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Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen–antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 Å resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

Tracking performance and stability play a major role in observer design for speed estimation purpose in motor drives used in vehicles. It is all the more prevalent at lower speed ranges. There was a need to have a tradeoff between these parameters ensuring the speed bandwidth remains as wide as possible. This work demonstrates an improved static and dynamic performance of a sliding mode state observer used for speed sensorless 3 phase induction motor drive employed in electric vehicles (EVs). The estimated torque is treated as a model disturbance and integrated into the state observer while the error is constrained in the sliding hyperplane. Two state observers with different disturbance handling mechanisms have been designed. Depending on, how they reject disturbances, based on their structure, their performance is studied and analyzed with respect to speed bandwidth, tracking and disturbance handling capability. The proposed observer with superior disturbance handling capabilities is able to provide a wider speed range, which is a main issue in EV. Here, a new dimension of model based design strategy is employed namely the Processor-in-Loop. The concept is validated in a real-time model based design test bench powered by RT-lab. The plant and the controller are built in a Simulink environment and made compatible with real-time blocksets and the system is executed in real-time targets OP4500/OP5600 (Opal-RT). Additionally, the Processor-in-Loop hardware verification is performed by using two adapters, which are used to loop-back analog and digital input and outputs. It is done to include a real-world signal routing between the plant and the controller thereby, ensuring a real-time interaction between the plant and the controller. Results validated portray better disturbance handling, steady state and a dynamic tracking profile, higher speed bandwidth and lesser torque pulsations compared to the conventional observer.

N -glycosylation is critical to the function of monoclonal antibodies (mAbs) and distinguishes various systems used for their production. We expressed human mAbs in the small aquatic plant Lemna minor , which offers several advantages for manufacturing therapeutic proteins free of zoonotic pathogens 1 . Glycosylation of a mAb against human CD30 was optimized by co-expressing the heavy and light chains of the mAb with an RNA interference construct targeting expression of the endogenous α-1,3-fucosyltransferase and β-1,2-xylosyltransferase genes. The resultant mAbs contained a single major N -glycan species without detectable plant-specific N -glycans and had better antibody-dependent cell-mediated cytotoxicity and effector cell receptor binding activities than mAbs expressed in cultured Chinese hamster ovary (CHO) cells.

The purpose of smart grid architecture as compared to the conventional grid is to ensure more stability, reliability and bi-directional communication between the utility and the consumer. The deployment of the same has succeeded in improving the efficiency of the distribution systems and effective co-ordination and interoperability among the different components of the grid. Smart inverters play a major role in seamless grid integration, control and conversion of power when the renewable energy sources are present. However, they come with several security challenges as well, which are of considerable concern. Certain cyber threats include physical and cyber attacks, natural phenomena which in turn can lead to grid failure, blackouts, commercial energy losses, privacy and safety issues, etc. Therefore, there is a need for critical examination of all these issues which must be considered for designing cyber secure smart inverters at the distribution level. In this comprehensive review, keeping the technological perspective in mind, the existing gaps and the necessity for the same are highlighted. The various topologies, IEEE protocols and the control strategy are presented in detail. This will enable prospective researchers to address the design issues of smart inverters with greater focus on security and reliability aspects.

Antibodies HyHEL8, HyHEL10, and HyHEL26 (HH8, HH10, and HH26, respectively) recognize highly overlapping epitopes on hen egg-white lysozyme (HEL) with similar affinities, but with different specificities. HH8 binding to HEL is least sensitive toward mutations in the epitope and thus is most cross-reactive, HH26 is most sensitive, whereas the sensitivity of HH10 lies in between HH8 and HH26. Here we have investigated intra- and intermolecular interactions in three antibody–protein complexes: theoretical models of HH8-HEL and HH26-HEL complexes, and the x-ray crystal structure of HH10-HEL complex. Our results show that HH8-HEL has the lowest number and HH26-HEL has the highest number of intra- and intermolecular hydrogen bonds. The number of salt bridges is lowest in HH8-HEL and highest in HH26-HEL. The binding site salt bridges in HH8-HEL are not networked, and are weak, whereas, in HH26-HEL, an intramolecular salt-bridge triad at the binding site is networked to an intermolecular triad to form a pentad. The pentad and each salt bridge of this pentad are exceptionally stabilizing. The number of binding-site salt bridges and their strengths are intermediate in HH10-HEL, with an intramolecular triad. Our further calculations show that the electrostatic component contributes the most to binding energy of HH26-HEL, whereas the hydrophobic component contributes the most in the case of HH8-HEL. A “hot-spot” epitope residue Lys-97 forms an intermolecular salt bridge in HH8-HEL, and participates in the intermolecular pentad in the HH26-HEL complex. Mutant modeling and surface plasmon resonance (SPR) studies show that this hot-spot epitope residue contributes significantly more to the binding than an adjacent epitope residue, Lys-96, which does not form a salt bridge in any of the three HH-HEL complexes. Furthermore, the effect of mutating Lys-97 is most severe in HH26-HEL. Lys-96, being a charged residue, also contributes the most in HH26-HEL among the three complexes. The SPR results on these mutants also highlight that the apparent “electrostatic steering” on net on rates actually act at post-collision level stabilization of the complex. The significance of this work is the observed variations in electrostatic interactions among the three complexes. Our work demonstrates that higher electrostatics, both as a number of short-range electrostatic interactions and their contributions, leads to higher binding specificity. Strong salt bridges, their networking, and electrostatically driven binding, limit flexibilities through geometric constrains. In contrast, hydrophobic driven binding and low levels of electrostatic interactions are associated with conformational flexibility and cross-reactivity.

In this paper, a comparative analysis of the average switch/inductor current between ideal and non-ideal buck and synchronous buck converters is performed and verified against a standard LTspice model. The mathematical modeling of the converters was performed using volt-sec and amp-sec balance equations and analyzed using MATLAB/Simulink. The transients in the output voltage and the inductor current were observed. The transfer function of the switch current to the duty cycle (Gid) in open loop configuration for low-power converters operating in continuous conduction mode (CCM) was modeled using thestate space averaging (SSA) technique and analyzed using MATLAB/Simulink. Initially, using the volt-sec and amp-sec, balance equations for the converters were modeled. The switch current to duty ratio (Gid) was derived using the SSA technique and verified using standard average models available in LTspice software. Though the Gid was derived using various methods in earlier works, the analyses of parameters such as low frequency gain, stability, resonant frequency and the location of poles and zeros were not presented. It was observed that the converters were stable, and the non-ideal converter showed smaller resonant frequency than the ideal converter due to the equivalent series resistances (ESR) of the inductor and the capacitor. The non-ideal converters showed higher stability than the ideal converters due to the placement of the poles closer to the s-plane. However, the Gid of the non-ideal converters remained the same in the open loop configuration.

Major histocompatibility complex class I chain-related A and B (MICA/B) are cell-surface proteins that act as ligands to natural killer cell receptors, NKG2D, expressed on immune cells. Prevention of proteolytic shedding of MICA/B to retain their integrity on the cell surface has become a therapeutic strategy in immuno-oncology. Given the unique mechanism of MICA/B shedding, structural characterization of MICA/B and therapeutic agent interaction is important in the drug discovery process. In this study, we describe the practical utility of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in epitope mapping studies of a cohort of four monoclonal antibodies targeting MICA in a rapid manner. HDX-MS followed by electron-transfer dissociation allows high-resolution refinement of binding epitopes. This integrated strategy offers, for the first time, molecular-level understanding of MICA’s conformational dynamics in solution as well as the unique mechanism of actions of these antibodies in targeting MICA.

IPT (inductive power transfer) charging is a highly flexible concept that allows for charging at any possible opportunity and is highly versatile for vehicles of all sizes. IPT wireless charging technology employs high-power inductive energy transfer between the components embedded into streets and the receiving equipment mounted below the vehicle. When the vehicle moves over the charging point, the contactless charging process is initiated between the components and the vehicle. In this work, the role of power converter topologies in IPT systems are studied for electric vehicle (EV) charging applications. Further, the predominant topologies are compared and analyzed in detail. The contingency in misalignment, loading and frequency shift are discussed for various converter topologies. The tolerance in misalignment poses serious challenges for wireless chargers in EVs. Therefore, there is currently a need to design a symmetric IPT system with multiple decoupled receiving coils. The significance of power inverter topologies for achieving resonance, as well as the generation of high-frequency supply, has been studied in detail. Experimental waveforms that are related to the explanations in this work are provided to substantiate the advantages regarding the converters.

The tubular gland of the chicken oviduct is an attractive system for protein expression as large quantities of proteins are deposited in the egg, the production of eggs is easily scalable and good manufacturing practices for therapeutics from eggs have been established. Here we examined the ability of upstream and downstream DNA sequences of ovalbumin, a protein produced exclusively in very high quantities in chicken egg white, to drive tissue-specific expression of human mAb in chicken eggs. To accommodate these large regulatory regions, we established and transfected lines of chicken embryonic stem (cES) cells and formed chimeras that express mAb from cES cell–derived tubular gland cells. Eggs from high-grade chimeras contained up to 3 mg of mAb that possesses enhanced antibody-dependent cellular cytotoxicity (ADCC), nonantigenic glycosylation, acceptable half-life, excellent antigen recognition and good rates of internalization.

Background. Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARSCoV) could provide protection for exposed individuals. Methods. Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection. Results. Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb (201) bound within the receptor-binding domain at aa 490–510, and the other MAb (68) bound externally to the domain at aa 130–150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection. Conclusions. Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region.