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Weakly coupled resonators (WCRs) predicated on the mode localization phenomenon have found widespread utility in the topological design of high-performance sensors. However, the pronounced nonlinearity derived from the loci veering around the zero point imposes a significant constraint on the measurement range of mode-localized sensors. This article introduces a novel single-port readout circuit aimed at realizing full-scale linear sensing for mode-localized sensors. In our proposed methodology, we employ not only the conventional frequency closed-loop control but also introduce an amplitude closed-loop system incorporating automatic gain control (AGC). This AGC-based approach is utilized to maintain the amplitude product of resonant units at a standardized value. Consequently, we can consider the difference of squared amplitudes as the sensor output, which serves to effectively capture and characterize the fluctuations in external input signals. Furthermore, we have applied our proposed readout circuit to test a prototype of a micro-electro-mechanical system (MEMS) mode-localized accelerometer. The experimental results unequivocally affirm that the tested accelerometer prototype achieves linear sensing throughout the entire measurement range. Remarkably, it demonstrates a mechanical sensitivity of 0.1182/g, coupled with a maximum nonlinearity of -6.54%, and a bias stability of 19.23 mg, alongside a noise floor of $1.022\times 10^{-4}$ V/Hz $^{1/2}$ . These outcomes align closely with the output metric based on the subtraction of reciprocal amplitude ratios (SRARs). Our proposed methodology not only facilitates full-scale linear sensing for mode-localized sensors but also streamlines the signal extraction process, all while preserving the electromechanical performance. This advancement holds significant promise for the expansion of the application landscape for mode-localized sensors.

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.

The development of new green fungicides is an effective way to solve the resistance of agricultural pathogens and plays an important role in promoting high-quality and sustainable development of modern agriculture. In this project, a series of aryloxy-, arylthio-, and arylamino-containing acethydrazide derivatives were designed, synthesized, and characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, and high-resolution mass spectrometry (HRMS). The fungicidal bioassays indicated that some compounds showed excellent and broad-spectrum fungicidal activity, and the structure–activity relationship was discussed. The in vivo fungicidal activity demonstrated that compounds C4and D8exhibited good preventative effects against Fusarium graminearuminfecting wheat leaves, of which the preventative activity of compound D8was almost equal to that of the positive agents. Transmission electron microscopy (TEM) observation revealed that the plasma membrane in the C4-treated F. graminearumhyphal cells was severely contracted and separated with the cell wall, coupling with the visible lysosomes and the disappeared cytoplasm and organelles, which may be the reasons for the shriveled and even ruptured hyphae observed by scanning electron microscopy (SEM). Subsequently, transcriptomics and metabolomics were performed to further elucidate the fungicidal mechanism. The regulatory networks of differential genes and metabolites in plasma membrane-related sphingolipid metabolism, linoleic acid metabolism, α-linoleic acid metabolism, and arachidonic acid metabolism were constructed and elaborated. Additionally, preliminary investigation of seeding growth suggested that compounds C4and D8may have different degrees of influence on the growth indicators of wheat seedlings; however, this effect may be negligible as the plant grows.

This paper describes the construction of a phase shifter with low loss and small volume. To construct it, we use the two graphene layers that are separated by a hexagonal boron nitride (hBN) and embedded in a silicon waveguide. The refractive index of the waveguide is adjusted by applying a bias voltage to the graphene sheet to create an optical phase shift. This waveguide is a compact device that only has a radius of 5 μm. It has a phase shift of 6π. In addition, the extinction ratio (ER) is 11.6 dB and the insertion loss (IL) is 0.031 dB. Due to its unique characteristics, this device has great potential in silicon on-chip optical interconnection and all-optical multiple-input multiple-output processing.

Self-assembly of the microtubule-associated protein tau into neurotoxic oligomers, fibrils, and paired helical filaments, and cell-to-cell spreading of these pathological tau species are critical processes underlying the pathogenesis of Alzheimer’s disease and other tauopathies. Modulating the self-assembly process and inhibiting formation and spreading of such toxic species are promising strategies for therapy development. A challenge in investigating tau self-assembly in vitro is that, unlike most amyloidogenic proteins, tau does not aggregate in the absence of posttranslational modifications (PTM), aggregation inducers, or preformed seeds. The most common induction method is addition of polyanions, such as heparin; yet, this artificial system may not represent adequately tau self-assembly in vivo, which is driven by aberrant phosphorylation and other PTMs, potentially leading to in vitro data that do not reflect the behavior of tau and its interaction with modulators in vivo. To tackle these challenges, methods for in vitro phosphorylation of tau to produce aggregation-competent forms recently have been introduced (Despres et al. (2017) Proc. Natl. Acad. Sci. U.S.A., 114, 9080−9085). However, the oligomerization, seeding, and interaction with assembly modulators of the different forms of tau have not been studied to date. To address these knowledge gaps, we compared here side-by-side the self-assembly and seeding activity of heparin-induced tau with two forms of in vitro phosphorylated tau and tested how the molecular tweezer CLR01, a negatively charged compound, affected these processes. Tau was phosphorylated by incubation either with activated extracellular signal-regulated kinase 2 or with a whole rat brain extract. Seeding activity was measured using a fluorescence-resonance energy transfer-based biosensor-cell method. We also used solution-state NMR to investigate the binding sites of CLR01 on tau and how they were impacted by phosphorylation. Our systematic structure–activity relationship study demonstrates that heparin-induced tau behaves differently from in vitro phosphorylated tau. The aggregation rates of the different forms are distinct as is the intracellular localization of the induced aggregates, which resemble brain-derived tau strains suggesting that heparin-induced tau and in vitro phosphorylated tau have different conformations, properties, and activities. CLR01 inhibits aggregation and seeding of both heparin-induced and in vitro phosphorylated tau dose-dependently, although heparin induction interferes with the interaction between CLR01 and tau.

Parkinson’s disease-causing leucine-rich repeat kinase 2 (LRRK2) mutations lead to varying degrees of Rab GTPase hyperphosphorylation. Puzzlingly, LRRK2 GTPase-inactivating mutations—which do not affect intrinsic kinase activity—lead to higher levels of cellular Rab phosphorylation than kinase-activating mutations. Here, we investigate whether mutation-dependent differences in LRRK2 cellular localization could explain this discrepancy. We discover that blocking endosomal maturation leads to the rapid formation of mutant LRRK2+endosomes on which LRRK2 phosphorylates substrate Rabs. LRRK2+endosomes are maintained through positive feedback, which mutually reinforces membrane localization of LRRK2 and phosphorylated Rab substrates. Furthermore, across a panel of mutants, cells expressing GTPase-inactivating mutants form strikingly more LRRK2+endosomes than cells expressing kinase-activating mutants, resulting in higher total cellular levels of phosphorylated Rabs. Our study suggests that the increased probability that LRRK2 GTPase-inactivating mutants are retained on intracellular membranes compared to kinase-activating mutants leads to higher substrate phosphorylation.

We propose an etching treatment to improve the photoresponse of a femtosecond (fs)-laser-irradiated silicon photodiode working at 1064 nm. We investigated its surface structure and optical and electrical properties after fs laser irradiation, and further demonstrated the evolution of textured surface morphology, hyperdoping concentration, and crystallinity with etching time. We found that the etching treatment can peel off the hyperdoped layer by an appropriate amount, control the dopant concentration, and repair the crystallinity and subsurface damage of the hyperdoped microstructured silicon induced by fs laser irradiation. Experimental results indicate that the photoresponse at 1064 nm can be enhanced from 0.2 to 0.45 A/W after etching treatment.