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"L. Levinson"
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The turn to infrastructure in Internet governance
\"Never in history have conflicts over Internet governance attracted such widespread attention. High-profile controversies include the disclosures about NSA surveillance by intelligence analyst Edward Snowden, controversy over a decision by the US government to relinquish its historic oversight of Internet names and numbers, and countless cybersecurity breaches involving unauthorized access to Internet users' personal data. Much of the Internet governance ecosystem--both technical architecture and coordinating institutions--is behind the scenes but increasingly carries significant public interest implications. An area once concealed in institutional and technological complexity is now rightly bracketed among other shared global issues--such as environmental protection and human rights--that have considerable global implications but are simply incongruous with national borders. This transformation into an era of global governance by Internet infrastructure presents a moment of opportunity for scholars to bring these politicized infrastructures to the foreground.\"-- Back cover.
Book
Plasma gelsolin levels are associated with diabetes, sex, race, and poverty
Background
The growing epidemic of the inflammation-related metabolic disease, type 2 diabetes mellitus, presents a challenge to improve our understanding of potential mechanisms or biomarkers to prevent or better control this age-associated disease. A gelsolin isoform is secreted into the plasma as part of the extracellular actin scavenger system which serves a protective role by digesting and removing actin filaments released from damaged cells. Recent data indicate a role for decreased plasma gelsolin (pGSN) levels as a biomarker of inflammatory conditions. Extracellular vesicles (EVs), a heterogeneous group of cell-derived membranous structures involved in intercellular signaling, have been implicated in metabolic and inflammatory diseases including type 2 diabetes mellitus. We examined whether pGSN levels were associated with EV concentration and inflammatory plasma proteins in individuals with or without diabetes.
Methods
We quantified pGSN longitudinally (n = 104) in a socioeconomically diverse cohort of middle-aged African American and White study participants with and without diabetes mellitus. Plasma gelsolin levels were assayed by ELISA. EV concentration (sub-cohort n = 40) was measured using nanoparticle tracking analysis. Inflammatory plasma proteins were assayed on the SomaScan® v4 proteomic platform.
Results
pGSN levels were lower in men than women. White individuals with diabetes had significantly lower levels of pGSN compared to White individuals without diabetes and to African American individuals either with or without diabetes. For adults living below poverty, those with diabetes had lower pGSN levels than those without diabetes. Adults living above poverty had similar pGSN levels regardless of diabetes status. No correlation between EV concentrations and pGSN levels was identified (r = − 0.03; p = 0.85). Large-scale exploratory plasma protein proteomics revealed 47 proteins that significantly differed by diabetes status, 19 of which significantly correlated with pGSN levels, including adiponectin.
Conclusions
In this cohort of racially diverse individuals with and without diabetes, we found differences in pGSN levels with diabetes status, sex, race, and poverty. We also report significant associations of pGSN with the adipokine, adiponectin, and other inflammation- and diabetes-related proteins. These data provide mechanistic insights into the relationship of pGSN and diabetes.
Journal Article
Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema
Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the
FLT4
locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.
Journal Article
Death of a Holy Land
Death of a Holy Land: Reflections in Contemporary Israeli Fiction, by Rose Levinson, uses the work of four contemporary Israeli authors as a lens into present-day Israel. Discussing the novels of Orly Castel-Bloom, Michal Govrin, Zeruya Shalev, and Yoram Kaniuk, the book argues for a new understanding of today’s Israel. Crucial to renewed awareness is a view of the country that jettisons the notion of Israel as an exceptional, sacred state immune from 21st century discontents. Attention is focused on ways in which many of Israel’s most pressing problems are linked to long-standing issues of Jewish identity. Continual reference to the novels gives weight and substance to Death of a Holy Land’s underlying insistence on the need for a critical view of Israel as a country deeply ill-at-ease with itself.
eBook
Adjunctive Recombinant Human Plasma Gelsolin for Severe Coronavirus Disease 2019 Pneumonia
Abstract
Background
Excessive inflammation contributes to the morbidity and mortality of severe coronavirus disease 2019 (COVID-19) pneumonia. Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse experimental models of infectious and noninfectious inflammation.
Methods
In a blinded, randomized study, 61 subjects with documented COVID-19 pneumonia having a World Health Organization (WHO) Severity Score of 4 to 6 and evidence of a hyperinflammatory state were treated with standard care and either adjunctive rhu-pGSN 12 mg/kg or an equal volume of saline placebo given intravenously at entry, 12 hours, and 36 hours. The prespecified coprimary outcomes were survival without major respiratory, hemodynamic, or renal support on Day 14 and the incidence of serious adverse events (SAEs) during the 90-day study period.
Results
All subjects receiving ≥1 dose of study drug were analyzed. Fifty-four of 61 subjects (88.5%) were WHO severity level 4 at entry. The proportions of subjects alive without support on Day 14 were 25 of 30 rhu-pGSN recipients (83.3%) and 27 of 31 placebo recipients (87.1%). Over the duration of the study, WHO Severity Scores improved similarly in both treatment groups. No statistically significant differences were observed between treatment groups at any time point examined. Two subjects died in each group. Numerically fewer subjects in the rhu-pGSN group had SAEs (5 subjects; 16.7%) or ≥ Grade 3 adverse events (5 subjects; 16.7%) than in the placebo group (8 subjects [25.8%] and 9 subjects [29.0%], respectively), mostly involving the lungs. Three rhu-pGSN recipients (10.0%) were intubated compared to 6 placebo recipients (19.4%).
Conclusions
Overall, subjects in this study did well irrespective of treatment arm. When added to dexamethasone and remdesivir, no definitive benefit was demonstrated for rhu-pGSN relative to placebo. Safety signals were not identified after the administration of 3 doses of 12 mg/kg rhu-pGSN over 36 hours. The frequencies of SAEs and intubation were numerically fewer in the rhu-pGSN group compared with placebo.
Excessive inflammation contributes to the morbidity of COVID-19. In a placebo-controlled trial of 61 hospitalized subjects with severe pneumonia, adjunctive rhu-pGSN did not provide a statistically significant benefit although SAEs and intubations were numerically fewer in rhu-pGSN than placebo recipients.
Journal Article
FELIX: a High-Throughput Network Approach for Interfacing to Front End Electronics for ATLAS Upgrades
The ATLAS experiment at CERN is planning full deployment of a new unified optical link technology for connecting detector front end electronics on the timescale of the LHC Run 4 (2025). It is estimated that roughly 8000 GBT (GigaBit Transceiver) links, with transfer rates up to 10.24 Gbps, will replace existing links used for readout, detector control and distribution of timing and trigger information. A new class of devices will be needed to interface many GBT links to the rest of the trigger, data-acquisition and detector control systems. In this paper FELIX (Front End LInk eXchange) is presented, a PC-based device to route data from and to multiple GBT links via a high-performance general purpose network capable of a total throughput up to O(20 Tbps). FELIX implies architectural changes to the ATLAS data acquisition system, such as the use of industry standard COTS components early in the DAQ chain. Additionally the design and implementation of a FELIX demonstration platform is presented and hardware and software aspects will be discussed.
Journal Article
Association of plasma gelsolin with frailty phenotype and mortality among octogenarian community-dwelling men: a cohort study
BackgroundBiomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle.AimsTo investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality.MethodsA homogenous cohort of males (born 1919–1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses.ResultsOf 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58–0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44–1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72–1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p < 0.001).DiscussionHigher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.
Journal Article
Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes
Plasma gelsolin (pGSN) is an abundant circulating protein that neutralizes actin exposed by damaged cells, modulates inflammatory responses, and enhances alveolar macrophage antimicrobial activity. We investigated whether adults with low pGSN at hospital admission for community-acquired pneumonia (CAP) were at high risk for severe outcomes.
Admission pGSN concentrations in 455 adults hospitalized with CAP were measured using enzyme-linked immunosorbent assay. Patients were grouped into the following 4 hierarchical, mutually exclusive categories based on maximum clinical severity experienced during their hospitalization: general floor care without intensive care unit (ICU) admission, invasive respiratory or vasopressor support (IRVS), or death; ICU care without IRVS or death; IRVS without death; or death. Admission pGSN concentrations were compared across these discrete outcome categories. Additionally, outcomes among patients in the lowest quartile of pGSN concentration were compared to those in the upper 3 quartiles.
Overall, median (interquartile range) pGSN concentration was 38.1 (32.1, 45.7) μg/mL. Patients with more severe outcomes had lower pGSN concentrations (P = .0001); median values were 40.3 μg/mL for floor patients, 36.7 μg/mL for ICU patients, 36.5 μg/mL for patients receiving IRVS, and 25.7 μg/mL for patients who died. Compared to patients with higher pGSN concentrations, patients in the lowest quartile (pGSN ≤ 32.1 μg/mL) more often required IRVS (21.2% vs 11.7%, P = .0114) and died (8.8% vs 0.9%, P < .0001).
Among adults hospitalized with CAP, lower pGSN concentrations were associated with more severe clinical outcomes. Future studies are planned to investigate possible therapeutic benefits of recombinant human pGSN in this population.
Journal Article
Effects of in vivo Administration of Insulin-Like Growth Factor-1 on Oocyte and Embryo Development in Mice under Chronic Psychosocial Stress
Chronic stress may affect folliculogenesis. Understanding the relationship between stress and insulin-like growth factor-1 (IGF-1) is essential for addressing fertility issues. This study aimed to investigate the effects of in vivo IGF-1 administration on oocyte and embryo development in mice in conditions of chronic psychosocial stress. Female CD1 mice were subjected to alternating periods of social isolation and overcrowding. The stress response was confirmed by elevated corticosterone levels in blood serum. There were no significant differences in the number of ovulated oocytes across the groups. However, stress reduced oocyte maturation, while IGF-1 treatment of stressed females improved oocyte maturation and reduced their degraded rate. Stressed females exhibited a reduction in mitochondrial membrane potential in oocytes. IGF-1 treatment improved oocyte quality, increased mitochondrial potential, and reduced ROS levels in the oocytes collected from stressed female mice. There were no significant changes in apoptosis levels within cumulus-oocyte complexes or preimplantation embryos across all the studied groups. IGF-1 treatment in stressed females led to a higher number of cells in embryos compared to embryos collected from non-stressed controls and from non IGF-1 treated stressed females. In conclusion, chronic psychosocial stress negatively affects oocyte development and mitochondrial function in particular, but IGF-1 treatment mitigates these effects, improving oocyte and embryo quality. These results suggest a promising therapeutic role for IGF-1 in enhancing reproductive outcomes under stress conditions.
Journal Article
Prevalence and Prognostic Impact of Lymphadenectomy and Lymph Node Metastasis in Clinically Early-Stage Ovarian Clear Cell Carcinoma
The objective of this study was to estimate the prevalence and prognostic impact of lymphadenectomy and lymph node involvement in patients with ovarian clear cell carcinoma (OCCC) grossly confined to the ovary.
Patients with a diagnosis of OCCC grossly confined to the ovary were identified from Surveillance, Epidemiology, and End Results program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t test, KaplanMeier survival methods, and Cox proportional hazards regression were performed.
One thousand eight hundred ninety-seven patients with OCCC who have undergone surgical treatment and deemed at time of the surgery to have disease grossly confined to the ovary were included: 538 (28.3%) had no lymphadenectomy (LND –1), and 1359 (71.7%) had lymphadenectomy. Of the 1359 patients who had lymphadenectomy, 1298 (95.5%) were International Federation of Gynecology and Obstetrics (FIGO) surgical stage I (LND +1), and 61 (4.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND +3C). The 5-year disease-specific survival was 84.9% for LND –1, 88.0% for LND + 1, and 65.0% for LND +3C (P < 0.001). Among those with histologically negative lymph nodes, the 5-year disease-specific survival was 85% for patients with 1 to 10 nodes removed, and 91% for those with more than 10 nodes removed (P = 0.054). On multivariate analysis after controlling for stage, age, and race, lymph node metastasis was an independent predictor of poor disease-specific survival (hazard ratio, 3.1; 95% confidence interval, 1.86-5.28; P < 0.001). On other hand, there was a trend toward an improved survival when more extensive lymphadenectomy is performed in patients with histologically negative nodes (1-10 vs >10 nodes), but it did not reach statistical significance (hazard ratio, 0.71; 95% confidence interval, 0.49-1.02; P = 0.064).
Lymph node metastasis was uncommon in patients diagnosed with OCCC grossly confined to the ovary; however, patients with positive nodes were more likely to die compared to those with negative nodes. More extensive lymphadenectomy plays an important role in providing accurate staging and prognostic information.
Journal Article