BF Theories and Group-Level Duality

It is known that the partition function and correlators of the two-dimensional topological field theory $G_K(N)/ G_K(N)$ on the Riemann surface $\Sigma_{g,s}$ is given by Verlinde numbers, dim($V_{g,s,K}$) and that the large $K$ limit of dim($V_{g,s,K}$) gives Vol(${\cal M}_s$), the volume of the moduli space of flat connections of gauge group $G(N)$ on $\Sigma_{g,s}$, up to a power of $K$. Given this relationship, we complete the computation of Vol(${\cal M}_s$) using only algebraic results from conformal field theory. The group-level duality of $G(N)_K$ is used to show that if $G(N)$ is a classical group, then $\displaystyle \lim_{N\rightarrow \infty} G_K(N) / G_K(N)$ is a BF theory with gauge group $G(K)$. Therefore this limit computes Vol(${\cal M}^\prime_s$), the volume of the moduli space of flat connections of gauge group $G(K)$

Photocatalytic activity of nitrogen-doped TiO2-based nanowires: a photo-assisted Kelvin probe force microscopy study

The emerging industrial business partnerships, which feature cross-functional and cross-company development efforts, raise the barrier for the establishment of effective knowledge sharing practices in the larger organization. This chapter aims to highlight the role of knowledge as a key enabler for effective engineering activities in the light of such emerging enterprise collaboration models. Knowledge Enabled Engineering (KEE) is presented as an approach to enhance the extended organization’s capability to establish effective collaboration among its parts, in spite of different organizational structures, technologies or processes. KEE is analysed in its constituent parts, highlighting areas, methods and tools that are particularly interesting for leveraging companies’ knowledge sharing capabilities

Ionospheric gas dynamics of satellites and diagnostic probes

The gas dynamics of interactions of a tenuous ionosphere with moving satellites and probes that have bearings on the diagnostics of the ionosphere are discussed. Emphasis is on the cases where the body is moving at mesothermal speeds, namely intermediate between the thermal speeds of ions and electrons of the ambient ionosphere. Methods of collision-free plasma kinetics with self-consistent field are used. The development of the topics for discussion starts with stationary Langmuir probe which entails the basic mechanism of body-plasma interaction that becomes further intricated as the body moves at a higher and higher speed. Applications of the theory of plasma interaction to meteors which move in the ionosphere are also presented.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43801/1/11214_2004_Article_BF00212707.pd

Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability

Anti-cancer antibody-drug conjugates (ADCs) aim to expand the therapeutic index of traditional chemotherapy by employing the targeting specificity of monoclonal antibodies (mAbs) to increase the efficiency of the delivery of potent cytotoxic agents to malignant cells. In the past three years, the number of ADCs approved by the Food and Drug Administration (FDA) has tripled. Although several ADCs have demonstrated sufficient efficacy and safety to warrant FDA approval, the clinical use of all ADCs leads to substantial toxicity in treated patients, and many ADCs have failed during clinical development due to their unacceptable toxicity profiles. Analysis of the clinical data has demonstrated that dose-limiting toxicities (DLTs) are often shared by different ADCs that deliver the same cytotoxic payload, independent of the antigen that is targeted and/or the type of cancer that is treated. DLTs are commonly associated with cells and tissues that do not express the targeted antigen (i.e., off-target toxicity), and often limit ADC dosage to levels below those required for optimal anti-cancer effects. In this manuscript, we review the fundamental mechanisms contributing to ADC toxicity, we summarize common ADC treatment-related adverse events, and we discuss several approaches to mitigating ADC toxicity

Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability

Anti-cancer antibody-drug conjugates (ADCs) aim to expand the therapeutic index of traditional chemotherapy by employing the targeting specificity of monoclonal antibodies (mAbs) to increase the efficiency of the delivery of potent cytotoxic agents to malignant cells. In the past three years, the number of ADCs approved by the Food and Drug Administration (FDA) has tripled. Although several ADCs have demonstrated sufficient efficacy and safety to warrant FDA approval, the clinical use of all ADCs leads to substantial toxicity in treated patients, and many ADCs have failed during clinical development due to their unacceptable toxicity profiles. Analysis of the clinical data has demonstrated that dose-limiting toxicities (DLTs) are often shared by different ADCs that deliver the same cytotoxic payload, independent of the antigen that is targeted and/or the type of cancer that is treated. DLTs are commonly associated with cells and tissues that do not express the targeted antigen (i.e., off-target toxicity), and often limit ADC dosage to levels below those required for optimal anti-cancer effects. In this manuscript, we review the fundamental mechanisms contributing to ADC toxicity, we summarize common ADC treatment-related adverse events, and we discuss several approaches to mitigating ADC toxicity

Half-Life Extension and Biodistribution Modulation of Biotherapeutics via Red Blood Cell Hitch-Hiking with Novel Anti-Band 3 Single-Domain Antibodies

Small therapeutic proteins are receiving increased interest as therapeutic drugs; however, their clinical success has been limited due to their rapid elimination. Here, we report a half-life extension strategy via strategy via red blood cell red blood cell (RBC) hitch-hiking. This manuscript details the development and characterization of novel anti-RBC single-domain antibodies (sdAbs), their genetic fusion to therapeutic antibody fragments (TAF) as bispecific fusion constructs, and their influence on TAF pharmacokinetics and biodistribution. Several sdAbs specific to the band 3 antigen were generated via phage-display technology. Binding affinity to RBCs was assessed via flow cytometry. Affinity maturation via random mutagenesis was carried out to improve the binding affinity of the sdAbs. Bi-specific constructs were generated by fusing the anti-RBC sdAbs with anti-tissue necrosis factor alpha (TNF-α) TAF via the use of a glycine-serine flexible linker, and assessments for binding were performed via enzyme-linked immunosorbent assay and flow cytometry. Pharmacokinetics of anti-RBC sdAbs and fusion constructs were evaluated following intravenous bolus dosing in mice at a 1 mg/kg dose. Two RBC-binding sdAbs, RB12 and RE8, were developed. These two clones showed high binding affinity to human RBC with an estimated KD of 17.7 nM and 23.6 nM and low binding affinity to mouse RBC with an estimated KD of 335 nM and 528 nM for RB12 and RE8, respectively. Two derivative sdAbs, RMA1, and RMC1, with higher affinities against mouse RBC, were generated via affinity maturation (KD of 66.9 nM and 30.3 nM, respectively). Pharmacokinetic investigations in mice demonstrated prolonged circulation half-life of an anti-RBC-TNF-α bispecific construct (75 h) compared to a non-RBC binding control (1.3 h). In summary, the developed anti-RBC sdAbs and fusion constructs have demonstrated high affinity in vitro, and sufficient half-life extension in vivo