Exploring calixarene-based clusters for efficient functional presentation of Streptococcus pneumoniae saccharides.

Calixarenes are promising scaffolds for an efficient clustered exposition of multiple saccharide antigenic units. Herein we report the synthesis and biological evaluation of a calix[6]arene functionalized with six copies of the trisaccharide repeating unit of Streptococcus pneumoniae (SP) serotype 19F. This system has demonstrated its ability to efficiently inhibit the binding between the native 19F capsular polysaccharide and anti-19F antibodies, despite a low number of exposed saccharide antigens, well mimicking the epitope presentations in the polysaccharide. The calix[6]arene mobile scaffold has been selected for functionalization with SP 19F repeating unit after a preliminary screening of four model glycocalixarenes, functionalized with N-acetyl mannosamine, and differing in the valency and/or conformational properties. This work is a step forward towards the development of new fully synthetic calixarenes comprising small carbohydrate antigens as potential carbohydrate-based vaccine scaffolds.

Molecular Architecture and Symmetry Properties of 1,3-Alternate Calix[4]arenes with Orientable Groups at the Para Position of the Phenolic Rings.

Two glycoclusters constituted by four fully acetylated ß-acetylmannosamine residues linked through trimethylenethioureido spacers to a calix[4]arene core and differing for the presence of methoxy or propoxy groups at the lower rim were synthesized. One of the two compounds is fixed in the 1,3-alternate geometry by the presence of the propoxy groups, while the other is potentially free to assume one of the different geometries allowed in calix[4]arene. Their similar NMR spectra in chloroform clearly suggest the same 1,3-alternate geometry. Both compounds were submitted to a conformational investigation with the DFT approach at the standard B3LYP/6-31G(d) level. The two glycocalixarenes showed a large conformational preference for the same geometry that put the mannosamine moiety of one substituent close to the thioureido group of the opposite substituent. This allows the formation of intramolecular hydrogen bonds and originates a series of through-space close contacts. A comparison with the NOESY maps evidence an excellent correspondence between experimental and theoretical data, thus giving an experimental validation of the highly symmetrical conformation that the two glycocalixarenes assume in apolar solvents.

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2 knockdown studies. To further validate the role of LPA2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.

A diagnostic circulating miRNA signature as orchestrator of cell invasion via TKS4/TKS5/EFHD2 modulation in human gliomas.

BACKGROUND: Altered microRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a stable form thus representing interesting biomarker candidates. This study aimed to identify a microRNA signature as a non-invasive biomarker and to investigate its impact on glioma biology. METHODS: MicroRNAs were selected using a global expression profile in preoperative serum samples from 37 glioma patients. Comparison between serum samples from age and gender-matched controls was performed by using the droplet digital PCR. The ROC curve and Kaplan-Meier survival analyses were used to evaluate the diagnostic/prognostic values. The functional role of the identified signature was assessed by gain/loss of function strategies in glioma cells. RESULTS: A three-microRNA signature (miR-1-3p/-26a-1-3p/-487b-3p) was differentially expressed in the serum of patients according to the isocitrate dehydrogenase (IDH) genes mutation status and correlated with both patient Overall and Progression Free Survival. The identified signature was also downregulated in the serum of patients compared to controls. Consistent with these results, the signature expression and release in the conditioned medium of glioma cells was lower in IDH-wild type cells compared to the mutated counterpart. Furthermore, in silico analysis of glioma datasets showed a consistent deregulation of the signature according to the IDH mutation status in glioma tumour tissues. Ectopic expression of the signature negatively affects several glioma functions. Notably, it impacts the glioma invasive phenotype by directly targeting the invadopodia-related proteins TKS4, TKS5 and EFHD2. CONCLUSIONS: We identified a three microRNA signature as a promising complementary or even an independent non-invasive diagnostic/prognostic biomarker. The signature displays oncosuppressive functions in glioma cells and impacts on proteins crucial for migration and invasion, providing potential targets for therapeutic intervention.

Factor Structure and Psychometric Properties of the Italian Version of the Homosexuality Scale of the Trueblood Sexual Attitudes Questionnaire.

The aim of the present study was to translate the Homosexuality scale of the Trueblood Sexual Attitudes Questionnaire into the Italian language and to assess its factor structure and psychometric properties in Italian psychology students. The questionnaire was originally developed and validated in U.S. college students, and later in Turkish social work students, showing high internal consistency. It measures attitudes toward several sexual practices and behaviors, regarding self and others. Particularly, the Homosexuality scale measures attitudes toward different sexual and romantic practices with people of the same sex. A total of 199 Italian psychology students participated to the study, and they were administered the Italian translation of the scale. We applied exploratory factor analysis and confirmatory factor analysis. Results showed that the scale has high internal consistency, and that the original two-factor model accounting for attitudes toward self and others fits the data well. Implications for education and assessment in student populations are discussed.

Correction: Moulding calixarenes for biomacromolecule targeting.

Correction for 'Moulding calixarenes for biomacromolecule targeting' by Marta Giuliani et al., Chem. Commun., 2015, 51, 14140-14159.

Moulding calixarenes for biomacromolecule targeting.

After their successful use as a preorganized platform for the preparation of receptors for metal ions and small neutral molecules over the last 15 years, calixarenes are enjoying a renaissance of popularity as scaffolds for ligands that are able to efficiently and selectively target macromolecules such as proteins/enzymes, nucleic acids and lipids. This feature article summarizes the peculiar factors characterizing the calixarene structure and properties, as well as outlines the main rules that can be used to turn such macrocycles into efficient and successful ligands for these classes of biomacromolecules. Factors that affect the multivalent properties of calixarenes, such as the size, conformation and stereochemical presentation of binding groups or their amphiphilicity and hybrid character, are described in detail with the use of a few selected examples from the literature. Perspectives and applications of these ligands in bionanotechnology and nanomedicine, such as protein sensing and inhibition, gene-delivery, targeted drug-delivery and cell imaging, are also discussed.

Delayed ejaculation and alexithymia: what is the relationship?

Delayed Ejaculation (DE) is probably the least studied and understood of the male sexual dysfunctions (MSD). There is still little unanimity concerning its psychological/interpersonal aetiology. Previous studies found that MSD are strongly related with alexithymia, a multifaceted personality construct that describes a disturbance in the regulation of emotions.The aim of this study was to investigate the presence of alexithymia in men with DE and correlate alexithymia levels with DE severity. According to specific features of the symptoms, we hypothesized that alexithymia would not be correlated with this specific sexual disorder. 54 outpatients with a diagnosis of DE assessed at the Institute of Clinical Sexology and the Urology Department of Sapienza, University in Rome were enrolled in the study. DE was diagnosed after a specialist examination and according to Diagnostic and Statistical Manual of Mental Disorders -IV-TR criteria. Participants were provided with the Toronto Alexithymia Scale (20 items; TAS-20), a self-measure of the Intravaginal Ejaculation Latency Time and an ad hoc questionnaire to collect anamnestic data. 9.3% of patients could be categorized as alexithymics, 9.3% of them as borderline, while 81.4% of the sample was found to be non-alexithymic. The overall average TAS-20 score was 45.46. Results show that alexithymia is correlated neither with the presence of DE nor with its severity, in contrast to other MSDs, where this condition was found in about 30% of patients. The data presented suggest that DE, although not correlated to alexithymia, is probably related to other psychogenic features such as hypercontrol configuration. This paper can contribute to the understanding of DE, by excluding one of the possible etiological factors, previously found to be important in the onset and the maintenance of the other MSDs. More studies are needed in order to better understand DE and provide recommendations about treatment.