The transcriptional corepressor complex CoREST is one of seven histone deacetylase complexes that regulate the genome through controlling chromatin acetylation. The CoREST complex is unique in ...containing both histone demethylase and deacetylase enzymes, LSD1 and HDAC1, held together by the RCOR1 scaffold protein. To date, it has been assumed that the enzymes function independently within the complex. Now, we report the assembly of the ternary complex. Using both structural and functional studies, we show that the activity of the two enzymes is closely coupled and that the complex can exist in at least two distinct states with different kinetics. Electron microscopy of the complex reveals a bi-lobed structure with LSD1 and HDAC1 enzymes at opposite ends of the complex. The structure of CoREST in complex with a nucleosome reveals a mode of chromatin engagement that contrasts with previous models.
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•The activities of LSD1 and HDAC1 are closely coupled in the CoREST complex•Both LSD1 and HDAC1 exist in two different kinetic states•CoREST has a bi-lobed, flexible structure with the two enzymes located at opposite ends•CoREST interacts with methylated nucleosomes via LSD1, but not HDAC1 or RCOR1
Using a real-time NMR assay, Song et al. characterize crosstalk between LSD1 and HDAC1 in the CoREST complex. Activation or inhibition of one enzyme strongly affects activity of the other. Electron microscopy studies of the complex reveal a bi-lobed structure with implications for the mode of interaction with nucleosomes.
MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle ...regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to ...their widespread use in the neuroscience laboratory is the cost, labor, skill and time-intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when the vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared with standard AAV. Here, we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood-brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV-transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing three-dimensional reconstruction of transduced Purkinje cells in the cerebellum using ex vivo serial two-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable the widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.
The association between an adolescent's own behavior and that of his or her peers remains a key empirical finding in the study of delinquency, and this similarity is often explained in criminology by ...invoking processes of social influence and homophily. Adolescence is a period of rapid change for both individuals and their surroundings, however, and influence and homophily are often discussed without attending to their development over time. In the current study, I employ longitudinal social network models to estimate social influence and homophily related to alcohol and cigarette use and to determine whether there is change in the strength of these processes. Furthermore, I test whether the broader social environment conditions these processes and their observed changes. The results from this study indicate that although influence from peers decreases from early to mid‐adolescence, homophily on drinking and smoking increases. There is also evidence that school‐level opportunities and expectations affect social influence and homophily but do not account for the average changes observed in these processes.
Abstract Objectives We test the hypothesis that an evidence-based preventive intervention will change adolescent friendship networks to reduce the potential for peer influence toward antisocial ...behavior. Altering adolescents' friendship networks in this way is a promising avenue for achieving setting-level prevention benefits such as expanding the reach and durability of program effects. Methods Beginning in 2002, the Promoting School-University Partnerships to Enhance Resilience (PROSPER) randomized control trial assigned two entire sixth-grade cohorts of 14 rural and small town school districts in Iowa and Pennsylvania to receive the intervention and of 14 to control. A family-based intervention was offered in sixth grade and a school-based intervention was provided in seventh grade. More than 11,000 respondents provided five waves of data on friendship networks, attitudes, and behavior in sixth through ninth grade. Antisocial influence potential was measured by the association between network centrality and problem behavior for each of 256 networks (time, grade cohort, and school specific). Results The intervention had a beneficial impact on antisocial influence potential of adolescents' friendship networks, with p < .05 for both of the primary composite measures. Conclusions Current evidence-based preventive interventions can alter adolescents' friendship networks in ways that reduce the potential for peer influence toward antisocial behavior.
The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect ...antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, d-cycloserine, several aminoglycosides, and quinolones. By employing organism-wide metabolomic and lipidomic approaches combined with phenotypic tests, we identified a time-dependent biphasic adaptive response after exposure of Mtb to physiological levels of NaCl. A first rapid, extensive, and reversible phase was associated with changes in core and amino acid metabolism. In a second phase, Mtb responded with a substantial remodelling of plasma membrane and outer lipid membrane composition. We demonstrate that phenotypic tolerance at physiological concentrations of NaCl is the result of changes in plasma and outer membrane lipid remodeling and not changes in core metabolism. Altogether, these results indicate that physiologic saline-induced antibacterial tolerance is kinetically coupled to cell envelope changes and demonstrate that metabolic changes and growth arrest are not the cause of phenotypic tolerance observed in Mtb exposed to physiologic concentrations of NaCl. Importantly, this work uncovers a role for bacterial cell envelope remodeling in antibacterial tolerance, alongside well-documented allterations in respiration, metabolism, and growth rate.
Objectives
Drawing on criminological research about peer delinquency and self-control, we employ a network perspective to identify the potential paths linking impulsivity, peers, and delinquency. We ...systematically integrate relevant processes into a set of dynamic network models that evaluate these interconnected pathways.
Methods
Our analyses use data from more than 14,000 students in Pennsylvania and Iowa collected from the evaluation of the PROSPER partnership model. We estimate longitudinal social network models to disentangle the paths through which impulsivity and delinquency are linked in adolescent friendship networks.
Results
We find evidence of both peer influence and homophilic selection for both impulsivity and delinquency. Further, results indicate that peer impulsivity is linked to individual delinquent behavior through peer influence on delinquency, but not on impulsivity. Finally, the results suggest that impulsivity moderates both influence and selection processes, as adolescents with higher levels of impulsivity are
more
likely to select delinquent peers but
less
likely to change their behavior due to peers.
Conclusions
In sum, this study offers a more holistic framework and stronger theoretical tests than similar studies of the past. Our results illustrate the need to consider the simultaneous network processes related to peers, impulsivity, and delinquency. Further, our findings reveal that a large dataset with ample statistical power is a valuable advantage for detecting the selection processes that shape friendship networks.
The association between delinquent peers and delinquent behavior is among the most consistent findings in the criminological literature, and several recent studies have raised the standards for ...determining the nature and extent of peer influence. Despite these advances, however, key questions about how deviant behavior is socially transmitted remain unresolved. In particular, much of the research examining peer influence has been limited to peer behavior, despite a rich literature supporting the salience of beliefs, such as expectations and moral approval, in shaping behaviors. In the current study, I model the peer influence and selection processes with longitudinal social network analysis to reexamine the contributions of peer beliefs and behaviors to adolescent drinking. I find evidence that beliefs related to peer drinking have both a direct and an indirect impact on behavior and play an important role in the friendship selection process. These results highlight the importance of understanding how peers influence deviant behavior and suggest that peer beliefs are an important part of this relationship.
This study addresses not only influence and selection of friends as sources of similarity in alcohol use, but also peer processes leading drinkers to be chosen as friends more often than nondrinkers, ...which increases the number of adolescents subject to their influence. Analyses apply a stochastic actor‐based model to friendship networks assessed five times from 6th through 9th grades for 50 grade cohort networks in Iowa and Pennsylvania, which include 13,214 individuals. Results show definite influence and selection for similarity in alcohol use, as well as reciprocal influences between drinking and frequently being chosen as a friend. These findings suggest that adolescents view alcohol use as an attractive, high‐status activity and that friendships expose adolescents to opportunities for drinking.
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