Structural basis of γ-secretase inhibition and modulation by small molecule drugs.

Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å. Remarkably, each of the GSIs occupies the same general location on presenilin 1 (PS1) that accommodates the ß strand from amyloid precursor protein or Notch, interfering with substrate recruitment. L685,458 directly coordinates the two catalytic aspartate residues of PS1. E2012 binds to an allosteric site of γ-secretase on the extracellular side, potentially explaining its modulating activity. Structural analysis reveals a set of shared themes and variations for inhibitor and modulator recognition that will guide development of the next-generation substrate-selective inhibitors.

Germ cell-specific eIF4E1b regulates maternal mRNA translation to ensure zygotic genome activation.

Translation of maternal mRNAs is detected before transcription of zygotic genes and is essential for mammalian embryo development. How certain maternal mRNAs are selected for translation instead of degradation and how this burst of translation affects zygotic genome activation remain unknown. Using gene-edited mice, we document that the oocyte-specific eukaryotic translation initiation factor 4E family member 1b (eIF4E1b) is the regulator of maternal mRNA expression that ensures subsequent reprogramming of the zygotic genome. In oocytes, eIF4E1b binds to transcripts encoding translation machinery proteins, chromatin remodelers, and reprogramming factors to promote their translation in zygotes and protect them from degradation. The protein products are thought to establish an open chromatin landscape in one-cell zygotes to enable transcription of genes required for cleavage stage development. Our results define a program for rapid resetting of the zygotic epigenome that is regulated by maternal mRNA expression and provide new insights into the mammalian maternal-to-zygotic transition.

Degradation and translation of maternal mRNA for embryogenesis.

Maternal mRNAs accumulate during egg growth and must be judiciously degraded or translated to ensure successful development of mammalian embryos. In this review we integrate recent investigations into pathways controlling rapid degradation of maternal mRNAs during the maternal-to-zygotic transition. Degradation is not indiscriminate, and some mRNAs are selectively protected and rapidly translated after fertilization for reprogramming the zygotic genome during early embryogenesis. Oocyte specific cofactors and pathways have been illustrated to control different futures of maternal mRNAs. We discuss mechanisms that control the fate of maternal mRNAs during late oogenesis and after fertilization. Issues to be resolved in current maternal mRNA research are described, and future research directions are proposed.

Structural basis of Notch recognition by human γ-secretase.

Aberrant cleavage of Notch by γ-secretase leads to several types of cancer, but how γ-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of human γ-secretase in complex with a Notch fragment at a resolution of 2.7 Å. The transmembrane helix of Notch is surrounded by three transmembrane domains of PS1, and the carboxyl-terminal ß-strand of the Notch fragment forms a ß-sheet with two substrate-induced ß-strands of PS1 on the intracellular side. Formation of the hybrid ß-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. These features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by γ-secretase.

Modulation of amyloid precursor protein cleavage by γ-secretase activating protein through phase separation.

Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase is closely associated with Alzheimer's disease (AD). γ-secretase activating protein (GSAP) specifically promotes γ-secretase­mediated cleavage of APP. However, the underlying mechanism remains enigmatic. Here, we demonstrate that the 16-kDa C-terminal fragment of GSAP (GSAP-16K) undergoes phase separation in vitro and forms puncta-like condensates in cells. GSAP-16K exerts dual modulation on γ-secretase cleavage; GSAP-16K in dilute phase increases APP­C-terminal 99-residue fragment (C99) cleavage toward preferred production of ß-amyloid peptide 42 (Aß42), but GSAP-16K condensates reduce APP-C99 cleavage through substrate sequestration. Notably, the Aß42/Aß40 ratio is markedly elevated with increasing concentrations of GSAP-16K. GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings mechanistically explain GSAP-mediated modulation of γ-secretase activity that may have ramifications on the development of potential therapeutics.

Reactive oxygen species (ROS) modulate nitrogen signaling using temporal transcriptome analysis in foxtail millet.

Reactive oxygen species (ROS) is a chemically reactive chemical substance containing oxygen and a natural by-product of normal oxygen metabolism. Excessive ROS affect the growth process of crops, which will lead to the decrease of yield. Nitrogen, as a critical nutrient element in plants and plays a vital role in plant growth and crop production. Nitrate is the primary nitrogen source available to plants in agricultural soil and various natural environments. However, the molecular mechanism of ROS-nitrate crosstalk is still unclear. In this study, we used the foxtail millet (Setaria italica L.) as the material to figure it out. Here, we show that excessive NaCl inhibits nitrate-promoted plant growth and nitrogen use efficiency (NUE). NaCl induces ROS accumulation in roots, and ROS inhibits nitrate-induced gene expression in a short time. Surprisingly, low concentration ROS slight promotes and high concentration of ROS inhibits foxtail millet growth under long-term H2O2 treatment. These results may open a new perspective for further exploration of ROS-nitrate signaling pathway in plants.

Accelerating the discovery of anticancer peptides targeting lung and breast cancers with the Wasserstein autoencoder model and PSO algorithm.

In the development of targeted drugs, anticancer peptides (ACPs) have attracted great attention because of their high selectivity, low toxicity and minimal non-specificity. In this work, we report a framework of ACPs generation, which combines Wasserstein autoencoder (WAE) generative model and Particle Swarm Optimization (PSO) forward search algorithm guided by attribute predictive model to generate ACPs with desired properties. It is well known that generative models based on Variational AutoEncoder (VAE) and Generative Adversarial Networks (GAN) are difficult to be used for de novo design due to the problems of posterior collapse and difficult convergence of training. Our WAE-based generative model trains more successfully (lower perplexity and reconstruction loss) than both VAE and GAN-based generative models, and the semantic connections in the latent space of WAE accelerate the process of forward controlled generation of PSO, while VAE fails to capture this feature. Finally, we validated our pipeline on breast cancer targets (HIF-1) and lung cancer targets (VEGR, ErbB2), respectively. By peptide-protein docking, we found candidate compounds with the same binding sites as the peptides carried in the crystal structure but with higher binding affinity and novel structures, which may be potent antagonists that interfere with these target-mediated signaling.

Interstitial Boron-Modulated Porous Pd Nanotubes for Ammonia Electrosynthesis.

Electrochemical conversion of nitrogen into ammonia at ambient conditions as a sustainable approach has gained significant attention, but it is still extremely challenging to simultaneously obtain a high faradaic efficiency (FE) and NH3 yield. In this work, the interstitial boron-doped porous Pd nanotubes (B-Pd PNTs) are constructed by combining the self-template reduction method with boron doping. Benefiting from distinctive one-dimensional porous nanotube architectonics and the incorporation of the interstitial B atoms, the resulting B-Pd PNTs exhibit high NH3 yield (18.36 µg h-1 mgcat.-1) and FE (21.95%) in neutral conditions, outperforming the Pd/PdO PNTs (10.4 µg h-1 mgcat.-1 and 8.47%). The present study provides an attractive method to enhance the efficiency of the electroreduction of nitrogen into ammonia by incorporating interstitial boron into porous Pd-based catalysts.

Amorphous/crystalline RhFeP metallene for hydrazine-assisted water splitting.

Replacing the slow oxygen evolution reaction with favorable hydrazine oxidation reaction (HzOR) is a green and efficient way to produce hydrogen. In this work, we synthesize amorphous/crystalline RhFeP metallene via phase engineering and heteroatom doping. RhFeP metallene has good catalytic activity and stability for HER and HzOR, and only an ultralow voltage of 18 mV is required to achieve 10 mA cm-2in a two-electrode hydrazine-assisted water splitting system. The superior result is mainly ascribed to the co-doping of Fe and P and the formation of amorphous/crystalline RhFeP metallene with abundant phase boundaries, thereby adjusting electronic structure and increasing active sites.

Klf4 methylated by Prmt1 restrains the commitment of primitive endoderm.

The second cell fate decision in the early stage of mammalian embryonic development is pivotal; however, the underlying molecular mechanism is largely unexplored. Here, we report that Prmt1 acts as an important regulator in primitive endoderm (PrE) formation. First, Prmt1 depletion promotes PrE gene expression in mouse embryonic stem cells (ESCs). Single-cell RNA sequencing and flow cytometry assays demonstrated that Prmt1 depletion in mESCs contributes to an emerging cluster, where PrE genes are upregulated significantly. Furthermore, the efficiency of extraembryonic endoderm stem cell induction increased in Prmt1-depleted ESCs. Second, the pluripotency factor Klf4 methylated at Arg396 by Prmt1 is required for recruitment of the repressive mSin3a/HDAC complex to silence PrE genes. Most importantly, an embryonic chimeric assay showed that Prmt1 inhibition and mutated Klf4 at Arg 396 induce the integration of mouse ESCs into the PrE lineage. Therefore, we reveal a regulatory mechanism for cell fate decisions centered on Prmt1-mediated Klf4 methylation.

Simulation research on aerodynamic noise characteristics of a compressor under different working conditions.

The shear stress transport turbulence model is employed to conduct a detailed study of flow characteristics at the highest efficiency point and near-stall point in a full-channel 1.5-stage compressor in this paper. The simulation results for the compressor's total pressure ratio and efficiency exhibit good agreement with experimental data. Emphasis is placed on examining the internal flow structure in the tip area of the compressor rotor under near-stall conditions. The results reveal that significant differences in flow structure primarily occur in the tip area as the compressor approaches stall. Specifically, a reduction in turbulent kinetic energy is observed in a region spanning approximately 20%-60% of the chord length on the rotor suction face near-stall conditions. Two additional peak frequencies, at 0.8 and 1.6 times the blade passage frequency, are observed, and the intricate flow phenomena are elaborated at the near-stall point. The near-stall point exhibits greater noise levels than the highest efficiency point, where the intensity of the surface source increases by more than 10 dB, peaking at 20 dB. This additional peak serves as a significant supplementary noise source near the stall point, leading to a maximum increase of 33.3 dB in the free radiated sound power. The acoustic response within the duct indicates that the compressor operating at the near-stall point continues to produce substantial noise on the actual test bench, showing an average increase of 6 dB in noise levels, and the distribution of the additional peak single-tone noise at the entrance significantly differs from that observed at the highest efficiency point.

High Overexpression of SiAAP9 Leads to Growth Inhibition and Protein Ectopic Localization in Transgenic Arabidopsis.

Amino acid permeases (AAPs) transporters are crucial for the long-distance transport of amino acids in plants, from source to sink. While Arabidopsis and rice have been extensively studied, research on foxtail millet is limited. This study identified two transcripts of SiAAP9, both of which were induced by NO3- and showed similar expression patterns. The overexpression of SiAAP9L and SiAAP9S in Arabidopsis inhibited plant growth and seed size, although SiAAP9 was found to transport more amino acids into seeds. Furthermore, SiAAP9-OX transgenic Arabidopsis showed increased tolerance to high concentrations of glutamate (Glu) and histidine (His). The high overexpression level of SiAAP9 suggested its protein was not only located on the plasma membrane but potentially on other organelles, as well. Interestingly, sequence deletion reduced SiAAP9's sensitivity to Brefeldin A (BFA), and SiAAP9 had ectopic localization on the endoplasmic reticulum (ER). Protoplast amino acid uptake experiments indicated that SiAAP9 enhanced Glu transport into foxtail millet cells. Overall, the two transcripts of SiAAP9 have similar functions, but SiAAP9L shows a higher colocalization with BFA compartments compared to SiAAP9S. Our research identifies a potential candidate gene for enhancing the nutritional quality of foxtail millet through breeding.

Structural insights into the Oryza sativa cation transporters HKTs in salt tolerance.

The high-affinity potassium transporters (HKTs), selectively permeable to either Na+ alone or Na+/K+, play pivotal roles in maintaining plant Na+/K+ homeostasis. Although their involvement in salt tolerance is widely reported, the molecular underpinnings of Oryza sativa HKTs remain elusive. In this study, we elucidate the structures of OsHKT1;1 and OsHKT2;1, representing two distinct classes of rice HKTs. The dimeric assembled OsHKTs can be structurally divided into four domains. At the dimer interface, a half-helix or a loop in the third domain is coordinated by the C-terminal region of the opposite subunit. Additionally, we present the structures of OsHKT1;5 salt-tolerant and salt-sensitive variants, a key quantitative trait locus associated with salt tolerance. The salt-tolerant variant of OsHKT1;5 exhibits enhanced Na+ transport capability and displays a more flexible conformation. These findings shed light on the molecular basis of rice HKTs and provide insights into their role in salt tolerance.

Effects of aromatherapy and music therapy on patients' anxiety during MRI examinations: a randomized controlled trial.

OBJECTIVES: Many patients experience anxiety during MRI examinations. However, little attention has been focused on decreasing patient anxiety and minimizing on-site cancellations. Here, we aimed to investigate the effects of aromatherapy and music therapy on alleviating anxiety during MRI examinations. METHODS: This single-center, double-blinded, randomized control trial was conducted between November 1, 2021, and January 10, 2022. Patients undergoing MRI examinations were assigned randomly into either the aromatherapy group (AG), music therapy group (MG), aromatherapy plus music therapy group (AMTG), or routine care group (RG) at a ratio of 1:1:1:1. Aromatherapy was conducted through inhalation of lavender oil. Music therapy was performed using Pachelbel's Canon in D major. The primary outcome was the change in anxiety before and after the MRI scan, assessed using both the State-Trait Anxiety Inventory form 1 (STAI-1) and Self-Rating Anxiety Scale (SAS). The second outcome was the participant's comfort, measured using Kolcaba's General Comfort Questionnaire (GCQ). RESULTS: A total of 200 participants (mean age: 48.3 ± 14.9 years; 126 [63.0%] females) were enrolled, with 50 per group. The mean anxiety scores of the AMTG showed greater reduction compared with the AG, MG, and RG (ΔSTAI-1: 6.5 vs 2.6 vs 2.7 vs 1.9, p < 0.001; ΔSAS: 4.0 vs 1.4 vs 1.7 vs 0.6, p < 0.001). The mean GCQ score of the AMTG was higher compared with the AG, MG, and RG (98.0 vs 92.6 vs 91.2 vs 89.2, respectively, p < 0.001). CONCLUSION: Aromatherapy combined with music therapy is effective for reducing patients' anxiety and improving their comfort level during MRI scans. KEY POINTS: • In this randomized control trial of 200 participants undergoing MRI scans, aromatherapy plus music therapy is effective in reducing STAI-1 and SAS, as well as improving GCQ scores. • Although there was a significant difference between the aromatherapy plus music therapy and the single-intervention modalities, no significant differences were observed between the aromatherapy and music therapy themselves for state anxiety and comfort score. • Aromatherapy plus music therapy is a safe, non-invasive, nonpharmacological, and inexpensive patient-centered intervention for reducing anxiety and improving comfort in adults undergoing MRI examinations.

Transformer-based deep learning method for optimizing ADMET properties of lead compounds.

A successful drug needs to exhibit both effective pharmacodynamics (PD) and safe pharmacokinetics (PK). However, the coordinated optimization of PD and PK properties in molecule generation tasks remains a great challenge for most existing methods, especially when they focus on the pursuit of affinity and selectivity for the lead compound. Thus, molecular optimization for PK properties is a critical step in the drug discovery pipeline, in which absorption, distribution, metabolism, excretion and toxicity (ADMET) property predictive models play an increasingly important role by providing an effective method to assess multiple PK properties of compounds. Here, we proposed a Graph Bert-based ADMET prediction model that achieves state-of-the-art performance on the public dataset Therapeutics Data Commons (TDC) by combining molecular graph features and descriptor features, with 11 tasks ranked first and 20 tasks ranked in the top 3. Based on this prediction model, we trained a Transformer model with multiple properties as constraints for learning the structural transformations involved in MMP and the accompanying property changes. The experimental results show that the trained Constraints-Transformer can implement targeted modifications to the starting molecule, while preserving the core scaffold. Moreover, molecular docking and binding mode analysis demonstrate that the optimized molecules still retain the activity and selectivity for biological targets. Therefore, the proposed method accounts for biological activity and ADMET properties simultaneously. Finally, a webserver containing ADMET property prediction and molecular optimization functions is provided, enabling chemists to improve the properties of starting molecules individually.

Ethyl Gallate Inhibits Bovine Viral Diarrhea Virus by Promoting IFITM3 Expression, Lysosomal Acidification and Protease Activity.

Bovine viral diarrhea virus (BVDV) is a highly contagious viral disease which causes economic losses to the cattle industry. Ethyl gallate (EG) is a phenolic acid derivative which has various potentials to modulate the host response to pathogens, such as via antioxidant activity, antibacterial activity, inhibition of the production of cell adhesion factors, and so on. This study aimed to evaluate if EG influences BVDV infection in Madin-Darby Bovine Kidney (MDBK) cells, and to understand the antiviral mechanism. Data indicated that EG effectively inhibited BVDV infection by co-treatment and post-treatment in MDBK cells with noncytotoxic doses. In addition, EG suppressed BVDV infection at an early stage of the viral life cycle by blocking entry and replication steps but not viral attachment and release. Moreover, EG strongly inhibited BVDV infection by promoting interferon-induced transmembrane protein 3 (IFITM3) expression, which localized to the cytoplasm. The protein level of cathepsin B was significantly reduced by BVDV infection, whereas with treatment with EG, it was significantly enhanced. The fluorescence intensities of acridine orange (AO) staining were significantly decreased in BVDV-infected cells but increased in EG-treated cells. Finally, Western blot and immunofluorescence analyses demonstrated that EG treatment significantly enhanced the protein levels of autophagy markers LC3 and p62. Chloroquine (CQ) significantly increased IFITM3 expression, and Rapamycin significantly decreased it. Thus, EG may regulate IFITM3 expression through autophagy. Our results showed that EG could have a solid antiviral activity on BVDV replication in MDBK cells via increased IFITM3 expression, lysosomal acidification, protease activity, and regulated autophagy. EG might have value for further development as an antiviral agent.

Paternally imprinted LATE-FLOWERING2 transcription factor contributes to paternal-excess interploidy hybridization barriers in wheat.

Interploidy hybridization between hexaploid and tetraploid genotypes occurred repeatedly during genomic introgression events throughout wheat evolution, and is commonly employed in wheat breeding programs. Hexaploid wheat usually serves as maternal parent because the reciprocal cross generates progeny with severe defects and poor seed germination, but the underlying mechanism is poorly understood. Here, we performed detailed analysis of phenotypic variation in endosperm between two interploidy reciprocal crosses arising from tetraploid (Triticum durum, AABB) and hexaploid wheat (Triticum aestivum, AABBDD). In the paternal- versus the maternal-excess cross, the timing of endosperm cellularization was delayed and starch granule accumulation in the endosperm was repressed, causing reduced germination percentage. The expression profiles of genes involved in nutrient metabolism differed strongly between these endosperm types. Furthermore, expression patterns of parental alleles were dramatically disturbed in interploidy versus intraploidy crosses, leading to increased number of imprinted genes. The endosperm-specific TaLFL2 showed a paternally imprinted expression pattern in interploidy crosses partially due to allele-specific DNA methylation. Paternal TaLFL2 binds to and represses a nutrient accumulation regulator TaNAC019, leading to reduced storage protein and starch accumulation during endosperm development in paternal-excess cross, as confirmed by interploidy crosses between tetraploid wild-type and clustered regularly interspaced palindromic repeats (CRISPR) - CRISPR-associated protein 9 generated hexaploid mutants. These findings reveal a contribution of genomic imprinting to paternal-excess interploidy hybridization barriers during wheat evolution history and explains why experienced breeders preferentially exploit maternal-excess interploidy crosses in wheat breeding programs.

Factorial structure and measurement invariance of the Chinese version of the Oral Health Impact Profile-14 among clinical populations and non-clinical populations: an evidence for public oral investigations.

OBJECTIVE: Oral health-related quality of life (OHRQoL) is a multidimensional concept that is commonly used to examine the impact of oral health status on quality of life. The purpose of this study was to examine the optimal factor model of the Chinese version of the Oral Health Impact Profile (OHIP-14) questionnaire in clinical populations, measurement invariance across clinical status and gender cohorts. This would ensure equal validity of the Chinese version of OHIP-14 in different populations and further support public oral investigations. METHODS: The Chinese version of OHIP-14 was used to investigate 490 dental patients and 919 college students. Confirmatory factor analysis (CFA), item analysis and reliability, measurement invariance, and the t-test were used for data analyses. RESULTS: We found that the 7-factor structure had the best-fit index in the sample (CFI = 0.970, TLI = 0.952; SRMR = 0.029, RMSEA = 0.052(0.040,0.063)). The reliability of the scales was satisfactory (Cronbach's α = 0.942). The error variance invariance fitted the data adequately in measurement invariance, indicating that measurement invariance is acceptable both across the clinical and non-clinical populations (∆CFI=-0.017, ∆RMSEA = 0.010) and across genders in the clinical population (∆CFI = 0.000, ∆RMSEA=-0.003). T-test for scores showed that the clinical populations scored significantly higher than the non-clinical populations, as did the overall score (t = 7.046, p < 0.001, d = 0.396), in terms of functional limitation (t = 2.178, p = 0.030, d = 0.125), physical pain (t = 7.880, p < 0.001,d = 0.436), psychological discomfort (t = 8.993, p < 0.001, d = 0.514), physical disability (t = 6.343, p < 0.001, d = 0.358), psychological disability (t = 5.592, p < 0.001, d = 0.315), social disability (t = 5.301, p < 0.001,d = 0.304), social handicap (t = 4.452, p < 0.001, d = 0.253), and that in the non-clinical populations, females scored significantly higher than males, as did in terms of physical pain (t = 3.055, p = 0.002, d = 0.280), psychological discomfort (t = 2.478, p = 0.014, d = 0.222), and psychological disability (t = 2.067, p = 0.039, d = 0.188). CONCLUSION: This study found that the Chinese version of OHIP-14 has measurement invariance between the clinical and non-clinical populations and across genders in the clinical populations, and can be widely used in OHRQoL assessment for public oral investigations.

A kelch-repeat superfamily gene, ZmNL4, controls leaf width in maize (Zea mays L.).

Leaf width (LW) is an important component of plant architecture that extensively affects both light capture during photosynthesis and grain yield, particularly under dense planting conditions. However, the genetic and molecular mechanisms regulating LW remain largely elusive in maize (Zea mays L.). In this study, qLW4a, a major quantitative trait locus controlling LW, was identified in a population constructed with maize inbred lines PH6WC, with wide leaves, and Lin387, with narrow leaves. Map-based cloning revealed that ZmNL4, a kelch-repeat superfamily gene, emerged to be the candidate for qLW4a, and a single-base deletion in the conserved SMC_prok_B domain of ZmNL4 in Lin387 caused a frame shift, leading to premature termination. Consistently, the knockout of ZmNL4 by CRISPR/Cas9 editing significantly reduced the LW, which was attributed to a reduction in the cell number instead of cell size, indicating a role of ZmNL4 in regulating cell division. Transcriptomic comparison of ZmNL4 knockout lines with the wild type B73-329 revealed that ZmNL4 might participate in cell wall biogenesis, asymmetric cell division, metabolic processes, transmembrane transport and response to external stimulus, etc. These results provide insights into the genetic and molecular mechanisms of ZmNL4 in controlling LW and could potentially contribute to optimizing plant architecture for maize breeding.

Synthesis of Nitrogen-Doped Aza-Helicenes with Chiral Optical Properties.

Aza-helicenes are one of the most important series of heterohelicenes; herein, a series of novel aza-helicenes (5H, 6H, 6S, and 8S) were prepared via Bischler-Napieralski cyclization, and the interconversion dynamic process of these aza-helicenes was revealed using density functional theory calculations. The novel nitrogen-doped [6]helicene (6H) possesses a very high interconversion energy barrier of 36.0 kcal/mol. Two enantiomers of 6H were successfully resolved by high-performance liquid chromatography and showed desired chiral optical properties. 6H with chiral optical activity and lone electrons can be a potential candidate for chiral switches, which was demonstrated using the UV and circular dichroism spectra obtained upon titration with an acid and a base.