Dissecting the intricacies of human antibody responses to SARS-CoV-1 and SARS-CoV-2 infection.

The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles. Notably, RBD-7 antibodies bound to a unique RBD region interfaced with the N-terminal domain of the neighboring protomer (NTD proximal) and were more prevalent in SARS-CoV-1 patients. Broadly neutralizing antibodies for SARS-CoV-1, SARS-CoV-2, and bat and pangolin coronaviruses were also identified. These results provide further insights into the antibody response to SARS-CoV-1 and inform the design of more effective strategies against diverse human and animal coronaviruses.

Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

Tet-mediated DNA methylation dynamics affect chromosome organization.

DNA Methylation is a significant epigenetic modification that can modulate chromosome states, but its role in orchestrating chromosome organization has not been well elucidated. Here we systematically assessed the effects of DNA Methylation on chromosome organization with a multi-omics strategy to capture DNA Methylation and high-order chromosome interaction simultaneously on mouse embryonic stem cells with DNA methylation dioxygenase Tet triple knock-out (Tet-TKO). Globally, upon Tet-TKO, we observed weakened compartmentalization, corresponding to decreased methylation differences between CpG island (CGI) rich and poor domains. Tet-TKO could also induce hypermethylation for the CTCF binding peaks in TAD boundaries and chromatin loop anchors. Accordingly, CTCF peak generally weakened upon Tet-TKO, which results in weakened TAD structure and depletion of long-range chromatin loops. Genes that lost enhancer-promoter looping upon Tet-TKO showed DNA hypermethylation in their gene bodies, which may compensate for the disruption of gene expression. We also observed distinct effects of Tet1 and Tet2 on chromatin organization and increased DNA methylation correlation on spatially interacted fragments upon Tet inactivation. Our work showed the broad effects of Tet inactivation and DNA methylation dynamics on chromosome organization.

Altered Impulsivity Across Drug-Naïve Parkinsonism, Isolated Rapid Eye Movement Sleep Behavior Disorder, and Their High-Risk Relatives.

OBJECTIVE: To determine multidimensional impulsivity levels across different early stages of α-synucleinopathy. METHODS: This cross-sectional study investigated motor and decisional impulsivity levels using a panel of computerized tasks among drug-naïve parkinsonism patients, isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) patients and their first-degree relatives (iRBD-FDRs), and control participants. Trait impulsivity and impulse control behaviors were assessed by self-reported questionnaires. RESULTS: A total of 27 drug-naïve parkinsonism patients, 157 iRBD patients, 66 iRBD-FDRs, and 82 control participants were recruited. Parkinsonism and iRBD patients had fewer numbers of extracted beads in beads task 1 and 2 (both p < 0.001), and a higher rate of irrational choice in task 1 (p = 0.046) before making decisions, and fewer numbers of pumps of unexploded blue balloons in the balloon analog risk task (p = 0.004) than control participants, indicating a higher level of reflection impulsivity and a lower level of risk taking, respectively. iRBD patients had more no-go errors in the go/no-go task than control participants (padjusted = 0.036), suggesting a higher level of motor impulsivity. iRBD-FDRs with dream-enactment behaviors had fewer numbers of extracted beads (p = 0.047) in beads task 2 than FDRs without dream-enactment behaviors, suggesting a possible higher level of reflection impulsivity. INTERPRETATION: A complex construct of altered impulsivity with decreased risk taking, but increased reflection and motor impulsivity, has already occurred at the prodromal and early stages of α-synucleinopathy, which have implications for underlying pathophysiology and clinical management of α-synucleinopathy, especially for impulse control behaviors upon dopaminergic drug treatment. ANN NEUROL 2024;95:544-557.

Social Isolation, Loneliness, and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes Mellitus.

RATIONALE & OBJECTIVE: Social disconnection has been associated with poor cardiometabolic health. This study sought to investigate the associations of social isolation and loneliness with diabetic microvascular complications (DMCs) among individuals with type 2 diabetes mellitus (T2DM) and compare these associations versus those related to traditional risk factors. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 24,297 UK Biobank participants with T2DM and no DMCs at baseline. EXPOSURE: Social isolation and loneliness were measured using self-reported questionnaires. OUTCOME: The incidence of DMCs defined as a composite of diabetic kidney disease, diabetic retinopathy, or diabetic neuropathy. ANALYTICAL APPROACH: Multivariable cause-specific hazards regression. To compare the relative importance of social disconnection with other established factors, the R2 values of the Cox models were calculated. RESULTS: During a median follow-up of 12.6 years, 5,530 patients were documented to experience DMCs (3,458 with diabetic kidney disease, 2,255 with diabetic retinopathy, and 1,146 with diabetic neuropathy). The highest level of social isolation was associated with an increased risk of any DMC component (most vs least: HR, 1.13; 95% CI, 1.05-1.22), especially diabetic kidney disease (HR, 1.14; 95% CI, 1.04-1.25) and neuropathy (HR, 1.31; 95% CI, 1.11-1.53). Any level of loneliness was associated with an increased risk of any DMC component (HR, 1.12; 95% CI, 1.02-1.23) and diabetic kidney disease (HR, 1.16; 95% CI, 1.03-1.30). Social isolation and loneliness exhibited associations with DMCs comparable to those of other conventional risk factors, including smoking, blood pressure, and physical activity. LIMITATIONS: Limited generalizability related to the composition of participants in the UK Biobank Study. CONCLUSIONS: Social isolation and loneliness were independently associated with a higher risk of incident DMCs among individuals with T2DM, with comparable importance to other traditional risk factors. These findings underscore social isolation and loneliness as novel and potentially modifiable risk factors for DMCs. PLAIN-LANGUAGE SUMMARY: Social isolation and loneliness are important social determinants that are associated with adverse cardiometabolic health. Individuals with diabetes are particularly vulnerable to social isolation and loneliness. However, the relationship of social isolation or loneliness with diabetic microvascular complications (DMCs) remains unclear. Our study used the UK Biobank study data to investigate the associations of social isolation and loneliness with the development of DMCs. We found that social isolation and loneliness were independently associated with a higher risk of incident DMCs. Remarkably, their association with DMCs was comparable to those of other lifestyle factors such as smoking, blood pressure, and physical activity. These findings collectively imply that social isolation and loneliness are 2 important potentially modifiable risk factors for DMCs among individuals with type 2 diabetes mellitus.

Carrier transport engineering in a polarization-interface-free ferroelectric PN junction for photovoltaic effect.

The carrier transport performances play key roles in the photoelectric conversion efficiency for photovoltaic effect. Hence, the low carrier mobility and high photogenerated carrier recombination in ferroelectric materials depress the separation of carriers. This work designs a ferroelectric polarization-interface-free PN junction composed with P-type semiconductor BiFeO3 (BFO) derived from the variable valence of Fe and N-type semiconductor BiFe0.98Ti0.02O3 (BFTO) through Ti donor doping. The integration of the ferroelectricity decides the PN junction without polarization coupling like the traditional heterojunctions but only existing carrier distribution differential at the interface. The carrier recombination in PN junction is significantly reduced due to the driving force of the built-in electric field and the existence of depletion layer, thereby enhancing the switching current 3 times higher than that of the single ferroelectric films. Meanwhile, the carrier separation at the interface is significantly engineered by the polarization, with open circuit voltage and short circuit current of photovoltaic effect increased obviously. This work provides an alternative strategy to regulate bulk ferroelectric photovoltaic effects by carrier transport engineering in the polarization-interface-free ferroelectric PN junction.

Compact and efficient photonic lanterns through multi-stage tapering.

Photonic lanterns (PLs) have been recently used in mode-division multiplexed systems with a low insertion loss, a low mode-dependent loss (MDL), and a wide bandwidth. However, the cross talk (XT) performance of the PLs requires further enhancement within a short taper length. In this Letter, a multi-stage cascaded scheme for short PLs is proposed to further improve the performance on losses and XT. The XT of the optimized 6-mode 3-stage PL is below -23.4 dB, while the total length is only 6 cm. To the best of our knowledge, this is the first quantitative optimization of a 3-stage tapered PL, resulting in a compact structure and excellent performance. Furthermore, we experimentally validate the feasibility of the 3-stage tapering process.

Fan-in/fan-out for heterogeneous 19-core fibers based on metasurfaces with nonuniform phase plates.

In space-division-multiplexed transmission systems, it is essential to realize fan-in/fan-out devices that connect the cores between multicore fibers and single-mode fibers. In this Letter, we propose a metasurface-based fan-in/fan-out device with nonuniform phase plates for heterogeneous 19-core fibers across the full C band. Our results show that an average insertion loss of 0.85 dB and a maximum crosstalk of -25.5 dB can be achieved at 1550 nm. Across the C band, the insertion loss and crosstalk are better than 2.78 dB and -19.96 dB, respectively. The proposed concept can flexibly handle various fiber configurations without additional complexity.

Mode conversion in graded-index few-mode fiber via hollow cylindrical long-period fiber gratings.

We demonstrate the realization of mode conversion using hollow cylindrical long-period fiber gratings (LPFGs) inscribed in graded-index few-mode fibers (FMFs) by a femtosecond laser. By precisely shaping the refractive index modulation into a hollow cylindrical structure, we enable efficient coupling from the fundamental mode to high-order modes (LP11, LP02, LP21, LP12, LP31, LP03, and LP22 modes). The method achieves high-efficiency and low-loss mode conversion across various mode groups, marking a first for graded-index FMFs with different grating periods. The influence of the hollow cylindrical LPFG radius on mode conversion efficiency and spectral characteristics is thoroughly investigated. Additionally, incorporating a linear polarizer allowed for distinguishing between LP modes within a mode group, enhancing the tunability of the mode converter. These mode conversion devices have significant potential for applications in mode gain equalization and mode scrambling for mode division multiplexing (MDM) systems.

Visuospatial dysfunction predicts dementia-first phenoconversion in isolated REM sleep behaviour disorder.

OBJECTIVE: While isolated rapid eye movement sleep behaviour disorder (iRBD) is known as a prodrome of α-synucleinopathies, the prediction for its future phenoconversion to parkinsonism-first or dementia-first subtype remains a challenge. This study aimed to investigate whether visuospatial dysfunction predicts dementia-first phenoconversion in iRBD. METHODS: Patients with iRBD and control subjects were enrolled in this prospective cohort study. Baseline neuropsychological assessment included the Unified Parkinson's Disease Rating Scale part III, Montreal Cognitive Assessment (MoCA), Rey-Osterrieth complex figure (ROCF), Colour Trails test (CTT), Farnsworth-Munsell 100-hue test and Digit Span test. The anterior and posterior subscores of MoCA as well as their modified versions were explored. A composite score derived from ROCF and CTT was also explored. Regular follow-up was conducted to determine the phenoconversion status of iRBD patients. RESULTS: The study included 175 iRBD patients and 98 controls. During a mean follow-up of 5.1 years, 25.7% of patients experienced phenoconversion. Most of the neuropsychological tests could differentiate dementia-first but not parkinsonism-first convertors from non-convertors. The modified posterior subscore of MoCA, by integrating the Alternating Trail Making and Clock Drawing components into original the posterior subscore, which mainly reflects visuospatial function, was the strongest predictor for dementia-first phenoconversion (adjusted HR 5.48, 95% CI 1.67 to 17.98). CONCLUSION: Visuospatial dysfunction, as reflected mainly by the modified posterior subscore of MoCA, is a predictive factor for dementia-first phenoconversion in iRBD, suggesting its potential for being a biomarker for clinical prognostic prediction and potential neuroprotective trials aiming to delay or prevent dementia.

Deep Eutectic Solvents for Essential-Oil Delivery and Bacterial-Infected Wound Healing.

Essential oils (EOs) are volatile secondary metabolites of natural plants with multitudinous pharmacological activities. However, limited by their properties, such as low solubility, high volatility, photothermal instability, irritation, release, etc., EOs encounter significant challenges in pharmaceutical applications. Deep eutectic solvents (DESs) have been developed for the transdermal delivery of biomolecules and lipid-soluble drugs. Herein, a series of DES carriers were synthesized to improve the undesirable properties of EOs. We first optimized the DESs according to solubilization and aqueous dispersity using Chimonanthus nitens Oliv. EO (COEO) as a model EO. Then, the EO-DES formulations were diluted to prepare optimal aqueous EO-DES nanoformulations (AqEDs). Mechanically, hydrogen bonding allowed the DES to dissolve the complex components in EOs; meanwhile, the interaction forces, such as π-π stacking and hydrogen bonding, drove the EO-DES to assemble into nanostructures in aqueous conditions, forming AqEDs. Lastly, a case study demonstrated that clove EO-AqEDscould effectively promote methicillin-resistant Staphylococcus aureus-infected wound healing in vivo, along with biocompatibility. This AqED strategy provides a generalized platform for solubilizing EOs and improving their transdermal/topical delivery.

A prediction nomogram for hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: The present study aimed to develop and validate a new nomogram for predicting the incidence of hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients receiving antiviral therapy from real-world data. METHODS: The nomogram was established based on a real-world retrospective study of 764 patients with HBV from October 2008 to July 2020. A predictive model for the incidence of HCC was developed by multivariable Cox regression, and a nomogram was constructed. The predictive accuracy and discriminative ability of the nomogram were assessed by the concordance index (C-index), calibration curves, and decision curve analysis (DCA). Risk group stratification was performed to assess the predictive capacity of the nomogram. The nomogram was compared to three current commonly used predictive models. RESULTS: A total of 764 patients with HBV were recruited for this study. Age, family history of HCC, alcohol consumption, and Aspartate aminotransferase-to-Platelet Ratio Index (APRI) were all independent risk predictors of HCC in CHB patients. The constructed nomogram had good discrimination with a C-index of 0.811. The calibration curve and DCA also proved the reliability and accuracy of the nomogram. Three risk groups (low, moderate, and high) with significantly different prognoses were identified (p < 0.001). The model's performance was significantly better than that of other risk models. CONCLUSIONS: The nomogram was superior in predicting HCC risk among CHB patients who received antiviral treatment. The model can be utilized in clinical practice to aid decision-making on the strategy of long-term HCC surveillance, especially for moderate- and high-risk patients.

Cryptic piperazine derivatives activated by knocking out the global regulator LaeA in Aspergillus flavipes.

Genome sequencing on an intertidal zone-derived Aspergillus flavipes strain revealed its great potential to produce secondary metabolites. To activate the cryptic compounds of A. flavipes, the global regulator flLaeA was knocked out, leading to substantial up-regulation of the expression of two NRPS-like biosynthetic gene clusters in the ΔflLaeA mutant. With a scaled-up fermentation of the ΔflLaeA strain, five compounds, including two previously undescribed piperazine derivatives flavipamides A and B (1 and 2), along with three known compounds (3-5), were obtained by LC-MS guided isolation. The new compounds were elucidated by spectroscopic analysis and electronic circular dichroism (ECD) calculations, and the biosynthetic pathway was proposed on the bias of bioinformatic analysis and 13C isotope labeling evidence. This is the first report to access cryptic fungi secondary metabolites by inactivating global regulator LaeA and may provide a new approach to discovering new secondary metabolites by such genetic manipulation.

NDC1 promotes hepatocellular carcinoma tumorigenesis by targeting BCAP31 to activate PI3K/AKT signaling.

Hepatocellular carcinoma (HCC) is among the world's worst malignancies. Nuclear division cycle 1 (NDC1) is an essential membrane-integral nucleoporin, found in this study to be significantly increased in primary HCC. A multivariate analysis revealed that higher NDC1 expression was linked to worse outcome in HCC patients. Mouse xenograft tumors overexpressing NDC1 grew rapidly, and HCC cells overexpressing NDC1 showed enhanced proliferation, invasion, and migration in vitro. In contrast, knocking down NDC1 had the opposite effects in vitro. Furthermore, co-immunoprecipitation and liquid chromatograph mass spectrometer analyses revealed that NDC1 activated PI3K/AKT signaling by interacting with BCAP31. In summary, NDC1 and BCAP31 cooperate to promote the PI3K/AKT pathway, which is essential for HCC carcinogenesis. This suggests that NDC1 is predictive of prognosis in HCC.

Influence of tuberculosis knowledge on acceptance of preventive treatment and the moderating role of tuberculosis stigma among China's general population: cross-sectional analysis.

BACKGROUND: Preventive treatment of tuberculosis infection (TBI) is considered a crucial strategy to prevent and control tuberculosis (TB). However, the acceptance and completion rates of preventive therapy for TBI are still far from optimistic. Evidence is mounting that TB knowledge and stigma may have a substantial effect on acceptance of TBI treatment. This study aimed to explore the effect of stigma on the relationship between the level of TB knowledge and acceptance of TBI treatment. METHODS: 7017 general population were included in the study. We adjusted for the covariates at the individual. Stepwise logistic regression was used to examine the moderating role of TB stigma and also explore the association between TB knowledge and acceptance of TBI treatment. RESULTS: The acceptance rate of TBI treatment among the respondents was 84.38% (n = 5921). Among respondents, a significant positive correlation between acceptance of TBI treatment and TB knowledge (OR = 1.096,95%CI = 1.073,1.118). Additionally, the association between TB knowledge and acceptance of TBI treatment was found to be moderated by TB stigma. In other words, TB stigma was found to weaken the impact of TB knowledge on acceptance of TBI treatment (OR = 0.994,95%CI = 0.991,0.996). CONCLUSION: The findings of the study indicated that having a high level of awareness about TB can enhance the general population's acceptability of TBI treatment. TB stigma moderated this association; it weakened the relationship between TB knowledge and individuals' willingness to accept TBI treatment. To mitigate TB stigma and enhance the intention of individuals with TBI to accept preventive therapy, it is imperative to enhance TB-related health education.

Association of serum total IgE and allergen-specific IgE with insulin resistance in adolescents: an analysis of the NHANES database.

BACKGROUND: Recent studies have found that total immunoglobulin E (IgE) and allergen-specific IgE were associated with some metabolic diseases. However, the role of IgE in metabolism among adolescents is still unclear. Herein, this study aims to investigate the associations of serum total IgE and allergen-specific IgE with insulin resistance (IR) in adolescents, in order to provide some reference for the prevention and treatment of metabolic diseases in a young age. METHODS: Data of 870 adolescents were extracted from the National Health and Nutrition Examination Survey (NHANES) database in 2005-2006 in this cross-sectional study. Weighted univariate and multivariate logistic regression analyses were utilized to screen covariates and explore the relationships of serum total IgE and allergen-specific IgE with IR. The evaluation indexes were odds ratios (ORs) and 95% confidence intervals (CIs). In addition, these relationships were also assessed in subgroups of allergy history, asthma history, and number of allergens. RESULTS: Among eligible adolescents, 168 had IR. No significant association between serum total IgE level and IR was found. However, adolescents with higher level of allergen-specific IgE to rye grass [OR = 0.47, 95%CI: (0.25-0.91)], white oak [OR = 0.57, 95%CI: (0.37-0.88)], or peanut [OR = 0.38, 95%CI: (0.15-0.97)] seemed to have lower odds of IR, whereas those had higher level of shrimp-specific IgE [OR = 2.65, 95%CI: (1.21-5.84)] have increased odds of IR. In addition, these associations between allergen-specific IgE and IR were also discovered in adolescents who had allergy history or asthma history, or had different numbers of allergens. CONCLUSION: Paying attention to different allergens in adolescents may be important in the early identification of IR among this high-risk population. The study results relatively provided some reference for further exploration on IR prevention.

Ethylene is the key phytohormone to enhance arsenic resistance in Arabidopsis thaliana.

The toxic metalloid arsenic is prevalent in the environment and poses a threat to nearly all organisms. However, the mechanism by which phytohormones modulate arsenic resistance is not well-understood. Therefore, we analyzed multiple phytohormones based on the results of transcriptome sequencing, content changes, and related mutant growth under arsenic stress. We found that ethylene was the key phytohormone in Arabidopsis thaliana response to arsenic. Further investigation showed the ethylene-overproducing mutant eto1-1 generated less malondialdehyde (MDA), H2O2, and O2•- under arsenic stress compared to wild-type, while the ethylene-insensitive mutant ein2-5 displayed opposite patterns. Compared to wild-type, eto1-1 accumulated a smaller amount of arsenic and a larger amount of non-protein thiols. Additionally, the immediate ethylene precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), enhanced resistance to arsenic in wide-type, but not in mutants with impaired detoxification capability (i.e., cad1-3, pad2-1, abcc1abcc2), which confirmed that ethylene regulated arsenic detoxification by enhancing arsenic chelation. ACC also upregulated the expression of gene(s) involved in arsenic detoxification, among which ABCC2 was directly transcriptionally activated by the ethylene master transcription factor ethylene-insensitive 3 (EIN3). Overall, our study shows that ethylene is the key phytohormone to enhance arsenic resistance by reducing arsenic accumulation and promoting arsenic detoxification at both physiological and molecular levels.

Associations between accelerometer-measured circadian rest-activity rhythm, brain structural and genetic mechanisms, and dementia.

AIM: Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. METHODS: Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. RESULTS: Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. CONCLUSIONS: Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.

Development of mRNA Lipid Nanoparticles: Targeting and Therapeutic Aspects.

Lipid nanoparticles (LNPs) have emerged as leading non-viral carriers for messenger RNA (mRNA) delivery in clinical applications. Overcoming challenges in safe and effective mRNA delivery to target tissues and cells, along with controlling release from the delivery vehicle, remains pivotal in mRNA-based therapies. This review elucidates the structure of LNPs, the mechanism for mRNA delivery, and the targeted delivery of LNPs to various cells and tissues, including leukocytes, T-cells, dendritic cells, Kupffer cells, hepatic endothelial cells, and hepatic and extrahepatic tissues. Here, we discuss the applications of mRNA-LNP vaccines for the prevention of infectious diseases and for the treatment of cancer and various genetic diseases. Although challenges remain in terms of delivery efficiency, specific tissue targeting, toxicity, and storage stability, mRNA-LNP technology holds extensive potential for the treatment of diseases.

Effects of Ultra-High-Pressure Treatment on Chemical Composition and Biological Activities of Free, Esterified and Bound Phenolics from Phyllanthus emblica L. Fruits.

Phyllanthus emblica L. fruits (PEFs) were processed by ultra-pressure (UHP) treatment and then extracted by the ultrasonic-assisted extraction method. The influence of UHP on the phenolic composition, enzyme inhibitory activity and antioxidant activity of the free, esterified, and bound phenolic fractions from PEFs were compared. UHP pretreatment of PEFs significantly increased the total phenolic and flavonoid contents (p < 0.05). A total of 24 chemical compositions were characterized in normal and UHP-treated PEFs by UHPLC-ESI-HRMS/MS. Compared with normal PEFs, these three different phenolic fractions had stronger antioxidant activities and inhibitory effects on the intracellular reactive oxygen species (ROS) production in H2O2-induced HepG2 cells (p < 0.05). The ROS inhibition might be due to an up-regulation of the expressions of superoxide dismutase (SOD) and glutathione (GSH) activities. In addition, these three different phenolic fractions also significantly inhibited the activities of metabolic enzymes, including α-glucosidase, α-amylase and pancreatic lipase. This work may provide some insights into the potential economics and applications of PEFs in food and nutraceutical industries.