Gonadal Steroid Hormone Receptors and Sex Differences in the Hypothalamo-Pituitary-Adrenal Axis

The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.     

On the etiology of aging

Amino acid racemization is presented as an hypothesis for the cause of aging. Effects on important biomolecules resulting from changes in their three-dimensional conformations and resulting changes in activities and specificities are discussed. Aging is viewed as a natural process associated with attaining thermodynamic equilibrium.     

Accuracy of diagnostic registers and management of chronic obstructive pulmonary disease: the Devon primary care audit

Background

Guidelines on COPD diagnosis and management encourage primary care physicians to detect the disease at an early stage and to treat patients according to their condition and needs. Problems in guideline implementation include difficulties in diagnosis, using spirometry and the disputed role of reversibility testing. These lead to inaccurate diagnostic registers and inadequacy of administered treatments. This study represents an audit of COPD diagnosis and management in primary care practices in Devon.

Methods

Six hundred and thirty two patients on COPD registers in primary care practices were seen by a visiting Respiratory Specialist Nurse. Diagnoses were made according to the NICE guidelines. Reversibility testing was carried out either routinely or based on clinical indication in two sub-samples. Dyspnoea was assessed. Data were entered into a novel IT-based software which computed guideline-based treatment recommendations. Current and recommended treatments were compared.

Results

Five hundred and eighty patients had spirometry. Diagnoses of COPD were confirmed in 422 patients (73%). Thirty nine patients were identified as asthma only, 94 had normal spirometry, 23 were restrictive and 2 had a cardiac disorder. Reversibility testing changed diagnosis of 11% of patients with airflow obstruction, and severity grading in 18%. Three quarters of patients with COPD had been offered practical help with smoking cessation. Short and long-acting anticholinergics and long acting beta-2 agonists had been under-prescribed; in 15–18% of patients they were indicated but not received. Inhaled steroids had been over-prescribed (recommended in 17%; taken by 60%), whereas only 4% of patients with a chronic productive cough were receiving mucolytics. Pulmonary rehabilitation was not available in some areas and was under-used in other areas.

Conclusion

Diagnostic registers of COPD in primary care contain mistakes leading to inaccurate prevalence estimates and inappropriate treatment decisions. Use of pre-bronchodilator readings for diagnosis overestimates the prevalence and severity in a significant minority, thus post bronchodilator readings should be used. Management of stable COPD does often not correspond to guidelines. The IT system used in this study has the potential to improve diagnosis and management of COPD in primary care.     

Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses

Background

A recent epidemiological study demonstrated a reduced risk of lung cancer mortality in breast cancer patients using antiestrogens. These and other data implicate a role for estrogens in lung cancer, particularly nonsmall cell lung cancer (NSCLC). Approximately 61% of human NSCLC tumors express nuclear estrogen receptor β (ERβ); however, the role of ERβ and estrogens in NSCLC is likely to be multifactorial. Here we tested the hypothesis that proteins interacting with ERβ in human lung adenocarcinoma cells that respond proliferatively to estradiol (E₂) are distinct from those in non-E₂-responsive cells.

Methods

FLAG affinity purification of FLAG-ERβ-interacting proteins was used to isolate ERβ-interacting proteins in whole cell extracts from E₂ proliferative H1793 and non-E₂-proliferative A549 lung adenocarcinoma cell lines. Following trypsin digestion, proteins were identified using liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). Proteomic data were analyzed using Ingenuity Pathway Analysis. Select results were confirmed by coimmunoprecipitation.

Results

LC-MS/MS identified 27 non-redundant ERβ-interacting proteins. ERβ-interacting proteins included hsp70, hsp60, vimentin, histones and calmodulin. Ingenuity Pathway Analysis of the ERβ-interacting proteins revealed differences in molecular and functional networks between H1793 and A549 lung adenocarcinoma cells. Coimmunoprecipitation experiments in these and other lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a gender-dependent manner and in response to E₂ or EGF. BRCA1 interacted with ERβ in A549 cell lines and in human lung adenocarcinoma tumors, but not normal lung tissue.

Conclusion

Our results identify specific differences in ERβ-interacting proteins in lung adenocarcinoma cells corresponding to ligand-dependent differences in estrogenic responses.

     

Polyconfiguron-model for the A-protein of coliphage MS2

An algorithm is presented for decoding mRNA to give the tertiary structure of A-protein of MS2 coliphage. The scale model for the A-protein was assembled by stepwise “translation” of each codon into the corresponding amino acid configuron, so that a polyconfiguron composed of the 393 amino acid residues of the A-protein was generated. This polyconfiguron has the topography of native A-protein, as it has been predicted by a variety of functional and physicochemical procedures.     

Flying lemurs – The 'flying tree shrews'? Molecular cytogenetic evidence for a Scandentia-Dermoptera sister clade

Background  

Flying lemurs or Colugos (order Dermoptera) represent an ancient mammalian lineage that contains only two extant species. Although molecular evidence strongly supports that the orders Dermoptera, Scandentia, Lagomorpha, Rodentia and Primates form a superordinal clade called Supraprimates (or Euarchontoglires), the phylogenetic placement of Dermoptera within Supraprimates remains ambiguous.