Pearsonibsen3944

Liquid-liquid phase separation (LLPS) of proteins into biomolecular condensates has emerged as a fundamental principle underpinning cellular function and malfunction. Indeed, many human pathologies, including protein misfolding diseases, are linked to aberrant liquid-to-solid phase transitions, and disease-associated protein aggregates often nucleate through phase separation. The molecular level determinants that promote pathological phase transitions remain, however, poorly understood. Here we study LLPS of the microtubule-associated protein Tau, whose aberrant aggregation is associated with a number of neurodegenerative diseases, including Alzheimer's disease. Using single molecule spectroscopy, we probe directly the conformational changes that the protein undergoes as a result of LLPS. We perform single-molecule FRET and fluorescence correlation spectroscopy experiments to monitor the intra- and intermolecular changes and demonstrate that the N- and C-terminal regions of Tau become extended, thus exposing the microtubule-binding region. These changes facilitate intermolecular interactions and allow for the formation of nanoscale clusters of Tau. Our results suggest that these clusters can promote the fibrillization of Tau, which can be dramatically accelerated by disease-related mutations P301L and P301S. Our findings thus provide important molecular insights into the mechanism of protein phase separation and the conversion of protein condensates from functional liquid assemblies to pathological aggregates.A novel insecticide flupyrimin (FLP) with a trifluoroacetyl pharmacophore acts as an antagonist at the insect nicotinic acetylcholine receptor (nAChR). This investigation examines a hypothesis that the FLP C(O)CF3 moiety is primarily recognized by the β subunit-face in the ligand-binding pocket (interface between α and β subunits) of the insect nAChR. Accordingly, we evaluate the atomic interaction between a fluorine atom of FLP and the partnering amino acid side chain on the β subunit employing a recombinant hybrid nAChR consisting of aphid Mpα2 and rat Rβ2 subunits (with a mutation at T77 on the Rβ2). The H-donating T77R, T77K, T77N, or T77Q nAChR enhances the FLP binding potency relative to that of the wild-type receptor, whereas the affinity of neonicotinoid imidaclprid (IMI) with a nitroguanidine pharmacophore remains unchanged. These results facilitate the establishment of the unique FLP molecular recognition at the Mpα2/Mpβ1 interface structural model, thereby underscoring a distinction in its binding mechanism from IMI.Herein, a fast, scalable, and transition-metal-free borylation of alkyl halides (X = I, Br, Cl) enabled by electroreduction is reported. This process provides an efficient and practical access to primary, secondary, and tertiary boronic esters at a high current. More than 70 examples, including the late-stage borylation of natural products and drug derivatives, are furnished at room temperature, thereby demonstrating the broad utility and functional-group tolerance of this protocol. Mechanistic studies disclosed that B2cat2 serves as both a reagent and a cathodic mediator, enabling electroreduction of difficult-to-reduce alkyl bromides or chlorides at a low potential.Household consumption carbon footprint and inequality reductions are vital for a sustainable society, especially for rural areas. This study, focusing on rural China, one of the fastest growing economies with a massive population, explored the carbon footprint and inequality of household consumption using the latest micro household survey data of 2018 linked to environmental extended input--output analysis. The results show that in 2018 in rural China, the average household carbon footprint is 2.46 tons CO2-eq per capita, which is around one-third of China's average footprint, indicating the large potential for further growth. Housing (45.32%), transportation (20.45%), and food (19.62%) are the dominant contributors to the carbon footprint. Meanwhile, great inequality, with a Gini coefficient of 0.488, among rural households is observed, which is largely due to differences in type of house built or purchased (explaining 24.44% of the variation), heating (18.10%), car purchase (12.44%), and petrol consumption (12.44%). Provinces, average education, and nonfarm income are among the important factors influencing the inequality. In the process of urbanization and rural revitalization, there is a high possibility that the household carbon footprint continues to increase, maintaining high levels of inequality. find more The current energy transition toward less carbon-intensive fuels in rural China is likely to dampen the growth rates of carbon footprints and potentially decrease inequality. Carbon intensity decrease could significantly reduce carbon footprints, but increase inequality. More comprehensive measures to reduce carbon footprint and inequality are needed, including transitioning to clean energy, poverty alleviation, reduction of income inequality, and better health care coverage.Microplastics (MPs) are an emerging threat to ecological conservation and biodiversity; however, little is known of the types and possible impacts of MPs in pollinators. To examine whether MPs were present in honeybees, we analyzed the honeybee samples collected in fields from six provinces in China. Four types MPs were identified in honeybee including polystyrene (PS) by Raman spectroscopic analysis, and these plastic polymers were detected in 66.7% bee samples. Then, we assessed the physical and biological impacts of PS of three sizes (0.5, 5, and 50 μm) on bees for 21 days. Next, we measured how the presence of PS affected the Israeli acute paralysis virus proliferation, a small RNA virus associated with bee colony decline. Experimental evidence showed that a large mass of PS was ingested and accumulated within the midgut and enhanced the susceptibility of bees to viral infection. Not only histological analysis showed that PS, especially 0.5 μm PS, damaged the midgut tissue and was subsequently transferred to the hemolymph, trachea, and Malpighian tubules, but also qPCR and transcriptomic results indicated that genes correlated with membrane lipid metabolism, immune response, detoxification, and the respiratory system were significantly regulated after PS ingestion. Our results highlight neglected MP contamination to the bees, a pollination ecosystem stressed by the anthropogenic pollution, and have implications for human health via ingestion of bee products.Addition of halomethyl radicals to form bioactive molecules has recently become an efficient strategy. The reaction has a bottleneck, however, which is the effective and selective generation of the proper halomethyl •CHnX3-n radical by combining CHnX4-n with a carbon radical. Understanding the reactivity and selectivity of carbon radicals in the hydrogen atom transfer (HAT) and halogen atom transfer (XAT) reactions of CHnX4-n is key to the development of such an attractive method. With the help of the emerging data-driven strategy, DFT calculations were used to explore various correlations. For selectivity, the relative energy barriers between HAT and XAT reactions (ΔG⧧H - ΔG⧧X) correlate reasonably well with the three parameters ΔGH, ΔGX, and IP, and the correlation studies reveal that the calculated IPinver and the experimental ΔBDE can be used to conveniently predict the selectivity. Predicted selectivities are consistent with experimental determinations. This work not only provides a possibility for selecting carbon radicals with the known or easily obtained physicochemical data but also demonstrates that the informatic workflow such as generating data and identifying correlations has potential applications in mining reaction rules.A series of novel tetradentate Pt(II) and Pd(II) complexes containing fused 6/6/6 or 6/6/5 metallocycles employing azacarbazolylcarbazole (ACzCz)-based ligands was developed. Systematic experimental and theoretical studies suggest that both the ligand structures and the central metal ions have great influences on the electrochemical and photophysical properties of the complexes. The time-dependent density functional theory (TD-DFT) calculations and natural transition orbital (NTO) analyses reveal that the Pt(II) complexes possess 10.8-15.2% metal-to-ligand charge transfer (3MLCT) mixed with ligand-centered (3LC) characters, by contrast, the Pd(II) complexes exhibit significantly decreased 4.2-7.1% 3MLCT characters and enhanced 3LC compositions. All of the Pt(II) and Pd(II) complexes possess various channels for the intersystem crossing (ISC) on the basis of small energy gaps ΔES1-Tn and matching transition orbital compositions; moreover, Pd(ACzCz-1) and Pd(ACzCz-2) also possess efficient reverse intersystem crossing (RISC) to show both delayed fluorescence (DF) and phosphorescence in PMMA films at room temperature (RT). Pt(ACzCz-3) has ΦPL values of 57% with a τ of 5.1 μs in dichloromethane at RT and 50% with 3.9 μs in PMMA at RT. Notably, Pd(ACzCz-1) exhibits ultralong low-temperature phosphorescence with a τ of 1307 μs. Pt(ACzCz-2)-based green OLED employing 26mCPy as the host demonstrated a peak EQE of 8.2% and a Lmax of 24065 cd/m2.We present Triplex-seq, a deep-sequencing method that systematically maps the interaction space between an oligo library of ssDNA triplex-forming oligos (TFOs) and a particular dsDNA triplex target site (TTS). We demonstrate the method using a randomized oligo library comprising 67 million variants, with five TTSs that differ in guanine (G) content, at two different buffer conditions, denoted pH 5 and pH 7. Our results show that G-rich triplexes form at both pH 5 and pH 7, with the pH 5 set being more stable, indicating that there is a subset of TFOs that form triplexes only at pH 5. In addition, using information analysis, we identify triplex-forming motifs (TFMs), which correspond to minimal functional TFO sequences. We demonstrate, in single-variant verification experiments, that TFOs with these TFMs indeed form a triplex with G-rich TTSs, and that a single mutation in the TFM motif can alleviate binding. Our results show that deep-sequencing platforms can substantially expand our understanding of triplex binding rules and aid in refining the DNA triplex code.Lewis-base coordinated iminoborane adducts, in contrast to their isoelectronic analogue imines, remain largely unexplored given the lack of efficient synthetic strategies for generating robust compounds. Herein, we report the preparation of a cyclic amino iminoborane carbene complex 2 obtained in quantitative yield by adding NHC to the 1,8-(trimethylsilyl)aminonaphthalene complex of boron 1 to induce the elimination of trimethylsilyl chloride (TMSCl). The iminoborane-NHC adduct 2 shows unprecedented thermal stability both in the solid and solution phases, due to the rigid, pre-established geometry of the 1,8-diaminonaphthalene scaffold. Theoretical calculations reveal an exceptionally strong iminoborane-NHC bond as a consequence of the enhanced boron-center acidity in combination with the lower steric and electronic shielding. We show that the chemical bond can be understood as donor-acceptor interaction, leading to a different kind of electronic situation of the B═N π-bond. The high conjugation between the pz-lone pair of the tricoordinated sp2 hybridized N atom and the B═N π-system results in a particularly long B═N double bond distance.