177 research outputs found
Phase modulation induced by cooperative effects in electromagnetically induced transparency
We analyze the influence of dipole-dipole interactions in an
electromagnetically induced transparency setup at high density. We show both
analytically and numerically that the polarization contribution to the local
field strongly modulates the phase of a weak pulse. We give an intuitive
explanation for this local field induced phase modulation and show that it
distinctively differs from the nonlinear self-phase modulation a strong pulse
experiences in a Kerr medium
Full counting statistics of laser excited Rydberg aggregates in a one-dimensional geometry
We experimentally study the full counting statistics of few-body Rydberg
aggregates excited from a quasi-one-dimensional Rydberg gas. We measure
asymmetric excitation spectra and increased second and third order statistical
moments of the Rydberg number distribution, from which we determine the average
aggregate size. Direct comparisons with numerical simulations reveal the
presence of liquid-like spatial correlations, and indicate sequential growth of
the aggregates around an initial grain. These findings demonstrate the
importance of dissipative effects in strongly correlated Rydberg gases and
introduce a way to study spatio-temporal correlations in strongly-interacting
many-body quantum systems without imaging.Comment: 6 pages plus supplemen
Nonlinear Effects in Pulse Propagation through Doppler-Broadened Closed-Loop Atomic Media
Nonlinear effects in pulse propagation through a medium consisting of
four-level double--type systems are studied theoretically. We apply
three continous-wave driving fields and a pulsed probe field such that they
form a closed interaction loop. Due to the closed loop and the finite frequency
width of the probe pulses the multiphoton resonance condition cannot be
fulfilled, such that a time-dependent analysis is required. By identifying the
different underlying physical processes we determine the parts of the solution
relevant to calculate the linear and nonlinear response of the system. We find
that the system can exhibit a strong intensity dependent refractive index with
small absorption over a range of several natural linewidths. For a realistic
example we include Doppler and pressure broadening and calculate the nonlinear
selfphase modulation in a gas cell with Sodium vapor and Argon buffer gas. We
find that a selfphase modulation of is achieved after a propagation of
few centimeters through the medium while the absorption in the corresponding
spectral range is small.Comment: 4 figure
Resource utilization and outcome at a university versus a community teaching hospital in tPA treated stroke patients: a retrospective cohort study
<p>Abstract</p> <p>Background</p> <p>Comparing patterns of resource utilization between hospitals is often complicated by biases in community and patient populations. Stroke patients treated with tissue plasminogen activator (tPA) provide a particularly homogenous population for comparison because of strict eligibility criteria for treatment. We tested whether resource utilization would be similar in this homogenous population between two hospitals located in a single Midwestern US community by comparing use of diagnostic testing and associated outcomes following treatment with t-PA.</p> <p>Methods</p> <p>Medical records from 206 consecutive intravenous t-PA-treated stroke patients from two teaching hospitals (one university, one community-based) were reviewed. Patient demographics, clinical characteristics and outcome were analyzed, as were the frequency of use of CT, MRI, MRA, echocardiography, angiography, and EEG.</p> <p>Results</p> <p>Seventy-nine and 127 stroke patients received t-PA at the university and community hospitals, respectively. The two patient populations were demographically similar. There were no differences in stroke severity. All outcomes were similar at both hospitals. Utilization of CT scans, and non-invasive carotid and cardiac imaging studies were similar at both hospitals; however, brain MR, TEE, and catheter angiography were used more frequently at the university hospital. EEG was obtained more often at the community hospital.</p> <p>Conclusions</p> <p>Utilization of advanced brain imaging and invasive diagnostic testing was greater at the university hospital, but was not associated with improved clinical outcomes. This could not be explained on the basis of stroke severity or patient characteristics. This variation of practice suggests substantial opportunities exist to reduce costs and improve efficiency of diagnostic resource use as well as reduce patient exposure to risk from diagnostic procedures.</p
The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein,so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability
Novel chimerized IgA CD20 antibodies : Improving neutrophil activation against CD20-positive malignancies
ABSTRACT Current combination therapies elicit high response rates in B cell malignancies, often using CD20 antibodies as the backbone of therapy. However, many patients eventually relapse or develop progressive disease. Therefore, novel CD20 antibodies combining multiple effector mechanisms were generated. To study whether neutrophil-mediated destruction of B cell malignancies can be added to the arsenal of effector mechanisms, we chimerized a panel of five previously described murine CD20 antibodies to the human IgG1, IgA1 and IgA2 isotype. Of this panel, we assessed in vitro antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and direct cell death induction capacity and studied the efficacy in two different in vivo mouse models. IgA antibodies outperformed IgG1 antibodies in neutrophil-mediated killing in vitro, both against CD20-expressing cell lines and primary patient material. In these assays, we observed loss of CD19 with both IgA and IgG antibodies. Therefore, we established a novel method to improve the assessment of B-cell depletion by CD20 antibodies by including CD24 as a stable cell marker. Subsequently, we demonstrated that only IgA antibodies were able to reduce B cell numbers in this context. Additionally, IgA antibodies showed efficacy in both an intraperitoneal tumor model with EL4 cells expressing huCD20 and in an adoptive transfer model with huCD20-expressing B cells. Taken together, we show that IgA, like IgG, can induce ADCC and CDC, but additionally triggers neutrophils to kill (malignant) B cells. We conclude that antibodies of the IgA isotype offer an attractive repertoire of effector mechanisms for the treatment of CD20-expressing malignancies.Peer reviewe
The Cascadia Initiative : a sea change In seismological studies of subduction zones
Author Posting. © The Oceanography Society, 2014. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 27, no. 2 (2014): 138-150, doi:10.5670/oceanog.2014.49.Increasing public awareness that the Cascadia subduction zone in the Pacific Northwest is capable of great earthquakes (magnitude 9 and greater) motivates the Cascadia Initiative, an ambitious onshore/offshore seismic and geodetic experiment that takes advantage of an amphibious array to study questions ranging from megathrust earthquakes, to volcanic arc structure, to the formation, deformation and hydration of the Juan De Fuca and Gorda Plates. Here, we provide an overview of the Cascadia Initiative, including its primary science objectives, its experimental design and implementation, and a preview of how the resulting data are being used by a diverse and growing scientific community. The Cascadia Initiative also exemplifies how new technology and community-based experiments are opening up frontiers for marine science. The new technologyâshielded ocean bottom seismometersâis allowing more routine investigation of the source zone of megathrust earthquakes, which almost exclusively lies offshore and in shallow water. The Cascadia Initiative offers opportunities and accompanying challenges to a rapidly expanding community of those who use ocean bottom seismic data.The Cascadia Initiative is supported by
the National Science Foundation; the
CIET is supported under grants OCE-
1139701, OCE-1238023, OCEâ1342503,
OCE-1407821, and OCE-1427663
to the University of Oregon
N6-Methyladenosine Directly Regulates CD40L Expression in CD4+ T Lymphocytes
T cell activation is a highly regulated process, modulated via the expression of various immune regulatory proteins including cytokines, surface receptors and co-stimulatory proteins. N6-methyladenosine (m6A) is an RNA modification that can directly regulate RNA expression levels and it is associated with various biological processes. However, the function of m6A in T cell activation remains incompletely understood. We identify m6A as a novel regulator of the expression of the CD40 ligand (CD40L) in human CD4+ lymphocytes. Manipulation of the m6A âeraserâ fat mass and obesity-associated protein (FTO) and m6A âwriterâ protein methyltransferase-like 3 (METTL3) directly affects the expression of CD40L. The m6A âreaderâ protein YT521-B homology domain family-2 (YTHDF2) is hypothesized to be able to recognize and bind m6A specific sequences on the CD40L mRNA and promotes its degradation. This study demonstrates that CD40L expression in human primary CD4+ T lymphocytes is regulated via m6A modifications, elucidating a new regulatory mechanism in CD4+ T cell activation that could possibly be leveraged in the future to modulate T cell responses in patients with immune-related diseases
HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3ÎČ) a key regulator of glycolysis. Pharmacological inhibition of GSK3ÎČ results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3ÎČ inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC
Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model
IMPORTANCE: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. OBJECTIVE: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. EXPOSURES: Type of acute symptomatic seizure. MAIN OUTCOMES AND MEASURES: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). RESULTS: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. CONCLUSIONS AND RELEVANCE: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up
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