Viral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 ...SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 severity, including the TRIM4 interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was associated with inhibited host protein translation whereas ORF6 localization with MAVS was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 protease, with specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2.
On May 24, 2006, the Foreign Intelligence Surveillance Court (FISC) approved an FBI application for an order, requiring Verizon to turn over all telephony metadata to the National Security Agency. ...The Court subsequently approved similar applications for all major US. telecommunication service providers. Over the next seven years, FISC issued orders renewing the bulk collection program thirty-four times. This program remained secret until mid-2013, when a combination of leaks by Edward Snowden, a former National Security Agency employee, and Freedom of Information Act litigation launched by the Electronic Frontier Foundation, forced key documents into the public domain. In response, the Obama Administration issued statements, fact sheets, redacted FISC opinions, and even a White Paper, acknowledging the existence of the program and arguing that it is both legal and constitutional. According to these documents, the purpose of the telephony metadata program is to collect information related to counter-terrorism efforts and foreign intelligence.
This article proceeds in three parts: the evolution of Section 702, a statutory analysis of PRISM and upstream collection, and the attendant constitutional concerns. The article begins by considering ...the origins of the current programs and the relevant authorities-particularly the transfer of part of the President's Surveillance Program, instituted just after September 11, to the 1978 Foreign Intelligence Surveillance Act (FISA). The first part ends with a brief discussion of the current state of foreign intelligence collection under Executive Order 12,333, outside either FISA or the FAA. The article next turns to statutory issues related to targeting, post-targeting analysis, and the retention and dissemination of information. In its constitutional analysis, the article finds certain practices instituted under Section 702 to fall outside acceptable Fourth Amendment bounds. Although lower courts had begun to recognize a domestic foreign intelligence exception to the warrant clause, in 1978 Congress introduced FISA to be the sole means via which domestic foreign intelligence electronic intercepts could be undertaken.
Headache is a common presenting complaint in emergency departments (EDs), with the goal of improving acute pain. However, youth with chronic headaches may demonstrate broad functional impairment in ...their lives due to headaches. Our objective was to determine if degree of functional impairment predicts ED course for patients with headache as part of a clinical protocol. One hundred and thirty-seven pediatric patients presenting to an ED with headache were included. Patients and parents were administered the Functional Disability Index (FDI) and ED charts were reviewed to evaluate outcomes. Higher child-reported FDI scores were associated with more medications, longer ED stay, and admission. High parent-proxy FDI score was associated with longer ED stay. Both pain score and parent-proxy FDI score were associated with imaging. The FDI was a more useful predictor of visit resources than pain score. FDI scores could be used to help anticipate patients who may require greater time and resources.
This case of everted third eyelid cartilage in a goat demonstrates that everted cartilage occurs in animals other than domestic dogs and cats. Everted cartilage in the goat can be treated ...successfully with surgical excision of the abnormally bent cartilage.
Third eyelid cartilage eversion is a common clinical disease seen in dogs and cats. This case demonstrates that the disease is also seen in goats. Surgical technique from correction in dogs and cats can be applied with an excellent clinical outcome.
We examined the effect of negative peer experiences (NPEs; peer victimization and exclusion) on mood (depressed, angry, positive). Seventy‐seven (43 female) fifth graders from elementary schools ...located in a small town in the Midwest completed a friendship quality measure, in addition to daily reports (seven school days) of mood and peer experiences. Multilevel modeling showed that children who had NPEs in which no one intervened had more negative and less positive mood. For negative mood, this result was attenuated if the child had a friend who was generally helpful. The results demonstrate the positive role of bystanders during NPEs and highlight the protective role of high‐quality friendships.
Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motif sequences in cis-regulatory elements (CREs). The combinations of DNA motifs acting within homeostasis and ...disease, however, are unclear. Gene expression, chromatin accessibility, TF footprinting, and H3K27ac-dependent DNA looping data were generated and a random-forest-based model was applied to identify 7,531 cell-type-specific cis-regulatory modules (CRMs) across 15 diploid human cell types. A co-enrichment framework within CRMs nominated 838 cell-type-specific, recurrent heterotypic DNA motif combinations (DMCs), which were functionally validated using massively parallel reporter assays. Cancer cells engaged DMCs linked to neoplasia-enabling processes operative in normal cells while also activating new DMCs only seen in the neoplastic state. This integrative approach identifies cell-type-specific cis-regulatory combinatorial DNA motifs in diverse normal and diseased human cells and represents a general framework for deciphering cis-regulatory sequence logic in gene regulation.
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•Profiling of 15 diploid human cell types via RNA-seq, ATAC-seq, and H3K27ac HiChIP•Identification of 838 cell-type-specific, recurrent heterotypic DNA motif combinations•Functional validation of regulatory DMCs via massively parallel reporter assays•Cancer-type-specific DMCs are linked to neoplasia-enabling processes
The cis-regulatory logic encoded within DNA sequences that mediate cell-type-specific gene expression is undefined. Here Donohue et al. generate multi-omics data across 15 diploid human cell types and present a new integrative framework for identifying regulatory DNA motif combinations (DMCs). Specifically, they identify cell-type- and -state-specific DMCs and anticipate broad applicability of the approach.
THE SHADOW OF STATE SECRETS Donohue, Laura K.
University of Pennsylvania law review,
12/2010, Letnik:
159, Številka:
1
Journal Article
Recenzirano
State secrets doctrine catapulted to prominence post-2001, as the executive responded to lawsuits alleging a range of constitutional and human rights violations by refusing to disclose information ...during discovery and, in some cases, requesting dismissal of suits altogether on national security grounds. More than 120 law review articles followed, and media outlets became outspoken in their criticism of the privilege. In both the Senate and the House, new bills sought to codify what had previously been a common law doctrine. And in September 2009, the Attorney General introduced new procedures for review and created a State Secrets Review Committee.
To determine the comparative efficacy of ganciclovir ophthalmic gel and famciclovir oral tablets in cats with experimentally induced ocular feline herpesvirus-1 (FHV-1) epithelial infection.
A ...randomized, placebo-controlled trial was performed using 16 nonvaccinated, specific pathogen-free cats with experimental FHV-1 infection induced by topical ocular inoculation. Cats received topical ganciclovir 0.15% ophthalmic gel (1 drop 3 times daily,
= 6 cats), oral famciclovir (90 mg/kg twice daily,
= 6), or topical artificial tear gel (1 drop 3 times daily,
= 4) for 14 days. Cats were monitored after inoculation for 30 days. Ophthalmic examinations were performed every 2 days and ocular disease scores calculated.
confocal microscopy was performed, and corneal leukocyte infiltrates quantified. Ocular samples for FHV-1 quantitative polymerase chain reaction (qPCR) and virus isolation assays were collected every 3 days. Hemograms and serum biochemistry panels were performed at intervals.
Clinical ocular disease scores and corneal leukocyte infiltrates were significantly lower in the ganciclovir and famciclovir groups compared with placebo, but no significant differences were detected between the antiviral treatment groups. Ocular viral loads determined by qPCR were significantly lower in the ganciclovir group compared with the placebo group, but there were no significant differences between the other study groups. Hemograms and biochemistry panels were unremarkable.
Topical application of ganciclovir gel 3 times daily was well-tolerated and displayed similar efficacy at reducing clinical ocular disease scores and corneal inflammation as twice daily oral famciclovir treatment in cats with experimental ocular FHV-1 infection.
This quality improvement (QI) project tracks a series of 2 Plan-Do-Study-Act (PDSA) cycles as we standardized and refined an ambulatory pediatric anesthesia strabismus protocol. We aimed to provide ...effective pain relief, reduce postoperative nausea and vomiting (PONV) rates, and be cost-efficient while minimizing perioperative opioids over 5 years.
We used statistical process control (SPC) charts to analyze real-world data captured from the medical record. We chose the following outcome and process measures to evaluate effectiveness: postoperative morphine rescue rate, maximum pain score in the postanesthesia care unit (PACU), and PONV rescue rate. We also used 2 balancing measures: postoperative length of stay (LOS) and total anesthesia time. We standardized our anesthesia protocol for our first PDSA cycle (April 2017) by removing intraoperative intravenous acetaminophen and utilizing fentanyl only. For the second PDSA cycle (January 2019), we replaced intraoperative fentanyl with dexmedetomidine.
There was a total of 325 pediatric strabismus repair surgeries performed between April 2015 and July 2020. There was no special cause variation detected in the SPC charts for the family of measures chosen to measure effectiveness: postoperative morphine rescue rate, maximum pain score in the PACU, or the PONV rescue rate. The PONV rescue rate was 0 with the removal of opioids. Also, there was no special cause variation for the balancing measures: postoperative LOS or total anesthesia time.
Throughout 2 PDSA cycles, this QI project enabled our team to standardize an opioid-free and cost-efficient anesthesia protocol for pediatric strabismus surgery over 5 years.
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