Programming Protocol-Independent Packet Processors

P4 is a high-level language for programming protocol-independent packet processors. P4 works in conjunction with SDN control protocols like OpenFlow. In its current form, OpenFlow explicitly specifies protocol headers on which it operates. This set has grown from 12 to 41 fields in a few years, increasing the complexity of the specification while still not providing the flexibility to add new headers. In this paper we propose P4 as a strawman proposal for how OpenFlow should evolve in the future. We have three goals: (1) Reconfigurability in the field: Programmers should be able to change the way switches process packets once they are deployed. (2) Protocol independence: Switches should not be tied to any specific network protocols. (3) Target independence: Programmers should be able to describe packet-processing functionality independently of the specifics of the underlying hardware. As an example, we describe how to use P4 to configure a switch to add a new hierarchical label

Berichte

BerichteUniversité + UCIP = UNICIP (L. Bosshart) Theologie der Befreiung im Urteil der Presse (R. Pitsch) Jean Frey AG kuaft Walter Verlag (T. Steinmaurer) Frankreichs katholische PResse expandiert (G. Lankes) Zehn Jahre Katholischer Kinderbuchpreis (R. Pitsch)

Agent-Based Modeling of Endotoxin-Induced Acute Inflammatory Response in Human Blood Leukocytes

Inflammation is a highly complex biological response evoked by many stimuli. A persistent challenge in modeling this dynamic process has been the (nonlinear) nature of the response that precludes the single-variable assumption. Systems-based approaches offer a promising possibility for understanding inflammation in its homeostatic context. In order to study the underlying complexity of the acute inflammatory response, an agent-based framework is developed that models the emerging host response as the outcome of orchestrated interactions associated with intricate signaling cascades and intercellular immune system interactions.An agent-based modeling (ABM) framework is proposed to study the nonlinear dynamics of acute human inflammation. The model is implemented using NetLogo software. Interacting agents involve either inflammation-specific molecules or cells essential for the propagation of the inflammatory reaction across the system. Spatial orientation of molecule interactions involved in signaling cascades coupled with the cellular heterogeneity are further taken into account. The proposed in silico model is evaluated through its ability to successfully reproduce a self-limited inflammatory response as well as a series of scenarios indicative of the nonlinear dynamics of the response. Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades.The ABM framework developed in this study provides insight on the stochastic interactions of the mediators involved in the propagation of endotoxin signaling at the cellular response level. The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components. The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system

Basolateral Sorting of Syntaxin 4 Is Dependent on Its N-terminal Domain and the AP1B Clathrin Adaptor, and Required for the Epithelial Cell Polarity

Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24–29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans-Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity

The provenance of Borneo's enigmatic alluvial diamonds:A case study from Cempaka, SE Kalimantan

Gem-quality diamonds have been found in several alluvial deposits across central and southern Borneo. Borneo has been a known source of diamonds for centuries, but the location of their primary igneous source remains enigmatic. Many geological models have been proposed to explain their distribution, including: the diamonds were derived from a local diatreme; they were brought to the surface through ophiolite obduction or exhumation of UHP metamorphic rocks; they were transported long distances southward via major Asian river systems; or, they were transported from the Australian continent before Borneo was rifted from its northwestern margin in the Late Jurassic. To assess these models, we conducted a study of the provenance of heavy minerals from Kalimantan's Cempaka alluvial diamond deposit. This involved collecting U–Pb isotopic data, fission track and trace element geochemistry of zircon as well as major element geochemical data of spinels and morphological descriptions of zircon and diamond. The results indicate that the Cempaka diamonds were likely derived from at least two sources, one which was relatively local and/or involved little reworking, and the other more distal which records several periods of reworking. The distal diamond source is interpreted to be diamond-bearing pipes that intruded the basement of a block that: (1) rifted from northwest Australia (East Java or SW Borneo) and the diamonds were recycled into its sedimentary cover, or: (2) were emplaced elsewhere (e.g. NW Australia) and transported to a block (e.g. East Java or SW Borneo). Both of these scenarios require the diamonds to be transported with the block when it rifted from NW Australia in the Late Jurassic. The local source could be diamondiferous diatremes associated with eroded Miocene high-K alkaline intrusions north of the Barito Basin, which would indicate that the lithosphere beneath SW Borneo is thick (~ 150 km or greater). The ‘local’ diamonds could also be associated with ophiolitic rocks that are exposed in the nearby Meratus Mountains

Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists: A New Paradigm for Treating Sepsis and Other Diseases

Abstract. Sepsis remains the most common cause of death in intensive care units in the USA, with a current estimate of at least 750,000 cases per year, and 215,000 deaths annually. Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury. Endotoxin (lipopolysaccharide from Gram-negative bacteria, or LPS) has been implicated as a major cause of this syndrome. Inflammatory shock as a consequence of LPS release remains a serious clinical concern. In humans, inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages, which can cause fever, shock, organ failure and death. A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria, including blockage of one or more of the cytokines induced by LPS. Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor, TLR4. This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling, in vitro pre-clinical and in vivo clinical evaluation of TLR4 antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction. KEY WORDS: drug discovery; LPS; sepsis; toll-like receptor antagonists

Single-Molecule Force Spectroscopy: Experiments, Analysis, and Simulations

International audienceThe mechanical properties of cells and of subcellular components are important to obtain a mechanistic molecular understanding of biological processes. The quantification of mechanical resistance of cells and biomolecules using biophysical methods matured thanks to the development of nanotechnologies such as optical and magnetic tweezers, the biomembrane force probe and atomic force microscopy (AFM). The quantitative nature of force spectroscopy measurements has converted AFM into a valuable tool in biophysics. Force spectroscopy allows the determination of the forces required to unfold protein domains and to disrupt individual receptor/ligand bonds. Molecular simulation as a computational microscope allows investigation of similar biological processes with an atomistic detail. In this chapter, we first provide a step-by-step protocol of force spectroscopy including sample preparation, measurement and analysis of force spectroscopy using AFM and its interpretation in terms of available theories. Next, we present the background for molecular dynamics (MD) simulations focusing on steered molecular dynamics (SMD) and the importance of bridging of computational tools with experimental technique

The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19)