Multiple Novel Signals Mediate Thyroid Hormone Receptor Nuclear Import and Export

Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor a1 that is absent in thyroid hormone receptor B1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor a1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the a-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor B1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in genera

Dynamics of SNARE Assembly and Disassembly during Sperm Acrosomal Exocytosis

The dynamics of SNARE assembly and disassembly during membrane recognition and fusion is a central issue in intracellular trafficking and regulated secretion. Exocytosis of sperm's single vesicle—the acrosome—is a synchronized, all-or-nothing process that happens only once in the life of the cell and depends on activation of both the GTP-binding protein Rab3 and of neurotoxin-sensitive SNAREs. These characteristics make acrosomal exocytosis a unique mammalian model for the study of the different phases of the membrane fusion cascade. By using a functional assay and immunofluorescence techniques in combination with neurotoxins and a photosensitive Ca(2+) chelator we show that, in unactivated sperm, SNAREs are locked in heterotrimeric cis complexes. Upon Ca(2+) entry into the cytoplasm, Rab3 is activated and triggers NSF/α-SNAP-dependent disassembly of cis SNARE complexes. Monomeric SNAREs in the plasma membrane and the outer acrosomal membrane are then free to reassemble in loose trans complexes that are resistant to NSF/α-SNAP and differentially sensitive to cleavage by two vesicle-associated membrane protein (VAMP)–specific neurotoxins. Ca(2+) must be released from inside the acrosome to trigger the final steps of membrane fusion that require fully assembled trans SNARE complexes and synaptotagmin. Our results indicate that the unidirectional and sequential disassembly and assembly of SNARE complexes drive acrosomal exocytosis

Occurrence of malignant neoplasia in patients with primary hyperparathyroidism

Introduction The association between primary hyperparathyroidism (1HPT) and cancer is debated. The present study was aimed to investigate the occurrence of neoplasia in 1HPT. Patients and methods All consecutive patients (n = 1750) referred to our \u201cOsteoporosis and Metabolic Disease\u201d outpatients clinic for osteoporosis or hypercalcemia were eligible for the study. The exclusion criteria were: the finding of osteoporosis and/or altered calcium-phosphorous metabolism in the context of investigations for malignancy, the presence of diseases known to influence the cancer risk and the heavy smoking habit. Eventually, 1606 patients (1407 females, 199 males) were enrolled. In all patients calcium-phosphorous metabolism, PTH and vitamin D levels were measured and the occurrence of cancer during the 10 years prior the study inclusion was recorded. Results One-hundred-sixty-three patients had 1HPT while 1443 had not. Patients with and without 1HPT were comparable for age and gender. In 1HPT patients the occurrence of all, breast, kidney and skin cancer was significantly higher (21.5%, 12.2%, 2.5%, 1.8%, respectively) than in patients without 1HPT (12.4%, 6.9%, 0.3%, 0.3%, p < 0.05 for all comparisons). The 1HPT presence was significantly associated with the occurrence of all neoplasia and of breast, skin and kidney neoplasia (odds ratio, 95% confidence interval, p value: 1.93, 1.27\u20132.92, 0.002; 1.93, 1.11\u20133.35, 0.002; 9.18, 2.16\u201338.8, 0.003; 8.23, 1.71\u201339.5, 0.008, respectively), after adjusting for age, gender (as appropriate), smoking habit and vitamin D levels. Conclusion During the 10 years prior the diagnosis of 1HPT, the occurrence of all, breast, skin and kidney neoplasia is increased

Nanotechnology and its applications in food and animal science

Nanotechnology has the potential to manipulate matter at the nanometre scale, creating and assembling substances at a molecular level with new and interesting properties. This has offered opportunities for applications in different sectors. Recently, nanotechnology has received particular attention due to its promising applications in animal nutrition, drugs and nutrients delivery, animal reproduction, disease diagnosis and treatment. In the food sector, nanotechnology is applied to the improvement of food packaging, processing, monitoring and the development of food with new functional properties that can respond to the needs of consumers. This review will focus on the advances of nanotechnology in food sector and animal science with particular attention to animal nutrition. The implications for safety and regulation will be also discussed