Alternative promoters and splicing create multiple functionally distinct isoforms of oestrogen receptor alpha in breast cancer and healthy tissues.

BACKGROUND: Oestrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. It affects, for example, bone, endometrium, ovaries and mammary epithelium. It is a key biomarker in clinical management of breast cancer, where it is used as a prognostic and treatment-predictive factor, and a therapeutical target. Several ER isoforms have been described, but transcript annotation in public databases is incomplete and inconsistent, and functional differences are not well understood. METHODS: We have analysed short- and long-read RNA sequencing data from breast tumours, breast cancer cell lines, and normal tissues to create a comprehensive annotation of ER transcripts and combined it with experimental studies of full-length protein and six alternative isoforms. RESULTS: The isoforms have varying transcription factor activity, subcellular localisation, and response to the ER-targeting drugs tamoxifen and fulvestrant. Antibodies differ in ability to detect alternative isoforms, which raises concerns for the interpretation of ER-status in routine pathology. CONCLUSIONS: Future work should investigate the effects of alternative isoforms on patient survival and therapy response. An accurate annotation of ER isoforms will aid in interpretation of clinical data and inform functional studies to improve our understanding of the ER in health and disease.

Posttraumatic Stress Disorder (PTSD) Patients Exhibit a Blunted Parasympathetic Response to an Emotional Stressor.

Diminished parasympathetic reactivity is a physiological feature of posttraumatic stress disorder (PTSD). The objective of this study was to compare female PTSD patients with non-traumatized healthy women with respect to autonomic cardiovascular regulation during exposure to two stressors. Hospitalized PTSD patients (n = 52) and controls (n = 37) completed standardized laboratory-based stress testing including a mental arithmetic test and a standardized audiotape recording of a crying infant. Controls and PTSD patients both showed a significantly increased heart rate and reduced pre-ejection period from baseline rest to the arithmetic stressor. However, as judged from nonsignificant changes in baroreflex sensitivity, parasympathetic activation caused by the crying infant stressor was blunted in PTSD patients as compared to healthy individuals. Under the crying infant condition, a vagal dominance was observed only in controls, and not in PTSD patients. Our data demonstrate that, in PTSD patients, diminished parasympathetic reactivity is not restricted to trauma-related events but can also be observed in response to a social stimulus such as listening to a crying infant. This finding suggests that the altered vagal reactivity in PTSD patients reflects the physiological consequences of a generally disturbed autonomous response to emotionally relevant stressors.

Managing protected areas under climate change: challenges and priorities.

The implementation of adaptation actions in local conservation management is a new and complex task with multiple facets, influenced by factors differing from site to site. A transdisciplinary perspective is therefore required to identify and implement effective solutions. To address this, the International Conference on Managing Protected Areas under Climate Change brought together international scientists, conservation managers, and decision-makers to discuss current experiences with local adaptation of conservation management. This paper summarizes the main issues for implementing adaptation that emerged from the conference. These include a series of conclusions and recommendations on monitoring, sensitivity assessment, current and future management practices, and legal and policy aspects. A range of spatial and temporal scales must be considered in the implementation of climate-adapted management. The adaptation process must be area-specific and consider the ecosystem and the social and economic conditions within and beyond protected area boundaries. However, a strategic overview is also needed: management at each site should be informed by conservation priorities and likely impacts of climate change at regional or even wider scales. Acting across these levels will be a long and continuous process, requiring coordination with actors outside the "traditional" conservation sector. To achieve this, a range of research, communication, and policy/legal actions is required. We identify a series of important actions that need to be taken at different scales to enable managers of protected sites to adapt successfully to a changing climate.

Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disorder caused by loss-of-function mutations in the thymidine phosphorylase gene (TYMP). We report here a patient compound heterozygous for two TYMP mutations: a novel g.4009G>A transition affecting the consensus splice donor site of intron 9, and a previously reported g.675G>C splice site mutation. The novel mutation causes exon 9 skipping but leaves the reading frame intact; however, TYMP protein was not detected by immunoblot analysis, suggesting that neither mutant allele is expressed as protein. The patient's fibroblasts showed gradual loss of the mitochondrial DNA-encoded subunit I of cytochrome-c oxidase, suggesting a progressive mitochondrial DNA defect in culture.

Functional relevant loss of long association fibre tracts integrity in early Alzheimer's disease.

The aim of our study was to quantify the structural integrity of the long association fibre tracts in early Alzheimer's disease (AD) and to correlate the findings with the cognitive performance of the patients. We conducted region-of-interest-based analyses of color-coded diffusion-tensor imaging in 12 patients with early AD (age 69.8+/-8.0 years; MMSE 25.3+/-1.8) and 16 age- and education-matched healthy controls. Early AD patients showed significantly decreased fractional anisotropy (FA) of the cingulate bundles and the inferior fronto-occipital fascicles bilaterally, whereas FA values of the superior longitudinal fascicles (second division) did not differ significantly between patients and controls. Neuropsychological performance of patients in the verbal episodic memory test domain correlated significantly with disturbances of left cingulate fibre tract integrity. Reduced left cingulate bundle integrity was most strongly correlated with impaired performance in a verbal recognition task (Spearman's rho=0.81, P=0.001). Moreover, Boston naming test performance also correlated with the left cingulate bundle integrity (Spearman's rho=0.71, P=0.009). These findings suggest substantial disturbances of the structural connectivity within long association fibre tracts, especially the cingulate bundles and the inferior fronto-occipital fascicles, in early AD and highlight the important role of the cingulate bundles in verbal recognition.

Quantification of brain tissue alterations in Fabry disease using diffusion-tensor imaging.

UNLABELLED: Central nervous system involvement is a major burden in Fabry disease. Conventional cranial magnetic resonance imaging (MRI) shows micro- and macroangiopathic changes such as severe and progressive white matter lesions (WMLs) at an early age on T2- and fluid-attenuated inversion recovery-weighted images, increased signal intensity in the pulvinar on T1-weighted MRI, as well as tortuosity and dilatation of the larger vessels (dolicho-ectasia). Using diffusion tensor imaging (DTI), a new structural MRI-technique that measures water diffusion characteristics, we showed marked brain tissue alterations in Fabry disease predominantly in the periventricular white matter. Even patients with few WMLs had significantly elevated brain tissue diffusivity. CONCLUSION: DTI is more sensitive in detecting brain tissue changes in Fabry disease than conventional MRI. DTI measurements could provide appropriate surrogate parameters with which to monitor the natural history of structural brain involvement and potential effects of therapy (such as enzyme replacement) in Fabry disease.

Oxygen and glucose deprivation induces major dysfunction in the somatosensory cortex of the newborn rat.

The mechanisms and functional consequences of ischemia-induced injury during perinatal development are poorly understood. Subplate neurons (SPn) play a central role in early cortical development and a pathophysiological impairment of these neurons may have long-term detrimental effects on cortical function. The acute and long-term consequences of combined oxygen and glucose deprivation (OGD) were investigated in SPn and compared with OGD-induced dysfunction of immature layer V pyramidal cortical neurons (PCn) in somatosensory cortical slices from postnatal day (P)0-4 rats. OGD for 50 min followed by a 10-24-h period of normal oxygenation and glucose supply in vitro or in culture led to pronounced caspase-3-dependent apoptotic cell death in all cortical layers. Whole-cell patch-clamp recordings revealed that the majority of SPn and PCn responded to OGD with an initial long-lasting ischemic hyperpolarization accompanied by a decrease in input resistance (R(in)), followed by an ischemic depolarization (ID). Upon reoxygenation and glucose supply, the recovery of the membrane potential and R(in) was followed by a Na+/K+-ATPase-dependent postischemic hyperpolarization, and in almost half of the investigated SPn and PCn by a postischemic depolarization. Whereas neither a moderate (2.5 mm) nor a high (4.8 mm) increase in extracellular magnesium concentration protected the SPn from OGD-induced dysfunction, blockade of NMDA receptors with MK-801 led to a significant delay and decrease of the ID. Our data demonstrate that OGD induces apoptosis and a profound dysfunction in SPn and PCn, and underline the critical role of NMDA receptors in early ischemia-induced neuronal damage.