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Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. A widely accepted assumption is that drugs of abuse result in disparate dopamine responses to cues that predict drug vs. natural rewards. The leading hypothesis is that drug-induced dopamine release represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation. However, this hypothesis has not been directly tested. Here, we develop Pavlovian and operant procedures in male rats to measure firing responses within the same dopamine neurons to drug versus natural reward cues, which we find to be similarly enhanced compared to cues predicting natural rewards in drug-naive controls. This enhancement is associated with increased behavioral reactivity to the drug cue, suggesting that dopamine neuronal activity may still be relevant to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting revised models of dopaminergic function in opioid addiction, and provide insights into the neurobiology of cue reactivity with potential implications for relapse prevention. A widely accepted assumption in addiction research is that overvaluation of drug cues is caused by enhanced dopaminergic response to these cues. Here, the authors show similar dopamine neuronal responses to cues predicting opioids vs. natural rewards.

Systemic lupus erythematosus (SLE) is a chronic disease characterized by progressive tissue damage. In recent decades, novel treatments have greatly extended the life span of SLE patients. This creates a high demand for identifying the overarching symptoms associated with SLE and developing therapies that improve their life quality under chronic care. We hypothesized that SLE patients would present dysphonic symptoms. Given that voice disorders can reduce life quality, identifying a potential SLE-related dysphonia could be relevant for the appraisal and management of this disease. We measured objective vocal parameters and perceived vocal quality with the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale in SLE patients and compared them to matched healthy controls. SLE patients also filled a questionnaire reporting perceived vocal deficits. SLE patients had significantly lower vocal intensity and harmonics to noise ratio, as well as increased jitter and shimmer. All subjective parameters of the GRBAS scale were significantly abnormal in SLE patients. Additionally, the vast majority of SLE patients (29/36) reported at least one perceived vocal deficit, with the most prevalent deficits being vocal fatigue (19/36) and hoarseness (17/36). Self-reported voice deficits were highly correlated with altered GRBAS scores. Additionally, tissue damage scores in different organ systems correlated with dysphonic symptoms, suggesting that some features of SLE-related dysphonia are due to tissue damage. Our results show that a large fraction of SLE patients suffers from perceivable dysphonia and may benefit from voice therapy in order to improve quality of life.

The statistical analysis of neuronal spike trains by models of point processes often relies on the assumption of constant process parameters. However, it is a well-known problem that the parameters of empirical spike trains can be highly variable, such as for example the firing rate. In order to test the null hypothesis of a constant rate and to estimate the change points, a Multiple Filter Test (MFT) and a corresponding algorithm (MFA) have been proposed that can be applied under the assumption of independent inter spike intervals (ISIs). As empirical spike trains often show weak dependencies in the correlation structure of ISIs, we extend the MFT here to point processes associated with short range dependencies. By specifically estimating serial dependencies in the test statistic, we show that the new MFT can be applied to a variety of empirical firing patterns, including positive and negative serial correlations as well as tonic and bursty firing. The new MFT is applied to a data set of empirical spike trains with serial correlations, and simulations show improved performance against methods that assume independence. In case of positive correlations, our new MFT is necessary to reduce the number of false positives, which can be highly enhanced when falsely assuming independence. For the frequent case of negative correlations, the new MFT shows an improved detection probability of change points and thus, also a higher potential of signal extraction from noisy spike trains.

Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. The leading hypothesis is that dopamine release by addictive drugs represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation compared to non-drug reward alternatives. However, this hypothesis has not been directly tested. Here we developed Pavlovian and operant procedures to measure firing responses, within the same dopamine neurons, to drug versus natural reward cues, which we found to be similarly enhanced compared to cues predicting natural rewards in drug-naïve controls. This enhancement was associated with increased behavioral reactivity to the drug cue, suggesting that dopamine release is still critical to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting new models of dopaminergic function in drug addiction, and provide critical insights into the neurobiology of cue reactivity with potential implications for relapse prevention.

The statistical analysis of neuronal spike trains by models of point processes often relies on the assumption of constant process parameters. However, it is a well-known problem that the parameters of empirical spike trains can be highly variable, such as for example the firing rate. In order to test the null hypothesis of a constant rate and to estimate the change points, a Multiple Filter Test (MFT) and a corresponding algorithm (MFA) have been proposed that can be applied under the assumption of independent inter spike intervals (ISIs). As empirical spike trains often show weak dependencies in the correlation structure of ISIs, we extend the MFT here to point processes associated with short range dependencies. By specifically estimating serial dependencies in the test statistic, we show that the new MFT can be applied to a variety of empirical firing patterns, including positive and negative serial correlations as well as tonic and bursty firing. The new MFT is applied to a data set of empirical spike trains with serial correlations, and simulations show improved performance against methods that assume independence. In case of positive correlations, our new MFT is necessary to reduce the number of false positives, which can be highly enhanced when falsely assuming independence. For the frequent case of negative correlations, the new MFT shows an improved detection probability of change points and thus, also a higher potential of signal extraction from noisy spike trains.

Midbrain dopamine neurons are essential for flexible control of adaptive behaviors. DA neurons that project to different target regions have unique biophysical properties, and it is thought that this diversity reflects functional specialization. This assumption implies the presence of specific genetic determinants with precise impacts on behavior. We tested this general hypothesis by homing in on one particular biophysical mechanism, Kv4 channel inactivation, using a combination of molecular, proteomic, electrophysiological, computational, and behavioral approaches. We demonstrate that KChIP4a, a singular Kv4 β-subunit splice variant, prolongs hyperpolarization-rebound delays selectively in dopamine neurons projecting to the nucleus accumbens core, shifts the integration of inhibitory inputs and, in turn, selectively regulates learning from negative prediction-errors. Our results reveal a highly specialized, gene-to-behavior mechanistic chain that is only operative in a particular dopaminergic subsystem, illuminating how molecularly defined biophysical switches are employed for neuron subtype-specific information processing in the brain.

The functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and synaptic connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and juxtacellular labelling in mouse brain to create the first single cell-resolved in vivo functional topography of the midbrain DA system. We identified surprising differences in burst firing among those DA neurons projecting to dorsolateral striatum, which were organized along the medio-lateral substantia nigra (SN) axis. Furthermore, burst properties also differentiated DA neurons in the medial SN that projected either to dorsal or ventral striatum. In contrast, DA neurons projecting to lateral shell of nucleus accumbens displayed identical firing properties, irrespective of whether they were located in the SN or ventral tegmental area (VTA), thus breaching classical anatomical boundaries. Finally, we found robust differences in mean firing rates and pause durations among VTA DA neurons projecting to either lateral or medial shell of nucleus accumbens. Together, our data set establishes a high-resolution functional landscape of midbrain DA neurons, which will facilitate the identification of selective functions and pathophysiological changes within the midbrain DA system.

Background: This study began with a search in three databases, totaling six libraries (ChemBridge-DIVERSet, ChemBridge-DIVERSet-EXP, Zinc_Drug Database, Zinc_Natural_Stock, Zinc_FDA_BindingDB, Maybridge) with approximately 2.5 million compounds with the aim of selecting potential inhibitors with antiproliferative activity on the chimeric tyrosine kinase encoded by the BCR-ABL gene. Methods: Through hierarchical biochemoinformatics, ADME/Tox analyses, biological activity prediction, molecular docking simulations, synthetic accessibility and theoretical synthetic routes of promising compounds and their lipophilicity and water solubility were realized. Results: Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the top100/base (600 structures), in comparison with the commercial drug imatinib, showed that only nine exhibited the desired properties. In the prediction of biological activity, the results of the nine selected structures ranged from 13.7% < Pa < 65.8%, showing them to be potential protein kinase inhibitors. In the molecular docking simulations, the promising molecules LMQC01 and LMQC04 showed significant values in molecular targeting (PDB 1IEP—resolution 2.10 Å). LMQC04 presented better binding affinity (∆G = −12.2 kcal mol−1 with a variation of ±3.6 kcal mol−1) in relation to LMQC01. The LMQC01 and LMQC04 molecules were advanced for molecular dynamics (MD) simulation followed by Molecular Mechanics with generalized Born and Surface Area solvation (MM-GBSA); the comparable, low and stable RMSD and ΔE values for the protein and ligand in each complex suggest that the selected compounds form a stable complex with the Abl kinase domain. This stability is a positive indicator that LMQC01 and LMQC04 can potentially inhibit enzyme function. Synthetic accessibility (SA) analysis performed on the AMBIT and SwissADME webservers showed that LMQC01 and LMQC04 can be considered easy to synthesize. Our in silico results show that these molecules could be potent protein kinase inhibitors with potential antiproliferative activity on tyrosine kinase encoded by the BCR-ABL gene. Conclusions: In conclusion, the results suggest that these ligands, particularly LMQC04, may bind strongly to the studied target and may have appropriate ADME/Tox properties in experimental studies. Considering future in vitro or in vivo assays, we elaborated the theoretical synthetic routes of the promising compounds identified in the present study. Based on our in silico findings, the selected ligands show promise for future studies in developing chronic myeloid leukemia treatments.

Background Emergency tracheal intubation in critically ill patients carries a high risk of complications, and practices vary substantially across different settings. Identifying risk factors and understanding how peri-intubation adverse events affect patient outcomes may guide standardization of care and improve survival. Methods This prospective cohort study involved 18 emergency departments in Brazil (March 2022–April 2024). We included adults (≥ 18 years) undergoing emergency intubation and excluded patients intubated electively or for cardiac arrest. We defined major peri-intubation adverse events as severe hypoxemia, new hemodynamic instability, or cardiac arrest occurring within 30 min of initiating intubation. The primary outcome was 28-day mortality. Multivariable regression analyses assessed associations between adverse events and mortality, controlling for potential confounders. Results Among 2846 patients, major adverse events occurred in 919 (32.3%) intubations, most frequently new hemodynamic instability (20.0%), followed by severe hypoxemia (12.5%) and cardiac arrest (3.5%). The overall 28-day mortality was 45.1%. Patients experiencing any major adverse event had a significantly higher 28-day mortality (57.6 vs 39.2%; aHR 1.43, 95% CI 1.26–1.62; p  < 0.001). Sensitivity analyses confirmed these findings. Successful first-attempt intubation was associated with a reduced likelihood of major adverse events (aOR 0.52; 95% CI 0.41–0.65; p  < 0.001). Conclusion One in three patients undergoing emergency intubation experienced a major peri-intubation adverse event, which was associated with higher 28-day mortality. These results underscore the importance of optimizing intubation strategies to reduce complications and potentially improve patient outcomes in critically ill patients.