Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.

Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.

Supramolecular nanoparticles based on elastin-like peptides modified capsid protein as drug delivery platform with enhanced cancer chemotherapy efficacy.

Cancer, a prevalent disease posing significant threats to human health and longevity, necessitates effective therapeutic interventions. Chemotherapy has emerged as a primary strategy following surgical procedures for combating most malignancies. Despite the considerable efficacy of conventional chemotherapeutic agents against cancer cells, their utility is hindered by profound challenges such as multidrug resistance and deleterious toxic side effects, thereby limiting their systemic application. To tackle these challenges, we have devised a promising nanomedicine platform based on a plant virus. Specifically, we have selected the cowpea melanoma mottled virus (CCMV) as our nano-delivery system owing to its monodisperse and homogeneous size, as well as its intrinsic ability for controlled self-assembly. Leveraging the potential of this platform, we have engineered CCMV-based nanoparticles functionalized with elastin-like peptides (ELPs) at their N-terminal region. The target protein, CP-ELP, was expressed via E.coli, enabling encapsulation of the model drug DOX upon structural domain modification of the protein. The resulting nanoparticles exhibit uniform size distribution, facilitating efficient internalization by tumor cells and subsequent intracellular drug release, leading to enhanced antitumor efficacy. In addition, EVLP@DOX nanoparticles were found to activate immune response of tumor microenvironment in vivo, which further inhibiting tumor growth. Our designed nanoparticles have also demonstrated remarkable therapeutic effectiveness and favorable biological safety profiles in both murine melanoma and colorectal cancer models.

Interface dissolution kinetics and porosity formation of calcite and dolomite (110) and (104) planes: An implication to the stability of geologic carbon sequestration.

Geologic carbon sequestration (GCS) via injecting CO2 into deep carbonate reservoirs (mainly calcite and dolomite) is a promising strategy to reduce CO2 level. However, the dissolution or precipitation of calcite/dolomite planes on minerals/solution interface during long-term GCS process develops intergranular porosity and thus affects the permeability and stability of reservoirs. To investigate this process, both calcite and dolomite were dissolved in acetic and carbonic acids. A diffusion-controlled process was identified, with greater diffusion rates in acetic acid than that in carbonic acid. Quantified planes activity of both minerals follows (110) > (116) > (101) > (113) > (018) > (104) through density functional theory. Accomplished with preferential dissolution of calcite (110) planes in carbonic acid, calcite crystals precipitated with (104) planes at 423.15 K, under which, more calcite crystals were observed on dolomite surface, producing Ca-deplete surface. Molecular dynamic calculations showed higher dissolution rates of calcite/dolomite (110) planes than (104). In addition, the dissolution coefficients of Ca2+ were approximately triple of that Mg2+. Therefore, this study reveals the interface dissolution mechanisms of calcite and dolomite, especially on (110) and (104) planes at an atomic level, for the first time, providing better understanding for the stability of long-term GCS process.

Functionalized Virus Nanoparticles Alleviates Osteoporosis via Targeting the Function of RANK-Specific Motifs.

Osteoporosis is a common skeletal disease characterized by excessive osteoclast-induced bone loss. RANKL/RANK signaling pathway is essential for osteoclastogenesis and is a key target for osteoporosis. However, regarding the fact that RANKL/RANK also functions beyond bone, the total block of RANKL/RANK will have unwanted impact on other organs. Our previous study revealed that mutation of RANK-specific motifs inhibited osteoclastogenesis without effects on other organs in mice. However, the instability and low cellular uptake efficiency limited the application of the therapeutic peptide originating from the amino acid sequence of RANK-specific motifs (RM). To this end, in this study, the peptide RM (SRPVQEQGGA (C to N terminal)) was chemically modified onto the surface of the plant virus-based nanoparticles cowpea chlorotic mottle virus (CCMV). Subsequent experiments showed that the novel virus nanoparticles RM-CCMV had excellent biocompatibility and stability, which ultimately facilitated its cellular uptake efficiency and improved its inhibitive effects on osteoclastogenesis. Moreover, RM-CCMV achieved bone enrichment and suppressed bone resorption by inhibiting osteoclastogenesis and improving the parameters of bone histomorphology in murine femurs. To be mentioned, the effective dose of CCMV conjugated RM was only 6.25% of free RM. In summary, these results have provided a promising therapeutic strategy for osteoporosis.

Construction of viral protein-based hybrid nanomaterials mediated by a macromolecular glue.

A generic strategy to construct virus protein-based hybrid nanomaterials is reported by using a macromolecular glue inspired by mussel adhesion. Commercially available poly(isobutylene-alt-maleic anhydride) (PiBMA) modified with dopamine (PiBMAD) is designed as this macromolecular glue, which serves as a universal adhesive material for the construction of multicomponent hybrid nanomaterials. As a proof of concept, gold nanorods (AuNRs) and single-walled carbon nanotubes (SWCNTs) are initially coated with PiBMAD. Subsequently, viral capsid proteins from the Cowpea Chlorotic Mottle Virus (CCMV) assemble around the nano-objects templated by the negative charges of the glue. With virtually unchanged properties of the rods and tubes, the hybrid materials might show improved biocompatibility and can be used in future studies toward cell uptake and delivery.

Mitochondria and Neurodegenerative Diseases: A New Hotspot.

Growing evidence suggests that the prevalence of neurodegenerative diseases (NDs) is on the rise with the aged population with substantially overlapping clinical and pathological features. The journal "Aging & Disease" portals are always responsive to publishing cutting-edge research on age-related neurodegeneration. Even though outstanding progress has recently been made in understanding NDs, the underlying mechanisms involved in neuronal degeneration are yet to be deciphered and addressed. There is credible evidence showing multiple links between mitochondria and NDs, gradually becoming the hotspot in mechanistic or drug development research. The editorial aims to reflect on and discuss some interesting and unique results from the papers published in "Aging & Disease" during the past three years (2020 - 2022).

Chemotaxis assay for evaluation of memory-like behavior in wild-type and Alzheimer's-disease-like C. elegans models.

Here, we present an olfactory-dependent chemotaxis assay for evaluating changes in memory-like behavior in both wild-type and Alzheimer's-disease-like C. elegans models. We describe steps for synchronizing and preparing C. elegans populations and for performing isoamyl alcohol conditioning during starvation and chemotaxis assaying. We then detail counting and quantification procedures. This protocol is applicable to mechanistic exploration and drug screening in neurodegenerative diseases and brain aging.

Engineered Plant Virus Complexes with a RANK Motif Modulator and Bone Targeting for Osteoporosis Treatment.

Osteoporosis is a systemic skeletal disorder characterized by excessive osteoclastic bone resorption and impaired osteoblastic bone formation. Traditional delivery of antiresorptive drugs lacks a specific biodistribution in the body and may cause adverse effects to the patients. In this study, the peptide BTRM is first synthesized consisting of the bone-targeting peptide Asp8 (BT) and the peptide derived from the amino acid sequences of RANK Motif2/3 (RM), two cytoplasmic RANK motifs (PVQEET560-565 and PVQEQG604-609) that have been reported to play an important role in osteoclastogenesis. Then, BTRM is conjugated on the plant virus-like nanoparticles (VNPs) obtained from cowpea chlorotic mottle viruses (CCMVs), forming the engineered plant viruses BTRM-VNPs. In vitro experiments demonstrate that BTRM-VNPs can effectively and safely inhibit osteoclast differentiation and function. Moreover, after injection into ovariectomized mice, BTRM-VNPs show excellent capability to target bone tissue and improve osteoporotic bone loss. Collectively, the findings may provide a novel and promising strategy in the treatment of osteoporotic defects via targeting bone tissue and regulating the function of RANK Motif2/3.

Self-Adaptive Antibacterial Scaffold with Programmed Delivery of Osteogenic Peptide and Lysozyme for Infected Bone Defect Treatment.

Bone defects caused by disease or trauma are often accompanied by infection, which severely disrupts the normal function of bone tissue at the defect site. Biomaterials that can simultaneously reduce inflammation and promote osteogenesis are effective tools for addressing this problem. In this study, we set up a programmed delivery platform based on a chitosan scaffold to enhance its osteogenic activity and prevent implant-related infections. In brief, the osteogenic peptide sequence (YGFGG) was modified onto the surface of cowpea chlorotic mottle virus (CCMV) to form CCMV-YGFGG nanoparticles. CCMV-YGFGG exhibited good biocompatibility and osteogenic ability in vitro. Then, CCMV-YGFGG and lysozyme were loaded on the chitosan scaffold, which exhibited a good antibacterial effect and promoted bone regeneration for infected bone defect treatment. As a delivery platform, the scaffold showed staged release of lysozyme and CCMV-YGFGG, which facilitates the regeneration of infected bone defects. Our study provides a novel and promising strategy for the treatment of infected bone defects.

Relationship between different types of complement syntax and false belief in Mandarin-speaking children with autism spectrum disorder and typically developing children.

Previous studies have shown that complement syntax is closely associated with false belief (FB) in children with autism spectrum disorder (ASD). However, the relationship between different types of complement syntax and FB remains unclear. This study examined the relationship between different types of complement syntax and FB in both ASD and typically developing (TD) children. Thirty Mandarin-speaking ASD and TD children, each matched for language ability, were included. Children completed different types of complement syntax tasks, verbal and nonverbal FB. For the ASD children, results demonstrated that sentential complement syntax independently predicted verbal and nonverbal FB, while phrasal complement syntax only predicted nonverbal FB. For the TD children group, sentential complement syntax only predicted verbal FB. This indicates that as the language demands of the FB task decrease, ASD children can use both types of complement syntax for its prediction. Moreover, the characteristics of ASD children differ from TD children in terms of the relationship between different types of complement syntax and FB. The results of this study support de Villiers' point of view from the Mandarin perspective and provide evidence for the social-cognitive component of the theory of mind.

New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

Which Seat Facilitates the Detection of Off-Seat Behaviours? An Inattentional Blindness Test on Location Effect in the Classroom.

Off-seat behaviour refers to students leaving their seats and walking out of a classroom without the teacher noticing. This behaviour occurs in special education for students with certain special needs, which would lead to serious safety problems. This study carried out an inattentional blindness test to explore whether the location of seats in classrooms would impact teachers' detection rate regarding off-seat behaviours. The participants were 126 pre-service teachers (Mage = 18.72 ± 0.723; 92% female) who were invited to perform the primary task of counting students raising their hands up whilst the disappearance of one of the students was introduced as an unexpected occurrence. The results show that peripheral seats were more detectable than the central ones for the teachers to notice the "missing student." Meanwhile, the left and below oriented seats were more likely to be ignored compared to those that were right and upper oriented. These results suggest the existence of a location effect in the classroom that is associated with teachers' attention regarding off-seat behaviour. This study has implications for classroom management in terms of arranging students' seats appropriately to assist in increasing teachers' identification of this hazard.

An update of nanotopographical surfaces in modulating stem cell fate: a narrative review.

Stem cells have been one of the ideal sources for tissue regeneration owing to their capability of self-renewal and differentiation. In vivo, the extracellular microenvironment plays a vital role in modulating stem cell fate. When developing biomaterials for regenerative medicine, incorporating biochemical and biophysical cues to mimic extracellular matrix can enhance stem cell lineage differentiation. More specifically, modulating the stem cell fate can be achieved by controlling the nanotopographic features on synthetic surfaces. Optimization of nanotopographical features leads to desirable stem cell functions, which can maximize the effectiveness of regenerative treatment. In this review, nanotopographical surfaces, including static patterned surface, dynamic patterned surface, and roughness are summarized, and their fabrication, as well as the impact on stem cell behaviour, are discussed. Later, the recent progress of applying nanotopographical featured biomaterials for altering different types of stem cells is presented, which directs the design and fabrication of functional biomaterial. Last, the perspective in fundamental research and for clinical application in this field is discussed.

P. edulis Extract Protects Against Amyloid-ß Toxicity in Alzheimer's Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway.

Alzheimer's disease (AD) is a common and devastating disease characterized by pathological aggregations of beta-amyloid (Aß) plaques extracellularly, and Tau tangles intracellularly. While our understandings of the aetiologies of AD have greatly expanded over the decades, there is no drug available to stop disease progression. Here, we demonstrate the potential of Passiflora edulis (P. edulis) pericarp extract in protecting against Aß-mediated neurotoxicity in mammalian cells and Caenorhabditis elegans (C. elegans) models of AD. We show P. edulis pericarp protects against memory deficit and neuronal loss, and promotes longevity in the Aß model of AD via stimulation of mitophagy, a selective cellular clearance of damaged and dysfunctional mitochondria. P. edulis pericarp also restores memory and increases neuronal resilience in a C. elegans Tau model of AD. While defective mitophagy-induced accumulation of damaged mitochondria contributes to AD progression, P. edulis pericarp improves mitochondrial quality and homeostasis through BNIP3/DCT1-dependent mitophagy and SOD-3-dependent mitochondrial resilience, both via increased nuclear translocation of the upstream transcriptional regulator FOXO3/DAF-16. Further studies to identify active molecules in P. edulis pericarp that could maintain neuronal mitochondrial homeostasis may enable the development of potential drug candidates for AD.

Psychological Capital and Occupational Well-Being: Mediating Effects of Work Engagement Among Chinese Special Education Teachers.

This study examines whether psychological capital (PsyCap) indirectly predicts occupational well-being among Chinese special education teachers through work engagement. In total, 615 Chinese special education teachers (female = 567) completed the Psychological Capital Questionnaire, the Special Education Teachers' Occupational Well-Being Questionnaire, and the Utrecht Work Engagement Scale. The results indicated that PsyCap was positively correlated with occupational well-being and work engagement. Furthermore, work engagement mediated the influence of PsyCap on occupational well-being. Notably, the multiple mediation model indicated that the indirect effects of PsyCap on occupational well-being were mainly due to dedication and absorption. The study's results illustrate the association between PsyCap, work engagement, and occupational well-being, which may help educational administrators and social workers assist with special education and special education teachers develop and maintain good working conditions.

Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-ß and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

Identification of Differentially Expressed Long Noncoding RNAs in Mice Intestines After Severe Burns and a Preliminary Study into the Key Gene H19.

The intestine is considered the key organ in stress response to severe burns and injury to the intestine after severe burns can be fatal. However, the injury and subsequent repair of intestinal tissues after severe burns at the genetic level are poorly understood. Long noncoding RNAs (lncRNAs) have important functions in regulating many biological processes, including gene transcription and translation. Autophagy is a process of intracellular degradation and reutilization of cytoplasmic proteins and organelles. We herein analyzed the genome-wide expression profile of lncRNAs and mRNAs after severe burns in the intestines of mice by lncRNA microarray. Quantitative reverse transcription-polymerase chain reaction was performed to verify the reliability of microarray analysis results, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for bioinformatics analysis of differentially expressed mRNAs. The common regulatory network between the top 10 differentially expressed lncRNAs and trans-related mRNAs were visualized by Cytoscape (v3.7.2). Next, we hypothesized that H19 is the key gene for intestinal mucosal repair. After H19 was overexpressed, the changes in downstream autophagy protein expression levels were observed. GO and KEGG analysis indicated that the differentially expressed mRNAs were mainly enriched in a cell cycle- and mitosis-related genes. Overexpression of lncRNA-H19 showed that the autophagy-related gene Trim21 was upregulated, while HIF1α was downregulated. LncRNA-H19 played a key role in repairing the intestinal mucosa, and overexpression of lncRNA-H19 activated autophagy and migration of intestinal epithelial cells (IEC-6).

Osteogenic growth peptide (OGP)-loaded amphiphilic peptide (NapFFY) supramolecular hydrogel promotes osteogenesis and bone tissue reconstruction.

Efficient bone reconstruction after bone injury remains a great challenge. Injectable supramolecular hydrogels based on amphiphilic peptide have been widely used due to their good biocompatability, non-immunogenicity, and manipulable physicochemical properties by sequence design. Herein, we used a well-studied hydrogelator, NapFFY, to coassemble with osteogenic growth peptide (OGP) to prepare a supramolecular hydrogel, NapFFY-OGP. Both in vitro and in vivo studies demonstrate that OGP was ideally synchronously, and continuously released from the hydrogel to effectively promote the regeneration and reconstruction of skull bone defects. More specifically, after the embedding the rat skull defect area with NapFFY-OGP hydrogels, a bone regeneration rate of 37.54% bone volume fraction (BV/TV) was achieved compared to that of NapFFY hydrogel group (25.09%). NapFFY-OGP hydrogel shows great promise in the clinic repair of bone defects in the future.

Key competencies of students with autism spectrum disorders: Perspectives of Chinese teachers and parents.

Well-defined key competencies for students with autism spectrum disorders (ASD) help develop curriculum and pedagogies that emphasize what students with ASD are expected to learn, to know and to do. Most of the current research on the key competencies of ASD is theoretical and based on the social and cultural backgrounds of western countries. The key competencies defined by most of the research lack of the support of empirical evidence. This study sought to identify the key competencies of school-age students with ASD from the perspectives of teachers and parents. Based on the review of existing key competencies frameworks, a key competencies instrument that consisted of 76 learning outcome items in eight domain areas was developed. An online survey to explore the teachers' and parents' views of the key competencies was conducted with 1,618 teachers and 2,430 parents of students with ASD across China. The results showed that teachers believed that the key competencies should consist of eight domain areas including social-communication, learning skills, healthy living, play, motor, emotion, sensory processing, and cognition, while the cognition related competencies were not recognized by parents. The competencies in social-communication, learning skills, healthy living had higher variance contribution. From the perspective of teachers, the variance contribution of social communication was the highest, while from the perspective of parents, the variance contribution of learning skills was the largest. Taken together, the key competencies framework for students with ASD should include eight dimensions and 75 learning outcome items. The similarities and differences between the perspectives of the two group were discussed. The findings could provide empirical data to assist in developing educational guidelines and guide the development of models of support for students with ASD.

Fluorescent nanodiamonds encapsulated by Cowpea Chlorotic Mottle Virus (CCMV) proteins for intracellular 3D-trajectory analysis.

Long-term tracking of nanoparticles to resolve intracellular structures and motions is essential to elucidate fundamental parameters as well as transport processes within living cells. Fluorescent nanodiamond (ND) emitters provide cell compatibility and very high photostability. However, high stability, biocompatibility, and cellular uptake of these fluorescent NDs under physiological conditions are required for intracellular applications. Herein, highly stable NDs encapsulated with Cowpea chlorotic mottle virus capsid proteins (ND-CP) are prepared. A thin capsid protein layer is obtained around the NDs, which imparts reactive groups and high colloidal stability, while retaining the opto-magnetic properties of the coated NDs as well as the secondary structure of CPs adsorbed on the surface of NDs. In addition, the ND-CP shows excellent biocompatibility both in vitro and in vivo. Long-term 3D trajectories of the ND-CP with fine spatiotemporal resolutions are recorded; their intracellular motions are analyzed by different models, and the diffusion coefficients are calculated. The ND-CP with its brilliant optical properties and stability under physiological conditions provides us with a new tool to advance the understanding of cell biology, e.g., endocytosis, exocytosis, and active transport processes in living cells as well as intracellular dynamic parameters.