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Role of Hsp70 in Post-Translational Protein Targeting: Tail-Anchored Membrane Proteins and Beyond
No full textThe Hsp70 family of molecular chaperones acts as a central 'hub' in the cell that interacts with numerous newly synthesized proteins to assist in their biogenesis. Apart from its central and well-established role in facilitating protein folding, Hsp70s also act as key decision points in the cellular chaperone network that direct client proteins to distinct biogenesis and quality control pathways. In this paper, we review accumulating data that illustrate a new branch in the Hsp70 network: the post-translational targeting of nascent membrane and organellar proteins to diverse cellular organelles. Work in multiple pathways suggests that Hsp70, via its ability to interact with components of protein targeting and translocation machineries, can initiate elaborate substrate relays in a sophisticated cascade of chaperones, cochaperones, and receptor proteins, and thus provide a mechanism to safeguard and deliver nascent membrane proteins to the correct cellular membrane. We discuss the mechanistic principles gleaned from better-studied Hsp70-dependent targeting pathways and outline the observations and outstanding questions in less well-studied systems
Urine cell-free DNA multi-omics to detect MRD and predict survival in bladder cancer patients
No full textCirculating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integrated ultra-low-pass whole genome sequencing (ULP-WGS) with urine cancer personalized profiling by deep sequencing (uCAPP-Seq) to achieve sensitive MRD detection and predict overall survival. Variant allele frequency, inferred tumor mutational burden, and copy number-derived tumor fraction levels in urine cell-free DNA (cfDNA) significantly predicted pathologic complete response status, far better than plasma ctDNA was able to. A random forest model incorporating these urine cfDNA-derived factors with leave-one-out cross-validation was 87% sensitive for predicting residual disease in reference to gold-standard surgical pathology. Both progression-free survival (HR = 3.00, p = 0.01) and overall survival (HR = 4.81, p = 0.009) were dramatically worse by Kaplan–Meier analysis for patients predicted by the model to have MRD, which was corroborated by Cox regression analysis. Additional survival analyses performed on muscle-invasive, neoadjuvant chemotherapy, and held-out validation subgroups corroborated these findings. In summary, we profiled urine samples from 74 patients with localized bladder cancer and used urine cfDNA multi-omics to detect MRD sensitively and predict survival accurately
Toward Improving the Selectivity of Organic Halide Electrocarboxylation with Mechanistically Informed Solvent Selection
No full textThe use of a liquid electrolyte is nearly ubiquitous in electrosynthetic systems and can have a significant impact on the selectivity and efficiency of electrochemical reactions. Solvent selection is thus a key step during optimization, yet this selection process usually involves trial-and-error. As a step toward more rational solvent selection, this work examines how the electrolyte solvent impacts the selectivity of electrocarboxylation of organic halides. For the carboxylation of a model alkyl bromide, hydrogenolysis is the primary side reaction. Isotope-labeling studies indicate the hydrogen atom in the hydrogenolysis product comes solely from the aprotic electrolyte solvent. Further mechanistic studies reveal that under synthetically relevant electrocarboxylation conditions, the hydrogenolysis product is formed via deprotonation of the solvent. Guided by these mechanistic findings, a simple computational descriptor based on the free energy to deprotonate a solvent molecule was shown to correlate strongly with carboxylation selectivity, overcoming limitations of traditional solvent descriptors such as pKₐ. Through careful mechanistic analysis surrounding the role of the solvent, this work furthers the development of selective electrocarboxylation systems and more broadly highlights the benefits of such analysis to electrosynthetic reactions
Electrocatalytic Nitrogen Reduction on a Molybdenum Complex Bearing a PNP Pincer Ligand
No full textElectrocatalytic nitrogen reduction (N2R) mediated by well-defined molecular catalysts is poorly developed by comparison with other reductive electrocatalytic transformations. Herein, we explore the viability of electrocatalytic N₂R mediated by a molecular Mo-PNP complex. A careful choice of acid, electrode material, and electrolyte mitigates electrode-mediated HER under direct electrolysis and affords up to 11.7 equiv of NH₃ (Faradaic efficiency < 43%) at −1.89 V versus Fc⁺/Fc. The addition of a proton-coupled electron transfer (PCET) mediator has no effect. The data presented are rationalized by an initial electron transfer (ET) that sets the applied bias needed and further reveal an important impact of [Mo] concentration, thereby pointing to potential bimolecular steps (e.g., N₂ splitting) as previously proposed during chemically driven N₂R catalysis. Finally, facile reductive protonation of [Mo(N)Br(ᴴPNP)] with pyridinium acids is demonstrated
Evidence of excited-state lifetime enhancement in dimyristoyl-phosphocholine nanodiscs by ultraviolet absorption spectroscopy
No full textUltraviolet absorption spectroscopy is an analytical tool that is commonly utilized to determine protein concentrations, primarily due to characteristic absorption of tryptophan and tyrosine at 280 nm. Accurate concentration determination is essential to the accuracy of many biophysical techniques, and ultraviolet absorption provides a convenient and rapid method to assess protein concentration. However, the widespread usage of this method assumes that ultraviolet absorption is the same for individual amino acids in aqueous solution (where the molar extinction coefficient was measured) as for the amino acid in the conformational environment of the protein of interest. We demonstrate that additional considerations may be necessary for the membrane scaffold protein in dimyristoyl-phosphocholine nanodiscs through ultraviolet absorption spectroscopy of nanodiscs, liposomes, the membrane scaffold protein, and a mixture of liposomes and the non-nanodisc-associated protein. The aromatic amino acids of the membrane scaffold protein absorb significantly less light at 280 nm when associated with lipids in a lipoprotein assembly, which we plausibly attribute to an enhancement of chromophore excited-state lifetimes due to reduced intramolecular motion in the nanodisc. We caution that using the molar absorptivity of the membrane scaffold protein alone to determine nanodisc concentrations may not yield accurate results. Instead, the molar absorptivity of each nanodisc formulation should be explored independently to account for the unique conformational environment of each nanodisc
Confined active matter in external fields
No full textWe analyze a dilute suspension of active particles confined between walls and subjected to fields that can modulate particle speed as well as orientation. Generally, the particle distribution is different in the bulk compared to near the walls. In the bulk, particles tend to accumulate in the regions of low speed, but in the presence of an orienting field normal to the walls, particles rotate to align with the field and accumulate in the field direction. At the walls, particles tend to accumulate pointing into the walls and thereby exert pressure on walls. But the presence of strong orienting fields can cause the particles to reorient away from the walls, and hence shows a possible mechanism for preventing contamination of surfaces. The pressure at the walls depends on the wall separation and the field strengths. This work demonstrates how multiple fields with different functionalities can be used to control active matter under confinement
Theoretical assessment of the ability of the MicroCarb satellite city-scan observing mode to estimate urban CO₂ emissions
No full textWe assess the theoretical capability of the upcoming France–UK MicroCarb satellite, which has a city-scan observing mode, to determine integrated urban emissions of carbon dioxide (CO₂). To achieve this we report results from a series of closed-loop numerical experiments that use an atmospheric transport model with anthropogenic and biogenic fluxes to determine the corresponding changes in atmospheric CO₂ column, accounting for changes in measurement coverage due to cloud loading. We use a maximum a posteriori inverse method to infer the CO₂ fluxes based on the measurements and the a priori information. Using an urban CO₂ inversion system, we explore the relative performance of alternative two-sweep and three-sweep city observing strategies to quantify CO₂ emissions over the cities of Paris and London in different months when biospheric fluxes vary in magnitude. We find that both the two-sweep and three-sweep observing modes are able to reduce a priori flux errors by 20 %–40 % over Paris and London. The three-sweep observing strategy, which generally outperforms the two-sweep mode by virtue of its wider scan area that typically yields more cloud-free observations, can retrieve the total emissions of the truth within 7 % over Paris and 21 % over London. The performance of the limited-domain city-mode observing strategies is sensitive to cloud coverage and particularly sensitive to the prevailing wind direction. We also find that seasonal photosynthetic uptake of CO₂ by the urban biosphere weakens atmospheric CO₂ gradients across both cities, thereby reducing the sensitivity of urban CO₂ enhancements and subsequently compromising the ability of MicroCarb to reduce bias in estimating urban CO₂ emissions. This suggests that additional trace gases co-emitted with anthropogenic CO₂ emissions, but unaffected by the land biosphere, are needed to quantify sub-city scale CO₂ emissions during months when the urban biosphere is particularly active
Numerical-relativity surrogate modeling with nearly extremal black-hole spins
No full textNumerical relativity (NR) simulations of binary black hole (BBH) systems provide the most accurate gravitational wave predictions, but at a high computational cost—especially when the black holes have nearly extremal spins (i.e. spins near the theoretical upper limit) or very unequal masses. Recently, the technique of reduced order modeling has enabled the construction of ‘surrogate models’ trained on an existing set of NR waveforms. Surrogate models enable the rapid computation of the gravitational waves emitted by BBHs. Typically these models are used for interpolation to compute gravitational waveforms for BBHs with mass ratios and spins within the bounds of the training set. Because simulations with nearly extremal spins are so technically challenging, surrogate models almost always rely on training sets with only moderate spins. In this paper, we explore how well surrogate models can extrapolate to nearly extremal spins when the training set only includes moderate spins. For simplicity, we focus on one-dimensional surrogate models trained on NR simulations of BBHs with equal masses and equal, aligned spins. We assess the performance of the surrogate models at higher spin magnitudes by calculating the mismatches between extrapolated surrogate model waveforms and NR waveforms, by calculating the differences between extrapolated and NR measurements of the remnant black-hole mass, and by testing how the surrogate model improves as the training set extends to higher spins. We find that while extrapolation in this one-dimensional case is viable for current detector sensitivities, surrogate models for next-generation detectors should use training sets that extend to nearly extremal spins
Redder than Red: Discovery of an Exceptionally Red L/T Transition Dwarf
No full textWe present the discovery of CWISE J050626.96+073842.4 (CWISE J0506+0738), an L/T transition dwarf with extremely red near-infrared colors discovered through the Backyard Worlds: Planet 9 citizen science project. Photometry from UKIRT and CatWISE give a (J − K)_(MKO) color of 2.97 ± 0.03 mag and a J_(MKO) − W2 color of 4.93 ± 0.02 mag, making CWISE J0506+0738 the reddest known free-floating L/T dwarf in both colors. We confirm the extremely red nature of CWISE J0506+0738 using Keck/NIRES near-infrared spectroscopy and establish that it is a low-gravity, late-type L/T transition dwarf. The spectrum of CWISE J0506+0738 shows possible signatures of CH₄ absorption in its atmosphere, suggesting a colder effective temperature than other known, young, red L dwarfs. We assign a preliminary spectral type for this source of L8γ–T0γ. We tentatively find that CWISE J0506+0738 is variable at 3–5 μm based on multiepoch WISE photometry. Proper motions derived from follow-up UKIRT observations combined with a radial velocity from our Keck/NIRES spectrum and a photometric distance estimate indicate a strong membership probability in the β Pic moving group. A future parallax measurement will help to establish a more definitive moving group membership for this unusual object
Measuring Photoexcited Electron and Hole Dynamics in ZnTe and Modeling Excited State Core-Valence Effects in Transient Extreme Ultraviolet Reflection Spectroscopy
No full textTransient extreme ultraviolet (XUV) spectroscopy is becoming a valuable tool for characterizing solar energy materials because it can separate photoexcited electron and hole dynamics with element specificity. Here, we use surface-sensitive femtosecond XUV reflection spectroscopy to separately measure photoexcited electron, hole, and band gap dynamics of ZnTe, a promising photocathode for CO₂ reduction. We develop an ab initio theoretical framework based on density functional theory and the Bethe–Salpeter equation to robustly assign the complex transient XUV spectra to the material’s electronic states. Applying this framework, we identify the relaxation pathways and quantify their time scales in photoexcited ZnTe, including subpicosecond hot electron and hole thermalization, surface carrier diffusion, ultrafast band gap renormalization, and evidence of acoustic phonon oscillations