Sequential proteolysis of the amyloid precursor protein (APP) by γ‐secretases generates amyloid‐β (Aβ) peptides and defines the proportion of short‐to‐long Aβ peptides, which is tightly connected to ...Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ‐secretases and Aβ peptide length. We found that polar interactions established by the APPC99 ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ‐secretases processive cleavage by destabilizing enzyme–substrate interactions. We show that increasing hydrophobicity, via mutation or ligand binding, at APPC99‐ECD attenuates substrate‐driven product release and rescues the effects of Alzheimer's disease‐associated pathogenic γ‐secretase and APP variants on Aβ length. In addition, our study reveals that APPC99‐ECD facilitates the paradoxical production of longer Aβs caused by some γ‐secretase inhibitors, which act as high‐affinity competitors of the substrate. These findings assign a pivotal role to the substrate ECD in the sequential proteolysis by γ‐secretases and suggest it as a sweet spot for the potential design of APP‐targeting compounds selectively promoting its processing by these enzymes.
Synopsis
Sequential proteolysis of amyloid precursor protein (APP) by γ‐secretase generates various amyloid‐β (Aβ) peptides, whose length correlates with pathogenicity of Alzheimer's disease (AD)‐associated mutations. Here, the ectodomain of the APP substrate is found to define Aβ length by promoting product release and destabilizing enzyme–substrate interactions.
Polar residues in the APPC99 ectodomain (APPC99‐ECD) drive product release by destabilizing enzyme–substrate interactions.
Increased hydrophobicity in the substrate ECD increases both efficiency and extent of sequential γ‐secretase‐mediated proteolysis of APP and Notch.
γ‐Secretase inhibitors (GSIs) DAPT and semagacestat act as high‐affinity competitors of substrates.
GSI‐mediated displacement of partially digested Aβ peptides, facilitated by the APPC99‐ECD, explains paradoxical increases in longer Aβ peptides.
Mitigation of APPC99‐ECD‐driven product release rescues the increased production of longer Aβ peptides linked to pathogenic variants in γ‐secretase and APP.
How γ‐secretase cleaves and processes the amyloid precursor protein depends on the hydrophobicity of its ectodomain, with implications for disease mechanism and drug discovery.
The development of novel anti‐infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed ...inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non‐essential in human cells. An LA‐based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry. Probe labeling served as a proxy of LPL activity, enabling in situ screenings for cell‐permeable LPL inhibitors. Profiling a focused compound library revealed two substrate analogs (LAMe and C3) as inhibitors, which were further validated by binding studies and co‐crystallography. Importantly, LAMe exhibited low toxicity in human cells and achieved killing of Plasmodium falciparum in erythrocytes with an EC50 value of 15 μM, making it the most effective LPL inhibitor reported to date.
Distinct from humans, lipoic acid (LA) salvage by lipoate protein ligase (LPL) is an essential scavenging pathway for auxotrophic bacteria and parasites. Probes as LA‐mimics were designed and shown to label LA‐dependent proteins in living cells on lysines. This tool enabled us to perform competitive screens in order to identify two cell‐permeable LPL inhibitors with activity against P. falciparum in erythrocytes.
Research has indicated victimization is pervasive among incarcerated women. Yet, there is little research that examines the linkage between various victimization among female prisoners. The empirical ...aim of this study is to examine the association between childhood maltreatment and victimization from physical intimate partner violence among incarcerated women in Taiwan. To understand the various pathways to victimization of physical intimate partner violence, we also assess the mediating effects of risky life styles, low self-control, and prostitution on victimization from physical intimate partner violence. Data were analyzed based on surveys conducted with 686 incarcerated women in various prisons in Taiwan. Structural equation analysis was conducted to examine the direct and indirect relationships between childhood maltreatment, risky life styles, low self-control, prostitution, and victimization of physical intimate partner violence. Individuals who experienced childhood maltreatment were found more likely to engage in risky leisure activities, and to enter prostitution. Additionally, such individuals usually experienced low self-control. Low self-control was found to mediate the relationship between childhood maltreatment and victimization from physical intimate partner violence. In other words, maltreated individuals in childhood were more likely to become victims of physical intimate partner violence through low self-control. The findings suggest that to prevent women offenders from re-victimization, it is important to address their childhood maltreatment issues. Early intervention may help deter these maltreated individuals from risky life styles and from engaging in prostitution, which may reduce their vulnerability to becoming victims of physical intimate partner violence.
Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this ...is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimer's disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular dynamics simulations revealed that important elements for substrate binding such as transmembrane domain 6a of PSH are more labile in micelles and stabilized in the lipid bilayer. Moreover, consistent with an enhanced interaction of PSH with a transition-state analog inhibitor, the bilayer promoted the formation of the enzyme´s catalytic active site geometry. Our data indicate that the lipid environment of an intramembrane protease plays a critical role in structural stabilization and active site arrangement of the enzyme-substrate complex thereby promoting intramembrane proteolysis.
Protein–protein interactions (PPIs) are essential for biological processes including immune reactions and diseases. Inhibition of PPIs by drug-like compounds is a common basis for therapeutic ...approaches. In many cases the flat interface of PP complexes prevents discovery of specific compound binding to cavities on one partner and PPI inhibition. However, frequently new pockets are formed at the PP interface that allow accommodation of stabilizers which is often as desirable as inhibition but a much less explored alternative strategy. Herein, we employ molecular dynamics simulations and pocket detection to investigate 18 known stabilizers and associated PP complexes. For most cases, we find that a dual-binding mechanism, a similar stabilizer interaction strength with each protein partner, is an important prerequisite for effective stabilization. A few stabilizers follow an allosteric mechanism by stabilizing the protein bound structure and/or increase the PPI indirectly. On 226 protein–protein complexes, we find in >75% of the cases interface cavities suitable for binding of drug-like compounds. We propose a computational compound identification workflow that exploits new PP interface cavities and optimizes the dual-binding mechanism and apply it to 5 PP complexes. Our study demonstrates a great potential for in silico PPI stabilizers discovery with a wide range of therapeutic applications.
Game-based learning activities that facilitate students' listening and speaking skills were designed in this study. To participate in learning activities, students in the control group used ...traditional methods, while students in the experimental group used a mobile system. In our study, we looked into the feasibility of mobile game-based learning activities. One experiment was carried out and the results revealed that the experimental-group students significantly outperformed the control-group students on the verbal post-test. However, the performance of the two groups was equal on the listening post-test. Two variables (the average score for the interactive jigsaw game and the number of designed cards) were found to be the most important factors for influencing students' performance in the verbal post-test. Furthermore, most students had positive perceptions toward learning activities that are supported by a mobile system. These results suggest that game-based learning activities can significantly improve students' speaking skills if driven by a mobile system. Furthermore, these results suggest that learning activities with a mobile system foster students to (1) practice speaking English as a foreign language (EFL) more frequently as well as to reflect on their speech; (2) create meaningful sentences and speak with greater accuracy and confidence; and (3) practice speaking EFL in an authentic context.
Lithium-ion batteries are popular energy storage devices due to their high energy density. Solid electrolytes appear to be a potential replacement for flammable liquid electrolytes in lithium ...batteries. This inorganic/hybrid solid electrolyte is a composite of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) salt, (poly(vinylidene fluoride-hexafluoro propylene) (PVDF-HFP) polymer and sodium superionic conductor (NASICON)-type Li1+xAlxTi2−x(PO4)3 (LATP) ceramic powder. The structure, morphology, mechanical behavior, and electrochemical performance of this composite solid electrolyte, based on various amounts of LiTFSI, were investigated. The lithium-ion transfer and conductivity increased as the LiTFSI lithium salt concentration increased. However, the mechanical strength apparently decreased once the percentage of LITFSI was over 60%. The hybrid electrolyte with 60% LiTFSI content showed high ionic conductivity of 2.14 × 10−4 S cm−1, a wide electrochemical stability window (3–6 V) and good electrochemical stability. The capacity of the Li|60% LiTFSI/PVDF-HFP/LATP| LiFePO4 solid-state lithium-metal battery was 103.8 mA h g−1 at 0.1 C, with a high-capacity retention of 98% after 50 cycles.
Dissolved organic matter (DOM) derived from organic fertilizers may increase soil phosphorus (P) availability. However, the frequently observed correlation between soil P availability and dissolved ...organic carbon (DOC) content has led to an excessive focus on DOC content at the expense of DOM properties. The present study investigated the influence of DOM characteristics on soil P availability by using a 6-year field experiment and microcosms of P sorption in paddy soil. Our results showed that partial replacement of chemical P fertilizer with manure or crop straw increased P fertilizer-use efficiency, even when decreasing chemical P input by 34%, compared to normal chemical fertilization. The microcosm experiment demonstrated that DOM properties, rather than total DOC content, determine soil P sorption capacity, despite the significant correlation between DOC content and P availability observed in the field experiment. Manure-DOM exerted stronger inhibitory effects on P sorption than straw-DOM, and high molecular weight (HMW)-fractionated DOM exerted stronger inhibitory effects on P sorption than low-molecular-weight-fractionated DOM by 16–20%. The mechanism is primarily attributed to high molecular weight (HMW) DOM, which possesses unique characteristics such as strong aromaticity. These attributes lead to competition for soil P sorption sites and a decrease in soil surface charge, collectively suppressing P sorption in paddy soil. Our study points out a promising avenue for regulating organic matter properties with organic fertilization to improve P use efficiency in agricultural soils.
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•DOM from organic fertilizers enhance soil P availability and crop yield sustainability.•Soil P sorption capacity is regulated by the properties and structure of DOM.•High molecular weight DOM plays a key role in the inhibitory effect on P sorption.•DOM decreases P sorption by competing sorption site and reducing surface charge on soil particles.
Shape interpolation has many applications in computer graphics such as morphing for computer animation. In this paper, we propose a novel data‐driven mesh interpolation method. We adapt patch‐based ...linear rotational invariant coordinates to effectively represent deformations of models in a shape collection, and utilize this information to guide the synthesis of interpolated shapes. Unlike previous data‐driven approaches, we use a rotation/translation invariant representation which defines the plausible deformations in a global continuous space. By effectively exploiting the knowledge in the shape space, our method produces realistic interpolation results at interactive rates, outperforming state‐of‐the‐art methods for challenging cases. We further propose a novel approach to interactive editing of shape morphing according to the shape distribution. The user can explore the morphing path and select example models intuitively and adjust the path with simple interactions to edit the morphing sequences. This provides a useful tool to allow users to generate desired morphing with little effort. We demonstrate the effectiveness of our approach using various examples.
Shape interpolation has many applications in computer graphics such as morphing for computer animation. In this paper, we propose a novel data‐driven mesh interpolation method. We adapt patch‐based linear rotational invariant coordinates to effectively represent deformations of models in a shape collection, and utilize this information to guide the synthesis of interpolated shapes. Unlike previous data‐driven approaches, we use a rotation/translation invariant representation which defines the plausible deformations in a global continuous space. By effectively exploiting the knowledge in the shape space, our method produces realistic interpolation results at interactive rates, outperforming state‐of‐the‐art methods for challenging cases.
Abstract
Background
Fleas are the most economically significant blood-feeding ectoparasites worldwide.
Ctenocephalides felis
and
Pulex irritans
can parasitize various animals closely related to ...humans and are of high veterinary significance.
Methods
In this study, 82 samples were collected from 7 provinces of China. Through studying the nuclear genes ITS1 and EF-1α and two different mitochondrial genes
cox
1 and
cox
2, the population genetics and genetic variation of
C. felis
and
P. irritans
in China were further investigated.
Results
The intraspecies differences between
C. felis
and
P. irritans
ranged from 0 to 3.9%. The interspecific variance in the EF-1α,
cox
1, and
cox
2 sequences was 8.2–18.3%, while the ITS1 sequence was 50.1–52.2%. High genetic diversity was observed in both
C. felis
and
P. irritans
, and the nucleotide diversity of
cox
1 was higher than that of
cox
2. Moderate gene flow was detected in the
C. felis
and
P. irritans
populations. Both species possessed many haplotypes, but the haplotype distribution was uneven. Fu's Fs and Tajima's D tests showed that
C. felis
and
P. irritans
experienced a bottleneck effect in Guangxi Zhuang Autonomous Region and Henan province. Evolutionary analysis suggested that
C. felis
may have two geographical lineages in China, while no multiple lineages of
P.irritans
were found.
Conclusions
Using sequence comparison and the construction of phylogenetic trees, we found a moderate amount of gene flow in the
C. felis
and
P. irritans
populations. Both species possessed many haplotypes, but the distribution of haplotypes varied among the provinces. Fu’s Fs and Tajima’s D tests indicated that both species had experienced a bottleneck effect in Guangxi and Henan provinces. Evolutionary analysis suggested that
C. felis
may have two geographical lineages in China, while no multiple lineages of
P.irritans
were found. This study will help better understand fleas' population genetics and evolutionary biology.
Graphical Abstract
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