1,223 research outputs found
Applying Social Science to Bring Resident Stakeholders into Pollution Governance: A Rural Environmental Justice Public Health Case Study
The purpose of this engaged public sociology study was to use social science to bring resident stakeholders into the process of governing pollution production in a rural community. The community has cancer clusters. Residents have concerns about direct exposure to pollution production in their neighborhood by a steel recycling plant that has been cited numerous times for environmental violations. The facility has been under voluntary remediation since 2009, but neighborhood residents were marginalized from the governance process. This case study details how social science was used to bring neighborhood residents’ concerns about direct exposure to toxic air pollution into remediation governance. A curricula-as-research model was developed to provide an engagement framework that guided the case study as it progressed through a series of six stages over five years. The Principle Investigator maintained this collaboration by integrating the project into courses, securing small grants, developing an affordable air pollution monitoring method, and convening multiple community meetings. The air monitoring results are analyzed and discussed. Finally, the impact of the case study on the company, the state environmental management agency, local government, the nonprofit partner, and residents’ sense of human agency is evaluated
Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.
OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture.
APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs.
CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies
Synergistic drug combinations from electronic health records and gene expression.
ObjectiveUsing electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.MethodWe applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.ResultsFrom EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.ConclusionsThis is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing
Very Red and Extremely Red Galaxies in the Fields of z ~ 1.5 Radio-Loud Quasars
We previously identified an excess of mostly red galaxies around 31 RLQs at
z=1-2. These fields have an ERO (extremely red object, R-K>6) density 2.7 times
higher than the field. Assuming the EROs are passively evolved galaxies at the
quasar redshifts, they have characteristic luminosities of only ~L^*. We also
present new observations of four z~1.54 RLQ fields: (1) Wide-field J & Ks data
confirm an Abell richness ~2 excess within 140" of Q0835+580 but an excess only
within 50" of Q1126+101. (2) In 3 fields we present deep narrow-band redshifted
H-alpha observations. We detect five candidate galaxies at the quasar
redshifts, a surface density 2.5x higher than the field. (3) SCUBA sub-mm
observations of 3 fields detect 2 quasars and 2 galaxies with SEDs best fit as
highly reddened galaxies at the quasar z. (4) H-band adaptive optics (AO)
imaging is used to estimate redshifts for 2 red, bulge-dominated galaxies using
the Kormendy relation. Both have structural redshifts foreground to the quasar,
but these are not confirmed by photometric redshifts, possibly because their
optical photometry is corrupted by scattered light from the AO guidestar. (5)
We use quantitative SED fits to constrain the photometric redshifts z_ph for
some galaxies. Most galaxies near Q0835+580 are consistent with being at its
redshift, including a candidate very old passively evolving galaxy. Many very &
extremely red objects have z_ph z_q, and dust reddening is required to fit most
of them, including many objects whose fits also require relatively old stellar
populations. Large reddenings of E(B-V)~0.6 are required to fit four J-K
selected EROs, though all but one of them have best-fit z_ph>z_q. These objects
may represent a population of dusty high-z galaxies underrepresented in
optically selected samples. (Abridged)Comment: Missing object 1126.424 added to Table 4; title changed to save
people the apparent trouble of reading the abstract. 38 pages, 16 figures, 2
in color; all-PostScript figure version available from
http://astro.princeton.edu/~pathall/tp3.ps.g
Gastrointestinal/pancreatic hormone concentrations in the portal venous system of nine patients with organic hyperinsulinism
Percutaneous transhepatic sampling of blood in the portal venous system (TPVS) was used to; (1) localize hormone secreting tumors and help in differentiating tumors from diffuse disease (nesideoblastosis and hyperplasia with adenomata) in 9 patients with fasting hypoglycemia and hyperinsulinism, and (2) study the concentration and distribution of the immunoreactive peptides: insulin (IRI), gastrin (IG), glucagon (IRG), pancreatic polypeptide (hPP), and somatostatin (SRIF-LI), in the venous drainage of the uninvolved portion of the pancreas and GI tract. Localized elevations of IRI (64-920 [mu]U/ml) predicted tumor localization in 6 patients with single tumors that were not demonstrable angiographically. In one patient with nesideoblastosis and another with islet cell hyperplasia with adenoma, elevated IRI concentrations at multiple locations suggested a diffuse or multicentric process. Elevations of SRIF-LI in the same region as IRI elevations in one patient and of IRG in another patient suggested that these tumor produced two hormones. Some problems in the interpretation of portal venous insulin concentrations are discussed. The locations of maximum portal venous system plasma concentrations and portal-arterial gradients (mean +/- SE pg/ml) in five patients with small single insulinomas were: IG, gastrocolic trunk (126 +/- 27, 46 +/- 22); IRG, proximal splenic vein (130 +/- 30, 47 +/- 13) and gastrocolic trunk (131 +/- 23, 60 +/- 13); hPP, portal vein (164 +/- 48, 49 +/- 22); SRIF-LI, superior mesenteric vein (186 +/- 50, 57 +/- 20) and gastrocolic trunk (178 +/- 59, 55 +/- 21). It is concluded; (1) TPVS can be used successfully to localize single insulin-secreting tumors of the pancreas and to help distinguish them from diffuse disease but problems in such differentiation do occur, (2) circulating SRIF-LI and IRG are derived from both the pancreas and the gut, IG predominantly from the proximal gut and hPP from the head of the pancreas, and (3) The data provide new information for the interpretation of portal insulin concentrations in patients with organic hyperinsulinism and of hormone concentrations for localization of peptide-producing tumors of the pancreas other than insulinomas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24249/1/0000512.pd
Elucidating Drivers for Variations in the Explosive Human Immunodeficiency Virus Epidemic among People Who Inject Drugs in Pakistan
BACKGROUND: Pakistan’s explosive human immunodeficiency virus (HIV) epidemic among people who inject drugs (PWID) varies widely across cities. We evaluated possible drivers for these variations. METHODS: Multivariable regression analyses were undertaken using data from 5 national surveys among PWID (n = 18 467; 2005–2017) to determine risk factors associated with variations in city-level HIV prevalence. A dynamic HIV model was used to estimate the population-attributable fraction (PAF; proportion of HIV infections prevented over 10 years when that risk factor is removed) of these risk factors to HIV transmission and impact on HIV incidence of reducing their prevalence. RESULTS: Regression analyses suggested that city-level HIV prevalence is strongly associated with the prevalence of using professional injectors at last injection, heroin use in last month, and injecting ≥4 times per day. Through calibrating a model to these associations, we estimate that the 10-year PAFs of using professional injectors, heroin use, and frequent injecting are 45.3% (95% uncertainty interval [UI], 4.3%–79.7%), 45.9% (95% UI, 8.1%–78.4%), and 22.2% (95% UI, 2.0%–58.4%), respectively. Reducing to lowest city-level prevalences of using professional injectors (2.8%; median 89.9% reduction), heroin use (0.9%; median 91.2% reduction), and frequent injecting (0.1%; median 91.8% reduction) in 2020 reduces overall HIV incidence by 52.7% (95% UI, 6.1%–82.0%), 53.0% (95% UI, 11.3%–80.2%), and 28.1% (95% UI, 2.7%–66.6%), respectively, over 10 years. CONCLUSIONS: Interventions should focus on these risk factors to control Pakistan’s explosive HIV epidemic among PWID, including a concomitant expansion of high-coverage needle/syringe provision, opioid substitution therapy, and antiretroviral therapy
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Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals.
Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme
Mechanical stimulation of human dermal fibroblasts regulates pro-inflammatory cytokines: potential insight into soft tissue manual therapies
Objective
Soft tissue manual therapies are commonly utilized by osteopathic physicians, chiropractors, physical therapists and massage therapists. These techniques are predicated on subjecting tissues to biophysical mechanical stimulation but the cellular and molecular mechanism(s) mediating these effects are poorly understood. Previous studies established an in vitro model system for examining mechanical stimulation of dermal fibroblasts and established that cyclical strain, intended to mimic overuse injury, induces secretion of numerous pro-inflammatory cytokines. Moreover, mechanical strain intended to mimic soft tissue manual therapy reduces strain-induced secretion of pro-inflammatory cytokines. Here, we sought to partially confirm and extend these reports and provide independent corroboration of prior results.
Results
Using cultures of primary human dermal fibroblasts, we confirm cyclical mechanical strain increases levels of IL-6 and adding long-duration stretch, intended to mimic therapeutic soft tissue stimulation, after cyclical strain results in lower IL-6 levels. We also extend the prior work, reporting that long-duration stretch results in lower levels of IL-8. Although there are important limitations to this experimental model, these findings provide supportive evidence that therapeutic soft tissue stimulation may reduce levels of pro-inflammatory cytokines. Future work is required to address these open questions and advance the mechanistic understanding of therapeutic soft tissue stimulation
MEN I pancreas: A histological and immunohistochemical study
The spectrum and extent of islet cell histopathological findings in patients with multiple endocrine neoplasia, type I (MEN I) syndrome has never been clearly defined. Although some patients have discreet tumors causing clinically evident syndromes, others may have no symptoms until metastatic islet cell carcinoma is apparent. Whether diffuse islet cell disease occurs in all patients with grossly apparent tumors is not known. This study is an attempt to define both the functional and anatomical extent of islet cell disease and its relationship with the clinical course of patients with MEN I syndrome. The resected specimens of pancreas from 14 patients with MEN I syndrome were evaluated for hyperplasia, nesidioblastosis, multiple tumors, and evidence of malignancy. In 12 cases, specimens consisted of distal pancreas and, in 2 cases, the entire pancreas was available. Multiple sections were taken from each specimen. Immunoperoxidase staining was done for gastrin, pancreatic polypeptide, glucagon, serotonin, VIP, somatostatin, and neuron-specific enolase in sections of 24 tumors from 10 patients. Five of the 10 patients with Zollinger-Ellison syndrome underwent total gastrectomy and 3 others underwent only pancreatic procedures to control their acid hypersecretion. The following is concluded. All MEN I patients with pancreatic neoplasms have diffuse islet cell involvement consisting of nesidioblastosis, micro- and macronodular hyperplasia. Some tumors produce multiple hormones and these patients are at risk to develop new tumors, but complete excision of grossly apparent tumors may result in long-term control of the endocrinopathy present. This is particularly true for patients with insulinoma and hypoglycemia. Selected patients with gastrinoma may also be considered for excision of their islet cell tumor(s) without concomitant gastrectomy, especially if transhepatic venous sampling demonstrates a single site of excess gastrin production. However, if transhepatic venous sampling demonstrates diffuse sources of hypergastrinemia, a local pancreatic procedure will invariably be unsuccessful. Total pancreatectomy in MEN I patients with disease localized to the pancreas is the only curative surgical procedure but is rarely indicated. L'histopathologie des cellules insulaires pancrĂ©atiques des malades qui prĂ©sentent un syndrome MEN I n'a jamais Ă©tĂ© parfaitement dĂ©finie. Si certains parmi eux sont porteurs de petites tumeurs qui se manifestent par des syndromes cliniques patents, d'autres n'accusent aucun symptĂ´me avant que des mĂ©tastases nĂ©oplasiques ne se manifestent. En particulier, on ne sait pas si les altĂ©rations des cellules insulaires sont diffuses quand les malades prĂ©sentent des tumeurs Ă©videntes. Cette Ă©tude a pour but de dĂ©finir Ă la fois l'importance anatomique et l'importance fonctionnelle de la maladie insulaire par rapport Ă son expression clinique chez les sujets concernĂ©s par ce syndrome. Pour ce faire, des spĂ©cimens provenant de 14 malades atteints du syndrome MEN I ont Ă©tĂ© Ă©tudiĂ©s eu Ă©gard Ă l'hyperplasie, Ă la nĂ©sidioblastose, Ă la multiplicitĂ© des Ă®lots tumoraux, Ă la malignitĂ©. Dans 12 cas, les spĂ©cimens rĂ©pondaient au pancrĂ©as distal, dans 2 cas Ă la totalitĂ© du pancrĂ©as. De multiples coupes furent pratiquĂ©es au niveau de chaque pièce soumise Ă l'examen. L'imprĂ©gnation Ă l'immunoperoxidase concerna les coupes de 24 tumeurs provenant de 10 patients. Cinq des 10 malades qui prĂ©sentaient un syndrome de Zollinger-Ellison avaient subi une gastrectomie totale et 3 une intervention pancrĂ©atique pour contrĂ´ler leur hypersĂ©crĂ©tion acide. Les conclusions tirĂ©es de cette Ă©tude furent les suivantes: tous les malades accusant un syndrome MEN I et porteurs d'un nĂ©opolasme pancrĂ©atique prĂ©sentaient des lĂ©sions insulaires diffuses rĂ©pondant Ă une nĂ©sidioblastose, Ă une hyperplasie micronodulaire et macronodulaire. Quelques tumeurs produisaient de multiples hormones: gastrine, polypeptide pancrĂ©atique, glucagon, sĂ©rotonine, V.I.P., somatostatine, testĂ©es par la mĂ©thode. Il rĂ©sulte de ces constatations que les risques de rĂ©cidive tumorale après exĂ©rèse complète des tumeurs Ă©videntes ne sont pas Ă Ă©carter, encore que l'exĂ©rèse permette de contrĂ´ler longtemps l'endocrinopathie. Ceci est particulièrement vrai pour les insulinomes hypoglycĂ©miants. En ce qui concerne les gastrinomes, leur exĂ©rèse peut ĂŞtre suffisante, en particulier lorsque les prĂ©lèvements veineux Ă©tagĂ©s montrent qu'ils sont uniques; la gastrectomie concomitante est alors inutile. En revanche, lorsque la gastrine est trouvĂ©e en excès au niveau de multiples Ă©chantillons veineux, l'exĂ©rèse tumorale est insuffisante et la pancrĂ©atectomie totale reprĂ©sente l'intervention indispensable; en fait, son indication est rare. La variedad del espectro de la histopatologĂa de las cĂ©lulas insulares en pacientes con sindrome de neoplasias endocrinas mĂşltiples tipo I (NEM I) todavĂa no ha sido claramente definido. AĂşn cuando algunos pacientes poseen tumores discretos que causan sĂndromes clĂnicamente evidentes, otros pueden no exhibir sintomatologĂa alguna hasta cuando se hace evidente un carcinoma metastásico de cĂ©lulas insulares. No se sabe si hay enfermedad difusa de las cĂ©lulas insulares en todo paciente con tumores macroscĂłpicamente aparentes, ni además se conoce con quĂ© frecuencia se desarrollan nuevos tumores en pacientes con sĂndrome NEM I despuĂ©s de resecciĂłn local o de pancreatectomĂa parcial para tumores primarios de cĂ©lulas insulares. El presente estudio intenta definir la extensiĂłn funcional y anatĂłmica de la enfermedad de las cĂ©lulas insulares y su relaciĂłn con la evoluciĂłn clĂnica en pacientes con el sĂndrome NEM I.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41313/1/268_2005_Article_BF01654938.pd
Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe
The Extragalactic Background Light (EBL) includes photons with wavelengths
from ultraviolet to infrared, which are effective at attenuating gamma rays
with energy above ~10 GeV during propagation from sources at cosmological
distances. This results in a redshift- and energy-dependent attenuation of the
gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts
(GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray
blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using
photons above 10 GeV collected by Fermi over more than one year of observations
for these sources, we investigate the effect of gamma-ray flux attenuation by
the EBL. We place upper limits on the gamma-ray opacity of the Universe at
various energies and redshifts, and compare this with predictions from
well-known EBL models. We find that an EBL intensity in the optical-ultraviolet
wavelengths as great as predicted by the "baseline" model of Stecker et al.
(2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication
in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A.
Reimer, L.C. Reye
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