Batemanwhitfield7401

These results illustrate additional design principles for electrosynthesis without sacrificial auxiliary reactions and the need for ion-selective RRs for modular electrochemical manufacturing.Novel methods for producing ammonia, a large-scale industrial chemical, are necessary for reducing the environmental impact of its production. Lithium-mediated electrochemical nitrogen reduction is one attractive alternative method for producing ammonia. In this work, we experimentally tested several classes of proton donors for activity in the lithium-mediated approach. From these data, an interpretable data-driven classification model is constructed to distinguish between active and inactive proton donors; solvatochromic Kamlet-Taft parameters emerged to be the key descriptors for predicting nitrogen reduction activity. A deep learning model is trained to predict these parameters using experimental data from the literature. The combination of the classification and deep learning models provides a predictive mapping from proton donor structure to activity for nitrogen reduction. We demonstrate that the two-model approach is superior to a purely mechanistic or a data-driven approach in accuracy and experimental data efficiency.Peptide-brush polymers (PBPs), wherein every side-chain of the polymers is peptidic, represent a new class of proteomimetic with unusually high proteolytic resistance while maintaining bioactivity. Here, we sought to determine the origin of this behavior and to assess its generality via a combined theory and experimental approach. A series of PBPs with various polymer backbone structures were prepared and examined for their proteolytic stability and bioactivity. We discovered that an increase in the hydrophobicity of the polymer backbones is predictive of an elevation in proteolytic stability of the side-chain peptides. Computer simulations, together with small-angle X-ray scattering (SAXS) analysis, revealed globular morphologies for these polymers, in which pendant peptides condense around hydrophobic synthetic polymer backbones driven by the hydrophobic effect. As the hydrophobicity of the polymer backbones increases, the extent of solvent exposure of peptide cleavage sites decreases, reducing their accessibility to proteolytic enzymes. This study provides insight into the important factors driving PBP aqueous-phase structures to behave as globular, synthetic polymer-based proteomimetics.Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that NFE2L2 was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system (HMME@Lip-Cas9) was meticulously designed and constructed, which precisely knocks down NFE2L2 to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.We herein report a series of high-brightness pH-activatable near-infrared (NIR) BODIPY probes for high-contrast intravital imaging of deep-seated early breast cancer bone metastasis by harnessing the axial substituent effect. These probes exhibit tunable pK a, higher brightness, and antiquenching capabilities in aqueous solution, which can be simultaneously adjusted by axial steric substituents. The optimized probe BODO-3 bearing axial dimethyl substituents exhibited a higher pK a value of 5.6 and a brighter NIR fluorescence under tumor acidic pH, showing 10.3-fold and 6.5-fold enhanced brightness (εΦ) at pH 5.5 and 6.5, respectively. Due to the higher brightness, BODO-3 with a brilliant NIR emission at 700 nm allows for deep optical penetrations of 5 and 8 mm at pH 6.5 and 4.5, respectively. Meanwhile, covalent functionalization with glucose (BODO-3-Glu) could further enhance breast cancer and its soft tissue metastasis imaging in vivo. Notably, covalent functionalization with bisphosphonate (BODO-3-PO 3 H 2 ) allowed the successful targeting and visualization of deep-seated bone metastases of breast cancer with a high tumor to normal contrast of 8/1, outperforming X-rays in early detection. This strategy may provide insights for designing high-brightness activatable NIR probes for detecting deep-seated tumors and metastases.Extreme fast charging (XFC), with a recharging time of 15 min, is the key to the mainstream adoption of battery electric vehicles. Lithium metal, in the meantime, has re-emerged as the ultimate anode because of its ultrahigh specific capacity and low electrochemical potential. However, the low lithium-ion concentration near the lithium electrode surface can result in uncontrolled dendrite growth aggravated by high plating current densities. Here, we reveal the beneficial effects of an adaptively enhanced internal electric field in a constant voltage charging mode in XFC via a molecular understanding of the electrolyte-electrode interfaces. With the same charging time and capacity, the increased electric field stress in dozens of millivolts, compared with that in a constant current mode, can facilitate Li+ migrating toward the negatively charged lithium electrode, mitigating Li+ depletion at the interface and thereby suppressing dendrites. In addition, more NO3 - ions are involved in the solvation sheath that is constructed on the lithium electrode surface, leading to the nitride-enriched solid electrolyte interphase and thus favoring lower barriers for Li+ transport. On the basis of these merits, the Li||Li4Ti5O12 battery runs steadily for 550 cycles with charging current peaks up to 27 mA cm-2, and the Li||S full cells exhibit extended life-spans charged within 12 min.The serine/threonine protein kinase Akt regulates a wide range of cellular functions via phosphorylation of various substrates distributed throughout the cell, including at the plasma membrane and endomembrane compartments. Disruption of compartmentalized Akt signaling underlies the pathology of many diseases such as cancer and diabetes. However, the specific spatial organization of Akt activity and the underlying regulatory mechanisms, particularly the mechanism controlling its activity at the lysosome, are not clearly understood. We developed a highly sensitive excitation-ratiometric Akt activity reporter (ExRai-AktAR2), enabling the capture of minute changes in Akt activity dynamics at subcellular compartments. In conjunction with super-resolution expansion microscopy, we found that growth factor stimulation leads to increased colocalization of Akt with lysosomes and accumulation of lysosomal Akt activity. We further showed that 3-phosphoinositides (3-PIs) accumulate on the lysosomal surface, in a manner dependent on dynamin-mediated endocytosis. Importantly, lysosomal 3-PIs are needed for growth-factor-induced activities of Akt and mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface, as targeted depletion of 3-PIs has detrimental effects. Thus, 3-PIs, a class of critical lipid second messengers that are typically found in the plasma membrane, unexpectedly accumulate on the lysosomal membrane in response to growth factor stimulation, to direct the multifaceted kinase Akt to organize lysosome-specific signaling.The interplay of enzyme active site electrostatics and chemical positioning is important for understanding the origin(s) of enzyme catalysis and the design of novel catalysts. We reconstruct the evolutionary trajectory of TEM-1 β-lactamase to TEM-52 toward extended-spectrum activity to better understand the emergence of antibiotic resistance and to provide insights into the structure-function paradigm and noncovalent interactions involved in catalysis. Utilizing a detailed kinetic analysis and the vibrational Stark effect, we quantify the changes in rates and electric fields in the Michaelis and acyl-enzyme complexes for penicillin G and cefotaxime to ascertain the evolutionary role of electric fields to modulate function. These data are combined with MD simulations to interpret and quantify the substrate-dependent structural changes during evolution. We observe that this evolutionary trajectory utilizes a large preorganized electric field and substrate-dependent chemical positioning to facilitate catalysis. this website This governs the evolvability, substrate promiscuity, and protein fitness landscape in TEM β-lactamase antibiotic resistance.Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.Molnupiravir (MK-4482) is an investigational antiviral agent that is under development for the treatment of COVID-19. Given the potential high demand and urgency for this compound, it was critical to develop a short and sustainable synthesis from simple raw materials that would minimize the time needed to manufacture and supply molnupiravir. The route reported here is enabled through the invention of a novel biocatalytic cascade featuring an engineered ribosyl-1-kinase and uridine phosphorylase. These engineered enzymes were deployed with a pyruvate-oxidase-enabled phosphate recycling strategy. Compared to the initial route, this synthesis of molnupiravir is 70% shorter and approximately 7-fold higher yielding. Looking forward, the biocatalytic approach to molnupiravir outlined here is anticipated to have broad applications for streamlining the synthesis of nucleosides in general.