► Substitution of linear carbonates in conventional electrolytes with adiponitrile allows the realization of high flash point electrolytes. ► EC:ADN based electrolytes display a higher anodic ...stability than a conventional electrolyte based on EC:DEC. ► Graphite and NCM electrodes used in combination with the EC:ADN based electrolyte display a performance comparable with that of conventional electrolytes.
The high flash point solvent adiponitrile (ADN) was investigated as co-solvent with ethylene carbonate (EC) for use as lithium-ion battery electrolyte. The flash point of this solvent mixture was more than 110
°C higher than that of conventional electrolyte solutions involving volatile linear carbonate components, such as diethyl carbonate (DEC) or dimethyl carbonate (DMC). The electrolyte based on EC:ADN (1:1
wt) with lithium tetrafluoroborate (LiBF
4) displayed a conductivity of 2.6
mS
cm
−1 and no aluminum corrosion. In addition, it showed higher anodic stability on a Pt electrode than the standard electrolyte 1
M lithium hexafluorophosphate (LiPF
6) in EC:DEC (3:7
wt). Graphite/Li half cells using this electrolyte showed excellent rate capability up to 5
C and good cycling stability (more than 98% capacity retention after 50 cycles at 1
C). Additionally, the electrolyte was investigated in NCM/Li half cells. The cells were able to reach a capacity of 104
mAh
g
−1 at 5
C and capacity retention of more than 97% after 50 cycles. These results show that an electrolyte with a considerably increased flash point with respect to common electrolyte systems comprising linear carbonates, could be realized without any negative effects on the electrochemical performance in Li-half cells.
This work is a comparative study on lithium cycling on copper in solutions based on ethylene carbonate (EC) and diethyl carbonate (DEC) (3:7, by wt.) and two lithium salts, lithium ...hexafluorophosphate (LiPF6) and lithium difluoro(oxalato)borate (LiDFOB). Coulombic efficiencies of the long term lithium deposition/dissolution experiments and dissolution-rate (D-rate) tests on copper demonstrated clearly the superior behavior of the LiDFOB-based electrolyte. To clarify the impact of the formed solid electrolyte interphase (SEI) on the Coulombic efficiencies achieved in the electrolytes, voltage drop values of the D-rate tests were compared with measured values of conductivities and AC impedance measurements of the electrolytes. The formed SEI has a larger influence on voltage drop values of a cell than the conductivity of the electrolyte. The correlation between surface chemistry, morphology, and Coulombic efficiencies of lithium deposition on copper was investigated by scanning electron microscopy (SEM) and Raman spectroscopy. All methods demonstrated the strong influence of the investigated lithium salts on the lithium deposition/dissolution performance on copper substrates. The LiDFOB-based electrolyte showed superior SEI properties than the LiPF6-based electrolyte.
ClpX, a AAA+ ring homohexamer, uses the energy of ATP binding and hydrolysis to power conformational changes that unfold and translocate target proteins into the ClpP peptidase for degradation. In ...multiple crystal structures, some ClpX subunits adopt nucleotide-loadable conformations, others adopt unloadable conformations, and each conformational class exhibits substantial variability. Using mutagenesis of individual subunits in covalently tethered hexamers together with fluorescence methods to assay the conformations and nucleotide-binding properties of these subunits, we demonstrate that dynamic interconversion between loadable and unloadable conformations is required to couple ATP hydrolysis by ClpX to mechanical work. ATP binding to different classes of subunits initially drives staged allosteric changes, which set the conformation of the ring to allow hydrolysis and linked mechanical steps. Subunit switching between loadable and unloadable conformations subsequently isomerizes or resets the configuration of the nucleotide-loaded ring and is required for mechanical function.
Display omitted
•Structures show nucleotide-loadable and unloadable subunits of AAA+ ClpX ATPase•Assays detects subunit-specific ATP binding and conformational changes•ATP binding drives staged allosteric changes in the ClpX ring•Work requires dynamic interconversion between loadable and unloadable conformations
A new assay for AAA+ machines reveals that subunits of the ClpX homohexamer convert between ATP-loadable and unloadable during the functional cycle of ClpX and that ATP binding initiates stepwise allosteric changes in the ClpX ring.
The geographic and temporal origins of the domestic dog remain controversial, as genetic data suggest a domestication process in East Asia beginning 15,000 years ago, whereas the oldest doglike ...fossils are found in Europe and Siberia and date to >30,000 years ago. We analyzed the mitochondrial genomes of 18 prehistoric canids from Eurasia and the New World, along with a comprehensive panel of modern dogs and wolves. The mitochondrial genomes of all modern dogs are phylogenetically most closely related to either ancient or modern canids of Europe. Molecular dating suggests an onset of domestication there 18,800 to 32,100 years ago. These findings imply that domestic dogs are the culmination of a process that initiated with European hunter-gatherers and the canids with whom they interacted.
The epidermal growth factor receptor (EGFR) is implicated in human cancers and is the target of several classes of therapeutic agents, including antibody-based drugs. Here, we describe X-ray crystal ...structures of the extracellular region of EGFR in complex with three inhibitory nanobodies, the variable domains of heavy chain only antibodies (VHH). VHH domains, the smallest natural antigen-binding modules, are readily engineered for diagnostic and therapeutic applications. All three VHH domains prevent ligand-induced EGFR activation, but use two distinct mechanisms. 7D12 sterically blocks ligand binding to EGFR in a manner similar to that of cetuximab. EgA1 and 9G8 bind an epitope near the EGFR domain II/III junction, preventing receptor conformational changes required for high-affinity ligand binding and dimerization. This epitope is accessible to the convex VHH paratope but inaccessible to the flatter paratope of monoclonal antibodies. Appreciating the modes of binding and inhibition of these VHH domains will aid in developing them for tumor imaging and/or cancer therapy.
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•Structures of three nanobodies/VHH domains bound to EGFR extracellular region•Two distinct modes of VHH binding indicate two different mechanisms of inhibition•One mimics the Erbitux/cetuximab mechanism, with a smaller antigen-binding module•The other exploits the convex VHH paratope to reach a key conformational epitope
Nanobodies/VHH domains are the smallest natural antigen-binding modules and important tools for diagnostic and therapeutic applications. Schmitz et al. describe molecular mechanisms of EGFR inhibition by three nanobodies, and compare their binding modes to those of the mAb drugs such as cetuximab.
Impfstatus von Erwachsenen in Deutschland Poethko-Müller, C.; Schmitz, R.
Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz,
05/2013, Letnik:
56, Številka:
5-6
Journal Article
Recenzirano
Zusammenfassung
In Deutschland werden Impfquoten nicht über ein Impfregister erfasst. Die bevölkerungsrepräsentative Studie zur Gesundheit Erwachsener in Deutschland (DEGS1) ist ein Baustein für das ...Monitoring der Durchimpfung. Zur Erhebung der Impfdaten wurden Impfpässe und Befragungsdaten genutzt. Der Tetanus- und Diphtherie-Impfstatus Erwachsener ist besser als vor 10 Jahren im „Bundes-Gesundheitssurvey 1998“, dennoch haben immer noch 28,6 % der Bevölkerung in den letzten 10 Jahren keine Tetanusimpfung und 42,9 % keine Diphtherieimpfung erhalten. Insbesondere bei Älteren, bei Erwachsenen mit niedrigem sozioökonomischem Status und in Westdeutschland bestehen Impflücken. Nur 11,8 % der Frauen und 9,4 % der Männer in Westdeutschland haben innerhalb der letzten 10 Jahre eine Impfung gegen Pertussis erhalten; die Durchimpfung ist in Ostdeutschland doppelt so hoch. Die seit 2009 bestehende Empfehlung, mit der nächstanstehenden Tetanusimpfung gleichzeitig gegen Pertussis zu impfen, lässt jedoch einen Anstieg der Durchimpfung erwarten. Im Vergleich zu den jährlichen Impfraten gegen Influenza ist der Anteil jemals gegen Influenza geimpfter Erwachsener höher. Allerdings liegt bei Frauen und Männern im Alter über 60 Jahren selbst die Lebenszeitprävalenz deutlich unter der von der Weltgesundheitsorganisation (WHO) empfohlenen jährlichen Impfrate von 75 %.
All clades of bacteria possess Hsp100/Clp family unfoldase enzymes that contribute to aspects of protein quality control. In Actinomycetota, these include ClpB, which functions as an independent ...chaperone and disaggregase, and ClpC, which cooperates with the ClpP1P2 peptidase to carry out regulated proteolysis of client proteins. We initially sought to algorithmically catalog Clp unfoldase orthologs from Actinomycetota into ClpB and ClpC categories. In the process, we uncovered a phylogenetically distinct third group of double-ringed Clp enzymes, which we term ClpI. ClpI enzymes are architecturally similar to ClpB and ClpC, with intact ATPase modules and motifs associated with substrate unfolding and translation. While ClpI possess an M-domain similar in length to that of ClpC, its N-terminal domain is more variable than the strongly conserved N-terminal domain of ClpC. Surprisingly, ClpI sequences are divisible into sub-classes that either possess or lack the LGF-motifs required for stable assembly with ClpP1P2, suggesting distinct cellular roles. The presence of ClpI enzymes likely provides bacteria with expanded complexity and regulatory control over protein quality control programs, supplementing the conserved roles of ClpB and ClpC.
Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important ...implications for activation and inhibition of these receptors. Here we describe the 2.8 Å resolution X-ray crystal structure of the antigen binding (Fab) fragment from cetuximab (Erbitux), an inhibitory anti-EGFR antibody, in complex with the soluble extracellular region of EGFR (sEGFR). The sEGFR is in the characteristic “autoinhibited” or “tethered” inactive configuration. Cetuximab interacts exclusively with domain III of sEGFR, partially occluding the ligand binding region on this domain and sterically preventing the receptor from adopting the extended conformation required for dimerization. We suggest that both these effects contribute to potent inhibition of EGFR activation.
In the absence of an immunisation register, vaccination coverage in Germany must be estimated. Ten years after the German National Health Interview and Examination Survey 1998 (GNHIES98), the ...population survey DEGS1 is one of the data sources to be used for monitoring vaccination coverage. In the survey, data on vaccination history were obtained from vaccination cards and self-reports. The prevalence of immunisation for tetanus and diphtheria was higher compared to the prevalence estimated ten years previously in GNHIES98. Nonetheless, 28.6 % of adults have not been vaccinated against tetanus and 42.9 % have not been vaccinated against diphtheria within the last ten years. Vaccination is especially low among the elderly, among adults with low socio-economic status and in western Germany. During the last ten years, only 11.8 % of women and 9.4 % of men were vaccinated against pertussis in western Germany; vaccination coverage was twice as high in eastern Germany. In 2009, recommendations were published to combine the next tetanus immunisation with a pertussis immunisation; therefore pertussis vaccination coverage might improve in the coming years. The lifetime prevalence of influenza vaccination obtained in DEGS1 is higher than the annual vaccination rate for influenza. However, the lifetime prevalence among adults aged 60 years or older is still below the annual rate of 75 % recommended by the WHO. An English full-text version of this article is available at SpringerLink as supplemental.
ClpXP and other AAA+ proteases recognize, mechanically unfold, and translocate target proteins into a chamber for proteolysis. It is not known whether these remarkable molecular machines operate by a ...stochastic or sequential mechanism or how power strokes relate to the ATP-hydrolysis cycle. Single-molecule optical trapping allows ClpXP unfolding to be directly visualized and reveals translocation steps of ∼1–4 nm in length, but how these activities relate to solution degradation and the physical properties of substrate proteins remains unclear. By studying single-molecule degradation using different multidomain substrates and ClpXP variants, we answer many of these questions and provide evidence for stochastic unfolding and translocation. We also present a mechanochemical model that accounts for single-molecule, biochemical, and structural results for our observation of enzymatic memory in translocation stepping, for the kinetics of translocation steps of different sizes, and for probabilistic but highly coordinated subunit activity within the ClpX ring.
Display omitted
•ClpXP takes physical translocation steps of 1–4 nm in a stochastic pattern•The stability of degron-proximal structure determines substrate unfolding rates•One ATP-hydrolysis event can drive more than one power stroke•Commitment to unfolding is the slow step in solution degradation
An optical trapping tool, which allows visualization of single-molecule degradation, reveals that ClpXP proteolytic machine operates by a stochastic rather than sequential mechanism. Depending upon which ATP-bound subunit in the hexameric ClpX ring hydrolyzes ATP first, kinetic bursts of 1–4 power strokes drive translocation steps of different sizes, requiring highly coordinated mechanisms of subunit-subunit communication.
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