P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy.

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.

Mechanofluorochromic behaviors and data security protection properties of salicylaldimine-based difluoroboron complexes with different aryl substituents.

To further explore the relationship between aryl substituents and mechanofluorochromic (MFC) behaviors, four salicylaldimine-based difluoroboron complexes (ts-Ph BF2, ts-Ph-NA BF2, ts-2NA BF2, and ts-triphenylamine [TPA] BF2), including aromatic substituents with different steric hindrance effects, were designed and successfully synthesized. Four complexes with twisted molecular conformation displayed intramolecular charge transfer and aggregation-induced emission properties. Under external mechanical stimuli, the as-synthesized powders of ts-Ph BF2, ts-Ph-NA BF2, and ts-TPA BF2 exhibited redshift fluorescence emission behaviors, and ts-Ph BF2 and ts-TPA BF2 could be recovered to original shifts by fuming, but ts-Ph-NA BF2 displayed irreversible switching. ts-2NA BF2 had no change during the grinding and fuming processes. The results indicated that the MFC behaviors could be attributed to the phase transformation between the well-defined crystalline and disordered amorphous states by X-ray diffraction measurement. Further research illustrated that ts-TPA BF2 with the most significant MFC phenomenon could be applied in data security protection in ink-free rewritable paper.

Customization options in consumer health information materials on type-2 diabetes mellitus-an analysis of modifiable features in different types of media.

Introduction: The understanding of health-related information is essential for making informed decisions. However, providing health information in an understandable format for everyone is challenging due to differences in consumers' health status, disease knowledge, skills, and preferences. Tailoring health information to individual needs can improve comprehension and increase health literacy. Objective: The aim of our research was to analyze the extent to which consumers can customize consumer health information materials (CHIMs) for type-2 diabetes mellitus through various media types. Methods: We conducted a comprehensive search for various CHIMs across various media types, such as websites, apps, videos, and printed or printable forms. A representative sample of CHIMs was obtained for analysis through blocked randomization across the various media types. We conducted a quantitative content analysis to determine the frequency of user-centered customization options. Cross-comparisons were made to identify trends and variations in modifiable features among the media. Results: In our representative sample of 114 CHIMs, we identified a total of 24 modifiable features, which we grouped into five main categories: (i) language, (ii) text, (iii) audiovisual, (iv) presentation, and (v) medical content. Videos offered the most customization opportunities (95%), while 47% of websites and 26% of apps did not allow users to tailor health information. None of the printed or printable materials provided the option to customize the information. Overall, 65% of analyzed CHIMs did not allow users to tailor health information according to their needs. Conclusion: Our results show that CHIMs for type-2 diabetes mellitus could be significantly improved by providing more customization options for users. Further research is needed to investigate the effectiveness and usability of these options to enhance the development and appropriate provision of modifiable features in health information.

[Virtual preoperative planning and 3D-printed templates for pre-contoured plates in treatment of acetabular posterior wall fractures].

OBJECTIVE: To evaluate the feasibility and accuracy of virtual preoperative planning and 3D-printed templates for pre-contoured plates for the treatment of posterior wall fractures of the acetabulum. METHODS: A retrospective analysis of 29 patients with posterior acetabular wall fractures treated between August 2017 and March 2021 were divided into 2 groups based on whether to use preoperative virtual planning and 3D printed template. In 3D-printing group, there were 14 patients, including 10 males and 4 females； aged from 21 to 53 years old；CT-based virtual surgical planning was done using Mimics and 3-Matic software and 3D-printed templates for pre-contoured plates were adopted. In conventional group, there were 15 patients, including 10 males and 5 females；aged from 19 to 55 years old；conventional method of intra-operative contouring to adapt the plate to the fracture region was adopted. Blood loss, surgical time, radiographic quality of reduction, and hip function were compared between groups. RESULTS: The difference in operation time and intraoperative blood loss was significant（P<0.05）. Twenty-three patients were followed up from 12 to 30 months, and the fractures in both groups healed with a healing time of 3 to 6 months. At the last follow-up, the Merle d'Aubign-Postel score of the 3D printed group was lower than that of the conventional group（P<0.05）, with no significant differences in walking ability, hip mobility and total score（P>0.05）. In 3D printing group, 6 cases were excellent, 5 cases were good, 3 cases were fair；in conventional group, 5 cases were excellent, 5 cases were good, 4 cases were fair, 1 case was worse；no significant difference between two groups（P>0.05）. CONCLUSION: Virtual preoperative planning and 3D-printed templates for pre-contoured plates can reduce operative time and the blood loss of surgery, improve the quality of reduction. This method is efficient, accurate and reliable to treat acetabular posterior wall fractures.

A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.

Autophagic mechanisms that maintain nuclear envelope homeostasis are bulwarks to aging and disease. By leveraging 4D lattice light sheet microscopy and correlative light and electron tomography, we define a quantitative and ultrastructural timeline of a nuclear macroautophagy (nucleophagy) pathway in yeast. Nucleophagy initiates with a rapid local accumulation of the nuclear cargo adaptor Atg39 at the nuclear envelope adjacent to the nucleus-vacuole junction and is delivered to the vacuole in ~300 seconds through an autophagosome intermediate. Mechanistically, nucleophagy incorporates two consecutive and genetically defined membrane fission steps: inner nuclear membrane (INM) fission generates a lumenal vesicle in the perinuclear space followed by outer nuclear membrane (ONM) fission to liberate a double membraned vesicle to the cytosol. ONM fission occurs independently of phagophore engagement and instead relies surprisingly on dynamin-like protein1 (Dnm1), which is recruited to sites of Atg39 accumulation at the nuclear envelope. Loss of Dnm1 compromises nucleophagic flux by stalling nucleophagy after INM fission. Our findings reveal how nuclear and INM cargo are removed from an intact nucleus without compromising its integrity, achieved in part by a non-canonical role for Dnm1 in nuclear envelope remodeling.

Novel aminothiazoximone-corbelled ethoxycarbonylpyrimidones with antibiofilm activity to conquer Gram-negative bacteria through potential multitargeting effects.

The emergence of drug-resistant microorganisms threatens human health, and it is usually exacerbated by the formation of biofilm, which forces the development of new antibacterial agents with antibiofilm activity. In this work, a novel category of aminothiazoximone-corbelled ethoxycarbonylpyrimidones (ACEs) was designed and synthesized, and some of the prepared ACEs showed potent bioactivity against the tested bacteria. In particular, imidazolyl ACE 6c showed better inhibitory activity towards Acinetobacter baumannii and Escherichia coli with MIC values both of 0.0066 mmol/L than norfloxacin. It was also revealed that imidazolyl ACE 6c not only possessed inconspicuous hemolytic rate and cytotoxicity, low drug resistance and no risk of penetrating the blood-brain barrier, but also exhibited obvious biofilm inhibition and eradication activities. The preliminary mechanism research suggested that imidazolyl ACE 6c could induce metabolic dysfunction by deactivating lactate dehydrogenase and promote the accumulation of reactive oxygen species to decrease the reduced glutathione and ultimately cause oxidative damage in bacteria. Furthermore, ACE 6c was also found that could insert into DNA to form the supramolecular complex of 6c-DNA and trigger cell death. The multidimensional effect might promote bacterial cell rupture, leading to the leakage of intracellular content. These findings manifested that novel imidazolyl ACE 6c as a potential multitargeting antibacterial agent with potent antibiofilm activity could provide new possibility for the treatment of refractory biofilm-intensified bacterial infections.

Proton-fluence dependent magnetic properties of exfoliable quasi-2D van der Waals Cr2Si2Te6magnet.

The discovery of long-range magnetic ordering in atomically thin materials catapulted the van der Waals (vdW) family of compounds into an unprecedented popularity, leading to potentially important technological applications in magnetic storage and magneto-transport devices, as well as photoelectric sensors. With the potential for the use of vdW materials in space exploration technologies it is critical to understand how the properties of such materials are affected by ionizing proton irradiation. Owing to their robust intra-layer stability and sensitivity to external perturbations, these materials also provide excellent opportunities for studying proton irradiation as a non-destructive tool for controlling their magnetic properties. Specifically, the exfoliable Cr2Si2Te6(CST) is a ferromagnetic semiconductor with the Curie temperature (TC) of ∼32 K. Here, we have investigated the magnetic properties of CST upon proton irradiation as a function of fluence (1 × 1015, 5 × 1015, 1 × 1016, 5 × 1016, and 1 × 1018H+/cm-2) by employing variable-temperature, variable-field magnetization measurements, and detail how the magnetization, magnetic anisotropy vary as a function of proton fluence across the magnetic phase transition. While theTCremains constant as a function of proton fluence, we observed that the saturation magnetization and magnetic anisotropy diverge at the proton fluence of 5 × 1016H+/cm-2, which is prominent in the ferromagnetic phase, in particular.This work demonstrates that proton irradiation is a feasible method for modifying the magnetic properties and local magnetic interactions of vdWs crystals, which represents a significant step forward in the design of future spintronic and magneto-electronic applications.

PPM1G promotes cell proliferation via modulating mutant GOF p53 protein expression in hepatocellular carcinoma.

The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p < 0.0001) and disease-free survival (p = 0.004) in HCC patients. Enhanced expression of PPM1G increases the cell proliferation rate, and knockdown of PPM1G led to a significant reduction in tumor volume in vivo. Further experiments illustrated that upregulated-PPM1G expression increased the protein expression of gain-of-function (GOF) mutant p53. Besides, the immunoprecipitation analysis revealed a direct interaction between PPM1G and GOF mutant p53. Collectively, PPM1G can be a powerful prognostic predictor and potential drug-target molecule.

Spatiotemporal transcriptomic atlas of rhizome formation in Oryza longistaminata.

Rhizomes are modified stems that grow underground and produce new individuals genetically identical to the mother plant. Recently, a breakthrough has been made in efforts to convert annual grains into perennial ones by utilizing wild rhizomatous species as donors, yet the developmental biology of this organ is rarely studied. Oryza longistaminata, a wild rice species featuring strong rhizomes, provides a valuable model for exploration of rhizome development. Here, we first assembled a double-haplotype genome of O. longistaminata, which displays a 48-fold improvement in contiguity compared to the previously published assembly. Furthermore, spatiotemporal transcriptomics was performed to obtain the expression profiles of different tissues in O. longistaminata rhizomes and tillers. Two spatially reciprocal cell clusters, the vascular bundle 2 cluster and the parenchyma 2 cluster, were determined to be the primary distinctions between the rhizomes and tillers. We also captured meristem initiation cells in the sunken area of parenchyma located at the base of internodes, which is the starting point for rhizome initiation. Trajectory analysis further indicated that the rhizome is regenerated through de novo generation. Collectively, these analyses revealed a spatiotemporal transcriptional transition underlying the rhizome initiation, providing a valuable resource for future perennial crop breeding.

Novel missense mutation c.797T>C (p.Met266Thr) gives rise to the rare B(A) phenotype in a Chinese family.

BACKGROUND AND OBJECTIVES: B(A) phenotype is usually formed by nucleotide mutations in the ABO*B.01 allele, with their products exhibiting glycosyltransferases (GTs) A and B overlapping functionality. We herein report a B(A) allele found in a Chinese family. MATERIALS AND METHODS: The entire ABO genes of the probands, including flanking regulatory regions, were sequenced through PacBio third-generation long-read single-molecule real-time sequencing. 3D molecular models of the wild-type and mutant GTB were generated using the DynaMut web server. The effect of the mutation on the enzyme function was predicted by PROVEAN and PolyPhen2. The predictions of stability changes were performed using DynaMut and SNPeffect. RESULTS: Based on serological and sequencing features, we concluded the two probands as possible cases of the B(A) phenotype. Crystallization analysis showed that Thr266 substitution does not disrupt the hydrogen bonds. However, some changes in interatomic contacts, such as loss of ionic interactions and hydrophobic contacts, and addition of weak hydrogen bonds, may have affected protein stability to some extent. This mutation was predicted to have a benign effect on enzyme function and slightly reduce protein stability. CONCLUSION: The probands had the same novel B(A) allele with a c.797T>C (p.Met266Thr) mutation on the ABO*B.01 backbone.

LR Aerial Photo Categorization by Cross-Resolution Perceptual Knowledge Propagation.

There are hundreds of high-and low-altitude earth observation satellites that asynchronously capture massive-scale aerial photographs every day. Generally, high-altitude satellites take low-resolution (LR) aerial pictures, each covering a considerably large area. In contrast, low-altitude satellites capture high-resolution (HR) aerial photos, each depicting a relatively small area. Accurately discovering the semantics of LR aerial photos is an indispensable technique in computer vision. Nevertheless, it is also a challenging task due to: 1) the difficulty to characterize human hierarchical visual perception and 2) the intolerable human resources to label sufficient training data. To handle these problems, a novel cross-resolution perceptual knowledge propagation (CPKP) framework is proposed, focusing on adapting the visual perceptual experiences deeply learned from HR aerial photos to categorize LR ones. Specifically, by mimicking the human vision system, a novel low-rank model is designed to decompose each LR aerial photo into multiple visually/semantically salient foreground regions coupled with the background nonsalient regions. This model can: 1) produce a gaze-shifting path (GSP) simulating human gaze behavior and 2) engineer the deep feature for each GSP. Afterward, a kernel-induced feature selection (FS) algorithm is formulated to obtain a succinct set of deep GSP features discriminative across LR and HR aerial photos. Based on the selected features, the labels from LR and HR aerial photos are collaboratively utilized to train a linear classifier for categorizing LR ones. It is worth emphasizing that, such a CPKP mechanism can effectively optimize the linear classifier training, as labels of HR aerial photos are acquired more conveniently in practice. Comprehensive visualization results and comparative study have validated the superiority of our approach.

Investigating the simultaneous impact of infrastructure and geographical factors on international trade: Evidence from asian economies.

Infrastructure and geography are the most important components of international trade. They provide trade-oriented amenities for the trade volume among trading partners. Thus, this study assesses the simultaneous impact of infrastructure and geographic factors on trade in Asian economies from 2004 to 2020. This work contributes to the existing literature by exploring the significance of infrastructure and geography in international trade. Furthermore, this research seeks to determine whether these factors have complementary or simultaneous effects. To examine these aspects, the augmented gravity model and cross-sectional autoregressive distributed lags are used in the current model. Then, the multilateral resistance terms are corrected. Results reveal that infrastructure has a significant and positive impact on trade. More precisely, transport infrastructure, communication infrastructure, financial infrastructure, and border-transport efficiency are productive influencers for trade over a certain period. Notably, the simultaneous impacts of infrastructure and geographic factors can lead to the deterioration of trade volume. The policy implications and future research direction of this study suggest that economies should improve infrastructure and geographic factors through gross domestic product.

Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates.

Unique benzopyridone cyanoacetates (BCs) as new type of promising broad-spectrum antibacterial candidates were discovered with large potential to combat the lethal multidrug-resistant bacterial infections. Many prepared BCs showed broad antibacterial spectrum with low MIC values against the tested strains. Some highly active BCs exhibited rapid sterilization capacity, low resistant trend and good predictive pharmacokinetic properties. Furthermore, the highly active sodium BCs (NaBCs) displayed low hemolysis and cytotoxicity, and especially octyl NaBC 5g also showed in vivo potent anti-infective potential and appreciable pharmacokinetic profiles. A series of preliminary mechanistic explorations indicated that these active BCs could effectively eliminate bacterial biofilm and destroy membrane integrity, thus resulting in the leakage of bacterial cytoplasm. Moreover, their unique structures might further bind to intracellular DNA, DNA gyrase and topoisomerase IV through various direct noncovalent interactions to hinder bacterial reproduction. Meanwhile, the active BCs also induced bacterial oxidative stress and metabolic disturbance, thereby accelerating bacterial apoptosis. These results provided a bright hope for benzopyridone cyanoacetates as potential novel multitargeting broad-spectrum antibacterial candidates to conquer drug resistance.

Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation.

Proliferating cancer cells are characterized by the Warburg effect, a metabolic alteration in which ATP is generated from cytoplasmic glycolysis instead of oxidative phosphorylation. The pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis plays a crucial role in this effect and has been identified as a potential target for anticancer drug development. Herein, we present the discovery and pharmacological evaluation of potent PDK inhibitors targeting the PDK/PDC axis. We successfully identified 6 compounds from a small molecule library through a structure-based virtual screening campaign and evaluated their enzymatic inhibitory potencies for PDK1-4. Our results indicated that compound 1 exhibited submicromolar inhibitory activities against PDK1-3 (IC50 = 109.3, 135.8, and 458.7 nM, respectively), but is insensitive to PDK4 (IC50 = 8.67 µM). Furthermore, compound 1 inhibited the proliferation of A549 cells with an EC50 value of 10.7 µM. In addition, compound 1 induced cell apoptosis, arrested the cell cycle at the S phase, and reduced cell invasion and migration, while showing low in vivo toxicity at a high dose. Based on these observations, it can be concluded that compound 1 is a promising anti-PDK1-3 lead that merits further investigation.

Role of solute carrier transporters in regulating dendritic cell maturation and function.

Dendritic cells (DCs) are specialized antigen-presenting cells that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases.

Development of membrane-targeting TPP+-chloramphenicol conjugates to combat methicillin-resistant staphylococcus aureus (MRSA) infections.

Infections caused by drug-resistant bacteria have become a new challenge in infection treatment, gravely endangering public health. Chloramphenicol (CL) is a well-known antibiotic which has lost its efficacy due to bacterial resistance. To address this issue, herein we report the design, synthesis and biological evaluations of novel triphenylphosphonium chloramphenicol conjugates (TPP+-CL). Study results indicated that compounds 39 and 42 possessed remarkable antibacterial effects against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 2 µg/mL, while CL was inactive to the tested MRSA strains. In addition, these conjugates exhibited rapid bactericidal properties and low toxicity, and did not readily induced bacterial resistance, obviously outperforming the parent drug CL. In a mouse model infected with a clinically isolated MRSA strain, compound 39 at a dose of 20 mg/kg exhibited a comparable or even better in vivo anti-MRSA efficacy than the golden standard drug vancomycin, while no toxicity was observed.