Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule

N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Subfunctionalization reduces the fitness cost of gene duplication in humans by buffering dosage imbalances

<p>Abstract</p> <p>Background</p> <p>Driven essentially by random genetic drift, subfunctionalization has been identified as a possible non-adaptive mechanism for the retention of duplicate genes in small-population species, where widespread deleterious mutations are likely to cause complementary loss of subfunctions across gene copies. Through subfunctionalization, duplicates become indispensable to maintain the functional requirements of the ancestral locus. Yet, gene duplication produces a dosage imbalance in the encoded proteins and thus, as investigated in this paper, subfunctionalization must be subject to the selective forces arising from the fitness bottleneck introduced by the duplication event.</p> <p>Results</p> <p>We show that, while arising from random drift, subfunctionalization must be inescapably subject to selective forces, since the diversification of expression patterns across paralogs mitigates duplication-related dosage imbalances in the concentrations of encoded proteins. Dosage imbalance effects become paramount when proteins rely on obligatory associations to maintain their structural integrity, and are expected to be weaker when protein complexation is ephemeral or adventitious. To establish the buffering effect of subfunctionalization on selection pressure, we determine the packing quality of encoded proteins, an established indicator of dosage sensitivity, and correlate this parameter with the extent of paralog segregation in humans, using species with larger population -and more efficient selection- as controls.</p> <p>Conclusions</p> <p>Recognizing the role of subfunctionalization as a dosage-imbalance buffer in gene duplication events enabled us to reconcile its mechanistic nonadaptive origin with its adaptive role as an enabler of the evolution of genetic redundancy. This constructive role was established in this paper by proving the following assertion: <it>If subfunctionalization is indeed adaptive, its effect on paralog segregation should scale with the dosage sensitivity of the duplicated genes</it>. Thus, subfunctionalization becomes adaptive in response to the selection forces arising from the fitness bottleneck imposed by gene duplication.</p

Survival in Norwegian BRCA1 mutation carriers with breast cancer

Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers

Tooth Brushing, Flossing, and Preventive Dental Visits by Detroit-area Residents in Relation to Demographic and Socioeconomic Factors

A survey was conducted to identify (a) factors that influence preventive dental behaviors and (b) target groups for interventions. Data were collected in face-to-face interviews with a probability sample of 662 dentate adults living in the Detroit tricounty area. The interviews included questions about demographic and socioeconomic variables and about three preventive behaviors: brushing, flossing, and preventive dental visits. All behaviors were positively associated with socioeconomic status. Females were more likely than males to perform each of the behaviors at the recommended frequency. The behaviors were only weakly associated with age. Whites were more likely than nonwhites to make regular dental visits, but frequency of brushing and flossing did not vary substantially across racial groups. The impact of race on frequency of dental visits was reduced when socioeconomic status was statistically controlled. Findings suggest that socioeconomic status, race, and sex remain important considerations when planning dental health education or other interventions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65274/1/j.1752-7325.1993.tb02692.x.pd

Fandom and Coercive Empowerment: The commissioned production of Chinese online literature

This article examines how the relationship between consumers and producers of cultural products is shaped by the proprietary nature of digital platforms. Drawing on 4 years of online observation and analysis, we examine the relationship between the producers of online Chinese fiction, amateur writers, and their consumers, that is, the fan communities of readers who respond to their work. Enabled by Chinese literary websites, readers act like sponsors who provide emotional and financial incentives for writers to produce online fictions by commenting, voting, and sending money. Readers become actively involved not just because of the content of the stories but because they form strong commitments to stories and their writers, and gain reciprocity and a sense of self-determination during the interactional process. We argue that although writers are freer from state control online, they are still beholden to the whims of their fans because of what we call the commissioned production of fictions. We contribute to fan community studies by analyzing how commercialized website settings structure the strategies available to participants, how these settings affect the content of the cultural products, and how the Chinese historical and cultural contexts impact the dynamics of the online community.postprin

Early and late morbidity and mortality and life expectancy following thoracoscopic talc insufflation for control of malignant pleural effusions: a review of 400 cases

<p>Abstract</p> <p>Background</p> <p>Malignant pleural effusion is a common sequelae in patients with certain malignancies. It represents a terminal condition with short median survival (in terms of months) and the goal is palliation. Aim of our study is to analyze morbidity, mortality and life expectancy following videothoracoscopic talc poudrage.</p> <p>Materials and methods</p> <p>From September 2004 to October 2009, 400 patients underwent video-assisted thoracic surgery (VATS) for malignant pleural effusion. The conditions of patients were assessed and graded before and after treatment concerning morbidity, mortality, success rate of pleurodesis and median survival.</p> <p>Results</p> <p>The median duration of follow up was 40 months (range 4-61 months). All patients demonstrated notable improvement in dyspnea. Intraoperative mortality was zero. The procedure was well tolerated and no significant adverse effects were observed. In hospital mortality was 2% and the pleurodesis success rate was 85%. A poor Karnofsky Performance Status and delay between diagnosis of pleural effusion and pleurodesis were statistically significant factors for in-hospital mortality. The best survival was seen in breast cancer, followed by ovarian cancer, lymphoma and pleural mesothelioma.</p> <p>Conclusions</p> <p>Video-assisted thoracoscopic talc poudrage is an effective and safe procedure that yields a high rate of successful pleurodesis and achieves long-term control with marked dyspnea decrease.</p