Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic,Antidepressant and Antipsychotic Effects

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4''-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.     

Metabolic Abnormalities Are Common among South American Hispanics Subjects with Normal Weight or Excess Body Weight: The CRONICAS Cohort Study

Objective

We aimed to characterize metabolic status by body mass index (BMI) status.

Methods

The CRONICAS longitudinal study was performed in an age-and-sex stratified random sample of participants aged 35 years or older in four Peruvian settings: Lima (Peru’s capital, costal urban, highly urbanized), urban and rural Puno (both high-altitude), and Tumbes (costal semirural). Data from the baseline study, conducted in 2010, was used. Individuals were classified by BMI as normal weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²), and obese (≥30 kg/m²), and as metabolically healthy (0–1 metabolic abnormality) or metabolically unhealthy (≥2 abnormalities). Abnormalities included individual components of the metabolic syndrome, high-sensitivity C-reactive protein, and insulin resistance.

Results

A total of 3088 (age 55.6±12.6 years, 51.3% females) had all measurements. Of these, 890 (28.8%), 1361 (44.1%) and 837 (27.1%) were normal weight, overweight and obese, respectively. Overall, 19.0% of normal weight in contrast to 54.9% of overweight and 77.7% of obese individuals had ≥3 risk factors (p<0.001). Among normal weight individuals, 43.1% were metabolically unhealthy, and age ≥65 years, female, and highest socioeconomic groups were more likely to have this pattern. In contrast, only 16.4% of overweight and 3.9% of obese individuals were metabolically healthy and, compared to Lima, the rural and urban sites in Puno were more likely to have a metabolically healthier profile.

Conclusions

Most Peruvians with overweight and obesity have additional risk factors for cardiovascular disease, as well as a majority of those with a healthy weight. Prevention programs aimed at individuals with a normal BMI, and those who are overweight and obese, are urgently needed, such as screening for elevated fasting cholesterol and glucose.     

LEA Gene Introns: is the Intron of Dehydrin Genes a Characteristic of the Serine-Segment?

Dehydrins, which belong to group 2 LEA proteins, are a family of intrinsically unstructured plant proteins that accumulate during the late stages of embryogenesis and in response to abiotic stresses. We have previously reported that the OpsDHN1 gene, encoding an SK₃-type acidic dehydrin protein from Opuntia streptacantha, contains an intron inserted within the sequence encoding the S-motif. Herein, we present an in silico analysis of intron sequences in dehydrin genes from mono- and dicotyledonous plants that reveals a preference for insertion within the nucleotide sequence encoding the S-motif. Sequence comparison of ten Dhn genes from Arabidopsis thaliana and the orthologous genes in Arabidopsis lyrata revealed that introns maintain considerable sequence identity and conserve the insertion pattern. Furthermore, syntenic regions were identified among eight orthologous genes of A. thaliana and A. lyrata, showing that correlated gene arrangements are conserved between these Arabidopsis species. Our study shows that most SKn-type dehydrins contain one intron that is conserved in phase and location; this intron is linked to the nucleotide sequence that encodes the S-motif.     

Proteomics: advances in biomarker discovery

The challenges encountered by proteomic researchers seeking diagnostic, prognostic and mechanistic markers were the subject of the 1-day meeting, Proteomics: Advances in Biomarker Discovery hosted by EuroSciCon. The speakers had a broad range of clinical and basic science interests, and presented data using a number of proteomic platforms to search for discriminant biomarkers of disease in easily accessible bodily fluids including serum and urine. Several potential pitfalls for proteomic researchers were mentioned and the potential of collaborative networks between research institutions to increase the size and power of clinical studies was discussed. Overall, the meeting highlighted the exciting opportunities that proteomic techniques offer for discovering not only diagnostic but also prognostic and mechanistic markers of a number of clinically important diseases.     

Copper catechol-driven Fenton reactions and their potential role in wood degradation

Metals can potentially play a role in the non-enzymatic processes involved in wood biodegradation. Dihydroxybenzenes reduce Cu(II)–Cu(I), which then react with H₂O₂ driving a Fenton reaction. In this work the degradation of veratryl alcohol (VA), the simplest non-phenolic lignin model compound, via a cuprous Fenton reaction mediated by 1,2-dihydroxybenzene (catechol, CAT) was studied. A factorial experimental design was performed to assess the impact of several experimental variables including, pH, and CAT, CuCl₂ and H₂O₂ concentrations on VA degradation. Optimized conditions were determined using a response surface modeling methodology (RSM). The greatest amount of VA degradation occurred at a CAT:CuCl₂:H₂O₂ ratio of 0.287:0.313:4.062, a pH of 3.6. A time-course measurement for VA degradation was performed under these experimental conditions and after an 8 h reaction period, 31% of the VA was degraded. Under the same experimental conditions, VA degradation by an iron CAT-driven Fenton reaction was more effective than the copper CAT-driven Fenton reaction. In a similar experiment, carboxymethyl cellulose (CMC) depolymerization was also determined. Only the iron CAT-driven Fenton reaction was found to depolymerize CMC. We suggest that the greater redox potential of the Fe(III)CAT complex compared to the Cu(II)CAT complex would dictate that under most environmental conditions, degradation of VA would occur by the iron complex only. This research has important implications for the mechanisms of brown rot fungal degradation in wood because it eliminates a pathway that had previously been proposed as a mechanism explaining free radical generation in the oxidative depolymerization of cellulose in the cell wall.     

Characterization of Carriage Isolates of Neisseria meningitidis in the Adolescents and Young Adults Population of Bogota (Colombia)

Background

Meningococcal carriage studies are important to improve our understanding of the epidemiology of meningococcal disease. The aim of this study was to determine the prevalence of meningococcal carriage and the phenotypic and genotypic characteristics of isolates collected from a sample of students in the city of Bogotá, Colombia.

Materials and Methods

A total of 1459 oropharyngeal samples were collected from students aged 15–21 years attending secondary schools and universities. Swabs were plated on a Thayer Martin agar and N. meningitidis was identified by standard microbiology methods and PCR.

Results

The overall carriage prevalence was 6.85%. Carriage was associated with cohabitation with smokers, and oral sex practices. Non-groupable and serogroup Y isolates were the most common capsule types found. Isolates presented a high genetic diversity, and circulation of the hypervirulent clonal complexes ST-23, ST-32 and ST-41/44 were detected.

Conclusion

The meningococcal carriage rate was lower than those reported in Europe and Africa, but higher than in other Latin American countries. Our data also revealed antigenic and genetic diversity of the isolates and the circulation of strains belonging to clonal complexes commonly associated with meningococcal disease.     

Dissimilarities in auditory tuning in midwife toads of the genus Alytes (Amphibia: Anura)

The auditory sensitivity in three species of the anuran genus Alytes (Alytidae) was examined to determine patterns of intra‐ and interspecific variation, relating these measurements to behavioural preferences measured in previous studies and to the adaptive and evolutionary significance of this sensory function. The audiograms obtained with multi‐unit recordings in the torus semicircularis of 13 Alytes cisternasii, 10 Alytes obstetricans, and eight Alytes dickhilleni show two regions of enhanced sensitivity, between approximately 100–500 and 1200–2400 Hz, with minimum thresholds at approximately 40 and 45 dB SPL, respectively. The mean and range of the high‐frequency region differed among species, although the sensitivity, measured as minimum thresholds, was similar. The region of high‐frequency sensitivity was centred at approximately the frequency of the advertisement call in A. cisternasii but, in A. obstetricans and A. dickhilleni, was centred at frequencies higher than the conspecific calls. These results contrast with preferences for lower frequencies exhibited by Alytes in female phonotactic and in male evoked vocal responses. Such loose relationships between signals and receivers suggest that the divergence of the sound communication system in Alytes has implied environmental and phylogenetic factors in addition to sexual selection processes.     

Learning generative models for protein fold families

We introduce a new approach to learning statistical models from multiple sequence alignments (MSA) of proteins. Our method, called GREMLIN (Generative REgularized ModeLs of proteINs), learns an undirected probabilistic graphical model of the amino acid composition within the MSA. The resulting model encodes both the position-specific conservation statistics and the correlated mutation statistics between sequential and long-range pairs of residues. Existing techniques for learning graphical models from MSA either make strong, and often inappropriate assumptions about the conditional independencies within the MSA (e.g., Hidden Markov Models), or else use suboptimal algorithms to learn the parameters of the model. In contrast, GREMLIN makes no a priori assumptions about the conditional independencies within the MSA. We formulate and solve a convex optimization problem, thus guaranteeing that we find a globally optimal model at convergence. The resulting model is also generative, allowing for the design of new protein sequences that have the same statistical properties as those in the MSA. We perform a detailed analysis of covariation statistics on the extensively studied WW and PDZ domains and show that our method out-performs an existing algorithm for learning undirected probabilistic graphical models from MSA. We then apply our approach to 71 additional families from the PFAM database and demonstrate that the resulting models significantly out-perform Hidden Markov Models in terms of predictive accuracy.