Xeroderma Pigmentosum Group C Deficiency Alters Cigarette Smoke DNA Damage Cell Fate and Accelerates Emphysema Development

Cigarette smoke (CS) exposure is a major risk factor for the development of emphysema, a common disease characterized by loss of cells comprising the lung parenchyma. The mechanisms of cell injury leading to emphysema are not completely understood but are thought to involve persistent cytotoxic or mutagenic DNA damage induced by CS. Using complementary cell culture and mouse models of CS exposure, we investigated the role of the DNA repair protein, xeroderma pigmentosum group C (XPC), on CS-induced DNA damage repair and emphysema. Expression of XPC was decreased in mouse lungs after chronic CS exposure and XPC knockdown in cultured human lung epithelial cells decreased their survival after CS exposure due to activation of the intrinsic apoptosis pathway. Similarly, cell autophagy and apoptosis were increased in XPC-deficient mouse lungs and were further increased by CS exposure. XPC deficiency was associated with structural and functional changes characteristic of emphysema, which were worsened by age, similar to levels observed with chronic CS exposure. Taken together, these findings suggest that repair of DNA damage by XPC plays an important and previously unrecognized role in the maintenance of alveolar structures. These findings support that loss of XPC, possibly due to chronic CS exposure, promotes emphysema development and further supports a link between DNA damage, impaired DNA repair, and development of emphysema

Gigantism in unique biogenic magnetite at the Paleocene-Eocene Thermal Maximum

We report the discovery of exceptionally large biogenic magnetite crystals in clay-rich sediments spanning the Paleocene-Eocene Thermal Maximum (PETM) in a borehole at Ancora, New Jersey. Aside from previously-described abundant bacterial magnetofossils, electron microscopy reveals novel spearhead-like and spindle-like magnetite up to 4 μm long and hexaoctahedral prisms up to 1.4 μm long. Similar to magnetite produced by magnetotactic bacteria, these single-crystal particles exhibit chemical composition, lattice perfection, and oxygen isotopes consistent with an aquatic origin. Electron holography indicates single-domain magnetization despite their large crystal size. We suggest that the development of a thick suboxic zone with high iron bioavailability – a product of dramatic changes in weathering and sedimentation patterns driven by severe global warming – drove diversification of magnetite-forming organisms, likely including eukaryotes

Peroxisome division in the yeast Yarrowia lipolytica is regulated by a signal from inside the peroxisome

We describe an unusual mechanism for organelle division. In the yeast Yarrowia lipolytica, only mature peroxisomes contain the complete set of matrix proteins. These mature peroxisomes assemble from several immature peroxisomal vesicles in a multistep pathway. The stepwise import of distinct subsets of matrix proteins into different immature intermediates along the pathway causes the redistribution of a peroxisomal protein, acyl-CoA oxidase (Aox), from the matrix to the membrane. A significant redistribution of Aox occurs only in mature peroxisomes. Inside mature peroxisomes, the membrane-bound pool of Aox interacts with Pex16p, a membrane-associated protein that negatively regulates the division of early intermediates in the pathway. This interaction inhibits the negative action of Pex16p, thereby allowing mature peroxisomes to divide

Exploring ethnic differences in lung function: the Size and Lung function In Children (SLIC) study protocol and feasibility

The Size and Lung function In Children (SLIC) study was designed as a prospective, cross-sectional and longitudinal study to investigate the factors contributing to ethnic differences in lung function. After adjusting for sex, age and height, the degree to which these differences can be reduced after further adjustment for body shape, size and composition was examined. The aim of this technical report is to describe the study design and protocol and to examine the feasibility of conducting complex physiological investigations in London primary schools. Methods: Recruitment and assessments were undertaken in London primary schools. Children with parental consent were eligible and categorised into 4 broad ethnic groups: White; Black; South-Asian and other/mixed ethnicities. Assessments were performed in children aged 5-11y, on 2 occasions a year apart and included detailed anthropometry; 3D photonic scanning for regional body shape; body composition using bioelectrical impedance analysis and isotope dilution technique; spirometry and saliva samples (for cotinine & DNA analysis of genetic ancestry). Information on country of origin (child-parents-grandparents); self-reported ethnicity; the child’s respiratory history, family socio-economic circumstances and tobacco smoking exposure were obtained, principally from parents via a questionnaire. Health status of the children was verified from medical records where feasible. Data linkages to pollution index and area deprivation scores were based on home postcodes. Results: Fourteen London primary schools participated with 52% parental consent for children to take part in the study. Consent rate for each type of assessment was generally high and ranged from near 100% for spirometry and anthropometry to 88% for DNA sample collection. With the exception of 3D scanning for body shape, where acceptable data were only achieved in 68% children assessed, success rate for all assessments ranged from 88% to 99%. In total, 2171 (47% boys; 34% White; 29% Black; 25% South-Asian; 12% Other/mixed) children were assessed on 3302 test occasions over the two year period, with successful spirometry being achieved in 90% (2986/3302) of assessments. After excluding 20% of children with acute or chronic illness and 10% with failed spirometry, data was available from 1520 healthy children for final analysis. Summary: This is the first study to demonstrate the feasibility (in terms of consent and success rate) of undertaking complex physiological assessments within the school environment in children as young as 5 years of age, including those for DNA. However, until software is refined and adapted for children, current technology for performing 3D scans for health related studies is not cost-effective. Approximately 30% of the children studied were preterm/LBW, had prior asthma or were symptomatic. Hence if the target population is healthy young children then the recruited sample size may need to be increased by 30% to ensure adequate power

Efficacy of Fidaxomicin Versus Vancomycin as Therapy for Clostridium difficile Infection in Individuals Taking Concomitant Antibiotics for Other Concurrent Infections

Concomitant antibiotic (CA) use compromised initial response to Clostridium difficile infection therapy and durability of that response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CAs and preventing recurrence regardless of CA use

Prioritizing problems in and solutions to homecare safety of people with dementia:supporting carers, streamlining care

Abstract Background Dementia care is predominantly provided by carers in home settings. We aimed to identify the priorities for homecare safety of people with dementia according to dementia health and social care professionals using a novel priority-setting method. Methods The project steering group determined the scope, the context and the criteria for prioritization. We then invited 185 North-West London clinicians via an open-ended questionnaire to identify three main problems and solutions relating to homecare safety of people with dementia. 76 clinicians submitted their suggestions which were thematically synthesized into a composite list of 27 distinct problems and 30 solutions. A group of 49 clinicians arbitrarily selected from the initial cohort ranked the composite list of suggestions using predetermined criteria. Results Inadequate education of carers of people with dementia (both family and professional) is seen as a key problem that needs addressing in addition to challenges of self-neglect, social isolation, medication nonadherence. Seven out of top 10 problems related to patients and/or carers signalling clearly where help and support are needed. The top ranked solutions focused on involvement and education of family carers, their supervision and continuing support. Several suggestions highlighted a need for improvement of recruitment, oversight and working conditions of professional carers and for different home safety-proofing strategies. Conclusions Clinicians identified a range of suggestions for improving homecare safety of people with dementia. Better equipping carers was seen as fundamental for ensuring homecare safety. Many of the identified suggestions are highly challenging and not easily changeable, yet there are also many that are feasible, affordable and could contribute to substantial improvements to dementia homecare safety

Cultural Capital and Attitudes Toward Homosexuals: Exploring the Relation Between Lifestyles and Homonegativity

This article explores the potential of cultural capital as explanatory factor in understanding homonegativity. Building on recent findings suggesting the need for a cultural component in understanding homonegativity, this article explores the relation between lifestyles (the measurable expression of cultural capital) and homonegativity. Using the “Social-Cultural Changes in Flanders 2006” survey (a population-wide survey in Flanders, the northern part of Belgium), we observed that homonegativity is lowest in lifestyle clusters where cultural capital is higher. This effect, furthermore, is maintained even after controlling for other homonegativity correlates. These results suggest that cultural capital, expressed by lifestyles, is a valuable addition to the understanding of homonegativity

Statistical support for the hypothesis of developmental constraint in marsupial skull evolution.

Background: In contrast to placental neonates, in which all cranial bones are ossified, marsupial young have only the bones of the oral region and the exoccipital ossified at birth, in order to facilitate suckling at an early stage of development. In this study, we investigated whether this heterochronic shift in the timing of cranial ossification constrains cranial disparity in marsupials relative to placentals. Methods: We collected three-dimensional (3D) landmark data about the crania of a wide range of extant placentals and marsupials, and from six fossil metatherians (the clade including extant marsupials and their stem relatives), using a laser scanner and a 3D digitizer. Principal components analysis and delta variance tests were used to investigate the distribution and disparity of cranial morphology between different landmark sets (optimizing either number of landmarks or number of taxa) of the whole skull and of individual developmental or functional regions (neurocranium, viscerocranium, oral region) for extant placentals and marsupials. Marsupial and placental data was also compared based on shared ecological aspects including diet, habitat, and time of peak activity. Results: We found that the extant marsupial taxa investigated here occupy a much smaller area of morphospace than the placental taxa, with a significantly (P<0.01) smaller overall variance. Inclusion of fossil taxa did not significantly increase the variance of metatherian cranial shape. Fossil forms generally plotted close to or within the realm of their extant marsupial relatives. When the disparities of cranial regions were investigated separately, significant differences between placentals and marsupials were seen for the viscerocranial and oral regions, but not for the neurocranial region. Conclusion: These results support the hypothesis of developmental constraint limiting the evolution of the marsupial skull, and further suggest that the marsupial viscerocranium as a whole, rather than just the early-ossifying oral region, is developmentally constrained

Agonist-Directed Desensitization of the β2-Adrenergic Receptor

The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level

Pleiotropy of Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Self-Renewal of Embryonic Stem Cells from Refractory Mouse Strains

Background: Inhibition of glycogen synthase kinase-3 (GSK-3) improves the efficiency of embryonic stem (ES) cell derivation from various strains of mice and rats, as well as dramatically promotes ES cell self-renewal potential. b-catenin has been reported to be involved in the maintenance of self-renewal of ES cells through TCF dependent and independent pathway. But the intrinsic difference between ES cell lines from different species and strains has not been characterized. Here, we dissect the mechanism of GSK-3 inhibition by CHIR99021 in mouse ES cells from refractory mouse strains. Methodology/Principal Findings: We found that CHIR99021, a GSK-3 specific inhibitor, promotes self-renewal of ES cells from recalcitrant C57BL/6 (B6) and BALB/c mouse strains through stabilization of b-catenin and c-Myc protein levels. Stabilized b-catenin promoted ES self-renewal through two mechanisms. First, b-catenin translocated into the nucleus to maintain stem cell pluripotency in a lymphoid-enhancing factor/T-cell factor–independent manner. Second, b-catenin binds plasma membrane-localized E-cadherin, which ensures a compact, spherical morphology, a hallmark of ES cells. Further, elevated c-Myc protein levels did not contribute significantly to CH-mediated ES cell self-renewal. Instead, the role of c-Myc is dependent on its transformation activity and can be replaced by N-Myc but not L-Myc. b-catenin and c-Myc have similar effects on ES cells derived from both B6 and BALB/c mice. Conclusions/Significance: Our data demonstrated that GSK-3 inhibition by CH promotes self-renewal of mouse ES cell