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Although androgen excess is considered detrimental to women’s health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b , which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSH-mediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome.

CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 Å structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined α-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport. CRM1/snurportin-1 complex CRM1 is a nuclear transport receptor that mediates export of a large number of proteins out of the nucleus through recognition of leucine-rich nuclear export signals (LR-NES). In this study, Chook and colleagues present the crystal structure of CRM1 in complex with a substrate called snurportin1. Snurportin1 binds CRM1 in a bipartite manner through an N-terminal LR-NES and its nucleotide-binding domain. Further analysis reveals a second NES epitope in the nucleotide-binding domain of snurportin1. The authors propose that multipartite recognition of individually weak NES epitopes may be a common feature of CRM1 binding. The crystal structure of CRM1 in complex with a substrate called snurportin 1 is presented. Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal leucine-rich nuclear export signal (LR-NES) and its nucleotide-binding domain. Further analysis reveals a second NES epitope in the nucleotide-binding domain of snurportin 1, and multipartite recognition of individually weak NES epitopes may be a common feature of CRM1 binding.

The nuclear transport receptor CRM1 mediates protein export from the nucleus through recognition of leucine-rich nuclear export signals on substrates. Structural analysis, based in part on the recent structure of a CRM1-SNUPN complex, reveal determinants for substrate binding and suggest a mechanism for binding partner-assisted dissociation of SNUPN in the cytoplasm. CRM1 (or exportin 1, Xpo1) transports proteins out of the cell nucleus through the nuclear pore complex. In the cytoplasm, GTP hydrolysis and consequent dissociation of Ran from CRM1 releases low-affinity substrates, while additional factors facilitate release of high-affinity substrates. Here we provide a model for human CRM1 export complex assembly and disassembly through structural and biochemical analyses of CRM1 bound to the substrate snurportin 1 (SNUPN, also called snuportin 1).

Blood investigations included serum creatinine kinase (CK), which showed extremely high levels (21559), (the normal range is 40-340 units/), along with high levels of alanine transaminase (ALT). [...]genetic tests and clinical evaluation by expert, led to diagnosis of Duchenne's muscular dystrophy. Discussion Muscular dystrophy is frequently associated with other neurodevelopmental problems like autism, learning difficulties and behavioural problems, which are sometimes more obvious than motor signs.

Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is characterized by metachronously occurring tumors including pheochromocytoma, renal cell carcinoma (RCC), and hemangioblastoma. Although VHL disease leads to reduced life expectancy, its diagnosis is often missed and tumor screening guidelines are sparse. VHL protein acts as a tumor suppressor by targeting hypoxia-inducible factors (HIFs) for degradation through an oxygen-dependent mechanism. VHL mutants with more severely reduced HIF degrading function carry a high risk of RCC, while mutants with preserved HIF degrading capacity do not cause RCC but still lead to other tumors. VHL disease is classified into clinical types (1 and 2A-2C) based on this genotype-phenotype relationship. We report a case of bilateral pheochromocytomas and no other VHL-related tumors in a patient with Y175C VHL and show that this mutant preserves the ability to degrade HIF in normal oxygen conditions but, similar to the wild-type VHL protein, loses its ability to degrade HIF under hypoxic conditions. This study adds to the current understanding of the structure-function relationship of VHL mutations, which is important for risk stratification of future tumor development in the patients.

It is well known that free fatty acids (FFAs) play a key role in implementing insulin resistance and type 2 diabetes. Resources of chemical compounds that intervene the derogatory effect of FFAs are indeed very limited. We have isolated mahanine, a carbazole alkaloid, from the leaves of Murraya koenegii that prevented palmitate-induced inhibition of insulin-stimulated phosphorylation of IRβ, PI3K, PDK1, and Akt in L6 myotubes. This was also reflected in the palmitate-induced inhibition of insulin-stimulated [ 3 H] 2-DOG uptake by L6 myotubes, where palmitate adverse effect was significantly blocked by mahanine. Previous reports indicated that one of the major targets of lipid-induced damage in insulin signaling pathway resulting impairment of insulin sensitivity is insulin receptor (IR). Here, we have observed that palmitate significantly increased pPKCε in both cytosol and nuclear region of L6 myotubes in comparison to control. Translocation of pPKCε to the nucleus was associated with the impairment of HMGA1, the architectural transcription factor of IR gene and all these were reversed by mahanine. Palmitate-induced activation of IKK/IκΒ/NF-κΒ pathway was also attenuated by mahanine. Taken together, mahanine showed encouraging possibility to deal with lipid induced insulin resistance. In order to examine it further, mahanine was administered on nutritionally induced type 2 diabetic golden hamsters; it significantly improved hyperglycemia in all the treated animals. Our results, therefore, suggest that mahanine acts on two important sites of lipid induced insulin resistance (i) impairment of IR gene expression and (ii) activation of NF-κΒ pathway, thus, showing promise for its therapeutic choice for type 2 diabetes.

Nature 458, 1136–1141 (2009) In the first paragraph of this Article, Leu was incorrectly listed as Lys. The correct sentence is: “Several mutagenesis and computational studies have led to a consensus sequence φ-X(2–3)-φ-X(2–3)-φ-X-φ (in which φ is Leu, Val, Ile, Phe or Met, X is any amino acid, and the numbers in parentheses denote the number of repeats) that matches most known LR-NESs, but it is so broad that it is found in most helix-containing proteins17,18,19,20,21.

Hair cells of the inner ear are responsible for hearing and balance. These hair cells are limited in number and do not regenerate following injury. To better appreciate the function of these cells it is important to understand the molecular basis of hearing and the roles of the various molecules involved in this process. The overall goal of our laboratory is to understand the molecular basis of mechanotransduction, a process that converts the mechanical sound wave to an electrical stimulus that is transmitted to the brain. We are specifically interested in the motor protein myosin-1c (Myo1c) that has been previously shown to be involved in the adaptation response, a process that makes the hair cells sensitive to prolonged stimulation. Myo1c is a mechanoenzyme that uses the energy of ATP hydrolysis to power its movement along F-actin. The goal of this research is to examine the motor properties of Myo1c, specifically the role of the neck region of the protein in its ATPase activity. Research with other myosins of the same class has elucidated the importance of the neck length of myosins in their enzyme activity and to date no such reports exist for Myo1c. In addition to hair cells, Myo1c is also expressed in other cell types, such as neurons and adipocytes in culture and is involved in motility and vesicle transport in these cells respectively. Thus understanding the regulation of Myo1c function will also enable us to understand its role in various physiological processes.

Scent marks play a crucial role in both territorial and sexual communication in many species. We investigated how free-ranging dogs respond to scent marks from individuals of different identities in terms of sex and group, across varying strategic locations within their territory. Both male and female dogs showed heightened interest in scent marks compared to control, exhibiting stronger territorial responses, with males being more territorial than females. Overmarking behavior was predominantly observed in males, particularly in response to male scent marks and those from neighboring groups. Behavioral cluster analysis revealed distinct responses to different scent marks, with neighboring group male scents eliciting the most distinct reactions. Our findings highlight the multifaceted role of scent marks in free-ranging dog communication, mediating both territorial defense and intrasexual competition. The differential responses based on the identity and gender of the scent-marker emphasize the complexity of olfactory signaling in this species. This study contributes to understanding the social behavior of dogs in their natural habitat, and opens up possibilities for future explorations in the role of olfactory cues in the social dynamics of the species.