data with no corresponding EUV signature seen by SDO/AIA, though in this case, it was due to an increase in emission measure of material at ∼ 2.6 MK and not a significant temperature change. So, in both cases, the discrepancy is likely due to the different temperature sensitivity of the instruments, with the X-ray variability difficult to detect in EUV due to cooler ambient bright point emission dominating. No non-thermal emission is detected, so we determine upper limits finding that only a steep non-thermal component between 3 and 4 keV could provide the required heating whilst being consistent with a null detection in NuSTAR. [ABSTRACT FROM AUTHOR]

Diffusion in confinement is an important fundamental problem with significant implications for applications of supported liquid phases. However, resolving the spatially dependent diffusion coefficient, parallel and perpendicular to interfaces, has been a standing issue and for objects of nanometric size, which structurally fluctuate on a similar time scale as they diffuse, no methodology has been established so far. We hypothesise that the complex, coupled dynamics can be captured and analysed by using a model built on the 2-dimensional Smoluchowski equation and systematic coarse-graining. For large, flexible species, a universal approach is offered that does not make any assumptions about the separation of time scales between translation and other degrees of freedom. The method is validated on Molecular Dynamics simulations of bulk systems of a family of ionic liquids with increasing cation sizes where internal degrees of freedom have little to major effects. After validation on bulk liquids, where we provide an interpretation of two diffusion constants for each species found experimentally, we clearly demonstrate the anisotropic nature of diffusion coefficients at interfaces. Spatial variations in the diffusivities relate to interface-induced structuring of the ionic liquids. Notably, the length scales in strongly confined ionic liquids vary consistently but differently at the solid–liquid and liquid–vapour interfaces. [ABSTRACT FROM AUTHOR]

Summary: The archaeal ATPase complex PAN, the homolog of the eukaryotic 26S proteasome-regulatory ATPases, was shown to associate transiently with the 20S proteasome upon binding of ATP or ATPγS, but not ADP. By electron microscopy (EM), PAN appears as a two-ring structure, capping the 20S, and resembles two densities in the 19S complex. The N termini of the archaeal 20S α subunits were found to function as a gate that prevents entry of seven-residue peptides but allows entry of tetrapeptides. Upon association with the 20S particle, PAN stimulates gate opening. Although degradation of globular proteins requires ATP hydrolysis, the PAN-20S complex with ATPγS translocates and degrades unfolded and denatured proteins. Rabbit 26S proteasomes also degrade these unfolded proteins upon ATP binding, without hydrolysis. Thus, although unfolding requires energy from ATP hydrolysis, ATP binding alone supports ATPase-20S association, gate opening, and translocation of unfolded substrates into the proteasome, which can occur by facilitated diffusion through the ATPase. [Copyright &y& Elsevier]

Abstract: The essentiality of marine invertebrate meals in diets for marine shrimp is unresolved. Three experiments were carried out with juvenile Penaeus monodon of 3–6 g initial weight to address this issue. In a 6-week growth experiment, shrimp head meal (SHM) or whole dried krill Euphausia spp. were included in a basal diet at 5% increments from 0 to 15% without altering the gross nutritional specification of the diet and fed to five tank replicates of shrimp. Shrimp daily growth coefficient (DGC) improved curvilinearly (P <0.05) from 0.95% per day for the basal to 1.66 and 1.68% per day for the 15% SHM and 15% krill diets respectively. The same SHM and krill meals were extracted with phosphate-buffered saline (PBS) and the recovered insoluble and soluble fractions compared with the original meals when incorporated into a basal diet at rates equivalent to 20% of the original (Experiment 2). Diets were fed to six tank replicates of shrimp for 2 weeks. DGCs of shrimp fed diets with krill and the krill PBS-insoluble fraction were identical (1.34% per day) and better than the krill PBS-soluble fraction (1.10% per day), SHM (1.15% per day) and both PBS-insoluble and -soluble SHM fractions (1.14 and 1.19% per day); all of these diets were better than the basal diet (0.92% per day). In Experiment 3, fresh shrimp waste was freeze-dried (SW) and then sequentially fractionated using PBS, followed by 6 M urea with subsequent dialysis and affinity chromatography, to produce three soluble fractions (PBS-soluble and PBS/urea soluble dialysed material of >3.5 kDa or <3.5 kDa) and an insoluble PBS/urea fraction. These fractions, individually, and when combined together, and the intact SW, were incorporated into a basal diet at amounts equivalent to 20% of the original product and evaluated against a commercial Marsupenaeus japonicus shrimp feed when fed to six tank replicates of shrimp in a 2-week experiment. The M. japonicus feed gave the best DGC (2.57% per day), and better than the SW diet (1.19% per day) which, with the diet containing the insoluble fraction (1.05% per day), were the only diets significantly better than the basal diet (0.79% per day). It is concluded that these crustacean meals contained a growth factor, which was present predominantly in the insoluble protein constituent of the meal. [Copyright &y& Elsevier]

Ab initio molecular orbital calculations have been used to study the mechanism of suicide inactivation of ethanolamine ammonia-lyase induced by three different substrate analogues. Analysis of the normal catalytic mechanism with 2-aminoethanol (ethanolamine) as substrate predicts that both the hydrogen-abstraction and hydrogen-reabstraction steps involving the B12-cofactor are likely to be exothermic. On the other hand, the proposed inactivation mechanism for the first substrate analogue, glycolaldehyde, leads to a highly stabilized radical that results in a very endothermic (by ca. 90 kJ mol-1) hydrogen-reabstraction step, which is thought to halt the normal function of the enzyme. Curiously, the energy requirements for a catalytically imposed mechanism in the case of the second substrate analogue, 2-hydroxyethylhydrazine (HEH), parallel those for the catalytic substrate, despite the fact that HEH is found to inactivate EAL experimentally. However, further analysis reveals the presence of a lower energy pathway for HEH that leads to the formation of the highly stabilized hydrazinium radical cation. In a manner similar to when glycoaldehyde is the substrate analogue, this results in an endothermicity for the hydrogen-reabstraction step that is prohibitively large. In contrast to these related inactivation mechanisms, the third substrate analogue, 2-aminoacetaldehyde, apparently accomplishes the inactivation of EAL in an entirely different manner. A pathway for the experimentally observed formation of acetic acid and ammonium cation has been identified and appears catalytic in the sense that 5'-deoxyadenosyl radical is regenerated. However, mechanisms to account for the subsequent formation of 4',5'-anhydroadenosine and degradation of the corrinoid ring of the cofactor have not been elucidated. [ABSTRACT FROM AUTHOR]

Terrestrial gamma-ray flashes (TCFs) from Earth's upper atmospherehave been detected with the Reuven Ramaty High Energy SolarSpectroscopic Imager (RHESSI) satellite. The gamma-ray spectra typicallyextend up to 10 to 20 megaelectron volts (MeV); a simple bremsstrahlungmodel suggests that most of the electrons that produce the gamma rayshave energies on the order of 20 to 40 MeV. RHESSI detects 10 to 20 TCFsper month, corresponding to ∼50 per day globally, perhaps many moreif they are beamed. Both the frequency of occurrence and maximum photonenergy are more than an order of magnitude higher than previously knownfor these events. [ABSTRACT FROM AUTHOR]

Cingulothalamic neurons develop topographic patterns of cue-elicited neuronal activity during discrimination learning. These patterns are context-related and are degraded by hippocampal lesions, suggesting that hippocampal modulation of cingulothalamic activity results in the expression of the patterns, which could promote the retrieval of context-appropriate responses and memories. This hypothesis was tested by training rabbits (Oryctolagus cuniculus) with fornix lesions concurrently on two discrimination tasks (approach and avoidance) in different contexts. Because the same conditioned stimuli were used for both tasks, contextual information was critical for overcoming intertask interference during concurrent task acquisition. The lesions degraded the topographic patterns and significantly impaired concurrent learning, suggesting that hippocampal-cingulothalamic interactions and the resulting topographic patterns are critical for processing contextual information needed to defeat interference. [ABSTRACT FROM AUTHOR]

To examine the regulation of midbrain dopamine neurons, recordings were obtained from single neurons of freely moving, genetically engineered dopamine-deficient (DD) mice. DD mice were tested without dopamine signaling (basal state) and with endogenous dopamine signaling (after L-dopa administration). In the basal state, when dopamine concentration in DD mice is <1% of that in control animals, the firing properties of midbrain dopamine neurons were remarkably similar among genotypes. However, L-dopa treatment, which restores dopamine and feeding and locomotor behavior in DD mice, profoundly inhibited the firing rate and bursting of dopamine neurons in DD mice. In addition, dopamine neurons in DD mice were hypersensitive to the dopamine receptor agonists quinpirole and SKF 81297. Anesthesia markedly reduced the firing rate of dopamine neurons in DD mice but did not significantly decrease the firing rate in control dopamine neurons. These data suggest that restoration of endogenous dopamine signaling activates hypersensitive long-loop feedback pathways that serve to limit dopamine release and underscore the importance of recording from awake animals. [ABSTRACT FROM AUTHOR]