Native Mass Spectrometry-Centric Approaches Revealed That Neuropeptides Frequently Interact with Amyloid-ß.

Amyloid-ß (Aß) aggregates are recognized as initiators of Alzheimer's disease, and their interaction with the nervous system contributes to the progression of neurodegeneration. Herein, we investigated the frequency at which neuropeptides interact with Aß and affect the aggregation kinetics and cytotoxicity of Aß. To this end, we established a native mass spectrometry (MS)-centric workflow for screening Aß-interacting neuropeptides, and six out of 12 neuropeptides formed noncovalent complexes with Aß species in the MS gas phase. Thioflavin-T fluorescence assays and gel separation indicated that leptin and cerebellin decreased Aß aggregation, whereas kisspeptin increased this process. In addition, leptin and cerebellin attenuated Aß-induced cytotoxicity, which was independent of the influence of metal ions. Leptin can chelate copper from copper-bound Aß species, reducing the cytotoxicity caused by the aggregation of Aß and metal ion complexes. Overall, our study demonstrated that neuropeptides frequently interact with Aß and revealed that leptin and cerebellin are potential inhibitors of Aß aggregation, providing great insight into understanding the molecular mechanism of Aß interacting with the nervous system and facilitating drug development.

Constructing Slip Stacking Diversity in Van der Waals Homobilayers.

The van der Waals (vdW) interface provides two important degrees of freedom-twist and slip-to tune interlayer structures and inspire unique physics. However, constructing diversified high-quality slip stackings (i.e., lattice orientations between layers are parallel with only interlayer sliding) is more challenging than twisted stackings due to angstrom-scale structural discrepancies between different slip stackings, sparsity of thermodynamically stable candidates and insufficient mechanism understanding. Here, using transition metal dichalcogenide (TMD) homobilayers as a model system, this work theoretically elucidates that vdW materials with low lattice symmetry and weak interlayer coupling allow the creation of multifarious thermodynamically advantageous slip stackings, and experimentally achieves 13 and 9 slip stackings in 1T″-ReS2 and 1T″-ReSe2 bilayers via direct growth, which are systematically revealed by atomic-resolution scanning transmission electron microscopy (STEM), angle-resolved polarization Raman spectroscopy, and second harmonic generation (SHG) measurements. This work also develops modulation strategies to switch the stacking via grain boundaries (GBs) and to expand the slip stacking library from thermodynamic to kinetically favored structures via in situ thermal treatment. Finally, density functional theory (DFT) calculations suggest a prominent dependence of the pressure-induced electronic band structure transition on stacking configurations. These studies unveil a unique vdW epitaxy and offer a viable means for manipulating interlayer atomic registries.

Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery.

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m6A writers Mettl3 and Mettl14, nor the m6A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

Application of a calcium and phosphorus biomineralization strategy in tooth repair: a systematic review.

Biomineralization is a natural process in which organisms regulate the growth of inorganic minerals to form biominerals with unique layered structures, such as bones and teeth, primarily composed of calcium and phosphorus. Tooth decay significantly impacts our daily lives, and the key to tooth regeneration lies in restoring teeth through biomimetic approaches, utilizing mineralization strategies or materials that mimic natural processes. This review delves into the types, properties, and transformations of calcium and phosphorus minerals, followed by an exploration of the mechanisms behind physiological and pathological mineralization in living organisms. It summarizes the mechanisms and commonalities of biomineralization and discusses the advancements in dental biomineralization research, guided by insights into calcium and phosphorus mineral biomineralization. This review concludes by addressing the current challenges and future directions in the field of dental biomimetic mineralization.

Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.

The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.

Testis tissue cryopreservation may be considered in boys with cryptorchidism.

ABSTRACT: This study assessed the feasibility of testis tissue cryopreservation (TTC) for fertility preservation in prepubescent boys with cryptorchidism. From January 2014 to December 2022, the University Hospital of Copenhagen (Rigshospitalet, Copenhagen, Denmark) implemented TTC for 56 boys with cryptorchidism to preserve their reproductive potential. Testis tissue samples were collected during orchiopexy (32 cases) or at subsequent follow-up procedures (24 cases), necessitated by an increased risk of infertility as indicated by hormonal assessments and/or findings from initial surgical biopsies. Testis samples were procured for TTC and pathological analysis. The cohort had an average age of 1.3 (range: 0.3-3.8) years at the time of orchiopexy, with 91.1% presenting bilateral cryptorchidism. The study revealed a median germ cell count of 0.39 (range: 0-2.88) per seminiferous tubule, with germ cells detected in 98.0% of the bilateral biopsies and 100% of the unilateral, indicating a substantial potential for fertility in these immature tissues. A dark spermatogonia (Ad) was detected in 37 out of 56 patients evaluated, with a median Ad spermatogonia count of 0.027 (range: 0.002-0.158) per seminiferous tubule. A total of 30.2% of the samples lacked Ad spermatogonia, indicative of potential gonadotrophin insufficiency. The median hormone levels measured were as follows: follicle-stimulating hormone (FSH) at 0.69 (range: 0.16-2.5) U l-1, luteinizing hormone (LH) at 0.21 (range: 0.05-3.86) U l-1, and inhibin B at 126 (range: 17-300) pg ml-1. Despite early orchiopexy, 20%-25% of boys with cryptorchidism remain at risk for future infertility, substantiating the necessity of TTC as a precaution. The study highlights the need for refined predictive techniques to identify boys at higher risk of future infertility.

Poly(Lysine)-Derived Carbon Quantum Dots Conquer Enterococcus faecalis Biofilm-Induced Persistent Endodontic Infections.

Introduction: Persistent endodontic infections (PEIs) mediated by bacterial biofilm mainly cause persistent periapical inflammation, resulting in recurrent periapical abscesses and progressive bone destruction. However, conventional root canal disinfectants are highly damaging to the tooth and periodontal tissue and ineffective in treating persistent root canal infections. Antimicrobial materials that are biocompatible with apical tissues and can eliminate PEIs-associated bacteria are urgently needed. Methods: Here, ε-poly (L-lysine) derived carbon quantum dots (PL-CQDs) are fabricated using pyrolysis to remove PEIs-associated bacterial biofilms. Results: Due to their ultra-small size, high positive charge, and active reactive oxygen species (ROS) generation capacity, PL-CQDs exhibit highly effective antibacterial activity against Enterococcus faecalis (E. faecalis), which is greatly dependent on PL-CQDs concentrations. 100 µg/mL PL-CQDs could kill E. faecalis in 5 min. Importantly, PL-CQDs effectively achieved a reduction of biofilms in the isolated teeth model, disrupting the dense structure of biofilms. PL-CQDs have acceptable cytocompatibility and hemocompatibility in vitro and good biosafety in vivo. Discussion: Thus, PL-CQDs provide a new strategy for treating E. faecalis-associated PEIs.

Metabolomics efficiently discriminates monozygotic twins in peripheral blood.

Monozygotic (MZ) twins cannot be distinguished using conventional forensic STR typing because they present identical STR genotypings. However, MZ twins do not always live in the same environment and often have different dietary and other lifestyle habits. Metabolic profiles are deyermined by individual characteristics and are also influenced by the environment in which they live. Therefore, they are potential markers capable of identifying MZ twins. Moreover, the production of proteins varies from organism to organism and is influenced by both the physiological state of the body and the external environment. Hence, we used metabolomics and proteomics to identify metabolites and proteins in peripheral blood to discriminate MZ twins. We identified 1749 known metabolites and 622 proteins in proteomic analysis. The metabolic profiles of four pairs of MZ twins revealed minor differences in intra-MZ twins and major differences in inter-MZ twins. Each pair of MZ twins exhibited distinct characteristics, and four metabolites-methyl picolinate, acesulfame, paraxanthine, and phenylbenzimidazole sulfonic acid-were observed in all four MZ twin pairs. These four differential exogenous metabolites conincidently show that the different external environments and life styles can be well distinguished by metabolites, considering that twins do not all have the same eating habits and living environments. Moreover, MZ twins showed different protein profiles in serum but not in whole blood. Thus, our results indicate that differential metabolites provide potential biomarkers for the personal identification of MZ twins in forensic medicine.

Unlocking Efficiency: Minimizing Energy Loss in Electrocatalysts for Water Splitting.

Catalysts play a crucial role in water electrolysis by reducing the energy barriers for hydrogen and oxygen evolution reactions (HER and OER). Research aims to enhance the intrinsic activities of potential catalysts through material selection, microstructure design, and various engineering techniques. However, the energy consumption of catalysts has often been overlooked due to the intricate interplay among catalyst microstructure, dimensionality, catalyst-electrolyte-gas dynamics, surface chemistry, electron transport within electrodes, and electron transfer among electrode components. Efficient catalyst development for high-current-density applications is essential to meet the increasing demand for green hydrogen. This involves transforming catalysts with high intrinsic activities into electrodes capable of sustaining high current densities. This review focuses on current improvement strategies of mass exchange, charge transfer, and reducing electrode resistance to decrease energy consumption. It aims to bridge the gap between laboratory-developed, highly efficient catalysts and industrial applications regarding catalyst structural design, surface chemistry, and catalyst-electrode interplay, outlining the development roadmap of hierarchically structured electrode-based water electrolysis for minimizing energy loss in electrocatalysts for water splitting.

Elastic Properties of Low-Dimensional Single-Crystalline Dielectric Oxides through Controlled Large-Area Wrinkle Generation.

Freestanding single-crystalline SrTiO3 membranes, as high-κ dielectrics, hold significant promise as the gate dielectric in two-dimensional (2D) flexible electronics. Nevertheless, the mechanical properties of the SrTiO3 membranes, such as elasticity, remain a critical piece of the puzzle to adequately address the viability of their applications in flexible devices. Here, we report statistical analysis on plane-strain effective Young's modulus of large-area SrTiO3 membranes (5 × 5 mm2) over a series of thicknesses (from 6.5 to 32.2 nm), taking advantage of a highly efficient buckling-based method, which reveals its evident thickness-dependent behavior ranging from 46.01 to 227.17 GPa. Based on microscopic and theoretical results, we elucidate these thickness-dependent behaviors and statistical data deviation with a bilayer model, which consists of a surface layer and a bulk-like layer. The analytical results show that the ∼3.1 nm surface layer has a significant elastic softening compared to the bulk-like layer, while the extracted modulus of the bulk-like layer shows a variation of ∼40 GPa. This variation is considered as a combined contribution from oxygen deficiency presenting in SrTiO3 membranes, and the alignment between applied strain and the crystal orientation. Upon comparison of the extracted elastic properties and electrostatic control capability to those of other typical gate dielectrics, the superior performance of single-crystalline SrTiO3 membranes has been revealed in the context of flexible gate dielectrics, indicating the significant potential of their application in high-performance flexible 2D electronics.

Sulfated Chitosan-Modified CuS Nanocluster: A Versatile Nanoformulation for Simultaneous Antibacterial and Bone Regenerative Therapy in Periodontitis.

Periodontitis, a prevalent chronic inflammatory disease worldwide, is triggered by periodontopathogenic bacteria, resulting in the progressive destruction of periodontal tissue, particularly the alveolar bone. To effectively address periodontitis, this study proposed a nanoformulation known as CuS@MSN-SCS. This formulation involves coating citrate-grafted copper sulfide (CuS) nanoparticles with mesoporous silica (MSNs), followed by surface modification using amino groups and sulfated chitosan (SCS) through electrostatic interactions. The objective of this formulation is to achieve efficient bacteria removal by inducing ROS signaling pathways mediated by Cu2+ ions. Additionally, it aims to promote alveolar bone regeneration through Cu2+-induced pro-angiogenesis and SCS-mediated bone regeneration. As anticipated, by regulating the surface charges, the negatively charged CuS nanoparticles capped with sodium citrate were successfully coated with MSNs, and the subsequent introduction of amine groups using (3-aminopropyl)triethoxysilane was followed by the incorporation of SCS through electrostatic interactions, resulting in the formation of CuS@MSN-SCS. The developed nanoformulation was verified to not only significantly exacerbate the oxidative stress of Fusobacterium nucleatum, thereby suppressing bacteria growth and biofilm formation in vitro, but also effectively alleviate the inflammatory response and promote alveolar bone regeneration without evident biotoxicity in an in vivo rat periodontitis model. These findings contribute to the therapeutic effect on periodontitis. Overall, this study successfully developed a nanoformulation for combating bacteria and facilitating alveolar bone regeneration, demonstrating the promising potential for clinical treatment of periodontitis.

Increased TMEM166 Level in Patients with Postoperative Stroke after Carotid Endarterectomy.

Postoperative stroke is a challenging and potentially devastating complication after elective carotid endarterectomy (CEA). We previously demonstrated that transmembrane protein 166 (TMEM166) levels were directly related to neuronal damage after cerebral ischemia-reperfusion injury in rats. In this subsequent clinical study, we aimed to evaluate the prognostic value of TMEM166 in patients suffering from post-CEA strokes. Thirty-five patients undergoing uncomplicated elective CEA and 8 patients who suffered ischemic strokes after CEA were recruited. We evaluated the protein level and expression of TMEM166 in patients diagnosed with postoperative strokes and compared it to those in patients who underwent uncomplicated elective CEA. Blood samples and carotid artery plaques were collected and analyzed. High expressions of TMEM166 were detected by immunofluorescence staining and Western Blot in carotid artery plaques of all patients who underwent CEA. Furthermore, circulating TMEM166 concentrations were statistically higher in post-CEA stroke patients than in patients allocated to the control group. Mean plasma concentrations of inflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP), were also elevated in patients with postoperative strokes. Therefore, based on these findings, we hypothesize that elevated TMEM166 levels, accompanied by a strong inflammatory response, serve as a useful biomarker for risk assessment of postoperative stroke following CEA.

An improved chromosome-level genome assembly and annotation of Echeneis naucrates.

Echeneis naucrates, as known as live sharksucker, is famous for the behavior of attaching to hosts using a highly modified dorsal fin with oval-shaped sucking disc. Here, we generated an improved high-quality chromosome-level genome assembly of E. naucrates using Illumina short reads, PacBio long reads and Hi-C data. Our assembled genome spans 572.85 Mb with a contig N50 of 23.19 Mb and is positioned to 24 pseudo-chromosomes. Additionally, at least one telomere was identified for 23 out of 24 chromosomes. Furthermore, we identified a total of 22,161 protein-coding genes, of which 21,402 genes (96.9%) were annotated successfully with functions. The combination of ab initio predictions and Repbase-based searches revealed that 15.57% of the assembled E. naucrates genome was identified as repetitive sequences. The completeness of the genome assembly and the gene annotation were estimated to be 97.5% and 95.4% with BUSCO analyses. This work enhances the utility of the live sharksucker genome and provides a valuable groundwork for the future study of genomics, biology and adaptive evolution in this species.

Peroxynitrite imaging in ferroptosis-mediated drug-induced liver injury with a near-infrared fluorescence probe.

BACKGROUND: Over-consumption of drugs can result in drug-induced liver damage (DILI), which can worsen liver failure. Numerous studies have shown the significant role ferroptosis plays in the pathophysiology of DILI, which is typified by a marked imbalance between the generation and breakdown of lipid reactive oxygen species (ROS). The content of peroxynitrite (ONOO-) rapidly increased during this process and was thought to be a significant marker of early liver injury. Therefore, the construction of fluorescence probe for the detection and imaging of ONOO- holds immense importance in the early diagnosis and treatment of ferroptosis-mediated DILI. RESULTS: We designed a probe DILI-ONOO based on the ICT mechanism for the purpose of measuring and visualizing ONOO- in ferroptosis-mediated DILI processes and associated studies. This probe exhibited significant fluorescence changes with good sensitivity, selectivity, and can image exogenous and endogenous ONOO- in cells with low cytotoxicity. Using this probe, we were able to show changes in ONOO- content in ferroptosis-mediated DILI cells and mice models induced by the intervention of acetaminophen (APAP) and isoniazid (INH). By measuring the concentration of ferroptosis-related indicators in mice liver tissue, we were able to validate the role of ferroptosis in DILI. It is worth mentioning that compared to existing alanine transaminase (ALT) and aspartate aminotransferase (AST) detection methods, this probe can achieve early identification of DILI prior to serious liver injury. SIGNIFICANCE: This work has significant reference value in researching the relationship between ferroptosis and DILI and visualizing research. The results indicate a strong correlation between the progression of DILI and ferroptosis. Additionally, the use of DILI-ONOO shows promise in investigating the DILI process and assessing the effectiveness of medications in treating DILI.

The first chromosomal-level genome assembly and annotation of white suckerfish Remora albescens.

Remora albescens, also known as white suckerfish, recognized for its distinctive suction-cup attachment behavior and medicinal significance. In this study, we produced a high-quality chromosome-level genome assembly of R. albescens through the integration of 23.87 Gb PacBio long reads, 64.54 Gb T7 short reads, and 88.63 Gb Hi-C data. Initially, we constructed a contig-level genome assembly totaling 605.30 Mb with a contig N50 of 23.12 Mb. Subsequently, employing Hi-C technology, approximately 99.68% (603.38 Mb) of the contig-level genome was successfully assigned to 23 pseudo-chromosomes. Through the integration of homologous-based predictions, ab initio predictions, and RNA-sequencing methods, we successfully identified a comprehensive set of 22,445 protein-coding genes. Notably, 96.36% (21,629 genes) of these were effectively annotated with functional information. The genome assembly achieved an estimated completeness of 98.1% according to BUSCO analysis. This work promotes the applicability of the R. albescens genome, laying a solid foundation for future investigations into genomics, biology, and medicinal importance within this species.

A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm.

Sepsis is an infection-triggered, rapidly progressive systemic inflammatory syndrome with a high mortality rate. Currently, there are no promising therapeutic strategies for managing this disease in the clinic. Heparanase plays a crucial role in the pathology of sepsis, and its inhibition can significantly relieve related symptoms. Here, a novel heparanase inhibitor CV122 is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)-induced sepsis mouse models are evaluated. It is found that CV122 potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, CV122 significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis-induced death. Mechanistically, CV122 inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that CV122 provides effective protection from organ damage and death caused by Crimean-Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that CV122 is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm.

SnO2/Au Microelectromechanical Systems Modified by Oxygen Vacancies for Enhanced Sensing of Dioctyl Phthalate.

Dioctyl phthalate (DOP) serves as a characteristic gas utilized in early electrical fire detection, its detection offers promising prospects for the prevention of electrical fires. In this study, we employed a modified photodeposition method to prepare Tin dioxide (SnO2) materials co-modified with Au and oxygen vacancies. Subsequently, microelectromechanical systems (MEMS) gas sensor for DOP detection were fabricated, utilizing 0.5 %Au/SnO2-I as the sensing material. Characterization results reveal the presence of abundant oxygen vacancies in 0.5 %Au/SnO2-I. The synergistic interplay of Au and oxygen vacancies resulted in a remarkable response of 9.98 to 20 ppm of DOP at operational temperature of 250 °C. This represents a significant 96 % enhancement in comparison to the response value of 4.50 exhibited by pure SnO2 at 300 °C. Notably, this gas sensor boasts low power consumption and demonstrates a quick response in the detection of overheating polyvinyl chloride (PVC) cables under simulated conditions.

Where to start: Use of the bilingual multidimensional ability scale (B-MAS) to identify developmental language disorder (DLD) in bilingual children.

PURPOSE: The identification of developmental language disorder (DLD) is challenging for clinicians who assess bilinguals. This paper introduces a protocol-based approach, the Bilingual Multidimensional Ability Scale (B-MAS), for expert raters to identify DLD in bilinguals. METHOD: Three bilingual speech-language pathologists (SLPs) reviewed 166 Spanish-English bilingual children's profiles, which included performance on direct (morphosyntax, semantics, and narrative tasks) and indirect (parent/teacher survey) measures in both languages. A multidimensional scale (0-5) was adopted to rate children's performance. A diagnosis of DLD was made if at least two raters assigned a summary rating of ≤2. RESULT: Analysis of the scores on the B-MAS resulted in the identification of 21 children as having DLD. Though different strategies were employed to make decisions, the three SLPs demonstrated high inter-rater agreement across different ratings (intraclass correlation coefficient values ranged from .83 to .90). CONCLUSION: For bilingual populations that are understudied and for which gold standards of assessment are not available, the B-MAS can be adopted as a starting point to study DLD or as a reference standard to develop new assessment tools in that population. Clinically, this protocol could be tailored and evaluated by a group of SLPs serving a large population of a particular bilingual group for diagnostic purposes.