Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major ...mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.
•This study shows antirelapse plasticity mechanisms induced by drug exposure•Shows experience-dependent generation of new neurocircuits via silent synapses•Two prefrontal cortex-to-accumbens afferents are differentially remodeled by cocaine•A mechanism of incubation of cocaine craving
Addiction remains a critical medical challenge. Here Ma et al. show that a specific prefrontal cortical projection is remodeled after cocaine exposure to reduce cocaine relapse. Such endogenously induced antirelapse circuitry mechanisms may be utilized for developing new antiaddiction treatments.
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•Hemicelluloses can interact with lignin through covalent cross-links in plant cell walls.•Different reaction mechanisms can lead to cross-linking using diverse hemicellulose ...residues.•A decrease in cross-linking correlates with a reduction in recalcitrance of cell walls.•Modulation of cross-linking will be a valuable tool to improve biomass utilisation.
The plant secondary cell wall is a complex structure composed of polysaccharides and lignin, and is a key evolutionary innovation of vascular land plants. Although cell wall composition is well understood, the cross-linking of the different polymers is only now yielding to investigation. Cross-linking between hemicelluloses and lignin occurs via two different mechanisms: incorporation into lignin by radical coupling of ferulate substitutions on xylan in commelinid monocots, and incorporation of hemicellulosic glycosyl residues by re-aromatisation of lignification intermediates. Recent genetic evidence indicates that hemicellulose:lignin cross-linking has a substantial impact on plant cell wall recalcitrance. Engineering plant biomass with modified frequencies of cross-links will have significant impacts on biomass utilisation.
Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. In an effort to explain ...this paradox, we found that both drugs induced NMDA receptor-containing, AMPA receptor-silent excitatory synapses, albeit in distinct cell types through opposing cellular mechanisms. Cocaine selectively induced silent synapses in D1-type neurons, likely via a synaptogenesis process, whereas morphine induced silent synapses in D2-type neurons via internalization of AMPA receptors from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses became 'unsilenced' by recruiting AMPA receptors to strengthen excitatory inputs to D1-type neurons, whereas morphine-generated silent synapses were likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell type-specific, opposing mechanisms produced the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.
There is a continuing debate on relative benefits of various mitigation and suppression strategies aimed to control the spread of COVID-19. Here we report the results of agent-based modelling using a ...fine-grained computational simulation of the ongoing COVID-19 pandemic in Australia. This model is calibrated to match key characteristics of COVID-19 transmission. An important calibration outcome is the age-dependent fraction of symptomatic cases, with this fraction for children found to be one-fifth of such fraction for adults. We apply the model to compare several intervention strategies, including restrictions on international air travel, case isolation, home quarantine, social distancing with varying levels of compliance, and school closures. School closures are not found to bring decisive benefits unless coupled with high level of social distancing compliance. We report several trade-offs, and an important transition across the levels of social distancing compliance, in the range between 70% and 80% levels, with compliance at the 90% level found to control the disease within 13-14 weeks, when coupled with effective case isolation and international travel restrictions.
Mitochondrial diseases are clinically heterogeneous disorders caused by a wide spectrum of mutations in genes encoded by either the nuclear or the mitochondrial genome. Treatments for mitochondrial ...diseases are currently focused on symptomatic management rather than improving the biochemical defect caused by a particular mutation. This review focuses on the latest advances in the development of treatments for mitochondrial disease, both small molecules and gene therapies, as well as methods to prevent transmission of mitochondrial disease through the germline.
Russell et al. review recent progress in the varied approaches to treat and prevent mitochondrial disease, including small-molecule-based approaches to improve mitochondrial function or turnover, manipulation of the mitochondrial genome, and mitochondrial replacement therapy.
Black Americans are systematically undertreated for pain relative to white Americans. We examine whether this racial bias is related to false beliefs about biological differences between blacks and ...whites (e.g., “black people’s skin is thicker than white people’s skin”). Study 1 documented these beliefs among white laypersons and revealed that participants who more strongly endorsed false beliefs about biological differences reported lower pain ratings for a black (vs. white) target. Study 2 extended these findings to the medical context and found that half of a sample of white medical students and residents endorsed these beliefs. Moreover, participants who endorsed these beliefs rated the black (vs. white) patient’s pain as lower and made less accurate treatment recommendations. Participants who did not endorse these beliefs rated the black (vs. white) patient’s pain as higher, but showed no bias in treatment recommendations. These findings suggest that individuals with at least some medical training hold and may use false beliefs about biological differences between blacks and whites to inform medical judgments, which may contribute to racial disparities in pain assessment and treatment.
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by ...time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.
Trust and the provision of trade credit Wu, Wenfeng; Firth, Michael; Rui, Oliver M.
Journal of banking & finance,
February 2014, 2014-2-00, 20140201, Letnik:
39
Journal Article
Recenzirano
State-controlled listed firms in China receive preferential treatment when borrowing from commercial banks; in contrast, private controlled firms rely on informal finance and on trade credit. We ...argue for and find evidence that private firms located in higher social trust regions use more trade credit from suppliers, extend more trade credit to customers, and collect receivables and pay payables more quickly. These findings are enhanced for firms located in provinces with weak protection of property rights. Our results are robust to different measures of social trust, legal environment, and endogeneity. Overall, our results show that social trust helps private firms overcome institutional difficulties in financing their activities.
The extracellular matrix (ECM) is a complex meshwork of insoluble fibrillar proteins and signaling factors interacting together to provide architectural and instructional cues to the surrounding ...cells. Alterations in ECM organization or composition and excessive ECM deposition have been observed in diseases such as fibrosis, cardiovascular diseases, and cancer. We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues, digest the proteins into peptides, analyze ECM peptides by mass spectrometry, and interpret the mass spectrometric data. In addition, we present here two novel R-script-based web tools allowing rapid annotation and relative quantification of ECM proteins, peptides, and intensity/abundance in mass spectrometric data output files. We illustrate this protocol with ECMs obtained from two pairs of tissues, which differ in ECM content and cellularity: triple-negative breast cancer and adjacent mammary tissue, and omental metastasis from high-grade serous ovarian cancer and normal omentum. The complete proteomics data set generated in this study has been deposited to the public repository ProteomeXchange with the data set identifier: PXD005554.
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