VmRDR2 of Valsa mali mediates the generation of VmR2-siR1 that suppresses apple resistance by RNA interference.

Cross-kingdom RNA interference (RNAi) is a crucial mechanism in host-pathogen interactions, with RNA-dependent RNA polymerase (RdRP) playing a vital role in signal amplification during RNAi. However, the role of pathogenic fungal RdRP in siRNAs generation and the regulation of plant-pathogen interactions remains elusive. Using deep sequencing, molecular, genetic, and biochemical approaches, this study revealed that VmRDR2 of Valsa mali regulates VmR2-siR1 to suppress the disease resistance-related gene MdLRP14 in apple. Both VmRDR1 and VmRDR2 are essential for the pathogenicity of V. mali in apple, with VmRDR2 mediating the generation of endogenous siRNAs, including an infection-related siRNA, VmR2-siR1. This siRNA specifically degrades the apple intracellular LRR-RI protein gene MdLRP14 in a sequence-specific manner, and overexpression of MdLRP14 enhances apple resistance against V. mali, which can be suppressed by VmR2-siR1. Conversely, MdLRP14 knockdown reduces resistance. In summary, this study demonstrates that VmRDR2 contributes to the generation of VmR2-siR1, which silences the host's intracellular LRR protein gene, thereby inhibiting host resistance. These findings offer novel insights into the fungi-mediated pathogenicity mechanism through RNAi.

A novel multidisciplinary machine learning approach based on clinical, imaging, colonoscopy, and pathology features for distinguishing intestinal tuberculosis from Crohn's disease.

OBJECTIVES: Differentiating intestinal tuberculosis (ITB) from Crohn's disease (CD) remains a diagnostic dilemma. Misdiagnosis carries potential grave implications. We aim to establish a multidisciplinary-based model using machine learning approach for distinguishing ITB from CD. METHODS: Eighty-two patients including 25 patients with ITB and 57 patients with CD were retrospectively recruited (54 in training cohort and 28 in testing cohort). The region of interest (ROI) for the lesion was delineated on magnetic resonance enterography (MRE) and colonoscopy images. Radiomic features were extracted by least absolute shrinkage and selection operator regression. Pathological feature was extracted automatically by deep-learning method. Clinical features were filtered by logistic regression analysis. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Delong's test was applied to compare the efficiency between the multidisciplinary-based model and the other four single-disciplinary-based models. RESULTS: The radiomics model based on MRE features yielded an AUC of 0.87 (95% confidence interval [CI] 0.68-0.96) on the test data set, which was similar to the clinical model (AUC, 0.90 [95% CI 0.71-0.98]) and higher than the colonoscopy radiomics model (AUC, 0.68 [95% CI 0.48-0.84]) and pathology deep-learning model (AUC, 0.70 [95% CI 0.49-0.85]). Multidisciplinary model, integrating 3 clinical, 21 MRE radiomic, 5 colonoscopy radiomic, and 4 pathology deep-learning features, could significantly improve the diagnostic performance (AUC of 0.94, 95% CI 0.78-1.00) on the bases of single-disciplinary-based models. DCA confirmed the clinical utility. CONCLUSIONS: Multidisciplinary-based model integrating clinical, MRE, colonoscopy, and pathology features was useful in distinguishing ITB from CD.

Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase-1A-induced lipid metabolism in diabetic nephropathy.

AIM: Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN. METHODS: The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR. RESULTS: ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN. CONCLUSION: Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.

Risk analysis of noise-induced hearing loss of workers in the automobile manufacturing industries based on back-propagation neural network model: a cross-sectional study in Han Chinese population.

OBJECTIVES: This study aims to predict the risk of noise-induced hearing loss (NIHL) through a back-propagation neural network (BPNN) model. It provides an early, simple and accurate prediction method for NIHL. DESIGN: Population based, a cross sectional study. SETTING: Han, China. PARTICIPANTS: This study selected 3266 Han male workers from three automobile manufacturing industries. PRIMARY OUTCOME MEASURES: Information including personal life habits, occupational health test information and occupational exposure history were collected and predictive factors of NIHL were screened from these workers. BPNN and logistic regression models were constructed using these predictors. RESULTS: The input variables of BPNN model were 20, 16 and 21 important factors screened by univariate, stepwise and lasso-logistic regression. When the BPNN model was applied to the test set, it was found to have a sensitivity (TPR) of 83.33%, a specificity (TNR) of 85.92%, an accuracy (ACC) of 85.51%, a positive predictive value (PPV) of 52.85%, a negative predictive value of 96.46% and area under the receiver operating curve (AUC) is: 0.926 (95% CI: 0.891 to 0.961), which demonstrated the better overall properties than univariate-logistic regression modelling (AUC: 0.715) (95% CI: 0.652 to 0.777). The BPNN model has better predictive performance against NIHL than the stepwise-logistic and lasso-logistic regression model in terms of TPR, TNR, ACC, PPV and NPV (p<0.05); the area under the receiver operating characteristics curve of NIHL is also higher than that of the stepwise and lasso-logistic regression model (p<0.05). It was a relatively important factor in NIHL to find cumulative noise exposure, auditory system symptoms, age, listening to music or watching video with headphones, exposure to high temperature and noise exposure time in the trained BPNN model. CONCLUSIONS: The BPNN model was a valuable tool in dealing with the occupational risk prediction problem of NIHL. It can be used to predict the risk of an individual NIHL.

Macrophage membrane-coated nanoparticles for the treatment of infectious diseases.

Infectious diseases severely threaten human health, and traditional treatment techniques face multiple limitations. As an important component of immune cells, macrophages display unique biological properties, such as biocompatibility, immunocompatibility, targeting specificity, and immunoregulatory activity, and play a critical role in protecting the body against infections. The macrophage membrane-coated nanoparticles not only maintain the functions of the inner nanoparticles but also inherit the characteristics of macrophages, making them excellent tools for improving drug delivery and therapeutic implications in infectious diseases (IDs). In this review, we describe the characteristics and functions of macrophage membrane-coated nanoparticles and their advantages and challenges in ID therapy. We first summarize the pathological features of IDs, providing insight into how to fight them. Next, we focus on the classification, characteristics, and preparation of macrophage membrane-coated nanoparticles. Finally, we comprehensively describe the progress of macrophage membrane-coated nanoparticles in combating IDs, including drug delivery, inhibition and killing of pathogens, and immune modulation. At the end of this review, a look forward to the challenges of this aspect is presented.

Protective effect of Lactiplantibacillus plantarum CCFM8661 against heavy metal mixture-induced liver and kidney injury in mice.

Human health and the ecological balance are both gravely threatened by heavy metal pollution brought on by global industrialization. Probiotics are thought to represent a novel class of medicinal products for reducing heavy metal toxicity. Though simultaneous poisoning of numerous heavy metals is more prevalent, the majority of current studies on probiotics in the treatment of heavy metal poisoning concentrate on a single heavy metal. Thus, a mouse damage model was created in this investigation using five heavy metals (Pb, Cd, Hg, Cr, and As), and Lactiplantibacillus plantarum CCFM8661 was utilized as an intervention therapy. The oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT), antioxidant capacity (T-AOC), and malondialdehyde (MDA), were evaluated in the blood, liver, and kidney tissues of mice throughout the experiment by tracking changes in body weight. Additionally, the amounts of five heavy metals were measured in the liver and kidney tissues. The alleviation of tissue damage and the detoxifying activity of L. plantarum CCFM8661 in mice with combined heavy metal intoxication were assessed by histopathological examination of liver and kidney tissues. Results revealed that during the test period, L. plantarum CCFM8661 significantly reduced the content of MDA and the contents of Pb, Cd, Hg, Cr, and As in liver and kidney tissues, while also significantly increasing weight gain and the activities of SOD, CAT, and T-AOC in mouse blood, liver, and kidney tissues compared to the model group. Mouse liver and kidney tissue damage from combined heavy metal exposure was considerably lessened by L. plantarum CCFM8661 when compared to the model group, according to H&E staining. This study demonstrates that L. plantarum CCFM8661 may be utilized as a useful intervention for the treatment of combined heavy metal poisoning by efficiently reducing the harm that heavy metals do to the body and maintaining bodily health.

Construction of photofunctional peptide conjugates through selective modification of N-terminal cysteine with cyclometallated iridium(III) 2-formylphenylboronic acid complexes for organelle-specific imaging, enzyme activity sensing and photodynamic therapy.

Luminescent cyclometallated iridium(III) complexes bearing a 2-formylphenylboronic acid moiety were designed; one of the complexes was utilised to modify peptides containing an N-terminal cysteine to afford luminescent conjugates with selective organelle-targeting or furin-responsive properties.

Identification and genetic validation of leukemia inhibitory factor super-enhancers in acute respiratory distress syndrome and lung cancer.

Super-enhancers play prominent roles in driving robust pathological gene expression, but they are hidden in human genome at noncoding regions, making them difficult to explore. Leukemia inhibitory factor (LIF) is a multifunctional cytokine crucially involved in acute respiratory distress syndrome (ARDS) and lung cancer progression. However, the mechanisms governing LIF regulation in disease contexts remain largely unexplored. In this study, we observed elevated levels of LIF in the bronchoalveolar lavage fluid (BALF) of patients with sepsis-related ARDS compared to those with nonsepsis-related ARDS. Furthermore, both basal and LPS-induced LIF expression were under the control of super-enhancers. Through analysis of H3K27Ac ChIP-seq data, we pinpointed three potential super-enhancers (LIF-SE1, LIF-SE2, and LIF-SE3) located proximal to the LIF gene in cells. Notably, genetic deletion of any of these three super-enhancers using CRISPR-Cas9 technology led to a significant reduction in LIF expression. Moreover, in cells lacking these super-enhancers, both cell growth and invasion capabilities were substantially impaired. Our findings highlight the critical role of three specific super-enhancers in regulating LIF expression and offer new insights into the transcriptional regulation of LIF in ARDS and lung cancer.

Extracellular perception of multiple novel core effectors from the broad host-range pear anthracnose pathogen Colletotrichum fructicola in the nonhost Nicotiana benthamiana.

Colletotrichum fructicola is emerging as a devastating pathogenic fungus causing anthracnose in a wide range of horticultural crops, particularly fruits. Exploitation of nonhost resistance (NHR) represents a robust strategy for plant disease management. Perception of core effectors from phytopathogens frequently leads to hypersensitive cell death and resistance in nonhost plants; however, such core effectors in C. fructicola and their signaling components in non-hosts remain elusive. Here, we found a virulent C. fructicola strain isolated from pear exhibits non-adaptation in the model plant Nicotiana benthamiana. Perception of secreted molecules from C. fructicola appears to be a dominant factor in NHR, and four novel core effectors-CfCE4, CfCE25, CfCE61, and CfCE66-detected by N. benthamiana were, accordingly, identified. These core effectors exhibit cell death-inducing activity in N. benthamiana and accumulate in the apoplast. With a series of CRISPR/Cas9-edited mutants or gene-silenced plants, we found the coreceptor BAK1 and helper NLRs including ADR1, NRG1, and NRCs mediate perceptions of these core effectors in N. benthamiana. Concurrently, multiple N. benthamiana genes encoding cell surface immune receptors and intracellular immune receptors were greatly induced by C. fructicola. This work represents the first characterization of the repertoire of C. fructicola core effectors responsible for NHR. Significantly, the novel core effectors and their signaling components unveiled in this study offered insights into a continuum of layered immunity during NHR and will be helpful for anthracnose disease management in diverse horticultural crops.

A randomized, double-blind, placebo-controlled phase I clinical trial of rotavirus inactivated vaccine (Vero cell) in a healthy adult population aged 18-49 years to assess safety and preliminary observation of immunogenicity.

We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %-51.09 %), 12.50 % (2.66 %-32.36 %), 50.00 % (29.12 %-70.88 %), and 41.67 % (22.11 %-63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12-760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73-1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28-1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35-5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67-10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27-14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82-3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64-7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66-4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18-49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).

Adaptive regulation of miRNAs/milRNAs in tissue-specific interaction between apple and Valsa mali.

In plant-pathogen interactions, pathogens display tissue specificity, infecting and causing disease in particular tissues. However, the involvement of microRNAs/microRNA-like RNAs (miRNAs/milRNAs) in tissue-specific regulation during plant-pathogen interactions remains largely unexplored. This study investigates the differential expression of miRNAs/milRNAs, as well as their corresponding target genes, in interactions between Valsa mali (Vm) and different apple tissues. The results demonstrated that both apple miRNAs and Vm milRNAs exhibited distinct expression profiles when Vm infected bark and leaves, with functionally diverse corresponding target genes. Furthermore, one apple miRNA (Mdo-miR482a) and one Vm milRNA (Vm-milR57) were identified as exhibiting tissue-specific expression in interactions between Vm and apple bark or leaves. Mdo-miR482a was exclusively up-regulated in response to Vm infection in bark and target a nucleotide-binding leucine-rich repeat (NLR) gene of apple. When Mdo-miR482a was transiently over-expressed or silenced, the resistance was significantly reduced or improved. Similarly, transient expression of the NLR gene also showed an increase in resistance. Vm-milR57 could target two essential pathogenicity-related genes of Vm. During Vm infection in bark, the expression of Vm-milR57 was down-regulated to enhance the expression of the corresponding target gene to improve the pathogenicity. The study is the first to reveal tissue-specific characteristics of apple miRNAs and Vm milRNAs in interactions between Vm and different apple tissues, providing new insights into adaptive regulation in tissue-specific interactions between plants and fungi.

Intrafractional motion detection for spine SBRT via X-ray imaging using ExacTrac Dynamic.

Purpose: Due to its close vicinity to critical structures, especially the spinal cord, standards for safety for spine stereotactic body radiotherapy (SBRT) should be high. This study was conducted, to evaluate intrafractional motion during spine SBRT for patients without individualized immobilization (e.g., vacuum cushions) using high accuracy patient monitoring via orthogonal X-ray imaging. Methods: Intrafractional X-ray data were collected from 29 patients receiving 79 fractions of spine SBRT. No individualized immobilization devices were used during the treatment. Intrafractional motion was monitored using the ExacTrac Dynamic (ETD) System (Brainlab AG, Munich, Germany). Deviations were detected in six degrees of freedom (6 DOF). Tolerances for repositioning were 0.7 mm for translational and 0.5° for rotational deviations. Patients were repositioned when the tolerance levels were exceeded. Results: Out of the 925 pairs of stereoscopic X-ray images examined, 138 (15 %) showed at least one deviation exceeding the predefined tolerance values. In all 6 DOF together, a total of 191 deviations out of tolerance were recorded. The frequency of deviations exceeding the tolerance levels varied among patients but occurred in all but one patient. Deviations out of tolerance could be seen in all 6 DOF. Maximum translational deviations were 2.6 mm, 2.3 mm and 2.8 mm in the lateral, longitudinal and vertical direction. Maximum rotational deviations were 1.8°, 2.6° and 1.6° for pitch, roll and yaw, respectively. Translational deviations were more frequent than rotational ones, and frequency and magnitude of deviations showed an inverse correlation. Conclusion: Intrafractional motion detection and patient repositioning during spine SBRT using X-ray imaging via the ETD System can lead to improved safety during the application of high BED in critical locations. When using intrafractional imaging with low thresholds for re-positioning individualized immobilization devices (e.g. vacuum cushions) may be omitted.

Biocontrol activity of an endophytic Alternaria alternata Aa-Lcht against apple Valsa canker.

Apple Valsa canker (AVC), caused by Valsa mali, is the most serious branch disease for apples in East Asia. Biocontrol constitutes a desirable alternative strategy to alleviate the problems of orchard environment pollution and pathogen resistance risk. It is particularly important to explore efficient biocontrol microorganism resources to develop new biocontrol technologies and products. In this study, an endophytic fungus, which results in the specific inhibition of the growth of V. mali, was isolated from the twig tissue of Malus micromalus with a good tolerance to AVC. The fungus was identified as Alternaria alternata, based on morphological observations and phylogenetic analysis, and was named Aa-Lcht. Aa-Lcht showed a strong preventive effect against AVC, as determined with an in vitro twig evaluation method. When V. mali was inhibited by Aa-Lcht, according to morphological and cytological observations, the hyphae was deformed and it had more branches, a degradation in protoplasm, breakages in cell walls, and then finally died completely due to mycelium cells. Transcriptome analysis indicated that Aa-Lcht could suppress the growth of V. mali by inhibiting the activity of various hydrolases, destroying carbohydrate metabolic processes, and damaging the pathogen membrane system. It was further demonstrated that Aa-Lcht could colonize apple twig tissues without damaging the tissue's integrity. More importantly, Aa-Lcht could also stimulate the up-regulated expression of defense-related genes in apples together with the accumulation of reactive oxygen species and callose deposition in apple leaf cells. Summarizing the above, one endophytic biocontrol resource was isolated, and it can colonize apple twig tissue and play a biocontrol role through both pathogen inhibition and resistance inducement.

A qualitative study of the experiences of interdisciplinary nurses during the COVID-19 outbreak following the announcement of the "Ten new guidelines" in China.

BACKGROUND: On December 7, 2022, the Joint Prevention and Control Mechanism of China's State Council released the "Ten New Guidelines" to optimize the coronavirus disease 2019 (COVID-19) prevention policies further. This signaled a broader shift from "dynamic clearing" to "coexisting with the virus" nationwide. OBJECTIVE: This study aims to examine the experiences and perspectives of interdisciplinary nurses during the COVID-19 outbreak in China after the implementation of the "Ten New Guidelines". The goal is to understand the challenges faced by this unique nursing group and inform organizational support to bolster their well-being and resilience. METHODS: Two tertiary hospitals in southeastern Zhejiang Province were selected, with interdisciplinary nurses chosen as subjects. A constructivist qualitative research approach was employed, using semi-structured face-to-face interviews. Research data were collected through interviews and analyzed using content analysis. RESULTS: Fifteen interdisciplinary nurses were included in this study. The analysis revealed four main themes and nine sub-themes. The main themes were: (1) ineffective organizational support (inadequate organizational care, poor PPE, excessive workload), (2) physiological distress after contracting COVID-19 (extreme physical fatigue, leakage of urine due to severe coughing), (3) fear of being wrong (fear of being reprimanded in public, psychological anxiety), and (4) family responsibility anxiety (difficulty of loyalty and filial piety, obligations to their children). CONCLUSION: We provide new evidence that organizations must proactively address the support, training, and communication needs of staff, particularly interdisciplinary nurses, to supplement epidemic containment. This is also essential in helping mitigate the work-family conflicts such roles can create.

Association between friends' hesitancy and personal COVID-19 vaccine hesitancy among Chinese medical staff.

COVID-19 vaccine hesitancy remains problematic among healthcare workers. Social network influences may shape vaccine decision-making, but few studies have examined this in this critical workforce. We assessed the relationship between friends' COVID-19 vaccination attitudes and personal hesitancy among Chinese healthcare personnel. In December 2022-January 2023, a cross-sectional online survey was conducted at a tertiary hospital in China using WeChat. Of the 1832 healthcare personnel who were invited to answer the structured questionnaire, 613 (33.5%) samples had valid data for data analysis. Logistic regression examined the association between friends' hesitancy and participants' own hesitancy, adjusting for confounders. Of 613 healthcare workers included, 266 (43.4%) were hesitant. Those with hesitant friends had 6.34 times higher adjusted odds of hesitating themselves versus those without hesitant friends (95% CI 2.97-13.52). Strong associations persisted across subgroups. Chinese healthcare workers' COVID-19 vaccination hesitancy was highly influenced by perceived friends' attitudes. Fostering pro-vaccine social norms through trusted peer networks could help promote vaccine acceptance in this critical workforce.

Mechanism of ameliorating cerebral ischemia/reperfusion injury by antioxidant inhibition of autophagy based on network pharmacology and experimental verification.

Cerebral ischemia-reperfusion injury (CIRI) is one of the most difficult challenges in cerebrovascular disease research. It is primarily caused by excessive autophagy induced by oxidative stress. Previously, a novel compound X5 was found, and the excellent antioxidant activity of it was verified in this study. Moreover, network pharmacological analysis suggested that compound X5 was closely associated with autophagy and the mTOR pathway. In vitro, X5 could significantly inhibit the expression of autophagy proteins Beclin-1 and LC3-ß, which are induced by H2O2, and promote the expression of SIRT1. In vivo, compound X5 significantly reduced the infarct size and improved the neurological function scores in the middle cerebral artery occlusion (MCAO) model of rats. In conclusion, ROS-induced autophagy is closely related to mTOR, SIRT1 and others, and X5 holds promise as a candidate for the treatment of CIRI.

Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline.

INTRODUCTION: Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and cognitive decline is undefined. METHODS: Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch-clamp experiments were conducted to investigate the synaptic function. RESULTS: NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age-dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1-overexpression in CA1 PyrNs. DISCUSSION: Our results elucidate the mechanism of Nr4a1-dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline. HIGHLIGHTS: Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1-induced cognitive improvement.

Novel Withanolides from Tubocapsicum anomalum Suppress Triple-Negative Breast Cancer by Triggering Apoptosis and p53-ASCT2-SLC7A11-Mediated Ferroptosis.

Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. Tubocapsicum anomalum (T. anomalum) has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe2+, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.

Age differences in the association of body mass index-defined obesity with abdominal aortic calcification.

Objectives: In cardiovascular disease, previous studies have suggested young age as one of the reasons to explain the obesity paradox. This study attempts to provide a different opinion on this claim through unexpected findings. Methods: We used a cross-sectional analysis of the US nationally representative data, total of 10,175 participants were recruited in 2013-2014 from NHANES. A total of 947 participants were selected to be included in this study through inclusion criteria and exclusion criteria for statistical analysis of the relationship between obesity and abdominal aortic calcification(AAC). Smooth curve fitting and multivariate regression analyses were conducted to examine the associations of obesity with AAC after adjusting for age, gender and associated variates. Results: Depending on the age of the population, the relationship between obesity and AAC showed the different outcome. Obesity was associated with the lower risk of AAC among individuals older than 52 years of age. According to the difference of adjusted covariates, the AAC scores in the obesity group decreased by 0.92, 0.87, and 1.11 for 52 years old or older individuals. In particular, the risk of AAC was lower for patients with obesity with the following characteristics: male, low LDL, low triglyceride, DM, non-cancer patient, smoking, drinking, vigorous work activity, low annual household income, education of 9 - 11th grades and non-Hispanic white. Conclusions: In US, adults aged 52 years or older, obesity was associated with decreased AAC risk. Older age may be one potential reason for the obesity paradox.

Enhancing precision medicine: Bispecific antibody-mediated targeted delivery of lipid nanoparticles for potential cancer therapy.

The precise delivery of therapeutic agents to specific cell populations, including cancer cells, remains a target in modern medicine, to enhance treatment efficacy, while minimizing unintended side effects. This study presents a strategy utilizing bispecific antibodies for the targeted delivery of nucleic acid drugs to the surface of glucose-regulated protein 78 (GRP78)-overexpressing cancer cells. Strong binding affinity of the bispecific antibodies to GRP78-overexpressing cancer cells, including HEPG2 cells, confirmed the tumor-targeting potential of this platform. Functional analyses demonstrated the role of the bispecific antibodies in enhancing lipid nanoparticle (LNP) uptake, causing increased gene expression levels of nucleic acid drugs loaded within LNPs. In vivo imaging confirmed the potency of the bispecific-antibody-modified LNPs in delivering nucleic acid drugs to tumors and sustaining therapeutic expression levels. In vivo therapy results indicated that the bispecific antibodies improved the antitumor activity of PE38-loaded LNPs in tumors overexpressing surface GRP78. This study pioneered a bispecific-antibody-centered platform for the targeted delivery of nucleic acid drugs. The robust antigen-antibody binding affinity, tumor-selective interactions, enhanced cellular uptake, and proficient gene expression promise to advance precision therapeutics in oncology. Continued refinement and translation of this drug delivery strategy are important to unlock its full clinical potential.