Gilesnilsson8668

In agreement with this hypothesis, DLPS but not DOPS strongly stimulated α-synuclein aggregation. Our results provide new insights into the critical contribution of bilayer stability in the membrane response to α-synuclein adsorption and in stimulation of aggregation.The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.β-N-Oxalyl-l-α,β-diaminopropionic acid (β-ODAP), found in Lathyrus sativus at first, causes a neurological disease, lathyrism, when over ingested in an unbalanced diet. Our previous research suggested that β-ODAP biosynthesis is related to sulfur metabolism. In this study, β-cyanoalanine synthase (β-CAS) was confirmed to be responsible for β-ODAP biosynthesis via in vitro enzymatic analysis. LsCAS was found to be pyridoxal phosphate (PLP)-dependent via spectroscopic analysis and dual functional via enzymatic activity analysis. Generation of a M135T/M235S/S239T triple mutant of LsCAS, which are the key sites to control the ratio of CAS/cysteine synthase (CS) activity, switches reaction chemistry to that of a CS. LsCAS interactions were further screened and verified via Y2H, BiFC and pull-down assay. It was suggested that LsSAT2 interacts and forms a cysteine regulatory complex (CRC) with LsCAS in mitochondria, which improves LsSAT while reduces LsCAS activities to affect β-ODAP content positively. These results provide new insights into the molecular regulation of β-ODAP content in L. sativus.The development of high-efficiency oxygen electrocatalysts with earth-abundant transition metals rather than scarce noble metals has aroused growing interests due to their potential for energy storage and conversion applications. Herein, we developed a facile strategy to synthesize hollow tubular bimetallic Ni-Co oxide rooted with dense nanosheets for enhanced bifunctionality and facilitated redox reaction kinetics. Owing to the rational design of morphology and well-dispersed Ni and Co ions, the bimetallic samples exhibit admirable bifunctional electrocatalytic activities. This bimetallic Ni-Co oxide shows superior oxygen electrocatalytic performance in comparison with the monometallic Ni and Co oxides, according to the electrocatalytic synergistic effect from the bimetallic system. The optimized sample with the specific mass ratio of Ni and Co displays the oxygen reduction reaction (ORR) property comparable to commercial Pt/C and oxygen evolution reaction (OER) performance superior to commercial RuO2. The electrochemical tests and structural characterizations offer in-depth dissection on the electrocatalytic behaviors, especially the superb stability in both ORR and OER tests, as well as the outstanding resistance to methanol poisoning, representing a promising candidate in the renewable energy field.The ligand/quantum dots (QDs) ratio is crucial for the liquid state ligand exchange process to ensure a high-quality surface passivation and stable QDs ink. Herein we report an electrochemical method to investigate the ligand exchanged PbS-PbI2 QDs. It is found that the shell and core Pb(II) are distinguished by their reduction peak position in the cyclic voltammogram and the peak charge ratio gives the shell/core composition of the QDs. Combined with XPS analysis and UV-vis spectroscopy, it is further indicated that the shell/core ratio of PbS-PbI2 QDs varies as the ligand PbI2 concentration changes. Specifically, below a certain concentration, more PbI2 binds to the QD surface, leading to better passivation when the PbI2 concentration increases; however, beyond that concentration, decomposition of QDs likely occurs via an anion exchange process. The presented electrochemical method provides a new and powerful tool to investigate and optimize QD surface chemistry for boosting the scale up applications of QD devices.The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.Photoacoustic (PA) probes absorbing in the second near-infrared (NIR-II 1000-1700 nm) window hold great promise for deep-tissue diagnosis and treatment. Currently, NIR-II PA probes typically involve complex synthesis and surfactant adjuvant for processing and delivery. Furthermore, these NIR-II PA probes are "always-on," leading to inadequate signal-to-background ratio and low specificity. To address these challenges, this study reports a pH-activatable and aggregation-enhanced NIR-II PA probe. Without using any toxic or exotic oxidants, the selected polymer (PPE) is readily doped by oxygen in an ambient environment and simultaneously red-shifts its absorption profile from visible to NIR-II region. By virtue of the carboxyl groups on the side chains, oxygen-doped PPE is readily water-soluble at a physiological pH but tends to aggregate in an acidic environment. The pH-induced aggregation results in a significant PA enhancement and thus allows specific PA imaging of acidic tumor microenvironment in vivo. Our study provides a facile and surfactant-free strategy for achieving water-soluble and pH-responsive NIR-II PA probes, which could be applied for diagnoses of cancer and other diseases associated with changes in pH. It paves the way for the development of new activatable NIR-II imaging probes and also could facilitate the investigation of biological and pathological processes in deep tissue.We explore the convergence of the many-body expansion for a prototypical hole-transfer reaction between Zn(0) and Zn(I) in a condensed-phase environment. Poor convergence of state energies is seen when the adiabatic representation is used, which can be understood from the fragment single-point calculations at low orders of the many-body expansion incorrectly localizing charges compared to the full system, thus leading to qualitative errors in the electronic structure of the adiabatic states between fragments. Using a charge-localized representation of the electronic Hamiltonian, we introduce a diabatic many-body expansion method with quantitative accuracy for ground- and excited-state potential energy surfaces of a charge-transfer reaction. Combining with a multiconfigurational self-consistent field affords a fragmentation approach that scales quadratically with system size while retaining chemical accuracy ( less then 1 kcal/mol) in total energies compared to full system calculations.We identified a set of thiosemicarbazone (TSC) metal ion chelators that reactivate specific zinc-deficient p53 mutants using a mechanism called zinc metallochaperones (ZMCs) that restore zinc binding by shuttling zinc into cells. We defined biophysical and cellular assays necessary for structure-activity relationship studies using this mechanism. We investigated an alternative class of zinc scaffolds that differ from TSCs by substitution of the thiocarbamoyl moiety with benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones. Members of this series bound zinc with similar affinity and functioned to reactivate mutant p53 comparable to the TSCs. Acute toxicity and efficacy assays in rodents demonstrated C1 to be significantly less toxic than the TSCs while demonstrating equivalent growth inhibition. We identified C85 as a ZMC with diminished copper binding that functions as a chemotherapy and radiation sensitizer. We conclude that the benzothiazolyl, benzoxazolyl, and benzimidazolyl hydrazones can function as ZMCs to reactivate mutant p53 in vitro and in vivo.Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Aprotinin Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.Antibiotic resistance is one of the greatest challenges of our time. This global health problem originated from a paucity of truly effective antibiotic classes and an increased incidence of multi-drug-resistant bacterial isolates in hospitals worldwide. Indeed, it has been recently estimated that 10 million people will die annually from drug-resistant infections by the year 2050. Therefore, the need to develop out-of-the-box strategies to combat antibiotic resistance is urgent. The biological world has provided natural templates, called antimicrobial peptides (AMPs), which exhibit multiple intrinsic medical properties including the targeting of bacteria. AMPs can be used as scaffolds and, via engineering, can be reconfigured for optimized potency and targetability toward drug-resistant pathogens. Here, we review the recent development of tools for the discovery, design, and production of AMPs and propose that the future of peptide drug discovery will involve the convergence of computational and synthetic biology principles.