Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrP
) that are able to template the conversion of the native form of the ...protein (PrP
), a property shared by in vitro-produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrP
(residues 23-231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170-229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrP
, we propose that two α-helices in the C-terminal domain of PrP
are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion.
The direct epitaxial growth of graphene on semi‐insulating SiC presents significant potential for a variety of technologically important applications, including next‐generation electronics, ...photonics, and quantum metrology. However, this approach also poses a competitive disadvantage in terms of quality and cost, primarily due to the uncontrollable and time‐consuming nature of the annealing process. Herein, a thermal shock annealing (TSA) method is reported that enables kinetics‐controlled epitaxial growth of graphene on SiC within 10 s, which efficiently fulfills the requirements for producing high‐quality, few‐layer, and low‐cost graphene on SiC. The epitaxial graphene (EG) grown on both β‐SiC nanoparticles (SiC@EG NPs) and centimeter‐scale α‐SiC wafer (EG/SiC) exhibits mono‐ or bi‐layer features with negligible structural defects. Moreover, the findings indicate that the TSA method can efficiently mitigate the persistent issue of step bunching conundrum and improve the flatness of EG/SiC. As an application demonstration, the significant enhancement of surface‐enhanced infrared absorption (SEIRA) by SiC@EG NPs is exhibited. The graphene plasmon arising on SiC@EG NPs enables SEIRA detection sensitivity of up to a monolayer of p‐nitrobenzenethiol (p‐NTP). Consequently, the precise regulation and comprehensive comprehension of TSA afford an exceedingly desirable approach to produce cost‐effective, high‐quality EG growth on SiC for diverse emerging application scenarios.
A thermal shock annealing method that enables kinetics‐controlled epitaxial growth of graphene on SiC within 10 s is reported, which efficiently fulfills the requirements for producing high‐quality, few‐layer, and low‐cost graphene on SiC.
A zirconium-porphyrin metal–organic framework/graphene oxide composite is successfully constructed and employed to fabricate an aptamer-based electrochemical aptasensor with ultra-sensitive detecting ...performance for chloramphenicol.
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More and more attentions have been focused on design and synthesis of novel metal-organic framework/graphene oxide (MOF/GO) composites with unique performance. Zirconium-porphyrin MOF (PCN-222) is in-situ synthesis with the existence of GO with −COOH group to artfully fabricate a PCN-222/GO composite. This composite can be employed as functional material to modify the working electrode. Thanks to excellent electrical conductivity of GO, abundant mesoporous channels and numerous Zr(IV) metal sites of PCN-222, this composite can immobilize a large amount of aptamer through strong π-π stacking interaction and high affinity between phosphate group of aptamer and Zr(IV) site of PCN-222 simultaneously. Hence, an ultra-sensitive electrochemical aptasensor based on PCN-222/GO composite can quantificationally detect trace chloramphenicol with limit of detection of 7.04 pg/mL (21.79 pmol/L) from 0.01 ng/mL to 50 ng/mL by electrochemical impedance spectroscopy even in real samples. Meanwhile, this fabricated aptasensor reveals good repeatability, outstanding selectivity and preferable long-term storage. This research provides a useful approach to construct MOF/GO composites for fabricating electrochemical aptasensors in the electrochemical detection field.
Distance metric learning (DML) aims to find a suitable measure to compute a distance between instances. Facilitated by side information, the learned metric can often improve the performance of ...similarity or distance based methods such as
k
NN. Theoretical analyses of DML focus on the learning effectiveness for squared Mahalanobis distance. Specifically, whether the Mahalanobis metric learned from the empirically sampled pairwise constraints is in accordance with the optimal metric optimized over the paired samples generated from the true distribution, and the sample complexity of this process. The excess risk could measure the quality of the generalization, i.e., the gap between the expected objective of empirical metric learned from a regularized objective with convex loss function and the one with the optimal metric. Given
N
training examples, existing analyses over this
non-i.i.d.
learning problem have proved the excess risk of DML converges to zero at a rate of
O
1
N
. In this paper, we obtain a faster convergence rate of DML,
O
1
N
, when learning the distance metric with a smooth loss function and a strongly convex objective. In addition, when the problem is relatively easy, and the number of training samples is large enough, this rate can be further improved to
O
1
N
2
. Synthetic experiments validate that DML can achieve the specified faster generalization rate, and results under various settings help explore the theoretical properties of DML a lot.
Pathological TDP‐43 aggregation is characteristic of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD‐TDP); however, how ...TDP‐43 aggregation and function are regulated remain poorly understood. Here, we show that O‐GlcNAc transferase OGT‐mediated O‐GlcNAcylation of TDP‐43 suppresses ALS‐associated proteinopathies and promotes TDP‐43's splicing function. Biochemical and cell‐based assays indicate that OGT's catalytic activity suppresses TDP‐43 aggregation and hyperphosphorylation, whereas abolishment of TDP‐43 O‐GlcNAcylation impairs its RNA splicing activity. We further show that TDP‐43 mutations in the O‐GlcNAcylation sites improve locomotion defects of larvae and adult flies and extend adult life spans, following TDP‐43 overexpression in Drosophila motor neurons. We finally demonstrate that O‐GlcNAcylation of TDP‐43 promotes proper splicing of many mRNAs, including STMN2, which is required for normal axonal outgrowth and regeneration. Our findings suggest that O‐GlcNAcylation might be a target for the treatment of TDP‐43‐linked pathogenesis.
SYNOPSIS
O‐GlcNAcylation of TDP‐43 suppresses TDP‐43 proteinophathies and promotes TDP‐43’s mRNA splicing activity, with potential implications for ALS/FTLD pathogenesis.
TDP‐43 can be O‐GlcNAcylated by the enzyme OGT in vitro and in vivo, and O‐GlcNAcylation of TDP‐43 suppresses protein aggregation and hyperphosphorylation.
TDP‐43 O‐GlcNAcylation affects the locomotion and longevity of Drosophila.
O‐GlcNAcylation of TDP‐43 prevents aberrant splicing of key neuron genes, such as STMN2, Dnajc5, and Sort1.
O‐GlcNAcylation of TDP‐43 suppresses TDP‐43 proteinophathies and promotes TDP‐43’s mRNA splicing activity, with potential implications for ALS/FTLD pathogenesis.
The emerging SARS-CoV-2 infection associated with the outbreak of viral pneumonia in China is ongoing worldwide. There are no approved antiviral therapies to treat this viral disease. Here we ...examined the antiviral abilities of three broad-spectrum antiviral compounds gemcitabine, lycorine and oxysophoridine against SARS-CoV-2 in cell culture. We found that all three tested compounds inhibited viral replication in Vero-E6 cells at noncytotoxic concentrations. The antiviral effect of gemcitabine was suppressed efficiently by the cytidine nucleosides. Additionally, combination of gemcitabine with oxysophoridine had an additive antiviral effect against SARS-CoV-2. Our results demonstrate that broad-spectrum antiviral compounds may have a priority for the screening of antiviral compounds against newly emerging viruses to control viral infection.
There still involve lots of challenges when applying machine learning algorithms in unknown environments, especially those with limited training data. To handle the data insufficiency and make a ...further step towards robust learning, we adopt the learnware notion Z.-H. Zhou, "Learnware: On the future of machine learning," Front. Comput. Sci. , vol. 10, no. 4 pp. 589-590, 2016 which equips a model with an essential reusable property-the model learned in a related task could be easily adapted to the current data-scarce environment without data sharing . To this end, we propose the REctiFy via heterOgeneous pRedictor Mapping ( ReForm ) framework enabling the current model to take advantage of a related model from two kinds of heterogeneous environment , i.e., either with different sets of features or labels. By Encoding Meta InformaTion ( Emit ) of features and labels as the model specification, we utilize an optimal transported semantic mapping to characterize and bridge the environment changes. After fine-tuning over a few labeled examples through a biased regularization objective, the transformed heterogeneous model adapts to the current task efficiently. We apply ReForm over both synthetic and real-world tasks such as few-shot image classification with either learned or pre-defined specifications. Experimental results validate the effectiveness and practical utility of the proposed ReForm framework.
•A Gaussia luciferase EV71 reporter virus was constructed.•The reporter virus was infectious and stable in cell culture.•The reporter virus was suitable for antiviral test.
We report a stable Gaussia ...luciferase enterovirus 71 (Gluc-EV71) reporter virus to facilitate drug discovery. The Gluc-EV71 reporter virus was generated by engineering the Gaussia luciferase (Gluc) gene between the 5′ untranslated region and VP4 gene of the EV71 genome. We could recover Gluc-EV71 after transfection of Vero cells with the cDNA clone-derived RNA. The reporter virus efficiently infects and replicates in various cell types (Vero, human rhabdomyosarcoma, and HeLa cells), producing robust luciferase activity. The Gluc-EV71 virus replicates slower than the wild-type virus in cell culture. The reporter virus is stable in maintaining the Gluc gene after five rounds of continuous passaging in Vero cells. Using known EV71 inhibitors, we demonstrate that the reporter virus can be used for antiviral testing. However, the Gluc-EV71 infection assay cannot be adapted to a homogenous format for high throughput screen, mainly due to the secreted nature of the Gluc protein and the short half-life of the Gluc luminescence signal. The Gluc-EV71 and its infection assay could be useful for antiviral drug discovery as well as for studying EV71 replication and pathogenesis.
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