High potent and selective arylpiperazine derivatives as ligands for the 5-HT1A receptor

This paper reports the synthesis and affinities on the 5-HT1A versus the alpha1A receptors of new arylpiperazinylalkylthiothienopyrimidine and thiadiazole derivatives 16-24. Arylpiperazines 16-23 show affinities values in the nanomolar range for the 5-HT1A receptor. The compound 16 is highly potent (Ki 0.26 nM, selectivity 28), the derivatives 20 and 21 are less potent, but highly selective (Ki 9.40 and 5.06 nM, selectivity 207 and 73, respectively).     

The antibiotic Furvina? targets the P-site of 30S ribosomal subunits and inhibits translation initiation displaying start codon bias

Furvina®, also denominated G1 (MW 297), is a synthetic nitrovinylfuran [2-bromo-5-(2-bromo-2-nitrovinyl)-furan] antibiotic with a broad antimicrobial spectrum. An ointment (Dermofural®) containing G1 as the only active principle is currently marketed in Cuba and successfully used to treat dermatological infections. Here we describe the molecular target and mechanism of action of G1 in bacteria and demonstrate that in vivo G1 preferentially inhibits protein synthesis over RNA, DNA and cell wall synthesis. Furthermore, we demonstrate that G1 targets the small ribosomal subunit, binds at or near the P-decoding site and inhibits its function interfering with the ribosomal binding of fMet-tRNA during 30S initiation complex (IC) formation ultimately inhibiting translation. Notably, this G1 inhibition displays a bias for the nature (purine vs. pyrimidine) of the 3′-base of the codon, occurring efficiently only when the mRNA directing 30S IC formation and translation contains the canonical AUG initiation triplet or the rarely found AUA triplet, but hardly occurs when the mRNA start codon is either one of the non-canonical triplets AUU or AUC. This codon discrimination by G1 is reminiscent, though of opposite type of that displayed by IF3 in its fidelity function, and remarkably does not occur in the absence of this factor.     

Does life along the sea carry greater risk of thyroid cancer?

Aim of this study was to determine whether there are any differences between coastal and inland Dalmatia in incidence rates and clinical characteristics of thyroid cancer. Data on 651 persons who suffer from and have undergone surgery for thyroid cancer have been analysed. All patients lived in Dalmatia between 1997 and 2006. Data were collected via surveys, insight into medical histories and results of histopathological analysis. In Dalmatia, in the overall sample, there are no statistically significant differences in incidence between coastal and inland areas (chi2=3.03; df=1; p=0.082). Somewhat higher overall incidence has been recorded in the inland (8.5%000) than in the coastal Dalmatia (7.3%000). In the overall sample, in Dalmatia, women make up 81.4% of patients and papillary cancer accounts for 80.0% of all thyroid cancers. The ratio of papillary to folicullar cancer is 7.8:1 in coastal and 4.2:1 in inland Dalmatia. Papillary and medullary types are more common in the coastal area and follicular and anaplastic cancer types in the inland area and the differences are statistically significant (p>0.033). Epidemiological characteristics of thyroid cancer in coastal Dalmatia are in accordance with the characteristics of this cancer as described in iodine-sufficient areas: the most common type is papillary cancer, and the ratio of papillary to follicular is 7.8:1. Sex-wise, the coastal area records a higher ratio of male patients (1:3.8) than the inland area (1:7.1). There are no statistically significant differences in thyroid cancer incidence rates between coastal and inland Dalmatia. Epidemiological characteristics of thyroid cancer in inland Dalmatia are in some ways more similar to those of continental Croatia. This result could be the consequence of previous iodine insufficiency in inland Dalmatia.     

Gangliosides,NGF, Brain Aging and Disease: A Mini-Review with Personal Reflections

In this mini-review I summarize our research efforts in ascertaining the possible neuro-reparative properties of the GM1 ganglioside and its cooperative effects with NGF in stroke-lesion models. We also review aspects of our NGF investigations which have recently led to the discovery that NGF is released in an activity-dependent manner in the form of its precursor molecule, proNGF. These studies support the notion that in the CNS NGF metabolism conversion and degradation occur in the extracellular milieu. We have also validated this pathway in vivo demonstrating that the pharmacological inhibition of the pro-to mature NGF conversion results in the brain accumulation of proNGF and loss and atrophy of cortical cholinergic synapses. Furthermore, we have gathered neurochemical evidence for a compromise of this newly discovered NGF metabolic pathway in Alzheimer’s disease, explaining the vulnerability of NGF-dependent forebrain cholinergic neurons in this disease despite normal NGF synthesis and abundance of NGF precursor.     

Infectious Agents and Neurodegeneration

A growing body of epidemiologic and experimental data point to chronic bacterial and viral infections as possible risk factors for neurodegenerative diseases, including Alzheimer??s disease, Parkinson??s disease and amyotrophic lateral sclerosis. Infections of the central nervous system, especially those characterized by a chronic progressive course, may produce multiple damage in infected and neighbouring cells. The activation of inflammatory processes and host immune responses cause chronic damage resulting in alterations of neuronal function and viability, but different pathogens can also directly trigger neurotoxic pathways. Indeed, viral and microbial agents have been reported to produce molecular hallmarks of neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in synergy with other recognized risk factors, such as aging, concomitant metabolic diseases and the host??s specific genetic signature. This review will focus on the contribution given to neurodegeneration by herpes simplex type-1, human immunodeficiency and influenza viruses, and by Chlamydia pneumoniae.     

Cheap and Long‐Life Reusable Polymer for Asymmetric Organozinc Catalysis Based on Camphor‐Derived Hydroxyamides

Polystyrene grafted with a chiral zinc‐complexing camphor‐derived N,N‐disubstituted hydroxyamide is proposed as a new type of functional polymer of high reusability for the development of sustainable organozinc‐catalyzed asymmetric reactions. The main goal of this new functional polymer is the ease of the hydroxyamide‐moiety preparation (cheap chiral ligand obtained straightforwardly from an enantiopure starting material coming from the chiral pool), as well as its chemical robustness when compared with other related zinc‐complexing functional groups. The latter allows the polymer to be active after multiple applications, without significant loss of its catalytic activity. This fact is exemplified by the design and preparation of a polymer functionalized with a bis(hydroxyamide) proved previously as active in the homogeneous enantioselective addition of diethylzinc to aldehydes. The result is a cheap functional polymer with a very high reusability (the enantioselectivity and chemical yield are maintained practically constant after 20 applications). Additionally, a methodology for the multicycle use of these functional polymers is presented. Chirality, 2012. © 2012 Wiley Periodicals, Inc.     

Axial speed of sound for the monitoring of injured equine tendons: a preliminary study

Equine superficial digital flexor tendons (SDFT) are often injured, and they represent an excellent model for human sport tendinopathies. While lesions can be precisely diagnosed by clinical evaluation and ultrasonography, a prognosis is often difficult to establish; the knowledge of the injured tendon's mechanical properties would help in anticipating the outcome. The objectives of the present study were to compare the axial speed of sound (SOS) measured in vivo in normal and injured tendons and to investigate their relationship with the tendons' mechanical parameters, in order to assess the potential of quantitative axial ultrasound to monitor the healing of the injured tendons. SOS was measured in vivo in the right fore SDFTs of 12 horses during walk, before and 3.5 months after the surgical induction of a bilateral core lesion. The 12 horses were then euthanized, their SDFTs isolated and tested in tension to measure their elastic modulus and maximal load (and corresponding stress). SOS significantly decreased from 2179.4 ± 31.4 m/s in normal tendons to 2065.8 ± 67.1 m/s 3.5 months after the surgical induction, and the tendons' elastic modulus (0.90 ± 0.17 GPa) was found lower than what has been reported in normal tendons. While SOS was not correlated to tendon maximal load and corresponding stress, the SOS normalized on its value in normal tendons was correlated to the tendons' elastic modulus. These preliminary results confirm the potential of axial SOS in helping the functional assessment of injured tendon.     

miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration

During keratinocyte differentiation and stratification, cells undergo extensive remodeling of their actin cytoskeleton, which is important to control cell mobility and to coordinate and stabilize adhesive structures necessary for functional epithelia. Limited knowledge exists on how the actin cytoskeleton is remodeled in epithelial stratification and whether cell shape is a key determinant to trigger terminal differentiation. In this paper, using human keratinocytes and mouse epidermis as models, we implicate miR-24 in actin adhesion dynamics and demonstrate that miR-24 directly controls actin cable formation and cell mobility. miR-24 overexpression in proliferating cells was sufficient to trigger keratinocyte differentiation both in vitro and in vivo and directly repressed cytoskeletal modulators (PAK4, Tks5, and ArhGAP19). Silencing of these targets recapitulated the effects of miR-24 overexpression. Our results uncover a new regulatory pathway involving a differentiation-promoting microribonucleic acid that regulates actin adhesion dynamics in human and mouse epidermis.     

A complex 'mRNA degradation code' controls gene expression during animal development

Current understanding of the molecular mechanisms underlying mRNA degradation indicates that specific mRNA degradation rates are primarily encoded within the mRNA message itself in the form of cis-regulatory elements bearing particular primary sequences and/or secondary-structures. Such control elements are operated by RNA-binding proteins (RBPs) and/or miRNA-containing complexes. Based on the large number of RBPs and miRNAs encoded in metazoan genomes, their complex developmental expression and that specific RBP and miRNA interactions with mRNAs can lead to distinct degradation rates, I propose that developmental gene expression is shaped by a complex 'mRNA degradation code' with high information capacity. Localised cellular events involving the modification of RBP and/or miRNA target sequences in mRNAs by alternative polyadenylation added to the activation of specific RBP and miRNA activities via cell signalling are predicted to further expand the capacity of the mRNA degradation code by coupling it to dynamic events experienced by cells at specific spatiotemporal coordinates within the developing embryo.