Multivariable stability analysis of position-controlled payloads to support shrink in semiconductor manufacturing

This paper addresses the challenge of ever-smaller structures in the semiconductor industry and the resulting requirements for high-performance mechatronic systems, especially wafer scanners, in lithography processes in the context of mechatronic system design and analysis. As a result, the development of sophisticated methods for modeling, control, and analysis of control systems has become necessary. To meet this need, advanced analysis methods of multivariable control systems are investigated, in particular the combination of classical stability analysis methods like the Nyquist criteria and use of Individual Channel Analysis and Design (ICAD) methods. For this purpose, the requirements for the analysis of multivariable control systems are summarized and put in the context of classical methods of system analysis, for example, the use of Nyquist methods to evaluate the stability of the control loop. Subsequently, the paper provides a rationale for why the use of Single-Input Single-Output (SISO) methods to assess stability and robustness is not sufficient and how these can be extended to Multiple-Input Multiple Output (MIMO) methods to meet the requirements. A set of tailored Nyquist-like MIMO analysis methods are theoretically derived, including the ICAD method and classical Nyquist stability analysis and its use in the analysis of multivariable control system is explained. A coupling ratio parameter, quantifying the coupling of multivariable systems, is derived from the extended ICAD method. The iterative design process is explained, which allows conclusions to be drawn about individual system parameters and how to optimize them to achieve high performance. To compare the methods, a model of a mechanical payload with variable eigenfrequencies is derived. Subsequently, the suitability of the respective method for multivariable stability analysis is tested in different system configurations. In conclusion, this paper provides insight into the analysis of stability and robustness of multivariable control systems and presents the challenges and opportunities of using these advanced methods to design high-performance mechatronics in the context of increasing requirements due to the shrink in semiconductor manufacturing. This provides a valuable contribution to the design of high-performance mechatronic systems

Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses

Global spread and regional endemicity of H5Nx Goose/Guangdong avian influenza viruses (AIV) pose a continuous threat for poultry production and zoonotic, potentially pre-pandemic, transmission to humans. Little is known about the role of mutations in the viral neuraminidase (NA) that accompanied bird-to-human transmission to support AIV infection of mammals. Here, after detailed analysis of the NA sequence of human H5N1 viruses, we studied the role of A46D, L204M, S319F and S430G mutations in virus fitness in vitro and in vivo. Although H5N1 AIV carrying avian- or human-like NAs had similar replication efficiency in avian cells, human-like NA enhanced virus replication in human airway epithelia. The L204M substitution consistently reduced NA activity of H5N1 and nine other influenza viruses carrying NA of groups 1 and 2, indicating a universal effect. Compared to the avian ancestor, human-like H5N1 virus has less NA incorporated in the virion, reduced levels of viral NA RNA replication and NA expression. We also demonstrate increased accumulation of NA at the plasma membrane, reduced virus release and enhanced cell-to-cell spread. Furthermore, NA mutations increased virus binding to human-type receptors. While not affecting high virulence of H5N1 in chickens, the studied NA mutations modulated virulence and replication of H5N1 AIV in mice and to a lesser extent in ferrets. Together, mutations in the NA of human H5N1 viruses play different roles in infection of mammals without affecting virulence or transmission in chickens. These results are important to understand the genetic determinants for replication of AIV in mammals and should assist in the prediction of AIV with zoonotic potential

Role of Vesicle-Associated Membrane Protein-Associated Proteins (VAP) A and VAPB in Nuclear Egress of the Alphaherpesvirus Pseudorabies Virus

The molecular mechanism affecting translocation of newly synthesized herpesvirus nucleocapsids from the nucleus into the cytoplasm is still not fully understood. The viral nuclear egress complex (NEC) mediates budding at and scission from the inner nuclear membrane, but the NEC is not sufficient for efficient fusion of the primary virion envelope with the outer nuclear membrane. Since no other viral protein was found to be essential for this process, it was suggested that a cellular machinery is recruited by viral proteins. However, knowledge on fusion mechanisms involving the nuclear membranes is rare. Recently, vesicle-associated membrane protein-associated protein B (VAPB) was shown to play a role in nuclear egress of herpes simplex virus 1 (HSV-1). To test this for the related alphaherpesvirus pseudorabies virus (PrV), we mutated genes encoding VAPB and VAPA by CRISPR/Cas9-based genome editing in our standard rabbit kidney cells (RK13), either individually or in combination. Single as well as double knockout cells were tested for virus propagation and for defects in nuclear egress. However, no deficiency in virus replication nor any effect on nuclear egress was obvious suggesting that VAPB and VAPA do not play a significant role in this process during PrV infection in RK13 cells

Light Sheet Microscopy-Assisted 3D Analysis of SARS-CoV-2 Infection in the Respiratory Tract of the Ferret Model

The visualization of viral pathogens in infected tissues is an invaluable tool to understand spatial virus distribution, localization, and cell tropism in vivo. Commonly, virus-infected tissues are analyzed using conventional immunohistochemistry in paraffin-embedded thin sections. Here, we demonstrate the utility of volumetric three-dimensional (3D) immunofluorescence imaging using tissue optical clearing and light sheet microscopy to investigate host–pathogen interactions of pandemic SARS-CoV-2 in ferrets at a mesoscopic scale. The superior spatial context of large, intact samples (>150 mm3) allowed detailed quantification of interrelated parameters like focus-to-focus distance or SARS-CoV-2-infected area, facilitating an in-depth description of SARS-CoV-2 infection foci. Accordingly, we could confirm a preferential infection of the ferret upper respiratory tract by SARS-CoV-2 and suggest clustering of infection foci in close proximity. Conclusively, we present a proof-of-concept study for investigating critically important respiratory pathogens in their spatial tissue morphology and demonstrate the first specific 3D visualization of SARS-CoV-2 infection