Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess ...whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma.
We employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses.
Allergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor alpha chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic allergen challenge, regardless of neonatal PVM infection, and were not dependent on signalling via the IL-4 receptor.
In this mouse model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of the characteristic features of childhood asthma, including allergic inflammation and a Th2-biased immune response.
The position of disabled people within criminal justice frameworks and scholarship is one of ambivalence, which leaves disabled people in the simultaneous and contradictory position of centrality and ...marginality. While disabled people are over-represented within the criminal justice system (as offenders, victims, and witnesses), their voices are often marginalized or silenced. So too, while disabled people are over-represented within the criminal justice system, they remain under-explored in policy, practice, research, and scholarship. Aligning with the shift to queer and queering criminology, in this article we deploy the lens of ‘crip’ and ‘cripping’ to facilitate a more critical engagement with the concerns of disabled people, along with the mechanisms by which abledness informs criminal justice encounters.
The atypical chemokine receptor CCX-CKR regulates bioavailability of CCL19, CCL21, and CCL25, homeostatic chemokines that play crucial roles in thymic lymphopoiesis. Deletion of CCX-CKR results in ...accelerated experimental autoimmunity induced by immunization. Here we show that CCX-CKR deletion also increases incidence of a spontaneous Sjögren's syndrome-like pathology, characterized by lymphocytic infiltrates in salivary glands and liver of CCX-CKR−/− mice, suggestive of a defect in self-tolerance when CCX-CKR is deleted. This prompted detailed examination of the thymus in CCX-CKR−/− mice. Negatively selected mature SP cells were less abundant in CCX-CKR−/− thymi, yet expansion of both DP and immature SP cells was apparent. Deletion of CCX-CKR also profoundly reduced proportions of DN3 thymocyte precursors and caused DN2 cells to accumulate within the medulla. These effects are likely driven by alterations in thymic stroma as CCX-CKR−/− mice have fewer cTECs per thymocyte, and cTECs express the highest level of CCX-CKR in the thymus. A profound decrease in CCL25 within the thymic cortex was observed in CCX-CKR−/− thymi, likely accounting for their defects in thymocyte distribution and frequency. These findings identify a novel role for CCX-CKR in regulating cTEC biology, which promotes optimal thymocyte development and selection important for self-tolerant adaptive immunity.
•The atypical chemokine receptor regulates T cell–development in the thymus and inhibits spontaneous autoimmunity.
In response to a call for criminologists to consider the impact of former President Donald Trump’s presumed criminality, we analyze verbal-textual hostility (VTH) in Trump’s campaign speeches. ...Politicians have particular power and reach with their speech and their use of VTH is an important part of the trifecta of violence. Using a framework informed by linguistic theory and previous analysis of hate speech in recorded hate crimes, we present the categories of deprecation and denigration, and discuss their relationship to domination. In context, these forms of VTH enhance and serve as precursors to more violent speech and acts.
PURPOSE OF REVIEWThe utility of cytokines as therapeutic targets in rheumatoid arthritis has been unequivocally demonstrated by the success of tumour necrosis factor blockade in clinical practice. ...Partial and non-responses to tumour necrosis factor blocking agents, however, together with the increasing clinical drive to remission induction, requires that further therapeutic targets be identified.
RECENT FINDINGSNumerous cytokine activities with pathogenetic potential have now been demonstrated in rheumatoid arthritis synovial membrane, including members of the IL-1 superfamily and the IL-12 superfamily. Continued efforts are ongoing to target IL-6 and IL-15 in clinical trials with promising data emerging. There is particular interest in the biology of IL-17 and of the recently described IL-32 as critical effector mediators.
SUMMARYNovel cytokine activities are emerging on an ongoing basis. There remain difficulties in ascribing the optimal regulatory hierarchy for given moieties on the basis of existing preclinical model systems. This in turn poses novel challenges in determining which cytokines represent the best therapeutic targets.
Fear of heterosexism—as distinct from actual experiences of heterosexism—plays a significant role in staff and students lives on campus. Ambient workplace heterosexism provides a context for staff ...and students about what to expect from their peers and colleagues, and shapes the daily activities of those who perceive heterosexism as a regulating force. In this article, we consider the psychometrics of the Fear of Heterosexism Scale (FoHS), which was integrated into a campus climate survey of Western Sydney University staff and students (N = 3,106; n = 412). This scale was considered in relation to a range of associated factors, including perceived safety on campus, bystander efficacy, responsibility to intervene, and awareness of lesbian, gay, bisexual, transgender, intersex, queer/questioning, asexual, and many other terms such as nonbinary and pansexual (LGBTIQA+) issues. In turn, the results of the FoHS are considered across a range of demographic factors such as gender, sexuality, role, dis/ability, and membership of campus-based support organizations. Supporting the findings from the initial operationalization of the FoHS by Fox and Asquith in 2018, this research identifies the consequences of fear of heterosexism on daily activities and engagement with study/work. Understanding the factors associated with fear of heterosexism is critical in creating more inclusive and respectful university environments.
Every year, stories emerge of cases involving the starvation of disabled people, such as Ann Marie Smith in 2020 in Adelaide, Australia. Despite this, starvation practices against disabled people ...remain under-theorized. This may reflect that starvation as a topic is largely confined to international relations literature (e.g. during war), or conversely, in medicalized accounts pathologising the individual body (e.g. anorexia, Munchausen syndrome by proxy). More broadly, the "unique" starvation practices against disabled people are sidelined as rubrics of "neglect" or "abuse" take precedence, meaning we fail to engage with the specificity/particularity of starvation practices as forms of violence. Starvation practices against disabled people in interpersonal (or familial) contexts are qualitatively different; this article addresses this gap by providing a preliminary theorization of such violence. We survey the existing literature before invoking two frames - "Vulnerability and Harm by Design" and "Disability's Deathly Status" - which we suggest provide an account of starvation as a form of violence. Rather than conceive these practices through an individualizing lens, we consider the broader social and institutional norms and practices that facilitate this conduct. We then turn to the promise of crip utopian futures in collective efforts to resist these cycles of violence and to promote interdependent, accessible, and crip socialities/futures.
Although the molecular basis of sperm-oocyte interaction is unclear, recent studies have implicated two chaperone proteins,
heat shock protein 1 (HSPD1; previously known as heat shock protein 60) and ...tumor rejection antigen gp96 (TRA1; previously
known as endoplasmin), in the formation of a functional zona-receptor complex on the surface of mammalian spermatozoa. The
current study was undertaken to investigate the expression of these chaperones during the ontogeny of male germ cells through
spermatogenesis, epididymal sperm maturation, capacitation, and acrosomal exocytosis. In testicular sections, both HSPD1 and
TRA1 were closely associated with the mitochondria of spermatogonia and primary spermatocytes. However, this labeling pattern
disappeared from the male germ line during spermiogenesis to become undetectable in testicular spermatozoa. Subsequently,
these chaperones could be detected in epididymal spermatozoa and in previously unreported âdense bodiesâ in the epididymal
lumen. The latter appeared in the precise region of the epididymis (proximal corpus), where spermatozoa acquire the capacity
to recognize and bind to the zona pellucida, implicating these structures in the functional remodeling of the sperm surface
during epididymal maturation. Both HSPD1 and TRA1 were subsequently found to become coexpressed on the surface of live mouse
spermatozoa following capacitation in vitro and were lost once these cells had undergone the acrosome reaction, as would be
expected of cell surface molecules involved in sperm-egg interaction. These data reinforce the notion that these chaperones
are intimately involved in the mechanisms by which mammalian spermatozoa both acquire and express their ability to recognize
the zona pellucida.
Abstract
The chaperones HSPD1 and TRA1 are sperm proteins that may be involved in sperm recognition
Fear of crime (FoC) has dominated the political landscape over the last 20 years, with many crime policy developments during this period linked not to actual experiences of violence but to the fear ...of victimization. Fear of crime studies, in most cases, are conducted with populations that have only a passing, mediated knowledge of crime victimization. The research discussed in this article, in contrast, considers the impact of FoC with a highly victimized community, and establishes psychometric testing to validate an instrument to measure the impact of that fear (Fear of Heterosexism Scale FoHS). If FoC is related to experiences of crime as the existing research suggests, then victims of heterosexist prejudice, discrimination, and/or violence would be more likely to fear such incidents in the future. It was also predicted that participants who concealed their sexual and/or gender identity and had lower levels of social connectedness would experience higher levels of fear. The findings highlight the importance of contextual factors in FoH, and identify the critical roles that disclosure and social connectedness play in ameliorating the damaging effects of heterosexist victimization.
In this issue of
Blood
,
Tochigi et al
made it their mission to understand the molecular mechanisms by which immunomodulatory drugs (IMiDs) induce thrombocytopenia. The authors use a combination of ...in vitro and ex vivo methods to show that treatment regimens, including IMiDs in multiple myeloma (MM), lead to aromatase degradation in human megakaryocytes. This has an impact on the estradiol signaling required for proplatelet formation, thus resulting in thrombocytopenia (see figure).
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