The Role of Smoking in Cocaine Addiction

The 2010 National Survey on Drug Use and Health reported that almost 37 million Americans,1 2 years of age or older, have tried cocaine in their lifetime, and 5.7 million have used it in the past year – making cocaine the second most commonly used drug of abuse in the United States. The reasons for its popularity are its immediate psychological effects. Snorted or injected cocaine induces self-confidence, euphoria and good feelings, magnifying the intensity of almost all normal pleasures. However, cocaine use also causes medical complications like respiratory failure, cardiovascular and gastrointestinal problems and paranoia. Moreover, after prolonged exposure, individuals become addicted to it, losing control over use of the drug and engaging in destructive behavior related to cocaine procurement. Cocaine addiction is a chronic relapsing condition with high risk of medical complications, cognitive impairment, financial ruin and social issues

The Auto-Generated Fragment of the Usp1 Deubiquitylase Is a Physiological Substrate of the N-End Rule Pathway

Deamidation of N-terminal Gln by the Ntaq1 Nt^Q-amidase is a part of the Arg/N-end rule pathway, a ubiquitin-dependent proteolytic system. Here we identify Gln-Usp1^(Ct), the C-terminal fragment of the autocleaved Usp1 deubiquitylase, as the first physiological Arg/N-end rule substrate that is targeted for degradation through deamidation of N-terminal Gln. Usp1 regulates genomic stability, in part through the deubiquitylation of monoubiquitylated PCNA, a DNA polymerase processivity factor. The autocleaved Usp1 remains a deubiquitylase because its fragments remain associated with Uaf1, an enhancer of Usp1 activity, until the Gln-Usp1^(Ct) fragment is selectively destroyed by the Arg/N-end rule pathway. We also show that metabolic stabilization of Gln-Usp1^(Ct) results in a decreased monoubiquitylation of PCNA and in a hypersensitivity of cells to ultraviolet irradiation. Thus, in addition to its other functions in DNA repair and chromosome segregation, the Arg/N-end rule pathway regulates genomic stability through the degradation-mediated control of the autocleaved Usp1 deubiquitylase

In Silico Analysis of Nanoplastics' and β-amyloid Fibrils' Interactions

: Plastic pollution has become a global environmental threat, which leads to an increasing concern over the consequences of plastic exposition on global health. Plastic nanoparticles have been shown to influence the folding of proteins and influence the formation of aberrant amyloid proteins, therefore potentially triggering the development of systemic and local amyloidosis. This work aims to study the interaction between nanoplastics and β-amyloid fibrils to better understand the potential role of nanoplastics in the outbreak of neurodegenerative disorders. Using microsecond-long coarse-grained molecular dynamics simulations, we investigated the interactions between neutral and charged nanoparticles made of the most common plastic materials (i.e., polyethylene, polypropylene, and polystyrene) and β-amyloid fibrils. We observe that the occurrence of contacts, region of amyloid fibril involved, and specific amino acids mediating the interaction depend on the type and charge of the nanoparticles

Heptad stereotypy, S/Q layering, and remote origin of the SARS-CoV-2 fusion core

The fusion of the SARS-CoV-2 virus with cells, a key event in the pathogenesis of Covid-19, depends on the assembly of a six-helix fusion core (FC) formed by portions of the spike protein heptad repeats (HRs) 1 and 2. Despite the critical role in regulating infectivity, its distinctive features, origin, and evolution are scarcely understood. Thus, we undertook a structure-guided positional and compositional analysis of the SARS-CoV-2 FC, in comparison with FCs of related viruses, tracing its origin and ongoing evolution. We found that clustered amino acid substitutions within HR1, distinguishing SARS-CoV-2 from SARS-CoV-1, enhance local heptad stereotypy and increase sharply the FC serine-to-glutamine (S/Q) ratio, determining a neat alternate layering of S-rich and Q-rich subdomains along the post-fusion structure. Strikingly, SARS-CoV-2 ranks among viruses with the highest FC S/Q ratio, together with highly syncytiogenic respiratory pathogens (RSV, NDV), whereas MERS-Cov, HIV, and Ebola viruses display low ratios, and this feature reflects onto S/Q segregation and H-bonding patterns. Our evolutionary analyses revealed that the SARS-CoV-2 FC occurs in other SARS-CoV-1-like Sarbecoviruses identified since 2005 in Hong Kong and adjacent regions, tracing its origin to >50 years ago with a recombination-driven spread. Finally, current mutational trends show that the FC is varying especially in the FC1 evolutionary hotspot. These findings establish a novel analytical framework illuminating the sequence/structure evolution of the SARS-CoV-2 FC, tracing its long history within Sarbecoviruses, and may help rationalize the evolution of the fusion machinery in emerging pathogens and the design of novel therapeutic fusion inhibitors

JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model

The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of human AD symptom progression. We tested the mice cognitive performance by using the radial arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates with a structural alteration of the post-synaptic density area and with memory impairment at this early stage of the disease that progressively declines to cause cell death. These findings pave the way for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic target for the development of new compounds able to tackle synaptic impairment in the early phase of AD pathology

Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5

Addiction to cocaine is commonly preceded by experiences with legal or decriminalized drugs, such as alcohol, nicotine, and marijuana. The biological mechanisms by which these gateway drugs contribute to cocaine addiction are only beginning to be understood. We report that in the rat, prior alcohol consumption results in enhanced addiction-like behavior to cocaine, including continued cocaine use despite aversive consequences. Conversely, prior cocaine use has no effect on alcohol preference. Long-term, but not short-term, alcohol consumption promotes proteasome-mediated degradation of the nuclear histone deacetylases HDAC4 and HDAC5 in the nucleus accumbens, a brain region critical for reward-based memory. Decreased nuclear HDAC activity results in global H3 acetylation, creating a permissive environment for cocaine-induced gene expression. We also find that selective degradation of HDAC4 and HDAC5, facilitated by the class II–specific HDAC inhibitor MC1568, enhances compulsive cocaine self-administration. These results parallel our previously reported findings that the gateway drug nicotine enhances the behavioral effects of cocaine via HDAC inhibition. Together, our findings suggest a shared mechanism of action for the gateway drugs alcohol and nicotine, and reveal a novel mechanism by which environmental factors may alter the epigenetic landscape of the reward system to increase vulnerability to cocaine addiction

APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage

APC/CCdh1-dependent degradation of USP1 allows for PCNA monoubiquitination and subsequent recruitment of trans-lesion synthesis polymerase to UV repair sites

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

Differential diagnosis of neurodegenerative dementias with the explainable MRI based machine learning algorithm MUQUBIA

Biomarker-based differential diagnosis of the most common forms of dementia is becoming increasingly important. Machine learning (ML) may be able to address this challenge. The aim of this study was to develop and interpret a ML algorithm capable of differentiating Alzheimer's dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal control subjects based on sociodemographic, clinical, and magnetic resonance imaging (MRI) variables. 506 subjects from 5 databases were included. MRI images were processed with FreeSurfer, LPA, and TRACULA to obtain brain volumes and thicknesses, white matter lesions and diffusion metrics. MRI metrics were used in conjunction with clinical and demographic data to perform differential diagnosis based on a Support Vector Machine model called MUQUBIA (Multimodal Quantification of Brain whIte matter biomArkers). Age, gender, Clinical Dementia Rating (CDR) Dementia Staging Instrument, and 19 imaging features formed the best set of discriminative features. The predictive model performed with an overall Area Under the Curve of 98%, high overall precision (88%), recall (88%), and F1 scores (88%) in the test group, and good Label Ranking Average Precision score (0.95) in a subset of neuropathologically assessed patients. The results of MUQUBIA were explained by the SHapley Additive exPlanations (SHAP) method. The MUQUBIA algorithm successfully classified various dementias with good performance using cost-effective clinical and MRI information, and with independent validation, has the potential to assist physicians in their clinical diagnosis