Ubiquitination and De-Ubiquitination in the Synthesis of Cow Milk Fat: Reality and Prospects.

Ubiquitination modifications permit the degradation of labelled target proteins with the assistance of proteasomes and lysosomes, which is the main protein degradation pathway in eukaryotic cells. Polyubiquitination modifications of proteins can also affect their functions. De-ubiquitinating enzymes reverse the process of ubiquitination via cleavage of the ubiquitin molecule, which is known as a de-ubiquitination. It was demonstrated that ubiquitination and de-ubiquitination play key regulatory roles in fatty acid transport, de novo synthesis, and desaturation in dairy mammary epithelial cells. In addition, natural plant extracts, such as stigmasterol, promote milk fat synthesis in epithelial cells via the ubiquitination pathway. This paper reviews the current research on ubiquitination and de-ubiquitination in dairy milk fat production, with a view to providing a reference for subsequent research on milk fat and exploring new directions for the improvement of milk quality.

The longitudinal relationships between problematic smartphone use and anxiety symptoms among Chinese college students: A cross-lagged panel network analysis.

Anxiety and problematic smartphone use (PSPU) are prevalent issues among college students, and traditional research has tended to focus on cross-sectional data and grounded only in overall levels, thereby ignoring the complex interactions between the two over time. The development of network analysis methods has provided a new perspective for in-depth exploration of the relationship. This study aimed to explore the complex longitudinal interactions and specific pathways between problematic smartphone use and anxiety among Chinese college students from an internal specific symptom perspective. This study constructed a cross-lagged network model using longitudinal data on problematic smartphone use and anxiety symptoms in two waves of college students collected from 2022 to 2023 (N=741, Mage = 18.49, SD=0.81, 45.6 % male). The study found that anxiety symptoms and problematic smartphone use interacted with each other and had a vicious cycle of symptoms over time, with the effects of anxiety symptoms being more pronounced. "Feeling afraid" and "Uncontrollable worrying" had the most significant effects on the other symptoms, with "Impatient without the phone" and "Can't stand not having a phone" were more likely to be influenced by other symptoms. "Feeling afraid" may be a bridge symptom in the network to connect the anxiety and problematic smartphone use communities. The findings suggest that accurately intervening in the intrinsic link between problematic smartphone use and anxiety symptoms can combat the exacerbation of both problems simultaneously, resulting in more effective and comprehensive treatment.

Microstructure-Reconfigured Graphene Oxide Aerogel Metamaterials for Ultrarobust Directional Sensing at Human-Machine Interfaces.

Graphene aerogels hold huge promise for the development of high-performance pressure sensors for future human-machine interfaces due to their ordered microstructure and conductive network. However, their application is hindered by the limited strain sensing range caused by the intrinsic stiffness of the porous microstructure. Herein, an anisotropic cross-linked chitosan and reduced graphene oxide (CCS-rGO) aerogel metamaterial is realized by reconfiguring the microstructure from a honeycomb to a buckling structure at the dedicated cross-section plane. The reconfigured CCS-rGO aerogel shows directional hyperelasticity with extraordinary durability (no obvious structural damage after 20 000 cycles at a directional compressive strain of ≤0.7). The CCS-rGO aerogel pressure sensor exhibits an ultrahigh sensitivity of 121.45 kPa-1, an unprecedented sensing range, and robust mechanical and electrical performance. The aerogel sensors are demonstrated to monitor human motions, control robotic hands, and even integrate into a flexible keyboard to play music, which opens a wide application potential in future human-machine interfaces.

Spatial Isoforms Reveal the Mechanisms of Metastasis.

In esophageal squamous cell carcinoma (ESCC), lymph node (LN) metastasis is associated with poor survival. Emerging evidence has demonstrated elevated CD8+ T-cell levels in metastatic LNs following immunotherapy and increased chemoresistance. However, the underlying regulatory mechanisms of CD8+ T cells in chemoresistant/metastatic patients have not been elucidated. Given that metastasis is linked to aberrant splicing patterns, transcripts with alternative splicing forms also play a critical role. With spatial transcriptomics (ST), spatial isoform transcriptomics (SiT), single-cell RNA sequencing (scRNA-seq), and T-cell receptor (TCR) sequencing, the spatial isoforms are analyzed quantitatively in human solid tumors and LNs. These isoforms are classified according to expression and spatial distribution patterns and proposed that the temporal heterogeneity in isoforms is attributed to isoform biogenesis dynamics. C1QC+ tumor-associated macrophages (TAMs) contribute to the formation of metastases in the context of both immunotherapy and chemotherapy. Additionally, CD74 isoforms can be targeted by mRNA drugs, such as antisense oligonucleotides (ASOs) and RNA interference (RNAi), to prevent chemoresistance and metastasis. Overall, this work suggests that C1QC+ TAMs interact with CD8+ CXCL13+ Tex cells via enrichment with the CD74 isoform in the ESCC 's metastatic lymph node.

Trapping Ions to Enhance High-Field Energy Harvesting Performance by Filling Polar Macromolecular Dielectrics.

In the quest for sustainable and renewable energy sources, researchers and engineers have explored innovative technologies to harvest energy from various environmental sources. Dielectric elastomer generators (DEGs) with high energy harvesting performance have been proven to be promising energy collectors, but achieving a high dielectric constant (ε') and low electrical conductivity (EC) under high electric fields of dielectric elastomer (DE) simultaneously is a struggle, which poses significant challenges. In this study, high-content carboxyl group-grafted liquid polybutadiene (HCPB) is synthesized and then adopted as an organic dielectric filler to blend and cocross-link with a butadiene rubber (BR) matrix to prepare DE composites with high energy harvesting performance. The introduction of carboxyl groups enhances polarization while trapping free Al3+ in the matrix, which revolutionarily achieves a significant increase in ε' under extremely low EC. Ultimately, the contradiction between increased ε' and decreased EC under high electric fields is reconciled, resulting in a 30 HCPB/BR composite with high energy density (w = 91.9 mJ/cm3) and fine power conversion efficiency (PCE = 24.1%). This advancement paves the way for the development of HCPB/BR composite-based DEGs with enhanced ε' and energy harvesting performance.

LFHP-1c improves cognitive function after TBI in mice by reducing oxidative stress through the PGAM5-NRF2-KEAP1 ternary complex.

Traumatic brain injury (TBI) is a leading cause of disability and death. Thus, timely and effective secondary brain injury intervention is crucial, with potential to improve the prognosis of TBI. Oxidative stress contributes to post-traumatic secondary cognitive impairment, and the reduction of post-traumatic oxidative stress effectively enhances cognitive function. Phosphoglycerate-mutating enzyme 5 (PGAM5), a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This further exacerbates damage following TBI. The present study focused on the small molecule drug, LFHP-1c, which is a novel inhibitor of PGAM5. The present study used an in vivo mouse model incorporating a controlled cortical impact-induced TBI, to examine the impact of LFHP-1c on oxidative stress and cognitive function. The present study aimed to determine the impact of LFHP-1c on the PGAM5-Kelch-like ECH-associated protein 1 (KEAP1)- nuclear factor erythroid 2-related factor 2 (NRF2) ternary complex within the TBI context. Results of the present study indicated that LFHP-1c suppresses PGAM5 expression and inhibits the development of the PGAM5-KEAP1-NRF2 ternary complex, thereby promoting the release of NRF2 and KEAP1. This in turn promotes the entry of NRF2 into the nucleus following TBI, leading to increased expression of anti-oxidative stress downstream factors, such as heme oxygenase-1, glutathione peroxidase 1 and superoxide dismutase 1. In addition, LFHP-1c also released KEAP1, leading to mitochondrial Rho GTPase 2 degradation and reducing perinuclear aggregation of mitochondria in the cell, which reduced oxidative stress and ultimately improved cognitive function after TBI.

Anti-HBc mirrors the activation of HBV-specific CD8+ T cell immune response and exhibits a direct effect on HBV control.

BACKGROUND: Hepatitis B core antibody (anti-HBc) is commonly present in patients with chronic hepatitis B virus (HBV) infection and serves as a marker of humoral immunity. Herein, we aim to investigate the correlation between anti-HBc and antiviral immune response and its putative role in HBV control. METHODS: Quantitative anti-HBc and levels of anti-HBc subtypes were measured in chronic hepatitis B (CHB) patients. The effects of anti-HBc on immune cells and HBV replication were evaluated using the HBV mouse models and human hepatoma cell lines. RESULTS: Baseline levels of IgG1 and IgG3 anti-HBc were elevated in CHB patients with favorable treatment response, and correlated with the virological response observed at week 52. Additionally, increased levels of IgM and IgG1 anti-HBc were observed exclusively in CHB patients with liver inflammation. Notably, significant correlations were identified between quantitative levels of anti-HBc and the frequencies of HBcAg-specific CD8+ T cells. Intriguingly, HBcAg efficiently activates T cells aided by B cells in vitro experiments. Moreover, anti-HBc inhibits HBV replication either by a direct effect or through complement-mediated cytotoxicity in HBV-producing cell lines. CONCLUSIONS: Anti-HBc reflects the activation of an HBV-specific CD8+ T cell immune response and may have anti-HBV activity.

Ultrafast Sintered Composite Cathode Incorporating a Negative Thermal Expansion Material for High-Performance Protonic Ceramic Fuel Cells.

Protonic ceramic fuel cells (PCFCs) offer a promising, clean, and efficient energy conversion solution. However, thermal mismatch between cathodes and electrolytes remains a critical obstacle, leading to interfacial damage such as cracking and delamination. Incorporating negative thermal expansion (NTE) materials into the cathode can mitigate this issue. The challenge lies in integrating NTE materials without compromising electrochemical performance or causing unwanted reactions during sintering. This study introduces a novel BaFe0.9Zr0.1O3-δ (BFZ)-NdMnO3-δ composite cathode fabricated using an ultrafast high-temperature sintering (UHS) process. This approach mitigates thermal expansion while boosting the cathode's catalytic activity compared to a single-phase BFZ cathode. The resulting fuel cell achieves a high peak power density of ∼550 mW cm-2 at 600 °C and demonstrates excellent stability during a 100 h test at 550 °C. These findings highlight the potential of UHS for developing high-performance, thermally compatible cathode materials that advance the field of PCFCs.

Examination of the masseter muscle in patients with hemifacial microsomia using high-frequency ultrasound and shear wave elastography.

BACKGROUND: This study aimed to prospectively investigate the reference values for masseter muscle thickness and hardness using ultrasonography and shear wave elastography, respectively, in patients with hemifacial microsomia (HFM). METHODS: We enrolled 51 patients, aged 5-20 years, with HFM including 31 males and 20 females. The upper-lower, left-right, and anterior-posterior diameters of 102 masseter muscles and stiffness of 98 masseter muscles were determined by examining the unaffected and affected sides of each participant's face. RESULTS: The upper-lower, left-right, and anterior-posterior diameters of the masseter muscle were significantly smaller at rest (4.26 ± 0.83, 2.94 ± 0.75, and- 0.80 ± 0.25 cm, respectively) and during contraction (3.95 ± 0.78, 2.71 ± 0.78, and 0.87 ± 0.29 cm, respectively) in the affected side than those in the healthy side (5.45 ± 0.66, 3.87 ± 0.49, and 0.97 ± 0.20 cm, respectively, at rest and 4.99 ± 0.45, 3.49 ± 0.53, and 1.07 ± 0.23 cm, respectively, during contraction, p < 0.05). In the resting state, the hardness of the masseter muscle on the affected side (0.77 ± 0.66 m/s) was significantly greater than that on the healthy side (0.42 ± 0.41 m/s; p < 0.05). The magnitude of changes in the upper-lower, left-right, and anterior-posterior diameters of the biting muscle in the occlusal state were significantly smaller on the affected side (-0.30 ± 0.27, -0.23 ± 0.17, and 0.08 ± 0.08 cm, respectively) than those in the healthy side (-0.47 ± 0.38, -0.37 ± 0.25, and 0.10 ± 0.12 cm, respectively, p < 0.05). CONCLUSIONS: The knowledge of these values allows for better understanding of the disease characteristics of HFM, which may be used for its diagnosis, treatment, and prognosis. Patients experiencing different severity levels exhibited significant differences in the morphology and function of the masseter muscle on the affected-side (p < 0.05). EVIDENCE LEVEL: Level III.

Metabolome and Transcriptome Unveil the Correlated Metabolites and Transcripts with 2-acetyl-1-pyrroline in Fragrant Rice.

Fragrance is a valuable trait in rice varieties, with its aroma significantly influencing consumer preference. In this study, we conducted comprehensive metabolome and transcriptome analyses to elucidate the genetic and biochemical basis of fragrance in the Shangsixiangnuo (SSXN) variety, a fragrant indica rice cultivated in Guangxi, China. Through sensory evaluation and genetic analysis, we confirmed SSXN as strongly fragrant, with an 806 bp deletion in the BADH2 gene associated with fragrance production. In the metabolome analysis, a total of 238, 233, 105 and 60 metabolic compounds exhibited significant changes at the seedling (S), reproductive (R), filling (F), and maturation (M) stages, respectively. We identified four compounds that exhibited significant changes in SSXN across all four development stages. Our analyses revealed a significant upregulation of 2-acetyl-1-pyrroline (2AP), the well-studied aromatic compound, in SSXN compared to the non-fragrant variety. Additionally, correlation analysis identified several metabolites strongly associated with 2AP, including ethanone, 1-(1H-pyrrol-2-yl)-, 1H-pyrrole, and pyrrole. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) analysis highlighted the magenta and yellow modules as particularly enriched in aroma-related metabolites, providing insights into the complex aromatic compounds underlying the fragrance of rice. In the transcriptome analysis, a total of 5582, 5506, 4965, and 4599 differential expressed genes (DEGs) were identified across the four developmental stages, with a notable enrichment of the common pathway amino sugar and nucleotide sugar metabolism in all stages. In our correlation analysis between metabolome and transcriptome data, the top three connected metabolites, phenol-, 3-amino-, and 2AP, along with ethanone, 1-(1H-pyrrol-2-yl)-, exhibited strong associations with transcripts, highlighting their potential roles in fragrance biosynthesis. Additionally, the downregulated expression of the P4H4 gene, encoding a procollagen-proline dioxygenase that specifically targets proline, in SSXN suggests its involvement in proline metabolism and potentially in aroma formation pathways. Overall, our study provides comprehensive insights into the genetic and biochemical mechanisms underlying fragrance production in rice, laying the foundation for further research aimed at enhancing fragrance quality in rice breeding programs.

A novel tetrahedral framework nucleic acid-derived chemodynamic therapy agent for effective glioblastoma treatment.

Chemodynamic therapy (CDT) has garnered significant attention for treating diverse malignant tumours due to its minimally invasive nature, reduced damage to healthy tissues, and potential mitigation of side effects. However, its application in glioblastoma (GBM) is hindered by the diminished capacity of CDT agents to traverse the blood-brain barrier (BBB), inadequate tumour targeting efficiency, and restricted availability of H2O2 within the tumour microenvironment (TME). To address these challenges, we devised a novel CDT agent (Fe@tFNAs-ANG-3AT) based on a tetrahedral framework nucleic acids (tFNAs). Fe@tFNAs-ANG-3AT was constructed by anchoring iron ions (Fe3+) onto the dual appendages-modified tFNAs. Specifically, one appendage, Angiopep-2 (ANG, a penetrating peptide), facilitates Fe@tFNAs-ANG-3AT penetration across the BBB and selective targeting of tumour cells. Simultaneously, the second appendage, 3-Amino-1,2,4-triazole (3AT, a H2O2 enzyme inhibitor), augments the H2O2 levels required for effective CDT treatment. Upon tumour cell internalization, the loaded Fe3+ in Fe@tFNAs-ANG-3AT is reduced to Fe2+ by the overexpressed glutathione (GSH) in the TME, catalysing the generation of cytotoxic hydroxyl radicals (·OH) and inducing tumour cell death via elevated oxidative stress levels within tumour cells. It is anticipated that Fe@tFNAs-ANG-3AT holds promise as a transformative treatment strategy for GBM.

DNA Methylation of Postnatal Liver Development in Pigs.

DNA methylation plays an important role in the development and tissue differentiation of eukaryotes. In this study, bisulfite sequencing (BS-seq) technology was used to analyze the DNA methylation profiles of liver tissues taken from Rongchang pigs at three postnatal feeding stages, including newborn, suckling, and adult. The DNA methylation pattern across the genomes or genic region showed little difference between the three stages. We observed 419 differentially methylated regions (DMRs) in promoters, corresponding to 323 genes between newborn and suckling stages, in addition to 288 DMRs, corresponding to 134 genes, between suckling and adult stages and 351 DMRs, corresponding to 293 genes, between newborn and adult stages. These genes with DMRs were mainly enriched in metabolic, immune-related functional processes. Correlation analysis showed that the methylation level of gene promoters was significantly negatively correlated with gene expression. Further, we found that genes related to nutritional metabolism, e.g., carbohydrate metabolism (FAHD1 and GUSB) or fatty acid metabolism (LPIN1 and ACOX2), lost DNA methylation in their promoter, with mRNA expression increased in newborn pigs compared with those in the suckling stage. A few fatty acid metabolism-related genes (SLC27A5, ACOX2) were hypomethylated and highly expressed in the newborn stage, which might satisfy the nutritional requirements of Rongchang pigs with high neonatal birth rates. In the adult stage, HMGCS2-which is related to fatty acid ß-oxidation-was hypomethylated and highly expressed, which explains that the characteristics of high energy utilization in adult Rongchang pigs and their immune-related genes (CD68, STAT2) may be related to the establishment of liver immunity. This study provides a comprehensive analysis of genome-wide DNA methylation patterns in pig liver postnatal development and growth. Our findings will serve as a valuable resource in hepatic metabolic studies and the agricultural food industry.

Acute Kidney Injury Following Acute Cholangitis: A Risk Multiplier for Adverse Outcomes and Healthcare Utilization.

BACKGROUND: Acute kidney injury (AKI) is a common, fatal complication of acute cholangitis (AC). The link between AC and AKI is poorly understood. AIMS: To delineate the incidence trends, clinical outcomes and healthcare utilization of inpatients with AKI following AC and to explore the risk factors for AKI following AC. METHODS: This population-based retrospective study used the National Inpatient Sample database from 2010 to 2018 to compare the demographics, complications, in-hospital mortality and healthcare utilization between AC patients with and without AKI. Predictors of AKI and the prognostic impact of AKI on in-hospital outcomes were defined using multivariate logistic regression. RESULTS: The overall incidence of AKI was 24.06% among AC patients. Its trend generally increased annually. AKI was associated with more complications, greater invasive therapy requirements, longer hospital stays, costlier total hospital charges, and higher in-hospital mortality. The risk factors for AKI following AC were advanced age, black race, multiple comorbidities, large hospitals, teaching hospitals, urban hospitals, hospitals in the southern and western USA, choledocholithiasis/cholelithiasis, surgery, percutaneous transhepatic biliary drainage, deficiency anemia, congestive heart failure, coagulopathy, diabetes, hypertension, chronic liver disease, obesity, chronic kidney disease excluding end-stage renal disease, weight loss, acute pancreatitis, and severe sepsis. Female sex, private insurance, elective admission, and endoscopic retrograde cholangiopancreatography were protective factors against AKI in AC patients. CONCLUSION: AKI often follows AC and is strongly associated with poor prognosis and increased healthcare utilization. Healthcare professionals should make more efforts to identify patients with AC at risk of AKI and start management promptly to limit adverse outcomes.

Nickel-Catalyzed Enantioconvergent Allenylic Amination of Allenols Activated by Hydrogen-Bonding Interaction with Methanol.

The ubiquitous nature of amines in drug compounds, bioactive molecules and natural products has fueled intense interest in their synthesis. Herein, we introduce a nickel-catalyzed enantioconvergent allenylic amination of methanol-activated allenols. This protocol affords a diverse array of functionalized allenylic amines in high yields and with excellent enantioselectivities. The synthetic potential of this method is demonstrated by employing bioactive amines as nucleophiles and conducting gram-scale reactions. Furthermore, mechanistic investigations and DFT calculations elucidate the role of methanol as an activator in the nickel-catalyzed reaction, facilitating the oxidative addition of the C-O bond of allenols through hydrogen-bonding interactions. The remarkable outcomes arise from a rapid racemization of allenols enabled by the nickel catalyst and from highly enantioselective dynamic kinetic asymmetric transformation of η3-alkadienylnickel intermediates.

Robust gesture recognition based on attention-deep fast convolutional neural network and surface electromyographic signals.

The surface electromyographic (sEMG) signals reflect human motor intention and can be utilized for human-machine interfaces (HMI). Comparing to the sparse multi-channel (SMC) electrodes, the high-density (HD) electrodes have a large number of electrodes and compact space between electrodes, which can achieve more sEMG information and have the potential to achieve higher performance in myocontrol. However, when the HD electrodes grid shift or damage, it will affect gesture recognition and reduce recognition accuracy. To minimize the impact resulting from the electrodes shift and damage, we proposed an attention deep fast convolutional neural network (attention-DFCNN) model by utilizing the temporary and spatial characteristics of high-density surface electromyography (HD-sEMG) signals. Contrary to the previous methods, which are mostly base on sEMG temporal features, the attention-DFCNN model can improve the robustness and stability by combining the spatial and temporary features. The performance of the proposed model was compared with other classical method and deep learning methods. We used the dataset provided by The University Medical Center Göttingen. Seven able-bodied subjects and one amputee involved in this work. Each subject executed nine gestures under the electrodes shift (10 mm) and damage (6 channels). As for the electrodes shift 10 mm in four directions (inwards; onwards; upwards; downwards) on seven able-bodied subjects, without any pre-training, the average accuracy of attention-DFCNN (0.942 ± 0.04) is significantly higher than LSDA (0.910 ± 0.04, p < 0.01), CNN (0.920 ± 0.05, p < 0.01), TCN (0.840 ± 0.07, p < 0.01), LSTM (0.864 ± 0.08, p < 0.01), attention-BiLSTM (0.852 ± 0.07, p < 0.01), Transformer (0.903 ± 0.07, p < 0.01) and Swin-Transformer (0.908 ± 0.09, p < 0.01). The proposed attention-DFCNN algorithm and the way of combining the spatial and temporary features of sEMG signals can significantly improve the recognition rate when the HD electrodes grid shift or damage during wear.

Hofmeister Effect-Assisted Facile Fabrication of Self-Assembled Poly(Vinyl Alcohol)/Graphite Composite Sponge-Like Hydrogel for Solar Steam Generation.

The use of hydrogel-based interfacial solar evaporators for desalination is a green, sustainable, and extremely concerned freshwater acquisition strategy. However, developing evaporators that are easy to manufacture, cheap, and have excellent porous structures still remains a considerable challenge. This work proposes a novel strategy for preparing a self-assembling sponge-like poly(vinyl alcohol)/graphite composite hydrogel based on the Hofmeister effect for the first time. The sponge-like hydrogel interfacial solar evaporator (PGCNG) is successfully obtained after combining with graphite. The whole process is environmental-friendly and of low-carbon free of freezing process. The PGCNG can be conventionally dried and stored. PGCNG shows impressive water storage performance and water transmission capacity, excellent steam generation performance and salt resistance. PGCNG has a high evaporation rate of 3.5 kg m-2 h-1 under 1 kW m-2 h-1 solar irradiation and PGCNG demonstrates stable evaporation performance over both 10 h of continuous brine evaporation and 30 cycles of brine evaporation. Its excellent performance and simple, scalable preparation strategy make it a valuable material for practical interface solar seawater desalination devices.

Synbiotic therapy with Clostridium sporogenes and xylan promotes gut-derived indole-3-propionic acid and improves cognitive impairments in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by cognitive impairment. Recent investigations have highlighted the potential of nutritional interventions that target the gut-brain axis, such as probiotics and prebiotics, in forestalling the onset of AD. In this study, whole-genome sequencing was employed to identify xylan as the optimal carbon source for the tryptophan metabolism regulating probiotic Clostridium sporogenes (C. sporogenes). Subsequent in vivo studies demonstrated that administration of a synbiotic formulation comprising C. sporogenes (1 × 1010 CFU per day) and xylan (1%, w/w) over a duration of 30 days markedly enhanced cognitive performance and spatial memory faculties in the 5xFAD transgenic AD mouse model. The synbiotic treatment significantly reduced amyloid-ß (Aß) accumulation in the cortex and hippocampus of the brain. Importantly, synbiotic therapy substantially restored the synaptic ultrastructure in AD mice and suppressed neuroinflammatory responses. Moreover, the intervention escalated levels of the microbial metabolite indole-3-propionic acid (IPA) and augmented the relative prevalence of IPA-synthesizing bacteria, Lachnospira and Clostridium, while reducing the dominant bacteria in AD, such as Aquabacterium, Corynebacterium, and Romboutsia. Notably, synbiotic treatment also prevented the disruption of gut barrier integrity. Correlation analysis indicated a strong positive association between gut microbiota-generated IPA levels and behavioral changes. In conclusion, this study demonstrates that synbiotic supplementation significantly improves cognitive and intellectual deficits in 5xFAD mice, which could be partly attributed to enhanced IPA production by gut microbiota. These findings provide a theoretical basis for considering synbiotic therapy as a novel microbiota-targeted approach for the treatment of metabolic and neurodegenerative diseases.

Programmable Lanthanide Metal-Organic Framework for Ultra-Efficient Nucleic Acids Extraction and Interaction Analysis.

Efficient, mild, and reversible adsorption of nucleic acids onto nanomaterials represents a promising analytical approach for medical diagnosis. However, there is a scarcity of efficient and reversible nucleic acid adsorption nanomaterials. Additionally, the lack of comprehension of the molecular mechanisms governing their interactions poses significant challenges. These issues hinder the rational design and analytical applications of the nanomaterials. Herein, we propose an ultra-efficient nucleic acid affinity nanomaterial based on programmable lanthanide metal-organic frameworks (Ln-MOFs). Through experiments and density functional theory calculations, a rational design guideline for nucleic acid affinity of Ln-MOF was proposed, and a modular and flexible preparation scheme was provided. Then, Er-TPA (terephthalic acid) MOF emerged as the optimal candidate due to its pore size-independent adsorption and desorption capabilities for nucleic acids, enabling ultra-efficient adsorption (about 150% mass ratio) within 1 min. Furthermore, we elucidate the molecular-level mechanisms underlying the Ln-MOF adsorption of single- and double-stranded DNA and G4 structures. The affinity nanomaterial based on Ln-MOF exhibits robust nucleic acid extraction capability (4-fold higher than commercial reagent kits) and enables mild and reversible CRISPR/Cas9 functional regulation. This method holds significant promise for broad application in DNA/RNA liquid biopsy and gene editing, facilitating breakthroughs in analytical chemistry, pharmacy, and medical research.

Isolation of potentially novel species expands the genomic and functional diversity of Lachnospiraceae.

The Lachnospiraceae family holds promise as a source of next-generation probiotics, yet a comprehensive delineation of its diversity is lacking, hampering the identification of suitable strains for future applications. To address this knowledge gap, we conducted an in-depth genomic and functional analysis of 1868 high-quality genomes, combining data from public databases with our new isolates. This data set represented 387 colonization-selective species-level clusters, of which eight genera represented multilineage clusters. Pan-genome analysis, single-nucleotide polymorphism (SNP) identification, and probiotic functional predictions revealed that species taxonomy, habitats, and geography together shape the functional diversity of Lachnospiraceae. Moreover, analyses of associations with atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD) indicated that several strains of potentially novel Lachnospiraceae species possess the capacity to reduce the abundance of opportunistic pathogens, thereby imparting potential health benefits. Our findings shed light on the untapped potential of novel species enabling knowledge-based selection of strains for the development of next-generation probiotics holding promise for improving human health and disease management.

Enhancing mitochondrial proteolysis alleviates alpha-synuclein-mediated cellular toxicity.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.