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

Innovation Policy and Chronic Emergencies

The COVID-19 pandemic has thrust the potential role of the state as a driver of scientific innovation onto center stage. Vaccines have been developed and brought to market in a timescale that seemed almost impossible when the crisis first struck. The pivotal nature of government intervention in this crisis has added to calls from academics and policy makers to adopt a more proactive, mission-oriented approach to innovation policy to tackle other key global challenges. This Article considers the merits of these calls and argues that an important distinction must be drawn between what this Article terms acute and chronic emergencies. COVID-19 is a paradigmatic example of an acute emergency: its onset was rapid, its impact was dramatic, and it is a problem that demands resolution for life to proceed “as normal.” Chronic emergencies, such as the problem of Anti-Microbial Resistance, can be just as, or more deadly than, acute emergencies but have a “frog in the pot” quality. They emerge over time, and, although they can have profound social and economic effects, they do so in ways that are less immediate and hence less demanding of government attention. Without the urgency, sense of purpose, and spirit of cooperation that accompany acute emergencies, there is a risk that mission-oriented approaches may fail to deliver new technologies the world urgently needs. This Article considers the problem of applying mission-oriented approaches to chronic emergencies. The analysis is grounded in an examination of Britain’s system of innovation rewards in the eighteenth and nineteenth centuries, drawing on an extensive historical data set that the authors are continuing to develop. The central argument put forward in this Article is that Britain’s historical system offers lessons for crafting state intervention to spur innovation aimed at chronic emergencies today. Britain’s historical system was effective because rewards were largely bestowed post hoc with relatively little prescription as to the problems at which innovators should direct their efforts, and still less as to the methods and means that should be used to tackle them. Perhaps most importantly, these rewards fed into and helped create a culture of innovation. The Article concludes with a proposal for change—namely, that the way innovation prizes are designed should be reconsidered. Prizes must preserve space for scientific and technical freedom and ought not to be built around the sort of rigidly defined criteria that proponents of mission-oriented innovation policies often advocate

Does fire influence the landscape-scale distribution of an invasive mesopredator?

Predation and fire shape the structure and function of ecosystems globally. However, studies exploring interactions between these two processes are rare, especially at large spatial scales. This knowledge gap is significant not only for ecological theory, but also in an applied context, because it limits the ability of landscape managers to predict the outcomes of manipulating fire and predators. We examined the influence of fire on the occurrence of an introduced and widespread mesopredator, the red fox (Vulpes vulpes), in semi-arid Australia. We used two extensive and complimentary datasets collected at two spatial scales. At the landscape-scale, we surveyed red foxes using sand-plots within 28 study landscapes - which incorporated variation in the diversity and proportional extent of fire-age classes - located across a 104 000 km2 study area. At the site-scale, we surveyed red foxes using camera traps at 108 sites stratified along a century-long post-fire chronosequence (0-105 years) within a 6630 km2 study area. Red foxes were widespread both at the landscape and site-scale. Fire did not influence fox distribution at either spatial scale, nor did other environmental variables that we measured. Our results show that red foxes exploit a broad range of environmental conditions within semi-arid Australia. The presence of red foxes throughout much of the landscape is likely to have significant implications for native fauna, particularly in recently burnt habitats where reduced cover may increase prey species\u27 predation risk

Alpha-1 antitrypsin deficiency.

OBJECTIVE: To review the topic of alpha-1 antitrypsin (AAT) deficiency. METHOD: Narrative literature review. RESULTS: Much work has been carried out on this condition with many questions being answered but still further questions remain. DISCUSSION AND CONCLUSIONS: AAT deficiency is an autosomal co-dominantly inherited disease which affects the lungs and liver predominantly. The clinical manifestations, prevalence, genetics, molecular pathophysiology, screening and treatment recommendations are summarised in this review

Anxious/depressed symptoms are related to microstructural maturation of white matter in typically developing youths

AbstractThere are multiple recent reports of an association between anxious/depressed (A/D) symptomatology and the rate of cerebral cortical thickness maturation in typically developing youths. We investigated the degree to which anxious/depressed symptoms are tied to age-related microstructural changes in cerebral fiber pathways. The participants were part of the NIH MRI Study of Normal Brain Development. Child Behavior Checklist A/D scores and diffusion imaging were available for 175 youths (84 males, 91 females; 241 magnetic resonance imagings) at up to three visits. The participants ranged from 5.7 to 18.4 years of age at the time of the scan. Alignment of fractional anisotropy data was implemented using FSL/Tract-Based Spatial Statistics, and linear mixed model regression was carried out using SPSS. Child Behavior Checklist A/D was associated with the rate of microstructural development in several white matter pathways, including the bilateral anterior thalamic radiation, bilateral inferior longitudinal fasciculus, left superior longitudinal fasciculus, and right cingulum. Across these pathways, greater age-related fractional anisotropy increases were observed at lower levels of A/D. The results suggest that subclinical A/D symptoms are associated with the rate of microstructural development within several white matter pathways that have been implicated in affect regulation, as well as mood and anxiety psychopathology.</jats:p

Integrin αvβ8-mediated TGF-β activation by effector regulatory T sells is essential for suppression of T-Cell-mediated inflammation

Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation

Improvements in 3D sediment transport modelling with application to water quality issues

Water Qualit

Bilateral enucleation alters gene expression and intraneocortical connections in the mouse

<p>Abstract</p> <p>Background</p> <p>Anatomically and functionally distinct sensory and motor neocortical areas form during mammalian development through a process called arealization. This process is believed to be reliant on both activity-dependent and activity-independent mechanisms. Although both mechanisms are thought to function concurrently during arealization, the nature of their interaction is not understood. To examine the potential interplay of extrinsic activity-dependent mechanisms, such as sensory input, and intrinsic activity-independent mechanisms, including gene expression in mouse neocortical development, we performed bilateral enucleations in newborn mice and conducted anatomical and molecular analyses 10 days later. In this study, by surgically removing the eyes of the newborn mouse, we examined whether early enucleation would impact normal gene expression and the development of basic anatomical features such as intraneocortical connections and cortical area boundaries in the first 10 days of life, before natural eye opening. We examined the acute effects of bilateral enucleation on the lateral geniculate nucleus of the thalamus and the neocortical somatosensory-visual area boundary through detailed analyses of intraneocortical connections and gene expression of six developmentally regulated genes at postnatal day 10.</p> <p>Results</p> <p>Our results demonstrate short-term plasticity on postnatal day 10 resulting from the removal of the eyes at birth, with changes in nuclear size and gene expression within the lateral geniculate nucleus as well as a shift in intraneocortical connections and <it>ephrin A5 </it>expression at the somatosensory-visual boundary. In this report, we highlight the correlation between positional shifts in <it>ephrin A5 </it>expression and improper refinement of intraneocortical connections observed at the somatosensory-visual boundary in enucleates on postnatal day 10.</p> <p>Conclusions</p> <p>Bilateral enucleation induces a positional shift of both <it>ephrin A5 </it>expression and intraneocortical projections at the somatosensory-visual border in only 10 days. These changes occur prior to natural eye opening, suggesting a possible role of spontaneous retinal activity in area border formation within the neocortex. Through these analyses, we gain a deeper understanding of how extrinsic activity-dependent mechanisms, particularly input from sensory organs, are integrated with intrinsic activity-independent mechanisms to regulate neocortical arealization and plasticity.</p

Female Sexual-offenders: Personality Pathology as a Mediator of the Relationship between Childhood Sexual Abuse History and Sexual Abuse Perpetration against Others

Objective: The goal was to examine, in an all-female sample, possible mechanisms for the relationship between a history of childhood sexual abuse and the likelihood of perpetrating sexual abuse as an adult. It was hypothesized that Borderline and Antisocial Personality Disorder tendencies would mediate the relationship between these two forms of abuse. Method: One hundred forty two female participants (61 sex-offenders and 81 non-sex offenders) were recruited from a women’s prison in the Midwest. The participants completed measures that included a childhood history of sexual abuse, socially desirable responding, primary and secondary psychopathy, and Borderline Personality Disorder tendencies. Results: Participants in the sexual-offender group reported more frequent instances of childhood sexual abuse (p \u3c .05, M = 16.4, SD = 7.2) than participants in the non-sex offender group (M = 12.2, SD = 7.7). Consistent with past research, childhood sexual abuse was related to Borderline Personality Disorder tendencies (r = .36, p \u3c .01). However, discriminant function analyses did not reveal support for our mediational hypotheses. Finally, the results indicated that participants in the sexual-offender group experienced childhood sexual abuse for a greater duration of time (p \u3c .05, M = 27.8, SD = 20.5 months) than participants in the non-sex offender group (M = 16.6, SD = 10.4). Conclusions: This study replicated previous research conducted on all-male samples, suggesting that the nature of the sexual abuse suffered in childhood is an important variable in predicting future sexual abuse perpetration