An Estimation of the Gamma-Ray Burst Afterglow Apparent Optical Brightness Distribution Function

By using recent publicly available observational data obtained in conjunction with the NASA Swift gamma-ray burst mission and a novel data analysis technique, we have been able to make some rough estimates of the GRB afterglow apparent optical brightness distribution function. The results suggest that 71% of all burst afterglows have optical magnitudes with mR < 22.1 at 1000 seconds after the burst onset, the dimmest detected object in the data sample. There is a strong indication that the apparent optical magnitude distribution function peaks at mR ~ 19.5. Such estimates may prove useful in guiding future plans to improve GRB counterpart observation programs. The employed numerical techniques might find application in a variety of other data analysis problems in which the intrinsic distributions must be inferred from a heterogeneous sample.Comment: 15 pages including 2 tables and 7 figures, accepted for publication in Ap

Protection Against a Bovine Viral Diarrhea Virus (BVDV) Type 1 Challenge in Calves Vaccinated with a Bovine Herpesvirus-1 (BHV-1)-BVDV Recombinant

A recently developed recombinant bovine herpesvirus 1 (BHV-1) virus containing the envelope protein gp53 of bovine viral diarrhea virus (BVDV) type 1, BHV-1 (v1V31), was assessed for its ability to protect against BVDV in calves. Four calves were vaccinated intranasally with the recombinant BHV-1-BVDV vaccine and did not exhibit any clinical signs following vaccination. The vaccine virus was recovered from all vaccinated calves on days 8 through 10 and the replication appeared to be restricted to nasal passages. Twenty-eight days after vaccination, the four vaccinated and four control calves were challenged with the type 1 BVDV, strain NY-1. All calves had slight temperature elevations but the clinical signs were more severe in the control calves. The platelet counts were significantly depressed in the control calves. Prior to challenge, neither group had BVDV serum neutralizing antibody. The vaccinated calves developed higher serum antibody levels 2 months following challenge, indicating a secondary immune response. Necropsy was performed six weeks following infection. No latent BHV-1 virus was detected from the trigeminal ganglion of any of the vaccinated calves. The recombinant BHV-1 virus vaccine containing a single BVDV protein provided partial protection against BVDV infection

Life-Cycle Assessment of Energy and Environmental Impacts of LED Lighting Products, Part 3: LED Environmental Testing

This report covers the third part of a larger U.S. Department of Energy (DOE) project to assess the life-cycle environmental and resource impacts in the manufacturing, transport, use, and disposal of light-emitting diode (LED) lighting products in relation to incumbent lighting technologies. All three reports are available on the DOE website (www.ssl.energy.gov/tech_reports.html). • Part 1: Review of the Life-Cycle Energy Consumption of Incandescent, Compact Fluorescent and LED Lamps; • Part 2: LED Manufacturing and Performance; • Part 3: LED Environmental Testing. Parts 1 and 2 were published in February and June 2012, respectively. The Part 1 report included a summary of the life-cycle assessment (LCA) process and methodology, provided a literature review of more than 25 existing LCA studies of various lamp types, and performed a meta-analysis comparing LED lamps with incandescent and compact fluorescent lamps (CFLs). Drawing from the Part 1 findings, Part 2 performed a more detailed assessment of the LED manufacturing process and used these findings to provide a comparative LCA taking into consideration a wider range of environmental impacts. Both reports concluded that the life-cycle environmental impact of a given lamp is dominated by the energy used during lamp operation—the upstream generation of electricity drives the total environmental footprint of the product. However, a more detailed understanding of end-of-life disposal considerations for LED products has become increasingly important as their installation base has grown. The Part 3 study (reported herein) was undertaken to augment the LCA findings with chemical analysis of a variety of LED, CFL, and incandescent lamps using standard testing procedures. A total of 22 samples, representing 11 different models, were tested to determine whether any of 17 elements were present at levels exceeding California or Federal regulatory thresholds for hazardous waste. Key findings include: • The selected models were generally found to be below thresholds for Federally regulated elements; • All CFLs and LED lamps and most incandescent lamps exceeded California thresholds for Copper; • Most CFL samples exceeded California thresholds for Antimony and Nickel, and half of the LED samples exceeded California thresholds for Zinc; • The greatest contributors were the screw bases, drivers, ballasts, and wires or filaments; • Overall concentrations in LED lamps were comparable to cell phones and other types of electronic devices, and were generally attributable to components other than the internal LED light sources; • Although the life-cycle environmental impact of the LED lamps is favorable when compared to CFLs and incandescent lamps, recycling will likely gain importance as consumer adoption increases. This study was exploratory in nature and was not intended to provide a definitive indication of regulatory compliance for any specific lamp model or technology. Further study would be needed to more broadly characterize the various light source technologies; to more accurately and precisely characterize a specific model; or to determine whether product redesign would be appropriate

Life-Cycle Assessment of Energy and Environmental Impacts of LED Lighting Products, Part 3: LED Environmental Testing

This report covers the third part of a larger U.S. Department of Energy (DOE) project to assess the life-cycle environmental and resource impacts in the manufacturing, transport, use, and disposal of light-emitting diode (LED) lighting products in relation to incumbent lighting technologies. All three reports are available on the DOE website (www.ssl.energy.gov/tech_reports.html). • Part 1: Review of the Life-Cycle Energy Consumption of Incandescent, Compact Fluorescent and LED Lamps; • Part 2: LED Manufacturing and Performance; • Part 3: LED Environmental Testing. Parts 1 and 2 were published in February and June 2012, respectively. The Part 1 report included a summary of the life-cycle assessment (LCA) process and methodology, provided a literature review of more than 25 existing LCA studies of various lamp types, and performed a meta-analysis comparing LED lamps with incandescent and compact fluorescent lamps (CFLs). Drawing from the Part 1 findings, Part 2 performed a more detailed assessment of the LED manufacturing process and used these findings to provide a comparative LCA taking into consideration a wider range of environmental impacts. Both reports concluded that the life-cycle environmental impact of a given lamp is dominated by the energy used during lamp operation—the upstream generation of electricity drives the total environmental footprint of the product. However, a more detailed understanding of end-of-life disposal considerations for LED products has become increasingly important as their installation base has grown. The Part 3 study (reported herein) was undertaken to augment the LCA findings with chemical analysis of a variety of LED, CFL, and incandescent lamps using standard testing procedures. A total of 22 samples, representing 11 different models, were tested to determine whether any of 17 elements were present at levels exceeding California or Federal regulatory thresholds for hazardous waste. Key findings include: • The selected models were generally found to be below thresholds for Federally regulated elements; • All CFLs and LED lamps and most incandescent lamps exceeded California thresholds for Copper; • Most CFL samples exceeded California thresholds for Antimony and Nickel, and half of the LED samples exceeded California thresholds for Zinc; • The greatest contributors were the screw bases, drivers, ballasts, and wires or filaments; • Overall concentrations in LED lamps were comparable to cell phones and other types of electronic devices, and were generally attributable to components other than the internal LED light sources; • Although the life-cycle environmental impact of the LED lamps is favorable when compared to CFLs and incandescent lamps, recycling will likely gain importance as consumer adoption increases. This study was exploratory in nature and was not intended to provide a definitive indication of regulatory compliance for any specific lamp model or technology. Further study would be needed to more broadly characterize the various light source technologies; to more accurately and precisely characterize a specific model; or to determine whether product redesign would be appropriate

Banff 2022 liver group meeting report: monitoring long term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participantsincluded hepatologists, surgeons, pathologists, immunologists and histocompatibility specialists.Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimisation and long-term structural changes.Potential revision of the rejection classification scheme to better accommodate and communicate lateT cell-mediated rejection patterns and related structural changes, such as nodular regenerativehyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression tomatch the heterogeneity of patient settings will be central to improving long-term patient survival.Such personalised therapeutics are in turn contingent on better understanding and monitoring ofallograft status within a rational decision-making approach, likely to be facilitated in implementationwith emerging decision support tools. Proposed revisions to rejection classification emerging fromthe meeting include incorporation of interface hepatitis and fibrosis staging. These will be opened toonline testing, modified accordingly and subject to consensus discussion leading up to the next Banffconference

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.

Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe