Changes in product labelling practices and the use of flavouring chemical additives in vaping products after enactment of statewide flavour legislation.

INTRODUCTION: On 18 May 2020, New York State enacted legislation banning the sale of vaping products with distinguishable flavours (other than tobacco). According to this new statute, vaping products are deemed flavoured if they include a statement, whether expressed or implied, that have distinguishable tastes or aromas other than tobacco. This study aimed to determine how manufacturers responded. METHODS: We collected 555 vaping products from daily vapers (238 preban and 317 postban). We compared preban and postban labelling of products for expressed and implied flavour descriptions, graphics and colours. Flavouring chemicals and concentrations were identified using chromatography methods and were compared preban and postban. RESULTS: Analysis of the labels preban and postban did not reveal a change in products with expressed flavoured descriptors (45.8% vs 44.2%) and a minimal decrease in implied descriptors (22.3% vs 14.5%). An increase in products without any descriptors was observed (28.2% vs 37.2%) notably within products from a popular pod brand. The average concentration of eight popular flavourings identified preban was 1.4±2.7 compared with 2.3±3.5 mg/mL (p<0.001) postban. No significant changes between individual flavouring concentrations in the most popular refill solutions and pods were found. CONCLUSION: While a majority of products appeared to remain non-compliant, this study suggests that enactment of legislation on vaping products making expressed or implied flavour claims may result in some manufacturer changes to product labelling including removal of flavour descriptors. However, use of flavouring additives in vaping products appeared not to be impacted by the ban.

Revealing the Structural Contributions to Thermal Adaptation of the TATA-Box Binding Protein: Molecular Dynamics and QSPR Analyses.

The TATA-box binding protein (TBP) is an important element of the transcription machinery in archaea and eukaryotic organisms. TBP is expressed in organisms adapted to different temperatures, indicating a robust structure, and experimental studies have shown that the mid-unfolding temperature (Tm) of TBP is directly correlated with the optimal growth temperature (OGT) of the organism. To understand which are the relevant structural requirements for its stability, we present the first structural and dynamic computational study of TBPs, combining molecular dynamics (MD) simulations and a quantitative structure-property relationship (QSPR) over a set of TBPs of organisms adapted to different temperatures. We found that the main structural properties of TBP used to adapt to high temperatures are an increase in the ease of desolvation of charged residues at the surface, an increase in the local resiliency, the presence of Leu clusters in the protein core, and an increase in the loss of hydrophobic packing in the N-terminal subdomain. In view of our results, we consider that TBP is a good model to study thermal adaptation, and our analysis opens the possibility of performing protein engineering on TBPs to study transcription at high or low temperatures.

QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT.

We have previously reported the synthesis, in vitro and in silico activities of new GABA analogues as inhibitors of the GABA-AT enzyme from Pseudomonas fluorescens, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds. With the goal of finding more potent inhibitors, we now report the synthesis of a new set of GABA analogues with a broader variation of heterocyclic scaffolds at the γ-position such as thiazolidines, methyl-substituted piperidines, morpholine and thiomorpholine and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These structural modifications led to compound 9b which showed a 73% inhibition against this enzyme. In vivo studies with PTZ-induced seizures on male CD1 mice show that compound 9b has a neuroprotective effect at a 0.50 mmole/kg dose. A QSAR study was carried out to find the molecular descriptors associated with the structural changes in the GABA scaffold to explain their inhibitory activity against GABA-AT. Employing 3D molecular descriptors allowed us to propose the GABA analogues enantiomeric active form. To evaluate the interaction with Pseudomonas fluorescens and human GABA-AT by molecular docking, the constructions of homology models was carried out. From these calculations, 9b showed a strong interaction with both GABA-AT enzymes in agreement with experimental results and the QSAR model, which indicates that bulky ligands tend to be the better inhibitors especially those with a sulfur atom on their structure.

Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme from Pseudomonas fluorescens and In Silico Molecular Modeling.

γ-Aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system, and a deficiency of GABA is associated with serious neurological disorders. Due to its low lipophilicity, there has been an intensive search for new molecules with increased lipophilicity to cross the blood-brain barrier to raise GABA concentrations. We have designed and evaluated in vitro and in silico some new analogues of GABA, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These modifications lead to compounds with inhibitory activity as it occurs with compounds 18a and 19a. The construction of Pseudomonas fluorescens and human GABA-AT models were carried out by homology modeling. Docking assays were done for these compounds over the GABA-AT enzyme models where 19a showed a strong interaction with both GABA-AT enzymes.

Effectivity and Cost-effectivity of the Maintenance Electroconvulsive Therapy: A mirror naturalistic analysis.

INTRODUCTION: Maintenance Electroconvulsive Therapy (mECT) is a biological long-term treatment in which patients receive ECT on periods from 2 to 4 weeks, during a variable period of time, usually for more than 6 months. Recent studies showed the efficacy of mECT in prevention of relapse and recurrences. Our study wants to demostrate the effectivity and cost-effectivity of this therapy in the naturalistic conditions of our area. DESIGN: Retrospective longitudinal study, with mirror analysis in naturalistic conditions. SUBJECTS: Patients attended at the Corporació Sanitària Parc Taulí (Sabadell, Catalonia), and included in the mECT program during more than six months. We performed diagnostic following DSM-IV criteria, subdividing the sample in three groups: patients affected of Recurrent Major Depression, Bipolar Disorder and Schizophrenia and Related Disorders. MEASURES: Number and duration of hospitalizations for the previous three years before the beginning of mECT, compared with the same data for the next three years following the beginning of mECT. Comparative analysis of direct hospitalization costs, costs of the mECT and pharmacologic costs. Statistic: Descriptive and non- parametric tests. RESULTS: Sample of 35 patients (1997-2008). There is a significative reduction the number of hospitalizations and days of hospitalization in the total sample and also in each of the three subgroups. The direct total cost decreased but it was only significant in the Bipolar Disorder subgroup, due to the increased pharmacological costs. CONCLUSIONS: mECT in our area is an effective and costeffective treatment with a great impact on the reduction of clinical decline and hospitalizations.

Single nucleotide polymorphisms of ANKK1, DDR4, and GRIN2B genes predict behavior in a prospective cohort of Mexican children and adolescents.

Numerous studies have established associations between single nucleotide polymorphisms (SNPs) and various behavioral and neurodevelopmental conditions. This study explores the links between SNPs in candidate genes involved in central nervous system (CNS) physiology and their implications for the behavioral and emotional aspects in children and teenagers. A total of 590 participants, aged 7-15 years, from the Early Life Exposures In Mexico To Environmental Toxicants (ELEMENT) cohort study in Mexico City, underwent genotyping for at least one of 15 CNS gene-related SNPs at different timepoints. We employed multiple linear regression models to assess the potential impact of genetic variations on behavioral and cognitive traits, as measured by the Behavioral Assessment System for Children (BASC) and Conners parent rating scales. Significant associations were observed, including the rs1800497 TC genotype (ANKK1) with the Cognitive Problems/Inattention variable (p value = 0.003), the rs1800955 CT genotype (DDR4) with the Emotional Lability Global index variable (p value = 0.01), and the rs10492138 GA and rs7970177 TC genotypes (GRIN2B) with the Depression variable (p values 0.007 and 0.012, respectively). These finds suggest potential genetic profiles associated with "risk" and "protective" behaviors for these SNPs. Our results provide valuable insights into the role of genetic variations in neurobehavior and highlight the need for further research in the early identification and intervention in individuals at risk for these conditions.

The Impact of a Sustained Virologic Response to Hepatitis C Virus Treatment on Liver Stiffness in the Puerto Rico Veterans Attending Liver Clinics in the Veterans Affairs Caribbean Healthcare System.

OBJECTIVE: To evaluate the impact of sustained virologic response (SVR) on liver stiffness, as measured by transient elastography (TE), in Hispanic patients treated with direct-acting antivirals (DAAs) in the outpatient clinics in the Veterans Affairs Caribbean Healthcare System. METHODS: We included hepatitis C virus (HCV) patients treated with DAA regimens from 11/2017 through 06/2019. Patient demographics and variables such as body mass index, HCV genotype, and treatment regimen were collected. The patients had a TE measurement before treatment initiation, and a repeat study 6 to 9 months after the achievement of SVR. A comparison between pre and post-treatment TE scores was performed via a paired t test. RESULTS: Forty-three subjects met all the inclusion criteria and completed a posttreatment TE. Most of the subjects were infected with genotypes 1a or 1b. Six to 9 months post SVR, we measured liver stiffness and found a statistically significant reduction in TE score (P value = .0003). The pretreatment median TE score was 10.2 kPa. On a repeat TE study at 6 to 9 months post-treatment, our subjects had a median score of 7.2 kPa. CONCLUSION: The eradication of HCV infection with DAAs is associated with improved TE scores. Fibrosis-stage reduction was more frequent in those who had stage 4 fibrosis prior to treatment. These results suggest that achieving SVR may spare patients from future clinical decompensation and complications. Adequate screening of this potentially deadly chronic infection can lead to early therapy with DAAs and the significant regression of fibrosis in this kind of patient.

A complete guide to human microbiomes: Body niches, transmission, development, dysbiosis, and restoration.

Humans are supra-organisms co-evolved with microbial communities (Prokaryotic and Eukaryotic), named the microbiome. These microbiomes supply essential ecosystem services that play critical roles in human health. A loss of indigenous microbes through modern lifestyles leads to microbial extinctions, associated with many diseases and epidemics. This narrative review conforms a complete guide to the human holobiont-comprising the host and all its symbiont populations- summarizes the latest and most significant research findings in human microbiome. It pretends to be a comprehensive resource in the field, describing all human body niches and their dominant microbial taxa while discussing common perturbations on microbial homeostasis, impacts of urbanization and restoration and humanitarian efforts to preserve good microbes from extinction.

Characterizing the Chemical Space of γ-Secretase Inhibitors and Modulators.

γ-Secretase (GS) is one of the most attractive molecular targets for the treatment of Alzheimer's disease (AD). Its key role in the final step of amyloid-ß peptides generation and its relationship in the cascade of events for disease development have caught the attention of many pharmaceutical groups. Over the past years, different inhibitors and modulators have been evaluated as promising therapeutics against AD. However, despite the great chemical diversity of the reported compounds, a global classification and visual representation of the chemical space for GS inhibitors and modulators remain unavailable. In the present work, we carried out a two-dimensional (2D) chemical space analysis from different classes and subclasses of GS inhibitors and modulators based on their structural similarity. Along with the novel structural information available for GS complexes, our analysis opens the possibility to identify compounds with high molecular similarity, critical to finding new chemical structures through the optimization of existing compounds and relating them with a potential binding site.

Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis.

The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.

The TATA-binding Protein DNA-binding domain of eukaryotic parasites is a potentially druggable target.

The TATA-binding protein (TBP) is a central transcription factor in eukaryotes that interacts with a large number of different transcription factors; thus, affecting these interactions will be lethal for any living being. In this work, we present the first structural and dynamic computational study of the surface properties of the TBP DNA-binding domain for a set of parasites involved in diseases of worldwide interest. The sequence and structural differences of these TBPs, as compared with human TBP, were proposed to select representative ensembles generated from molecular dynamics simulations and to evaluate their druggability by molecular ensemble-based docking of drug-like molecules. We found that potential druggable sites correspond to the NC2-binding site, N-terminal tail, H2 helix, and the interdomain region, with good selectivity for Plasmodium falciparum, Necator americanus, Entamoeba histolytica, Candida albicans, and Taenia solium TBPs. The best hit compounds share structural similarity among themselves and have predicted dissociation constants ranging from nM to µM. These can be proposed as initial scaffolds for experimental testing and further optimization. In light of the obtained results, we propose TBP as an attractive therapeutic target for treatment of parasitic diseases.

The human adenovirus type 5 E1B 55kDa protein interacts with RNA promoting timely DNA replication and viral late mRNA metabolism.

The E1B 55kDa produced by human adenovirus type 5 is a multifunctional protein that participates in the regulation of several steps during the viral replication cycle. Previous studies suggest this protein plays an important role in postranscriptional regulation of viral and cellular gene expression, as it is required for the selective accumulation of maximal levels of viral late mRNA in the cytoplasm of the infected cell; however the molecular mechanisms that are altered or regulated by this protein have not been elucidated. A ribonucleoprotein motif that could implicate the direct interaction of the protein with RNA was initially predicted and tested in vitro, but the interaction with RNA could not be detected in infected cells, suggesting the interaction may be weak or transient. Here it was determined that the E1B 55kDa interacts with RNA in the context of the viral infection in non-transformed human cells, and its contribution to the adenovirus replication cycle was evaluated. Using recombinant adenoviruses with amino acid substitutions or a deletion in the ribonucleoprotein motif the interaction of E1B 55kDa with RNA was found to correlate with timely and efficient viral DNA replication and viral late mRNA accumulation and splicing.

FRET-based analysis and molecular modeling of the human GPN-loop GTPases 1 and 3 heterodimer unveils a dominant-negative protein complex.

GPN-loop GTPases 1 and 3 are required for RNA polymerase II (RNAPII) nuclear import. Gpn1 and Gpn3 display some sequence similarity, physically associate, and their protein expression levels are mutually dependent in human cells. We performed here Fluorescence Resonance Energy Transfer (FRET), molecular modeling, and cell biology experiments to understand, and eventually disrupt, human Gpn1-Gpn3 interaction in live HEK293-AD cells. Transiently expressed EYFP-Gpn1 and Gpn3-CFP generated a strong FRET signal, indicative of a very close proximity, in the cytoplasm of HEK293-AD cells. Molecular modeling of the human Gpn1-Gpn3 heterodimer based on the crystallographic structure of Npa3, the Saccharomyces cerevisiae Gpn1 ortholog, revealed that human Gpn1 and Gpn3 associate through a large interaction surface formed by internal α-helix 7, insertion 2, and the GPN-loop from each protein. In site-directed mutagenesis experiments of interface residues, we identified the W132D and M227D EYFP-Gpn1 mutants as defective to produce a FRET signal when coexpressed with Gpn3-CFP. Simultaneous but not individual expression of Gpn1 and Gpn3, with either or both proteins fused to EYFP, retained RNAPII in the cytoplasm and markedly inhibited global transcription in HEK293-AD cells. Interestingly, the W132D and M227D Gpn1 mutants that showed an impaired ability to interact with Gpn3 by FRET were also unable to delocalize RNAPII in this assay, indicating that an intact Gpn1-Gpn3 interaction is required to display the dominant-negative effect on endogenous Gpn1/Gpn3 function we described here. Altogether, our results suggest that a Gpn1-Gpn3 strong interaction is critical for their cellular function.

Cerebral Small Vessel Disease: A Review Focusing on Pathophysiology, Biomarkers, and Machine Learning Strategies.

Cerebral small vessel disease (cSVD) has a crucial role in lacunar stroke and brain hemorrhages and is a leading cause of cognitive decline and functional loss in elderly patients. Based on underlying pathophysiology, cSVD can be subdivided into amyloidal and non-amyloidal subtypes. Genetic factors of cSVD play a pivotal role in terms of unraveling molecular mechanism. An important pathophysiological mechanism of cSVD is blood-brain barrier leakage and endothelium dysfunction which gives a clue in identification of the disease through circulating biological markers. Detection of cSVD is routinely carried out by key neuroimaging markers including white matter hyperintensities, lacunes, small subcortical infarcts, perivascular spaces, cerebral microbleeds, and brain atrophy. Application of neural networking, machine learning and deep learning in image processing have increased significantly for correct severity of cSVD. A linkage between cSVD and other neurological disorder, such as Alzheimer's and Parkinson's disease and non-cerebral disease, has also been investigated recently. This review draws a broad picture of cSVD, aiming to inculcate new insights into its pathogenesis and biomarkers. It also focuses on the role of deep machine strategies and other dimensions of cSVD by linking it with several cerebral and non-cerebral diseases as well as recent advances in the field to achieve sensitive detection, effective prevention and disease management.

Paced right bundle branch block: identification and management of a malpositioned left ventricular pacemaker lead.

Malpositioning of a permanent pacemaker lead in the left ventricle is rare. Usually, a paced right bundle branch pattern is the initial finding that fosters other confirmatory studies such as chest films and transthoracic echocardiogram. We describe the unusual case of an asymptomatic 83-year-old male patient who was incidentally found with a permanent pacemaker lead placed through the atrial septum into the left ventricle. This patient had contraindications for chronic anticoagulation and was placed on antiplatelet therapy instead. He has been well after three years without evidence of embolic episodes.

Cardiac monitoring in stroke units: importance of diagnosing atrial fibrillation in acute ischemic stroke.

In patients with stroke, atrial fibrillation is an independent risk factor and indicates a poor prognosis. Cardiac monitoring is carried out for longer periods in stroke units. The aim of this study was to determine the frequency at which atrial fibrillation is detected in stroke units and the percentage of patients with acute ischemic stroke or transient ischemic attack who receive anticoagulant therapy. The study included 465 patients, who were monitored in a stroke unit for an average of 54.55+/-35.74 h. Atrial fibrillation was detected in 33 (48.5% had paroxysmal atrial fibrillation and 51.5% had persistent atrial fibrillation). The most common risk factor was hypertension. Anticoagulation therapy was started in 57.5%. In conclusion, use of cardiac monitoring in a stroke unit was useful for detecting atrial fibrillation in patients with acute stroke and resulted in treatment modification in more than half the affected patients.

Construcción y validación del Cuestionario de Experiencias de Violencia en las Relaciones de Pareja y Familia en Estudiantes Universitarios / Construction and validation of Experiences Questionnaire on Violence in Couple and Family Relations in University Students

Este estudio presenta el proceso de desarrollo del Cuestionario de Experiencias de Violencia en las Relaciones de Pareja y Familia en Estudiantes Universitarios, así como sus propiedades psicométricas y hallazgos a través de un estudio piloto. El diseño utilizado fue no experimental, transversal correlacional con una muestra por disponibilidad de 267 estudiantes. En la versión final, el instrumento consta de 41 reactivos y cuatro subescalas: Violencia de la Pareja hacia el Estudiante, Violencia del Estudiante hacia la Pareja, Violencia Observada entre los Padres y Violencia de los Padres hacia el Estudiante. La escala total y las subescalas obtuvieron índices de confiabilidad adecuados. En promedio, la muestra endosó diez experiencias de violencia en diversos contextos. Los hallazgos de este estudio aportan al conocimiento de la prevalencia de la violencia en múltiples contextos, viabilizando el diseño de intervenciones pertinentes en el manejo y prevención de la violencia en poblaciones universitarias.

This study describes the process of developing the Experiences of Violence in Couple and Family Relationships in University Students Questionnaire, its psychometric properties and the results of the pilot study. The research design used for this study was a nonexperimental, transversal co relational design. The nonrandomized sample consisted of 267 students. The final version of the questionnaire consisted of 41 items and four sub-scales which measured experiences with violence in a relationship as an Aggressor and as a Victim, Observed between the Parents and in the Parent-child relationship as a victim. The total scale and the subscales obtained adequate reliability indexes. On average, the sample reported ten experiences with violence in different contexts. The results of this study contribute data on the prevalence of violence in college students' romantic and family relationships which in turn, provide valuable information for planning prevention and early intervention efforts with this population.