Description: Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with α 1A -adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of α 1D -adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT) 1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N -phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on- or off-target receptors. LDTs’ potency was estimated in intracellular Ca 2+ elevation assays using cells overexpressing human α 1 -adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs’ effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of α 1A -, α 1D -adrenoceptors, and 5-HT 1A receptors ( K i values in the nanomolar range), and fully inhibited phenylephrine- and 5-HT–induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED 50 of 0.15 and 0.09 μ g.kg –1 , respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment.

Description: The occurrence of a generalized remagnetization at 100 Ma makes the Cameros basin, a 8 km-thick Cretaceous extensional trough inverted during the Cenozoic, a perfect natural frame to apply paleomagnetic vectors to geometrical reconstructions. The widespread remagnetization that occurred between the extensional and the compressional episodes, linked to low-grade metamorphism, provides a tool to reconstruct the attitude of beds at the remagnetization time, thus giving a picture of basin geometry during the Cretaceous. This snapshot is compared with the present-day geometry to constrain the large-scale kinematic evolution of folds between these two stages. According to this methodology, a syncline, pre-inversion geometry of the sedimentary basin was determined and the position of its main axial surface was accurately located. Comparing with the present-day, post-inversion geometry, a northwards hinge migration of around 5 km is inferred. This migration is the result of the southwards backthrusting in the southern basin border, favored by the detachment level at the base of the Mesozoic cover. Conversely, the main northwards-directed thrust, which involved both the Paleozoic basement and the Mesozoic cover, did not significantly affect the internal structure of the basin in spite of its overall displacement of more than 20 km.

Description: G protein–coupled receptors are sensors that interact with a large variety of elements, including photons, ions, and large proteins. Not surprisingly, these receptors participate in the numerous normal physiologic processes that we refer to as health and in its perturbations that constitute disease. It has been estimated that a large percentage of drugs currently used in therapeutics target these proteins, and this percentage is larger when illegal drugs are included. The state of the art in this field can be defined with the oxymoron "constant change," and enormous progress has been made in recent years. A group of scientists working in Latin America were invited to contribute minireviews for this special section to present some of the work performed in this geographical region and foster further international collaboration.

Description: BRCA2 is a multi-faceted protein critical for the proper regulation of homology-directed repair of DNA double-strand breaks. Elucidating the mechanistic features of BRCA2 is crucial for understanding homologous recombination and how patient-derived mutations impact future cancer risk. Eight centrally located BRC repeats in BRCA2 mediate binding and regulation of RAD51 on resected DNA substrates. Herein, we dissect the biochemical and cellular features of the BRC repeats tethered to the DNA binding domain of BRCA2. To understand how the BRC repeats and isolated domains of BRCA2 contribute to RAD51 binding, we analyzed both the biochemical and cellular properties of these proteins. In contrast to the individual BRC repeat units, we find that the BRC5–8 region potentiates RAD51-mediated DNA strand pairing and provides complementation functions exceeding those of BRC repeats 1–4. Furthermore, BRC5–8 can efficiently repair nuclease-induced DNA double-strand breaks and accelerate the assembly of RAD51 repair complexes upon DNA damage. These findings highlight the importance of the BRC5–8 domain in stabilizing the RAD51 filament and promoting homology-directed repair under conditions of cellular DNA damage.

Description: Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4R rs2107356 and IL8 rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA ( IL4R rs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8 rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12B rs3212227 and IFN rs2069705 variants were significantly associated with a decreased risk of developing the infection ( IL12B rs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFN rs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4R rs2107356 and IFN rs2069705 SNPs was stronger in allo-HSCT ( IL4R rs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFN rs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFN rs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia ( P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFN) mRNA ( P = 0.049) and IFN and tumor necrosis factor alpha (TNF-α) cytokines ( P value for 96 h of treatment with lipopolysaccharide [ P LPS-96 h ], 0.057; P value for 96 h of treatment with phytohemagglutinin [ P PHA-96 h ], 0.036; P LPS+PHA-96 h = 0.030; P PHA-72 h = 0.045; P LPS+PHA-72 h = 0.018; P LPS-96 h = 0.058; P LPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P –2 log likehood ratio test = 5.2 · 10 –4 and P 50.000 permutation test = 9.34 · 10 –5 ). These findings suggest that the IFN rs2069705 SNP influences the risk of IA and that predictive models built with IFN , IL8 , IL12p70 , and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

Description: Upon agonist stimulation, α 1B -adrenergic receptors couple to G q proteins, calcium signaling and protein kinase C activation; subsequently, the receptors are phosphorylated, desensitized, and internalized. Internalization seems to involve scaffolding proteins, such as β -arrestin and clathrin. However, the fine mechanisms that participate remain unsolved. The roles of protein kinase C and the small GTPase, Rab9, in α 1B -AR vesicular traffic were investigated by studying α 1B -adrenergic receptor–Rab protein interactions, using Förster resonance energy transfer (FRET), confocal microscopy, and intracellular calcium quantitation. In human embryonic kidney 293 cells overexpressing Discosoma spp. red fluorescent protein (DsRed)-tagged α 1B -ARs and enhanced green fluorescent protein–-tagged Rab proteins, pharmacological protein kinase C activation mimicked α 1B -AR traffic elicited by nonrelated agents, such as sphingosine 1-phosphate (i.e., transient α 1B -AR-Rab5 FRET signal followed by a sustained α 1B -AR-Rab9 interaction), suggesting brief receptor localization in early endosomes and transfer to late endosomes. This latter interaction was abrogated by blocking protein kinase C activity, resulting in receptor retention at the plasma membrane. Similar effects were observed when a dominant-negative Rab9 mutant (Rab9-GDP) was employed. When α 1B -adrenergic receptors that had been mutated at protein kinase C phosphorylation sites (S396A, S402A) were used, phorbol ester-induced desensitization of the calcium response was markedly decreased; however, interaction with Rab9 was only partially decreased and internalization was observed in response to phorbol esters and sphingosine 1-phosphate. Finally, Rab9-GDP expression did not affect adrenergic-mediated calcium response but abolished receptor traffic and altered desensitization. Data suggest that protein kinase C modulates α 1B -adrenergic receptor transfer to late endosomes and that Rab9 regulates this process and participates in G protein-mediated signaling turn-off.