Surface enhanced Raman scattering (SERS) is a trace detection technique that extends even to single molecule detection. Its potential application to the noninvasive recognition of lung malignancies by detecting volatile organic compounds (VOCs) that serve as biomarkers would be a breakthrough in early cancer diagnostics. This application, however, is currently limited by two main factors: (1) most VOC biomarkers exhibit only weak Raman scattering; and (2) the high mobility of gaseous molecules results in a low adsorptivity on solid substrates. To enhance the adsorption of gaseous molecules, a ZIF-8 layer is coated onto a self-assembly of gold superparticles (GSPs) in order to slow the flow rate of gaseous biomarkers and depress the exponential decay of the electromagnetic field around the GSP surfaces. Gaseous aldehydes that are released as a result of tumor-specific tissue composition and metabolism, thereby acting as indicators of lung cancer, are guided onto SERS-active GSPs substrates through a ZIF-8 channel. Through a Schiff base reaction with 4-aminothiophenol pregrafted onto gold GSPs, gaseous aldehydes are captured with a 10 ppb limit of detection, demonstrating tremendous prospects for in vitro diagnoses of early stage lung cancer.

Subcellular membrane-less organelles consist of proteins with low complexity domains. Many of them, such as hnRNPA1, can assemble into both a polydisperse liquid phase and an ordered solid phase of amyloid fibril. The former mirrors biological granule assembly, while the latter is usually associated with neurodegenerative disease. Here, we observe a reversible amyloid formation of hnRNPA1 that synchronizes with liquid–liquid phase separation, regulates the fluidity and mobility of the liquid-like droplets, and facilitates the recruitment of hnRNPA1 into stress granules. We identify the reversible amyloid-forming cores of hnRNPA1 (named hnRACs). The atomic structures of hnRACs reveal a distinct feature of stacking Asp residues, which contributes to fibril reversibility and explains the irreversible pathological fibril formation caused by the Asp mutations identified in familial ALS. Our work characterizes the structural diversity and heterogeneity of reversible amyloid fibrils and illuminates the biological function of reversible amyloid formation in protein phase separation.

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Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson’s disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 α-syn fibril, which reveals a fold of α-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.

Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-β2 (Kapβ2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kapβ2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminates structural understandings of the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kapβ2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.

Optimising the supported modes of atom or ion dispersal onto substrates, to synchronously integrate high reactivity and robust stability in catalytic conversion, is an important yet challenging area of research. Here, theoretical calculations first show that three-coordinated copper (Cu) sites have higher activity than four-, two- and one-coordinated sites. A site-selective etching method is then introduced to prepare a stacked-nanosheet metal–organic framework (MOF, CASFZU-1)-based catalyst with precisely controlled coordination number sites on its surface. The turnover frequency value of CASFZU-1 with three-coordinated Cu sites, for cycloaddition reaction of CO 2 with epoxides, greatly exceed those of other catalysts reported to date. Five successive catalytic cycles reveal the superior stability of CASFZU-1 in the stacked-nanosheet structure. This study could form a basis for the rational design and construction of highly efficient and robust catalysts in the field of single-atom or ion catalysis.

Often as the most important arithmetic modules in a processor, adders, multipliers, and dividers determine the performance and energy efficiency of many computing tasks. The demand of higher speed and power efficiency, as well as the feature of error resilience in many applications (e.g., multimedia, recognition, and data analytics), have driven the development of approximate arithmetic design. In this article, a review and classification are presented for the current designs of approximate arithmetic circuits including adders, multipliers, and dividers. A comprehensive and comparative evaluation of their error and circuit characteristics is performed for understanding the features of various designs. By using approximate multipliers and adders, the circuit for an image processing application consumes as little as 47% of the power and 36% of the power-delay product of an accurate design while achieving similar image processing quality. Improvements in delay, power, and area are obtained for the detection of differences in images by using approximate dividers.