Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome
oxidase (C
O), which mediates the rate-limiting step in mitochondrial respiration, is remodeled ...during development and in response to changes of oxygen availability, but there has been little study of C
O remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript
, which orchestrates the substitution of the C
O subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of
is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis,
mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission.
is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.
Despite its diverse applications, such as identification of the protein binding partners of small molecules and investigation of intracellular drug-target engagement, photoaffinity labelling (PAL) is ...intrinsically challenging, primarily due to the difficulty in discovering functionally active photoaffinity probes. Here we describe the creation of a chemoproteomic library to discover a novel photoaffinity probe for DcpS, an mRNA decapping enzyme that is a putative target for Spinal Muscular Atrophy. This library approach expedites the discovery of photoaffinity probes and expands the chemical biology toolbox to include RNA cap-binding proteins.
Background
Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from ...surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report.
Methods
We performed a retrospective analysis of brain tumor autopsies at Boston Children’s Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses.
Results
Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry.
Conclusion
Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.
This paper presents an innovative, quantitative assessment of pollution avoidance attributable to environmental regulation enforced through integrated licensing, using Ireland's ...pharmaceutical-manufacturing sector as a case study. Emissions data reported by pharmaceutical installations were aggregated into a pollution trend using an Environmental Emissions Index (EEI) based on Lifecycle Assessment methodologies. Complete sectoral emissions data from 2001 to 2007 were extrapolated back to 1995, based on available data. Production volume data were used to derive a sectoral production index, and determine ‘no-improvement’ emission trends, whilst questionnaire responses from 20 industry representatives were used to quantify the contribution of integrated licensing to emission avoidance relative to these trends. Between 2001 and 2007, there was a 40% absolute reduction in direct pollution from 27 core installations, and 45% pollution avoidance relative to hypothetical ‘no-improvement’ pollution. It was estimated that environmental regulation avoided 20% of ‘no-improvement’ pollution, in addition to 25% avoidance under business-as-usual. For specific emissions, avoidance ranged from 14% and 30 kt a
−
1
for CO
2 to 88% and 598 t a
−
1
for SO
x
. Between 1995 and 2007, there was a 59% absolute reduction in direct pollution, and 76% pollution avoidance. Pollution avoidance was dominated by reductions in emissions of VOCs, SO
x
and NO
x
to air, and emissions of heavy metals to water. Pollution avoidance of 35% was attributed to integrated licensing, ranging from between 8% and 2.9 t a
−
1
for phosphorus emissions to water to 49% and 3143 t a
−
1
for SO
x
emissions to air. Environmental regulation enforced through integrated licensing has been the major driver of substantial pollution avoidance achieved by Ireland's pharmaceutical sector — through emission limit values associated with Best Available Techniques, emissions monitoring and reporting requirements, and performance targets specified in environmental management plans. This compliant sector offers a positive, but not necessarily typical, case study of IPPC effectiveness.
Abstract
This paper is motivated by the potential advantages of higher doping and lower contact barriers in CdTe photovoltaic devices that may be realized by using n-type rather than the conventional ...p-type solar absorber layers. We present post-growth doping trials for indium in thin polycrystalline CdTe films using the diffusion of indium metal with indium chloride. Chemical concentrations of indium up to 10
19
cm
−3
were achieved and the films were verified as n-type by hard x-ray photoemission. Post-growth chlorine treatment (or InCl
3
) was found to compensate the n-doping. Trial structures comprising CdS/CdTe:In verified that the doped absorber structures performed as expected both before and after chloride treatment, but it is recognized that this is not an optimum combination. Hence, in order to identify how the advantages of n-type absorbers might be fully realized in future work, we also report simulations of a range of p–n junction combinations with n-CdTe, a number of which have the potential for high
V
oc
.
Abstract
Recent Nobel awards in immune checkpoint inhibitor biology, phage display discovery and protein evolution highlight our current golden age of immune oncology research. While it took 15 years ...to bring anti-CTLA4 and anti-PD1 therapeutics from conception to global patient populations, new advances in synthetic and data driven immune engineering are enabling new therapeutics to be discovered and engineered in weeks rather than years. Here we review ten years of progress in computational optimization of antibody discovery libraries through the lens of high-throughput data collection technologies, with specific case studies of modern repertoire design principles applied to a panel of immune checkpoint targets. We emphasize the case study of PD1, where a computationally optimized library generated over 6500 unique anti-PD1 antibodies in two weeks, including picomolar binders, mouse/cyno/human triple cross-reactive epitopes, antagonists, agonists, and saturated epitope coverage of the target.
Citation Format: Sarah Ives, David Maurer, Christina Pettus, Raymond Newland, Valerie Chiou, Shahrad Daraeikia, Chelsea Jones, Kieran Hervold, Giles Day, Chris Smith, Ian D. Waddell, Sawsan Youssef, Jacob Glanville. Bruteforcing immune oncology discovery with computational immuno-engineering abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1550.
To ensure patients continue to get early access to antibiotics at admission, while also safely reducing antibiotic use in hospitals, one needs to target the continued need for antibiotics as more ...diagnostic information becomes available. UK Department of Health guidance promotes an initiative called 'Start Smart then Focus': early effective antibiotics followed by active 'review and revision' 24-72 h later. However in 2017, < 10% of antibiotic prescriptions were discontinued at review, despite studies suggesting that 20-30% of prescriptions could be stopped safely.
Antibiotic Review Kit for Hospitals (ARK-Hospital) is a complex 'review and revise' behavioural intervention targeting healthcare professionals involved in antibiotic prescribing or administration in inpatients admitted to acute/general medicine (the largest consumers of non-prophylactic antibiotics in hospitals). The primary study objective is to evaluate whether ARK-Hospital can safely reduce the total antibiotic burden in acute/general medical inpatients by at least 15%. The primary hypotheses are therefore that the introduction of the behavioural intervention will be non-inferior in terms of 30-day mortality post-admission (relative margin 5%) for an acute/general medical inpatient, and superior in terms of defined daily doses of antibiotics per acute/general medical admission (co-primary outcomes). The unit of observation is a hospital organisation, a single hospital or group of hospitals organised with one executive board and governance framework (National Health Service trusts in England; health boards in Northern Ireland, Wales and Scotland). The study comprises a feasibility study in one organisation (phase I), an internal pilot trial in three organisations (phase II) and a cluster (organisation)-randomised stepped-wedge trial (phase III) targeting a minimum of 36 organisations in total. Randomisation will occur over 18 months from November 2017 with a further 12 months follow-up to assess sustainability. The behavioural intervention will be delivered to healthcare professionals involved in antibiotic prescribing or administration in adult inpatients admitted to acute/general medicine. Outcomes will be assessed in adult inpatients admitted to acute/general medicine, collected through routine electronic health records in all patients.
ARK-Hospital aims to provide a feasible, sustainable and generalisable mechanism for increasing antibiotic stopping in patients who no longer need to receive them at 'review and revise'.
ISRCTN Current Controlled Trials, ISRCTN12674243 . Registered on 10 April 2017.
The influence of gut microbiota on the toxicity and metabolism of hydrazine has been investigated in germ-free and 'conventional' Sprague Dawley rats using 1H NMR based metabonomic analysis of urine ...and plasma. Toxicity was more severe in germ-free rats compared with conventional rats for equivalent exposures indicating that bacterial presence altered the nature or extent of response to hydrazine and that the toxic response can vary markedly in the absence of a functional microbiome.
The diffuse cm wave IR-correlated signal, the 'anomalous' CMB foreground, is thought to arise in the dust in cirrus clouds. We present Cosmic Background Imager (CBI) cm wave data of two translucent ...clouds, ζ Oph and LDN 1780 with the aim of characterizing the anomalous emission in the translucent cloud environment.
In ζ Oph, the measured brightness at 31 GHz is 2.4σ higher than an extrapolation from 5-GHz measurements assuming a free-free spectrum on 8 arcmin scales. The SED of this cloud on angular scales of 1° is dominated by free-free emission in the cm range. In LDN 1780 we detected a 3σ excess in the SED on angular scales of 1° that can be fitted using a spinning dust model. In this cloud, there is a spatial correlation between the CBI data and IR images, which trace dust. The correlation is better with near-IR templates (IRAS 12 and 25 μm) than with IRAS 100 μm, which suggests a very small grain origin for the emission at 31 GHz.
We calculated the 31-GHz emissivities in both clouds. They are similar and have intermediate values between that of cirrus clouds and dark clouds. Nevertheless, we found an indication of an inverse relationship between emissivity and column density, which further supports the VSGs origin for the cm emission since the proportion of big relative to small grains is smaller in diffuse clouds.
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