Estrogen and testosterone secretion from the mouse brain.

Estrogen and testosterone are typically thought of as gonadal or adrenal derived steroids that cross the blood brain barrier to signal via both rapid nongenomic and slower genomic signalling pathways. Estrogen and testosterone signalling has been shown to drive interlinked behaviours such as social behaviours and cognition by binding to their cognate receptors in hypothalamic and forebrain nuclei. So far, acute brain slices have been used to study short-term actions of 17β-estradiol, typically using electrophysiological measures.

Steroid hormone-mediated regulation of sexual and aggressive behaviour by non-genomic signalling.

Sex and aggression are well studied examples of social behaviours that are common to most animals and are mediated by an evolutionary conserved group of interconnected nuclei in the brain called the social behaviour network. Though glucocorticoids and in particular estrogen regulate these social behaviours, their effects in the brain are generally thought to be mediated by genomic signalling, a slow transcriptional regulation mediated by nuclear hormone receptors. In the last decade or so, there has been renewed interest in understanding the physiological significance of rapid, non-genomic signalling mediated by steroids.

Does GPER1 Play a Role in Sexual Dimorphism?

Estrogens are critical in driving sex-typical social behaviours that are ethologically relevant in mammals. This is due to both production of local estrogens and signaling by these ligands, particularly in an interconnected set of nuclei called the social behavioural network (SBN). The SBN is a sexually dimorphic network studied predominantly in rodents that is thought to underlie the display of social behaviour in mammals.

Thermoneutrality improves skeletal impairment in adult Prader-Willi syndrome mice.

Human Prader-Willi syndrome (PWS) is characterised by impairments of multiple systems including the growth hormone (GH) axis and skeletal growth. To address our lack of knowledge of the influence of PWS on skeletal integrity in mice, we have characterised the endocrine and skeletal phenotype of the PWS-ICdel mouse model for "full" PWS and determined the impact of thermoneutrality. Tibial length, epiphyseal plate width and marrow adiposity were reduced by 6%, 18% and 79% in male PWS-ICdel mice, with osteoclast density being unaffected.

Inhibition of v5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The v5 integrin may have an important role in acute injury, including septic shock and acute lung injury.

Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.

Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors.

Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.

Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer.

Structure-Based Design of Potent and Selective CK1γ Inhibitors.

Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We describe a structure-based approach that led to the discovery of a series of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors.

Multiple isoforms of CDC25 oppose ATM activity to maintain cell proliferation during vertebrate development.

The early development of vertebrate embryos is characterized by rapid cell proliferation necessary to support the embryo's growth. During this period, the embryo must maintain a balance between ongoing cell proliferation and mechanisms that arrest or delay the cell cycle to repair oxidative damage and other genotoxic stresses. The ataxia-telangiectasia mutated (ATM) kinase is a critical regulator of the response to DNA damage, acting through downstream effectors, such as p53 and checkpoint kinases (CHK) to mediate cell-cycle checkpoints in the presence of DNA damage.

Vertebral artery dissection in weightlifter with performance enhancing drug use.

This case report describes a transient ischaemic attack secondary to vertebral artery dissection (VAD) in a young male body builder. This occurred following weight training with weights across the back and shoulders. The patient was also known to take multiple performance enhancing agents including anabolic steroids, slimming agents, stimulants and human growth hormone.

Identification of a heritable model of testicular germ cell tumor in the zebrafish.

Germ cell tumors (GCTs) affect infants, children, and adults and are the most common cancer type in young men. Progress in understanding the molecular basis of GCTs has been hampered by a lack of suitable animal models. Here we report the identification of a zebrafish model of highly penetrant, heritable testicular GCT isolated as part of a forward genetic screen for cancer susceptibility genes.

Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion.

Understanding the pathways that control epithelial carcinogenesis is vital to the development of effective treatments. The Polycomb group family member Bmi1 is overexpressed in numerous epithelial tumors, but its role in their development has not been established. We now show a key role for Bmi1 in lung adenocarcinoma.

Acute hospital admissions from nursing homes: some may be avoidable.

A retrospective survey of acute hospital admissions from nursing homes over a year to a district hospital revealed high overall hospital admission rates and wide variations of admission rates from similar homes. Medical admissions dominated, infections and poorly controlled heart failure being notably common. A significant proportion of admissions may have been avoided by active chronic disease management, together with better information for doctors responding to emergency calls and specialist support programmes facilitating in situ treatment.