Franckboisen2011

This Letter examines the interplay of important tunneling mechanisms-Fermi level pinning, Marcus inverted transport, and orbital gating-in a molecular rectifier. The temperature dependence of the rectifying molecular junction containing 2,2'-bipyridyl terminated n-alkanethiolate was investigated. A bell-shaped trend of activation energy as a function of applied bias evidenced the dominant occurrence of unusual Marcus inverted transport, while retention of rectification at low temperatures implied that the rectification obeyed the resonant tunneling regime. The results allowed reconciling two separately developed transport models, Marcus-Landauer energetics and Fermi level pinning-based rectification. Our work shows that the internal orbital gating can be substituted with the pinning effect, which pushes the transport mechanism into the Marcus inverted regime.ConspectusRedox active organic and polymeric materials have witnessed the rapid development and commercialization of lithium-ion batteries (LIBs) over the last century and the increasing interest in developing various alternatives to LIBs in the past 30 years. As a kind of potential alternative, organic and polymeric materials have the advantages of flexibility, tunable performance through molecular design, potentially high specific capacity, vast natural resources, and recyclability. However, until now, only a handful inorganic materials have been adopted as electrodes in commercialized LIBs. Although the development of carbonyl-based materials revived organic batteries and stimulated plentiful organic materials for batteries in the past 10 years due to their high theoretical capacities and long-term cycleabilities compared with their pioneers (e.g., conducting polymers), organic batteries are still facing many challenges. For example, it is still essential to enhance the theoretical and experimental capacitl performance of organic batteries. Regarding the possible dissolution of active materials, the modification of separators through addition of selectively permeable membranes as ionic sieves is the most efficient and universal strategy to mitigate the shuttling of dissolved molecules but allow smaller sized cations to pass and hence is able to enhance the cyclability. On the basis of these findings, the challenges and several future trends for organic batteries are discussed. This Account provides a summary of our recent progress, understanding of the fundamentals for high performance organic batteries, insight into the intramolecular and intermolecular interactions, and prospects for future development of organic materials for next-generation rechargeable batteries.Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC, and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol for the modeling of a ternary complex induced by a given PROTAC. Our protocol alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol-PRosettaC-to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts. To enable wide access to this protocol, we have made it available through a web server (https//prosettac.weizmann.ac.il/).Binding of N2 by the FeMo-cofactor of nitrogenase is believed to occur after transfer of 4 e- and 4 H+ equivalents to the active site. Although pulse EPR studies indicate the presence of two Fe-(μ-H)-Fe moieties, the structural and electronic features of this mixed valent intermediate remain poorly understood. Toward an improved understanding of this bioorganometallic cluster, we report herein that diiron μ-carbyne complex (P6ArC)Fe2(μ-H) can be oxidized and reduced, allowing for the first time spectral characterization of two EPR-active Fe(μ-C)(μ-H)Fe model complexes linked by a 2 e- transfer which bear some resemblance to a pair of E n and En+2 states of nitrogenase. Both species populate S = 1/2 states at low temperatures, and the influence of valence (de)localization on the spectroscopic signature of the μ-hydride ligand was evaluated by pulse EPR studies. Compared to analogous data for the Fe2(μ-H)2 state of FeMoco (E4(4H)), the data and analysis presented herein suggest that the hydride ligands in E4(4H) bridge isovalent (most probably FeIII) metal centers. Although electron transfer involves metal-localized orbitals, investigations of [(P6ArC)Fe2(μ-H)]+1 and [(P6ArC)Fe2(μ-H)]-1 by pulse EPR revealed that redox chemistry induces significant changes in Fe-C covalency (-50% upon 2 e- reduction), a conclusion further supported by X-ray absorption spectroscopy, 57Fe Mössbauer studies, and DFT calculations. Combined, our studies demonstrate that changes in covalency buffer against the accumulation of excess charge density on the metals by partially redistributing it to the bridging carbon, thereby facilitating multielectron transformations.Coronaviruses (CoVs) are documented in a wide range of animal species, including terrestrial and aquatic, domestic and wild. The geographic distribution of animal CoVs is worldwide and prevalences were reported in several countries across the five continents. The viruses are known to cause mainly gastrointestinal and respiratory diseases with different severity levels. In certain cases, CoV infections are responsible of huge economic losses associated or not to highly public health impact. Despite being enveloped, CoVs are relatively resistant pathogens in the environment. Coronaviruses are characterized by a high mutation and recombination rate, which makes host jumping and cross-species transmission easy. In fact, increasing contact between different animal species fosters cross-species transmission, while agriculture intensification, animal trade and herd management are key drivers at the human-animal interface. If contacts with wild animals are still limited, humans have much more contact with farm animals, during breeding, transport, slaughter and food process, making CoVs a persistent threat to both humans and animals. A global network should be established for the surveillance and monitoring of animal CoVs.Medicare Part D plans make coverage decisions according to FDA-labeled indications and off-label uses endorsed by two CMS-recognized compendia. Patients who rely on Medicare Part D for immunosuppressive drug coverage are at risk for denied coverage when these medications are prescribed off-label. The purpose of this multicenter collaboration was to assemble a case series documenting situations where immunosuppressive therapies prescribed for transplant patients were denied by Medicare Part D prescription drug plans. This case series documents 66 instances in 39 patients where immunosuppressive drug claims were denied coverage due to off-label use not endorsed by the compendia. Patients were recipients of lung (n = 28, 72%), heart (n = 7, 18%), or liver (n = 4, 10%) transplants. Denied claims were for mycophenolate mofetil (n = 22, 33%), azathioprine (n = 18, 27%), sirolimus (n = 15, 23%), mycophenolate sodium (n = 5, 8%), everolimus (n = 5, 8%), and belatacept (n = 1, 1%). Most denials were upheld across all the levels of attempted appeal, including those escalated to a Medicare Administrative Law Judge. This case series demonstrates a critical flaw in the construct of the Medicare Prescription Drug Benefit. The currently referenced compendia are not up to date and do not reflect best practices in organ transplantation.

Immune checkpoint inhibitor therapy has revolutionized lung adenocarcinoma therapy. Treatment with antibodies against the immune checkpoint molecules programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) can induce a durable response in a subset of patients. Immunohistochemistry characterization of tumor PD-L1 expression using either a histopathology specimen or a cytopathology specimen has been shown to correlate with treatment response. However, the current practice relies on pathologists' visual estimation of tumor PD-L1 staining, which can be variable in certain conditions. Highlighting tumor cells via double immunostaining with PD-L1 and thyroid transcription factor-1 (TTF-1) may improve estimation accuracy.

We performed PD-L1 single staining and PD-L1/TTF-1 double staining in 42 pairs of cytopathology and histopathology specimens from lung adenocarcinoma patients. An experienced pathologist visually estimated PD-L1 expression in each case and placed tumor PD-L1 expression into 1 of 3 categistry technique can be applied successfully to cytopathology specimens in better identifying patients who can potentially benefit from immune checkpoint blockade treatment.Protein S-acylation, predominately in the form of palmitoylation, is a reversible lipid post-translational modification on cysteines that plays important roles in protein localization, trafficking, activity, and complex assembly. The functions and regulatory mechanisms of S-acylation have been extensively studied in mammals owing to remarkable development of high-resolution proteomics and the discovery of the S-acylation-related enzymes. However, the advancement of S-acylation studies in plants lags behind that in mammals, mainly due to the lack of knowledge about proteins responsible for this process, such as protein acyltransferases and their substrates. In this article, a set of systematic protocols to study global S-acylation in Arabidopsis seedlings is described. The procedures are presented in detail, including preparation of Arabidopsis seedlings, enrichment of plasma membrane (PM) proteins, ensuing enrichment of S-acylated proteins/peptides based on the acyl-biotin exchange method, and large-scale identification of S-acylated proteins/peptides via mass spectrometry. This approach enables researchers to study S-acylation of PM proteins in plants in a systematic and straightforward way. © 2020 Wiley Periodicals LLC. Basic Protocol 1 Preparation of Arabidopsis seedling materials Basic Protocol 2 Isolation and enrichment of plasma membrane proteins Support Protocol 1 Determination of protein concentration using BCA assay Basic Protocol 3 Enrichment of S-acylated proteins by acyl-biotin exchange method Support Protocol 2 Protein precipitation by methanol/chloroform method Basic Protocol 4 Trypsin digestion and proteomic analysis Alternate Protocol Pre-resin digestion and peptide-level enrichment.