Effects of tooth loss on behavioral and psychological symptoms of dementia in app knock-in mice.

OBJECTIVES: Many patients with Alzheimer's disease experience behavioral and psychological symptoms of dementia (BPSD), which significantly affect their quality of life. It is known that 5-Hydroxytryptamine (5-HT) plays a crucial role in the development of BPSD. However, the relationship between tooth loss and Alzheimer's disease symptoms, particularly aggression, has remained unexplored. Although nutritional status is known to influence the progression of dementia, the specific effect of tooth loss on peripheral symptoms, notably aggression, is not well understood. METHODS: In our study, we conducted maxillary molar extractions in aged C57BL6J and AppNL-G-F mice and observed their condition over a 3-month period. During this time, we documented significant behavioral and genetic differences between mice in the control groups and mice that underwent tooth extraction. Notably, mice that underwent tooth extraction exhibited a considerable decline in cognitive function and an increase in aggression at 3 months after tooth extraction compared with the control groups (C57BL6J or AppNL-G-Fmice). RESULTS: Our findings suggest that molar loss may lead to reduced 5-HT levels in the hippocampus, possibly mediated by the trigeminal nerve, contributing to the development of aggression and BPSD in Alzheimer's disease. CONCLUSION: This study sheds light on the intricate relationships between oral health, 5-HT, and Alzheimer's disease symptoms, offering valuable insights into potential therapeutic avenues for managing BPSD in patients with dementia.

Long-term sorbitol consumption affects the hippocampus and alters cognitive function in aged mice.

The systemic effects of the artificial sweetener sorbitol on older adult individuals have not been elucidated. We assessed the effects of sorbitol consumption on cognitive and gingival health in a mouse model. Aged mice were fed 5% sorbitol for 3 months before their behavior was assessed, and brain and gingival tissues were collected. Long-term sorbitol consumption inhibited gingival tissue aging in aged mice. However, it caused cognitive decline and decreased brain-derived neurotrophic factor (BDNF) in the hippocampus. Sorbitol consumption did not affect homeostatic function; however, it may exert effects within the brain, particularly in the hippocampus.

Correction: Furukawa et al. Long-Term Soft-Food Rearing in Young Mice Alters Brain Function and Mood-Related Behavior. Nutrients 2023, 15, 2397.

In the original publication [...].

Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer.

BACKGROUND: The current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoid models to find potential drugs for cancer patients. METHODS: Colorectal cancer (CRC) patients were prospectively enrolled and blood samples were collected from patients before the start of treatment. Targeted deep sequencing of cfDNA samples was performed using a 14-gene panel. Gastrointestinal (GI) cancer organoids were established and PI3K and mTOR inhibitors were evaluated on organoid models. RESULTS: A total of 195 mutations were detected across 58 cfDNA samples. The most frequently mutated genes were KRAS, TP53, PIK3CA, and BRAF, all of which exhibited higher mutation rates than tissue biopsy. Although 81% of variants had an allele frequency of less than 1%, certain mutations in KRAS, TP53, and SMAD4 had high allele frequencies exceeding 10%. Notably, among the seven patients with high allele frequency mutations, six had metastatic tumors, indicating that a high allele frequency of ctDNA could potentially serve as a biomarker of later-stage cancer. A high rate of PIK3CA mutation (31 out of 67, or 46.3%) was discovered in CRC patients, suggesting possible tumor progression mechanisms and targeted therapy opportunities. To evaluate the value of anti PI3K strategy in GI cancer, different lines of GI cancer organoids were established. The organoids recapitulated the morphologies of the original tumors. Organoids were generally insensitive to PI3K inhibitors. However, CRC-3 and GC-4 showed response to mTOR inhibitor Everolimus, and GC-3 was sensitive to PI3Kδ inhibitor Idelalisib. The CRC organoid with a PIK3CA mutation showed greater sensitivity to the PI3K inhibitor Alpelisib than wildtype organoids, suggesting potential treatment options for the corresponding patients. CONCLUSION: Liquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment.

Genome-wide identification, phylogeny and expressional profile of the Dmrt gene family in Chinese sturgeon (Acipenser sinensis).

Chinese sturgeon Dmrt gene family was identified and characterized for the first time. A total of 5 putative Dmrt genes were identified. The gene structure, conserved protein domain and the phylogenetic relationship of Dmrt gene family were systematically analyzed. The expressed profile of Chinese sturgeon Dmrt genes in gonad, pituitary and hypothalamus in the male and female were investigated. The results indicated that the accumulation of Dmrt genes was involved in different tissues, and the expression profile also differed among each Dmrt genes. ASDmrt1A, ASDmrt2, ASDmrt3, and ASDmrtA1 were highly expressed in the testis in comparison with other tissue. This result showed that ASDmrt1A, ASDmrt2, ASDmrt3, and ASDmrtA1 played an important role in the development of testicle, and may be useful tool in distinguishing between male and female of Chinese sturgeon. Our study will provide a basis for additional analyses of Chinese sturgeon Dmrt genes. This systematic analysis provided a foundation for further functional characterization of Dmrt genes with an aim of study of Chinese sturgeon Dmrt gene family.

Premature gray hair development in the interbrow region owing to the loss of maxillary first molars in young mice.

The exact sites of premature hair graying and whether tooth loss causes this condition remain unknown. In this study, we aimed to explore the effect of reduced mastication on premature hair graying. Maxillary first molars were extracted from young mice, and the mice were observed for 3 months, along with non-extraction control group mice. After 3 months, gray hair emerged in the interbrow region of mice in the tooth extraction group but not in the control group. The expression of tyrosinase-related protein-2 (TRP-2) mRNA was lower in the interbrow tissues of young mice without maxillary molars than in those with maxillary molars. Tooth loss leads to interbrow gray hair growth, possibly because of weakened trigeminal nerve input, suggesting that reduced mastication causes premature graying. Thus, prompt prosthetic treatment after molar loss is highly recommended.

Comparison of cow's milk allergy models highlighted higher humoral and Th2 immune responses in BALB/c than C3H/HeNCrl mice.

Cow's milk allergy (CMA) is common in early childhood and the incidence is increasing. However, its mechanisms of action are still not fully understood due to the range of different clinical symptoms. So far, the development of different mouse models has been the best choice to study the molecular mechanisms triggering allergy. However, the selection of suitable strains for the establishment of animal models truly representative of associated human pathologies is still a challenge. Hence, we focused on both C3H/HeNCrl and BALB/c mice to characterize their susceptibility to CMA. After intraperitoneal sensitization, BALB/c and C3H/HeNCrl strains were challenged with ß-lactoglobulin (BLG), and compared in allergic symptoms and active immune response, which assessed by specific antibody production and cytokine release. At first, both groups exhibited anaphylaxis, showed specific BLG-related IgE, Th2 response and seemed both suitable for the development of CMA models. However, a detailed analysis revealed that BALB/c had both stronger humoral and Th2 immune responses, producing more antibodies (IgE and IgG/IgG1/IgG2a), and releasing higher levels of Th2-associated cytokines (IL-4, IL-5, IL-13) compared to C3H/HeNCrl mice. Therefore, BALB/c strain would represent a preferential choice in the establishment of CMA models. This study highlights the subtle differences and major outcomes in the selection of mouse strains for the development of suitable food allergy models.

Infernape uncovers cell type-specific and spatially resolved alternative polyadenylation in the brain.

Differential polyadenylation sites (PAs) critically regulate gene expression, but their cell type-specific usage and spatial distribution in the brain have not been systematically characterized. Here, we present Infernape, which infers and quantifies PA usage from single-cell and spatial transcriptomic data and show its application in the mouse brain. Infernape uncovers alternative intronic PAs and 3'-UTR lengthening during cortical neurogenesis. Progenitor-neuron comparisons in the excitatory and inhibitory neuron lineages show overlapping PA changes in embryonic brains, suggesting that the neural proliferation-differentiation axis plays a prominent role. In the adult mouse brain, we uncover cell type-specific PAs and visualize such events using spatial transcriptomic data. Over two dozen neurodevelopmental disorder-associated genes such as Csnk2a1 and Mecp2 show differential PAs during brain development. This study presents Infernape to identify PAs from scRNA-seq and spatial data, and highlights the role of alternative PAs in neuronal gene regulation.

Erythritol Can Inhibit the Expression of Senescence Molecules in Mouse Gingival Tissues and Human Gingival Fibroblasts.

Oral aging causes conditions including periodontal disease. We investigated how the sugar alcohol erythritol, which has anti-caries effects, impacts aging periodontal tissues and gingival fibroblasts in mice and humans in vivo and in vitro. Mice were classified into three groups: control groups of six-week-old (YC) and eighteen-month-old mice (AC) and a group receiving 5% w/w erythritol water for 6 months (AE). After rearing, RNA was extracted from the gingiva, and the levels of aging-related molecules were measured using PCR. Immunostaining was performed for the aging markers p21, γH2AX, and NF-κB p65. p16, p21, γH2AX, IL-1ß, and TNFα mRNA expression levels were higher in the gingiva of the AC group than in the YC group, while this enhanced expression was significantly suppressed in AE gingiva. NF-κB p65 expression was high in the AC group but was strongly suppressed in the AE group. We induced senescence in cultured human gingival fibroblasts using H2O2 and lipopolysaccharide before erythritol treatment, which reduced elevated senescence-related marker (p16, p21, SA-ß-gal, IL-1ß, and TNFα) expression levels. Knockdown of PFK or PGAM promoted p16 and p21 mRNA expression, but erythritol subsequently rescued pyruvate production. Overall, intraoral erythritol administration may prevent age-related oral mucosal diseases.

A co-precipitation route for the preparation of eco-friendly Cu-Al-layered double hydroxides with efficient tetracycline degradation.

The construction of novel efficient catalysts for the treatment of organic pollutants in the aqueous environment is essential. The lamellar-like Cu-Al layered double hydroxides (CuAl-LDHs) with various mole ratios were synthesized by a simple route of co-precipitation, and the corresponding degradation characteristic was tested for the removal of tetracycline (TC) using PMS activation. The degradation efficiency of TC over CuAl-LDHs increased up to 93% within 10 min for the Cu/Al mole ratio of 3:1 and almost not changed at a higher mole ratio. For further calcining the optimal catalyst at 300 ℃, the degradation efficiency of TC was found to be increased to 96%. Sulfuric radicals and singlet oxygen were analyzed to be the main reason for the change in degradation characteristics, which was proved by radical quenching experiments and electron paramagnetic resonance technique. The parameters including PMS concentration, catalyst dosage, and reaction temperature on the TC degradation as well as the degradation mechanism for PMS activation were elaborated. The best proportion of CuAl-LDHs owned splendid stability and catalytic activity after reusing, which showed enormous potential in practical application.

Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer.

Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.

Long-Term Capsaicin Administration Ameliorates the Dysfunction and Astrogliosis of the Brain in Aged Mice with Missing Maxillary Molars.

Tooth loss and decreased masticatory function reportedly affect cognitive function; tooth loss allegedly induces astrogliosis and aging of astrocytes in the hippocampus and hypothalamus, which is a response specific to the central nervous system owing to homeostasis in different brain regions. Capsaicin, a component of red peppers, has positive effects on brain disorders in mice. Decreased expression of transient receptor potential vanilloid 1, a receptor of capsaicin, is associated with the development of dementia. In this study, we investigated the effect of capsaicin administration in aged mice (C57BL/6N mice) with reduced masticatory function owing to the extraction of maxillary molars to investigate preventive/therapeutic methods for cognitive decline attributed to age-related masticatory function loss. The results demonstrated that mice with impaired masticatory function showed decreased motor and cognitive function at the behavioral level. At the genetic level, neuroinflammation, microglial activity, and astrogliosis, such as increased glial fibrillary acidic protein levels, were observed in the mouse brain. The mice with extracted molars fed on a diet containing capsaicin for 3 months demonstrated improved behavioral levels and astrogliosis, which suggest that capsaicin is useful in maintaining brain function in cases of poor oral function and prosthetic difficulties.

Long-Term Soft-Food Rearing in Young Mice Alters Brain Function and Mood-Related Behavior.

The relationship between caloric and nutrient intake and overall health has been extensively studied. However, little research has focused on the impact of the hardness of staple foods on health. In this study, we investigated the effects of a soft diet on brain function and behavior in mice from an early age. Mice fed a soft diet for six months exhibited increased body weight and total cholesterol levels, along with impaired cognitive and motor function, heightened nocturnal activity, and increased aggression. Interestingly, when these mice were switched back to a solid diet for three months, their weight gain ceased, total cholesterol levels stabilized, cognitive function improved, and aggression decreased, while their nocturnal activity remained high. These findings suggest that long-term consumption of a soft diet during early development can influence various behaviors associated with anxiety and mood regulation, including weight gain, cognitive decline, impaired motor coordination, increased nocturnal activity, and heightened aggression. Therefore, the hardness of food can impact brain function, mental well-being, and motor skills during the developmental stage. Early consumption of hard foods may be crucial for promoting and maintaining healthy brain function.

Analysis of the Value of Physical Activity to Children's Mental Health Education in the Epidemic Era / Análisis del valor de la actividad física para la educación sobre salud mental de los niños en la era epidémica

This research aims to examine the contribution of physical activity to children's mental health education during the epidemic era. In this study, 50 5- to 6-year-old children from a city were recruited as research subjects using interviews, literature review, and experimental statistics and then randomly divided into two groups: the experimental group and the control group. The psychological index data before and after the happy exercise were measured using a questionnaire survey. The psychological index data before and after 12 weeks of experimental practice were evaluated using data statistics. Six mental health indices demonstrated a significant difference between the experimental group and the control group, with the improvement value of the experimental group's movement score being 3.68 and the improvement value of the control group's movement score being 0.15. Social score improvement in the experimental group was 1.76, whereas, in the control group, it was 0.12. The value of language score improvement was 1.16, while the language score improvement in the control group was 0.14. The gymnastics sports curriculum is favorable to the mental health development of 56-year-old children and has significantly enhanced children's mental health.(AU)

Weak-Coordination Electrolyte Enabling Fast Li+ Transport in Lithium Metal Batteries at Ultra-Low Temperature.

Lithium metal batteries (LMBs) are promising for next-generation high-energy-density batteries owing to the highest specific capacity and the lowest potential of Li metal anode. However, the LMBs are normally confronted with drastic capacity fading under extremely cold conditions mainly due to the freezing issue and sluggish Li+ desolvation process in commercial ethylene carbonate (EC)-based electrolyte at ultra-low temperature (e.g., below -30 °C). To overcome the above challenges, an anti-freezing carboxylic ester of methyl propionate (MP)-based electrolyte with weak Li+ coordination and low-freezing temperature (below -60 °C) is designed, and the corresponding LiNi0.8 Co0.1 Mn0.1 O2 (NCM811) cathode exhibits a higher discharge capacity of 84.2 mAh g-1 and energy density of 195.0 Wh kg-1 cathode than that of the cathode (1.6 mAh g-1 and 3.9 Wh kg-1 cathode ) working in commercial EC-based electrolytes for NCM811‖ Li cell at -60 °C. Molecular dynamics simulation, Raman spectra, and nuclear magnetic resonance characterizations reveal that rich mobile Li+ and the unique solvation structure with weak Li+ coordination are achieved in MP-based electrolyte, which collectively facilitate the Li+ transference process at low temperature. This work provides fundamental insights into low-temperature electrolytes by regulating solvation structure, and offers the basic guidelines for the design of low-temperature electrolytes for LMBs.

Is Helicobacter pylori infection associated with pancreatic cancer? A systematic review and meta-analysis of observational studies.

Background and Objectives: Recent observational studies have investigated the association between Helicobacter pylori (H. pylori) infection and pancreatic cancer with conflicting data. Therefore, we conducted a systematic review and meta-analysis to assess the potential association. Design: This is a systematic review and meta-analysis. Methods: We searched three databases (PubMed, Embase, and Web of Science) from inception to 30 August 2022. The summary results as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were pooled by generic inverse variance method based on random-effects model. Results: A total of 20 observational studies involving 67,718 participants were included in the meta-analysis. Meta-analysis of data from 12 case-control studies and 5 nested case-control studies showed that there was no significant association between H. pylori infection and the risk of pancreatic cancer (OR = 1.20, 95% CI = 0.95-1.51, p = 0.13). Similarly, we also did not find significant association between cytotoxin-associated gene A (CagA) positive strains, CagA negative strains, vacuolating cytotoxin gene A (VacA) positive strains H. pylori infection, and the risk of pancreatic cancer. Meta-analysis of data from three cohort studies showed that H. pylori infection was not significantly associated with an increased risk of incident pancreatic cancer (HR = 1.26, 95% CI = 0.65-2.42, p = 0.50). Conclusion: We found insufficient evidence to support the proposed association between H. pylori infection and increased risk of pancreatic cancer. To better understand any association, future evidence from large, well-designed, high-quality prospective cohort studies that accounts for diverse ethnic populations, certain H. pylori strains, and confounding factors would be useful to settle this controversy.

Electron and ion transport behavior of Vanadium based MXene induced by pressure for Lithium ion intercalated electrodes.

Pressure, analogous with temperature and composition, is other meaningful variant for tuning the structure-activity properties of layered materials. In-situ high-pressure electrical results discover that Vanadium based MXene (V2CTx MXene) conductivity is increased by one order of magnitude from ambient to 10.4 GPa, and then the conductivity is still fixated on meeting growth as pressure releasing. Increased carrier concentration due to denser compactness is the most important factor in improving sample conductivity. Furthermore, abundant of V2CTx samples after preloading different pressures are prepared by the mean of the double-anvil hydraulic press for the first time, and results of increased conductivity were reproduced at ambient conditions. The first-principles calculation of V2C (non-functional group), V2CF, V2CO, and V2COH explains for the lattice expansion by tracing emotion of different function groups upon decompression. Electrochemical results obtain that once forming V2CTx MXene anode rapidly quenched from 2.0 GPa in hydraulic press shows better performance, obviously weakening electric polarization and increasing Li-ion transport rate due to its proper interlaminar densification and improved conductivity. This work opens up a new, simple, and universal approach to develop MXene materials with superior electrical and electrochemical properties, as well as expanding the potential applications for energy storage.