Inter‐ and intra‐software reproducibility of computed tomography lung density measurements

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156221/2/mp14130.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156221/1/mp14130_am.pd

Heat shock protein 90 inhibition abrogates TLR4-mediated NF-kB activity and reduces renal ischemia-reperfusion injury

Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury. Toll-like receptor 4 (TLR4) mediates sterile inflammation following renal IRI. Heat shock protein 90 (Hsp90) inhibition is a potential strategy to reduce IRI, and AT13387 is a novel Hsp90 inhibitor with low toxicity. This study assessed if pre-treatment with AT13387 could reduce renal IRI and established if the mechanism of protection involved a reduction in inflammatory signalling. Mice were pre-treated with AT13387 prior to renal IRI. 24 h later, renal function was determined by serum creatinine, kidney damage by tubular necrosis score, renal TLR4 expression by PCR and inflammation by cytokine array. In vitro, human embryonic kidney cells were co-transfected to express TLR4 and a secreted alkaline phosphatase NF-κB reporter. Cells were pre-treated with AT13387 and exposed to endotoxin-free hyaluronan to stimulate sterile TLR4-specific NF-κB inflammatory activation. Following renal IRI, AT13387 significantly reduced serum creatinine, tubular necrosis, TLR4 expression and NF-κB-dependent chemokines. In vitro, AT13387-treatment resulted in breakdown of IκB kinase, which abolished TLR4-mediated NF-κB activation by hyaluronan. AT13387 is a new agent with translational potential that reduces renal IRI. The mechanism of protection may involve breakdown of IκB kinase and repression of TLR4-mediated NF-κB inflammatory activity

HCMV pUL135 remodels the actin cytoskeleton to impair immune recognition of infected cells

Immune evasion genes help human cytomegalovirus (HCMV) establish lifelong persistence. Without immune pressure, laboratory-adapted HCMV strains have undergone genetic alterations. Among these, the deletion of the UL/b’ domain is associated with loss of virulence. In a screen of UL/b’, we identified pUL135 as a protein responsible for the characteristic cytopathic effect of clinical HCMV strains that also protected from natural killer (NK) and T cell attack. pUL135 interacted directly with abl interactor 1 (ABI1) and ABI2 to recruit the WAVE2 regulatory complex to the plasma membrane, remodel the actin cytoskeleton and dramatically reduce the efficiency of immune synapse (IS) formation. An intimate association between F-actin filaments in target cells and the IS was dispelled by pUL135 expression. Thus, F-actin in target cells plays a critical role in synaptogenesis, and this can be exploited by pathogens to protect against cytotoxic immune effector cells. An independent interaction between pUL135 and talin disrupted cell contacts with the extracellular matrix

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher prepulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors

Whiteness and loss in outer East London: tracing the collective memories of diaspora space

This paper explores collective memory in Newham, East London. It addresses how remembering East London as the home of whiteness and traditional forms of community entails powerful forms of forgetting. Newham's formation through migration – its ‘great time’ – has ensured that myths of indigeneity and whiteness have never stood still. Through engaging with young people's and youth workers' memory practices, the paper explores how phantasms of whiteness and class loss are traced over, and how this tracing reveals ambivalence and porosity, at the same time as it highlights the continued allure of race. It explores how whiteness and class loss are appropriated across ethnic boundaries and how they are mobilized to produce new forms of racial hierarchy in a ‘super-diverse’ place

The ‘one who knocks’ and the ‘one who waits’: Gendered violence in Breaking Bad

This article provides a cultural criminological analysis of the acclaimed US television series, Breaking Bad. It is argued here that – as a cultural text – Breaking Bad is emblematic of an agenda for change surrounding criminological theories of peoples’ propensity to do harm to one another. To exemplify this, the show’s central (male) protagonist is revealed to undergo a complete biosocial transformation into a violent offender and, as such, to demonstrate the need for criminological theory to recognise and further reflect upon this process. However, at the same time, the (re)presented inability of the show’s female characters to do the same is indicative of a number of gender-related questions that progressive criminological theories of violence need to answer. In considering these two fields in tandem, the show’s criminological significance is established; it is symbolic of the need for criminology to afford greater recognition to the nuanced intersections of both biological and sociological factors in the genesis and evolution of violent human subjectivities

From bits to bites: Advancement of the Germinate platform to support prebreeding informatics for crop wild relatives

Management and distribution of experimental data from prebreeding projects is important to ensure uptake of germplasm into breeding and research programs. Being able to access and share this data in standard formats is essential. The adoption of a common informatics platform for crops that may have limited resources brings economies of scale, allowing common informatics components to be used across multiple species. The close integration of such a platform with commonly used breeding software, visualization, and analysis tools reduces the barrier for entry to researchers and provides a common framework to facilitate collaborations and data sharing. This work presents significant updates to the Germinate platform and highlights its value in distributing prebreeding data for 14 crops as part of the project ‘Adapting Agriculture to Climate Change: Collecting, Protecting and Preparing Crop Wild Relatives’ (hereafter Crop Trust Crop Wild Relatives project) led by the Crop Trust (https://www.cwrdiversity.org). The addition of data on these species compliments data already publicly available in Germinate. We present a suite of updated Germinate features using examples from these crop species and their wild relatives. The use of Germinate within the Crop TrustCropWildRelatives project demonstrates the usefulness of the system and the benefits a shared informatics platform provides. These data resources provide a foundation on which breeding and research communities can develop additional online resources for their crops, harness new data as it becomes available, and benefit collectively from future developments of the Germinate platform

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis (DEFINE):A Phase Ib/IIa Randomised Controlled Trial

RATIONALE: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. OBJECTIVES: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. METHODS: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. MEASUREMENTS AND MAIN RESULTS: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2–7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. CONCLUSIONS: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020–002230–32)