Low velocity zone under Long Valley as determined from teleseismic events

This is the published version. Copyright 1976 American Geophysical Union. All Rights Reserved.A temporary seismograph station network was used to estimate teleseismic P wave residuals in the vicinity of Long Valley geothermal area, California. Relative P wave delays of 0.3 s persist at stations in the west central part of the Long Valley caldera after regional and near-surface effects have been removed. Ray tracing indicates that low-velocity material exists beneath the caldera at depths greater than 7 km and less than 40 km, probably less than 25 km. The velocity contrast with normal crust must be at least 5% to satisfy the data and is probably in the range 10–15%. We believe that the low velocity indicates anomalously hot rock at depth and that relative teleseismic P residuals may be useful for investigation of sources of geothermal energy

University Autonomy Decline

This book provides empirically grounded insights into the causes, trajectories, and effects of a severe decline in university autonomy and the relationship to other dimensions of academic freedom by comparing in-depth country studies and evidence from a new global timeseries dataset. Drawing attention to ongoing discussions on standards for monitoring and assessment of academic freedom at regional and international organizations, this book identifies a need for clearer standards on academic freedom and a human rights-based definition of university autonomy. Further, the book calls for accompanying international oversight and the inclusion of criteria related to academic freedom in international university rankings. Five expert-authored case studies on academic freedom from diverse nations (Bangladesh, Mozambique, India, Poland, and Turkey) are included in the volume. Drawing on both qualitative and quantitative evidence, the book offers a unique and timely contribution to the field and will be of great interest to scholars, researchers, and students in the fields of higher education, human rights, political science and public policy

University Autonomy Decline

This book provides empirically grounded insights into the causes, trajectories, and effects of a severe decline in university autonomy and the relationship to other dimensions of academic freedom by comparing in-depth country studies and evidence from a new global timeseries dataset. Drawing attention to ongoing discussions on standards for monitoring and assessment of academic freedom at regional and international organizations, this book identifies a need for clearer standards on academic freedom and a human rights-based definition of university autonomy. Further, the book calls for accompanying international oversight and the inclusion of criteria related to academic freedom in international university rankings. Five expert-authored case studies on academic freedom from diverse nations (Bangladesh, Mozambique, India, Poland, and Turkey) are included in the volume. Drawing on both qualitative and quantitative evidence, the book offers a unique and timely contribution to the field and will be of great interest to scholars, researchers, and students in the fields of higher education, human rights, political science and public policy

Use of a folding model and in situ spectroscopic techniques for rational formulation development and stability testing of Monoclonal antibody therapeutics

Aggregation is a critical issue that hampers the development of monoclonal antibody therapeutics (Mabs). Traditionally, aggregation is considered a process in which native forms of proteins are transformed into an unstable highly associated form through an intermediate formation step. Here we describe the unfolding of an anti CD40 antibody using a folding model based on Lumry-Eyring nucleated polymerization (LENP) model. This model captures several experimental features of the thermal unfolding of this protein as studied by common in situ biophysical techniques such as circular dichroism, fluorescence spectroscopy and turbidity measurements. According to this model, the unfolding and aggregation of the anti CD40 antibody is determined by several distinct steps that include conformational change(s) to generate aggregation prone states, reversible oligomer formation, nucleation and growth as well as their kinetics and the formation of higher order assemblies/aggregates. Furthermore, the loss of monomer is controlled by both thermodynamic (equilibrium unfolding) and kinetic determinants of the unfolding process. This approach captures both of these rate-limiting steps. It can be concluded that this approach is sensitive to formulation conditions such as protein concentration, changes in buffer conditions, and temperature stress. The potential use of this approach in formulation development and stability testing of Mabs is discussed

Mitoxantrone Loaded Superparamagnetic Nanoparticles for Drug Targeting: A Versatile and Sensitive Method for Quantification of Drug Enrichment in Rabbit Tissues Using HPLC-UV

In medicine, superparamagnetic nanoparticles bound to chemotherapeutics are currently investigated for their feasibility in local tumor therapy. After intraarterial application, these particles can be accumulated in the targeted area by an external magnetic field to increase the drug concentration in the region of interest (Magnetic-Drug-Targeting). We here present an analytical method (HPLC-UV), to detect pure or ferrofluid-bound mitoxantrone in a complex matrix even in trace amounts in order to perform biodistribution studies. Mitoxantrone could be extracted in high yields from different tissues. Recovery of mitoxantrone in liver tissue (5000 ng/g) was 76 ± 2%. The limit of quantification of mitoxantrone standard was 10 ng/mL ±12%. Validation criteria such as linearity, precision, and stability were evaluated in ranges achieving the FDA requirements. As shown for pilot samples, biodistribution studies can easily be performed after application of pure or ferrofluid-bound mitoxantrone

Are All Types of Morality Compromised in Psychopathy

A long-standing puzzle for moral philosophers and psychologists alike is the concept of psychopathy, a personality disorder marked by tendencies to defy moral norms despite cognitive knowledge about right and wrong. Previously, discussions of the moral deficits of psychopathy have focused on willingness to harm and cheat others as well as reasoning about rule-based transgressions. Yet recent research in moral psychology has begun to more clearly define the domains of morality, en- compassing issues of harm, fairness, loyalty, authority, and spiritual purity. Clinical descriptions and theories of psychopathy suggest that deficits may exist primarily in the areas of harm and fairness, although quantitative evidence is scarce. Within a broad sample of participants, we found that scores on a measure of psychopathy predicted sharply lower scores on the harm and fairness subscales of a measure of moral concern, but showed no relationship with authority, and very small relationships with ingroup and purity. On a measure of willingness to violate moral standards for money, psychopathy scores predicted greater willingness to violate moral concerns of any type. Results are further explored via potential mediators and analyses of the two factors of psychopathy

Magnetic Accumulation of SPIONs under Arterial Flow Conditions: Effect of Serum and Red Blood Cells

Magnetic drug targeting utilizes an external magnetic field to target superparamagnetic iron oxide nanoparticles (SPIONs) and their cargo to the diseased vasculature regions. In the arteries, the flow conditions affect the behavior of magnetic particles and the efficacy of their accumulation. In order to estimate the magnetic capture of SPIONs in more physiological-like settings, we previously established an ex vivo model based on human umbilical cord arteries. The artery model was employed in our present studies in order to analyze the effects of the blood components on the efficacy of magnetic targeting, utilizing 2 types of SPIONs with different physicochemical characteristics. In the presence of freshly isolated human plasma or whole blood, a strong increase in iron content measured by AES was observed for both particle types along the artery wall, in parallel with clotting activation due to endogenous thrombin generation in plasma. Subsequent studies therefore utilized SPION suspensions in serum and washed red blood cells (RBCs) at hematocrit 50%. Interestingly, in contrast to cell culture medium suspensions, magnetic accumulation of circulating SPION-3 under the external magnet was achieved in the presence of RBCs. Taken together, our data shows that the presence of blood components affects, but does not prevent, the magnetic accumulation of circulating SPIONs

Functionalized Superparamagnetic Iron Oxide Nanoparticles (SPIONs) as Platform for the Targeted Multimodal Tumor Therapy

Standard cancer treatments involve surgery, radiotherapy, chemotherapy, and immunotherapy. In clinical practice, the respective drugs are applied orally or intravenously leading to their systemic circulation in the whole organism. For chemotherapeutics or immune modulatory agents, severe side effects such as immune depression or autoimmunity can occur. At the same time the intratumoral drug doses are often too low for effective cancer therapy. Since monotherapies frequently cannot cure cancer, due to their synergistic effects multimodal therapy concepts are applied to enhance treatment efficacy. The targeted delivery of drugs to the tumor by employment of functionalized nanoparticles might be a promising solution to overcome these challenges. For multimodal therapy concepts and individualized patient care nanoparticle platforms can be functionalized with compounds from various therapeutic classes (e.g. radiosensitizers, phototoxic drugs, chemotherapeutics, immune modulators). Superparamagnetic iron oxide nanoparticles (SPIONs) as drug transporters can add further functionalities, such as guidance or heating by external magnetic fields (Magnetic Drug Targeting or Magnetic Hyperthermia), and imaging-controlled therapy (Magnetic Resonance Imaging)

Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice

The administration of recombinant Factor VIII (FVIII) is the first line therapy for Hemophilia A (HA), but 25–35% of patients develop an inhibitory antibody response. In general, the presence of aggregates contributes to unwanted immunogenic responses against therapeutic proteins. FVIII has been shown to form both native-like and non-native aggregates. Previously, we showed that non-native aggregates of FVIII are less immunogenic compared to the native protein. Here we investigated the effect of native-like aggregates of FVIII on immunogenicity in HA and von Willebrand Factor knockout (vWF−/−) mice. Mice immunized with native-like aggregates showed significantly higher inhibitory antibody titers compared to animals that received native FVIII. Following re-stimulation in vitro with native FVIII, the activation of CD4+ T cells isolated from mice immunized with native-like aggregates is ~4 fold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of pro-inflammatory cytokines IL-6 and IL-17 in the native-like aggregate treatment group. The results indicate that the native-like aggregates of FVIII are more immunogenic than native FVIII for both the B cell and T cell responses