Overcoming flumatinib resistance in chronic myeloid leukaemia: Insights into cellular mechanisms and ivermectin's therapeutic potential.

Chronic myeloid leukaemia (CML) is a haematological malignancy characterized by the constitutive tyrosine kinase activity of the BCR-ABL1 fusion protein. Flumatinib, a second-generation tyrosine kinase inhibitor, has exhibited superior clinical efficacy compared to its precursor, imatinib. However, with increased clinical use, resistance to flumatinib has emerged as a significant challenge. To investigate the mechanisms of flumatinib resistance in CML, we induced the human CML cell line K562 using a flumatinib concentration gradient method in vitro, successfully establishing a flumatinib-resistant K562/FLM cell line. This cell line exhibited cross-resistance to imatinib and doxorubicin, but remained sensitive to the antiparasitic agent ivermectin, which possesses antitumoural effects. Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins. Moreover, it was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. Collectively, the increased autophagy, higher expression of drug-efflux proteins and hyperactivation of the EGFR/ERK/STAT3 signalling pathway were identified as pivotal elements promoting resistance to flumatinib. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.

Coreactant-Free Zirconium Metal-Organic Framework with Dual Emission for Ratiometric Electrochemiluminescence Detection of HIV DNA.

Owing to the limitations of dual-signal luminescent materials and coreactants, constructing a ratiometric electrochemiluminescence (ECL) biosensor based on a single luminophore is a huge challenge. This work developed an excellent zirconium metal-organic framework (MOF) Zr-TBAPY as a single ECL luminophore, which simultaneously exhibited cathodic and anodic ECL without any additional coreactants. First, Zr-TBAPY was successfully prepared by a solvothermal method with 1,3,6,8-tetra(4-carboxyphenyl)pyrene (TBAPY) as the organic ligand and Zr4+ cluster as the metal node. The exploration of ECL mechanisms confirmed that the cathodic ECL of Zr-TBAPY originated from the pathway of reactive oxygen species (ROS) as the cathodic coreactant, which is generated by dissolved oxygen (O2), while the anodic ECL stemmed from the pathway of generated Zr-TBAPY radical itself as the anodic coreactant. Besides, N,N-diethylethylenediamine (DEDA) was developed as a regulator to ECL signals, which quenched the cathodic ECL and enhanced the anodic ECL, and the specific mechanisms of its dual action were also investigated. DEDA can act as the anodic coreactant while consuming the cathodic coreactant ROS. Therefore, the coreactant-free ratiometric ECL biosensor was skillfully constructed by combining the regulatory role of DEDA with the signal amplification reaction of catalytic hairpin assembly (CHA). The ECL biosensor realized the ultrasensitive ratio detection of HIV DNA. The linear range was 1 fM to 100 pM, and the limit of detection (LOD) was as low as 550 aM. The outstanding characteristic of Zr-TBAPY provided new thoughts for the development of ECL materials and developed a new way of fabricating the coreactant-free and single-luminophore ratiometric ECL platform.

3D hUC-MSC spheroids exhibit superior resistance to autophagy and apoptosis of granulosa cells in POF rat model.

In brief: This study reveals that orthotopic transplantation of 3D hUC-MSC spheroids is more effective than monolayer-cultured hUC-MSCs in improving POF and distinctly reducing oxidative stress through the paracrine effect, thereby preventing apoptosis and autophagy of GCs. Abstract: Premature ovarian failure (POF) is a common reproductive disease in women younger than 40 years old, and studies have demonstrated that the application of human umbilical cord mesenchymal stem cells (hUC-MSCs) is a promising therapy strategy for POF. Given the previously established therapeutic advantages of 3D MSC spheroids, and to evaluate their effectiveness, both 3D hUC-MSC spheroids and monolayer-cultured hUC-MSCs were employed to treat a cyclophosphamide-induced POF rat model through orthotopic transplantation. The effects of these two forms on POF were subsequently assessed by examining apoptosis, autophagy, and oxidative damage in ovarian granulosa cells (GCs). The results indicated that hUC-MSC spheroids exhibited superior treatment effects on resisting autophagy, apoptosis, and oxidative damage in GCs compared to monolayer-cultured hUC-MSCs. To further elucidate the impact of hUC-MSC spheroids in vitro, a H2O2-induced KGN cells model was established and co-cultured with both forms of hUC-MSCs. As expected, the hUC-MSC spheroids also exhibited superior effects in resisting apoptosis and autophagy caused by oxidative damage. Therefore, this study demonstrates that 3D hUC-MSC spheroids have potential advantages in POF therapy; however, the detailed mechanisms need to be further investigated. Furthermore, this study will provide a reference for the clinical treatment strategy of POF.

Dual-emission Tb-based coordination polymer as a ratiometric fluorescence probe for the detection of phosphate.

A simple, sensitive dual-emission probe was developed for the detection of phosphate (Pi). The probe Tb-BTB/DPA was synthesized by mixing dual-ligand, 1,3,5-tri(4-carboxyphenyl) benzene (H3BTB) and dipicolinic acid (DPA), with metal ions Tb3+ in ethanol-water solution at 40℃ for 2 h. Tb-BTB/DPA exhibits two emission peaks, the emission at 362 nm is attributed to H3BTB, an energy transfer between Tb3+ nodes, and DPA further enhances the fluorescence of Tb3+ at 544 nm. Pi competes with ligand H3BTB to coordinate Tb3+, resulting in partial collapse of the Tb-BTB/DPA structure and interrupting the electron transfer between H3BTB and Tb3+. Therefore, the emission at 362 nm is enhanced, while the emission at 544 nm is unchanged, and a ratiometric fluorescence method is developed to detect Pi. Tb-BTB/DPA exhibits good linearity within the Pi concentration range (0.1-50 µmol/L), and the detection limit was 25.8 nmol/L. This study provides a new way to prepare probes with dual emission sensing properties.

Interaction of physical activity and low-level air pollution on cardiovascular disease: a prospective cohort study in UK Biobank.

To investigate the associations of physical activity (PA), low-level air pollution, and interaction on cardiovascular diseases (CVD) incidence based on the UK Biobank. PA was measured by the International Physical Activity Questionnaire and five air pollutants were estimated using Land Use Regression. All association estimates were based on Cox regression. Dose-response relationship was explored by restricted cubic spline, while multiplicative and additive interaction were examined by Pinteraction and relative excess risk due to interaction (RERI). As deviating proportional hazards assumption, we analyzed data as follow-up < 4 years and ≥ 4 years, separately. PA with 1000-4000 Metabolic Equivalent Task (MET) min/week showed the strongest protective impact on CVD incidence, while only low-level nitrogen dioxides (NO2) showed negative impact among five air pollutants and was considered for further analysis. Multiplicative interaction between PA and NO2 was observed during ≥ 4 years follow-up (Pinteraction = 0.049) while not during < 4 years (Pinteraction = 0.290). Positive additive interactions were found for high PA and low NO2 (< 20 µg/m3) group (RERI: 0.07, 95% confidence intervals: 0.02-0.11) during < 4 years, and for moderate PA with NO2 at 40- µg/m3 (0.07, 0.02-0.13) and < 20 µg/m3 (0.07, 0.02-0.12), while high PA showed similar results with NO2 at 40-, 20- and < 20 µg/m3 during ≥ 4 years. PA about 1000-4000 METs min/week showed the lowest CVD risk. Possibility of interaction with PA and NO2 is more likely to present with the increase in follow-up duration. We call for the optimal thresholds of PA, and exploring interaction thoroughly by considering types of PA.

Human umbilical cord mesenchymal stem cells alleviate chemotherapy-induced premature ovarian insufficiency mouse model by suppressing ferritinophagy-mediated ferroptosis in granulosa cells.

Primary ovarian insufficiency (POI) in younger women (under 40) manifests as irregular periods, high follicle-stimulating hormone (FSH), and low estradiol (E2), often triggered by chemotherapy. Though mesenchymal stem cell (MSC) therapy shows promise in treating POI, its exact mechanism remains unclear. This study reveals that human umbilical cord-derived MSCs (hUC-MSCs) can protect ovarian granulosa cells (GCs) from cyclophosphamide (CTX)-induced ferroptosis, a form of cell death driven by iron accumulation. CTX, commonly used to induce POI animal model, triggered ferroptosis in GCs, while hUC-MSCs treatment mitigated this effect, both in vivo and in vitro. Further investigations using ferroptosis and autophagy inhibitors suggest that hUC-MSCs act by suppressing ferroptosis in GCs. Interestingly, hUC-MSCs activate a protective antioxidant pathway in GCs via NRF2, a stress-response regulator. Overall, our findings suggest that hUC-MSCs improve ovarian function in CTX-induced POI by reducing ferroptosis in GCs. This study not only clarifies the mechanism behind the benefits of hUC-MSCs but also strengthens the case for their clinical use in treating POI. Additionally, it opens up a new avenue for protecting ovaries from chemotherapy-induced damage by regulating ferroptosis.

Nrf2-mediated ferroptosis of spermatogenic cells involved in male reproductive toxicity induced by polystyrene nanoplastics in mice. / Nrf2ä»‹å¯¼çš„ç”Ÿç²¾ç»†èƒžé“æ­»äº¡å‚ä¸Žäº†èšè‹¯ä¹™çƒ¯çº³ç±³å¡‘æ–™å¯¼è‡´çš„å°é¼ é›„æ€§ç”Ÿæ®–æ¯’æ€§.

Microplastics (MPs) and nanoplastics (NPs) have become hazardous materials due to the massive amount of plastic waste and disposable masks, but their specific health effects remain uncertain. In this study, fluorescence-labeled polystyrene NPs (PS-NPs) were injected into the circulatory systems of mice to determine the distribution and potential toxic effects of NPs in vivo. Interestingly, whole-body imaging found that PS-NPs accumulated in the testes of mice. Therefore, the toxic effects of PS-NPs on the reproduction systems and the spermatocytes cell line of male mice, and their mechanisms, were investigated. After oral exposure to PS-NPs, their spermatogenesis was affected and the spermatogenic cells were damaged. The spermatocyte cell line GC-2 was exposed to PS-NPs and analyzed using RNA sequencing (RNA-seq) to determine the toxic mechanisms; a ferroptosis pathway was found after PS-NP exposure. The phenomena and indicators of ferroptosis were then determined and verified by ferroptosis inhibitor ferrostatin-1 (Fer-1), and it was also found that nuclear factor erythroid 2-related factor 2 (Nrf2) played an important role in spermatogenic cell ferroptosis induced by PS-NPs. Finally, it was confirmed in vivo that this mechanism of Nrf2 played a protective role in PS-NPs-induced male reproductive toxicity. This study demonstrated that PS-NPs induce male reproductive dysfunction in mice by causing spermatogenic cell ferroptosis dependent on Nrf2.

A novel perspective on di-hexyl phthalate (2-ethylhexyl)-induced reproductive toxicity in females: Lipopolysaccharide synergizes with mono-2-ethylhexyl ester to cause inflammatory apoptosis rather than autophagy in ovarian granulosa cells.

Di-hexyl phthalate (2-ethylhexyl) (DEHP) has been confirmed to cause female reproductive toxicity in humans and model animals by affecting the survival of ovarian granulosa cells (GCs), but the interrelationships between DEHP's on autophagy, apoptosis, and inflammation in GCs are not clear. Our previous study demonstrated that DEHP exposure resulted in the disturbance of intestinal flora associated with serum LPS release, which in turn led to impaired ovarian function. LPS has also been shown to determine cell fate by modulating cellular autophagy, apoptosis, and inflammation. Therefore, this study investigated the role and link between LPS and autophagy, apoptosis, and inflammation of GCs in DEHP-induced ovarian injury. Here, we constructed an in vivo injury model by continuous gavage of 0-1500 mg/kg of DEHP in female mice for 30 days and an in vitro injury model by treatment of human ovarian granulosa cells (KGN) cells with mono-2- ethylhexyl ester (MEHP, an active metabolite of DEHP in vivo). In addition, the expression of relevant pathway molecules was detected by immunohistochemistry, immunofluorescence, qRT-PCR, and Western blotting after the addition of the autophagy inhibitor 3-methyladenine (3-MA), the apoptosis inhibitor Z-VAD- FMK and the NF-κB inhibitor BAY11-7082. The current study found that autophagy and apoptosis were significantly activated in GCs of DEHP-induced atretic follicles in vivo and found that MEHP-induced KGN cells autophagy and apoptosis were independent and potentially cytotoxic of each other in vitro. Further studies confirmed that DEHP exposure resulted in LPS release from the intestinal tract and entering the ovary, thereby participating in DEHP-induced inflammation of GCs. In addition, we found that exogenous LPS synergized with MEHP could activate the NF-κB signaling pathway to induce inflammation and apoptosis of GCs in a relatively prolonged exposure condition. Meanwhile, inhibition of inflammatory activation could rescue apoptosis and estrogen secretion function of GCs induced by MEHP combined with LPS. These results indicated that the increased LPS influenced by DEHP might cooperate with MEHP to induce inflammatory apoptosis of GCs, an important cause of ovarian injury in mice.

Development and Validation of Knowledge Assessment Scales for Dementia and Urinary Incontinence in Community Older People.

To develop and validate scales for reliably assessing dementia and urinary incontinence knowledge of older adults in the community. Items were generated through a literature review, refined through a Delphi study (n = 19), and then revised through a pilot study (n = 29). Item analysis and exploratory factor analysis were applied to finalize the scales (n = 244). Construct validity, reliability, and acceptability were evaluated (n = 243). The two knowledge assessment scales for dementia and urinary incontinence, respectively, comprised 12 items and 8 items. Model fit indicators of both met the criteria of confirmatory factor analysis. Cronbach's α were .82 and .70, respectively. Completion ratio and completion time of the two scales was 83.51% and 4.22 ± 1.90 minutes. The knowledge assessment scales for dementia and urinary incontinence with satisfactory validity, reliability, and acceptability, could be served as valid tools for disease prevention and management among older adults in the community.

Predictive model for identifying mild cognitive impairment in patients with type 2 diabetes mellitus: A CHAID decision tree analysis.

BACKGROUND: As the population ages, mild cognitive impairment (MCI) and type 2 diabetes mellitus (T2DM) become common conditions that often coexist. Evidence has shown that MCI could lead to reduced treatment compliance, medication management, and self-care ability in T2DM patients. Therefore, early identification of those with increased risk of MCI is crucial from a preventive perspective. Given the growing utilization of decision trees in prediction of health-related outcomes, this study aimed to identify MCI in T2DM patients using the decision tree approach. METHODS: This hospital-based case-control study was performed in the Endocrinology Department of Xiangya Hospital affiliated to Central South University between March 2021 and December 2022. MCI was defined based on the Petersen criteria. Demographic characteristics, lifestyle factors, and T2DM-related information were collected. The study sample was randomly divided into the training and validation sets in a 7:3 ratio. Univariate and multivariate analyses were performed, and a decision tree model was established using the chi-square automatic interaction detection (CHAID) algorithm to identify key predictor variables associated with MCI. The area under the curve (AUC) value was used to evaluate the performance of the established decision tree model, and the performance of multivariate regression model was also evaluated for comparison. RESULTS: A total of 1001 participants (705 in the training set and 296 in the validation set) were included in this study. The mean age of participants in the training and validation sets was 60.2  ±  10.3 and 60.4  ±  9.5 years, respectively. There were no significant differences in the characteristics between the training and validation sets (p > .05). The CHAID decision tree analysis identified six key predictor variables associated with MCI, including age, educational level, household income, regular physical activity, diabetic nephropathy, and diabetic retinopathy. The established decision tree model had 15 nodes composed of 4 layers, and age is the most significant predictor variable. It performed well (AUC = .75 [95% confidence interval (CI): .71-.78] and .67 [95% CI: .61-.74] in the training and validation sets, respectively), was internally validated, and had comparable predictive value compared to the multivariate logistic regression model (AUC = .76 [95% CI: .72-.80] and .69 [95% CI: .62-.75] in the training and validation sets, respectively). CONCLUSION: The established decision tree model based on age, educational level, household income, regular physical activity, diabetic nephropathy, and diabetic retinopathy performed well with comparable predictive value compared to the multivariate logistic regression model and was internally validated. Due to its superior classification accuracy and simple presentation as well as interpretation of collected data, the decision tree model is more recommended for the prediction of MCI in T2DM patients in clinical practice.

The effect of naringenin-phospholipid complex on thermal oxidative stability of soybean oil under heating condition.

Naringenin (NGE), a typical flavanone abundant in citrus fruits, exhibits remarkable antioxidant activities. However, its low solubility in oil restricts its widespread use in inhibiting lipid oxidation. In this study, we present a novel and effective approach to address this limitation by developing a naringenin-phospholipid complex (NGE-PC COM). Comprehensive analytical techniques including Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were employed to confirm the formation of the NGE-PC COM and elucidate the interaction mechanism between NGE and phospholipids molecules. Notably, the oil-solubility of NGE was significantly enhanced by approximately 2700-fold when formulated as a phospholipid complex in soybean oil. The improved oil-solubility of NGE-PC COM enabled effective inhibition of oil thermal oxidation under high temperature conditions. Generally, this investigation proposed a novel and promising strategy for employing flavanones with strong antioxidant activities to enhance the thermal oxidative stability of edible oil during heating processes.

Metabolomic analysis of plasma biomarkers in children with autism spectrum disorders.

Autism spectrum disorder (ASD) presents a significant risk to human well-being and has emerged as a worldwide public health concern. Twenty-eight children with ASD and 33 healthy children (HC) were selected for the quantitative determination of their plasma metabolites using an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) platform. A total of 1997 metabolites were detected in the study cohort, from which 116 metabolites were found to be differentially expressed between the ASD and HC groups. Through analytical algorithms such as least absolute shrinkage selection operator (LASSO), support vector machine (SVM), and random forest (RF), three potential metabolic markers were identified as FAHFA (18:1(9Z)/9-O-18:0), DL-2-hydroxystearic acid, and 7(S),17(S)-dihydroxy-8(E),10(Z),13(Z),15(E),19(Z)-docosapentaenoic acid. These metabolites demonstrated superior performance in distinguishing the ASD group from the HC group, as indicated by the area under curves (AUCs) of 0.935, 0.897, and 0.963 for the three candidate biomarkers, respectively. The samples were divided into training and validation sets according to 7:3. Diagnostic models were constructed using logistic regression (LR), SVM, and RF. The constructed three-biomarker diagnostic model also exhibited strong discriminatory efficacy. These findings contribute to advancing our understanding of the underlying mechanisms involved in the occurrence of ASD and provide a valuable reference for clinical diagnosis.

Sleep quality and its associated factors among patients with type 2 diabetes mellitus in Hunan, China: a cross-sectional study.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a serious public health issue. Compared with the general population, patients with T2DM have a higher risk of poor sleep quality, which could ultimately result in poor prognosis. Therefore, this study aimed to evaluate sleep quality and its associated factors among patients with T2DM in Hunan, China. DESIGN: This was a cross-sectional study. SETTING: A tertiary hospital in Hunan, China. PARTICIPANTS: Patients with T2DM hospitalised at the Endocrinology Department were consecutively enrolled between March 2021 and December 2022. Sociodemographic characteristics, lifestyle factors and T2DM-related information were collected retrospectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Sleep quality was evaluated using the Pittsburgh Sleep Quality Index, with a cut-off value of >7 suggesting poor sleep quality. Multivariate logistic regression analysis was used to determine factors associated with poor sleep quality. RESULTS: Of the 1039 participants included, 1001 provided complete data. The mean age of the study sample was 60.24±10.09 years, and 40.5% (95% CI 37.5% to 43.5%) of patients had poor sleep quality. Multivariate logistic regression analysis showed that female sex (adjusted OR (aOR) 1.70, 95% CI 1.25 to 2.29), unmarried status (aOR 1.72, 95% CI 1.05 to 2.83), diabetic retinopathy (aOR 1.38, 95% CI 1.04 to 1.83), diabetic foot (aOR 1.80, 95% CI 1.11 to 2.93) and a per capita monthly household income of >5000 RMB (aOR 0.66, 95% CI 0.47 to 0.93) were associated with poor sleep quality. CONCLUSIONS: Nearly two-fifths of patients with T2DM reported poor sleep quality in Hunan, China. Sex, marital status, diabetic retinopathy, diabetic foot and household income were independently associated with sleep quality among patients with T2DM in Hunan, China.

Relationship between dietary macronutrients intake and biological aging: a cross-sectional analysis of NHANES data.

PURPOSE: This study aimed to investigate the association between macronutrient intake and biological age. METHODS: Data were collected from 26,381 adults who participated in the United States National Health and Nutrition Examination Survey (NHANES). Two biological ages were estimated using the Klemera-Doubal method (KDM) and PhenoAge algorithms. Biological age acceleration (AA) was computed as the difference between biological age and chronological age. The associations between macronutrient intakes and AA were investigated. RESULTS: After fully adjusting for confounding factors, negative associations were observed between AA and fiber intake (KDM-AA: ß - 0.53, 95% CI - 0.62, - 0.43, P < 0.05; PhenoAge acceleration: ß - 0.30, 95% CI - 0.35, - 0.25, P < 0.05). High-quality carbohydrate intake was associated with decreased AA (KDM-AA: ß - 0.57, 95% CI - 0.67, - 0.47, P < 0.05; PhenoAge acceleration: ß - 0.32, 95% CI - 0.37, - 0.26, P < 0.05), while low-quality carbohydrate was associated with increased AA (KDM-AA: ß 0.30, 95% CI 0.21, 0.38, P < 0.05; PhenoAge acceleration: ß 0.16, 95% CI 0.11, 0.21, P < 0.05). Plant protein was associated with decreased AA (KDM-AA: ß - 0.39, 95% CI - 0.51, - 0.27, P < 0.05; PhenoAge acceleration: ß - 0.21, 95% CI - 0.26, - 0.15, P < 0.05). Long-chain SFA intake increased AA (KDM-AA: ß 0.16, 95% CI 0.08, 0.24, P < 0.05; PhenoAge acceleration: ß 0.11, 95% CI 0.07, 0.15, P < 0.05). ω-3 PUFA was associated with decreased KDM-AA (ß - 0.18, 95% CI - 0.27, - 0.08, P < 0.05) and PhenoAge acceleration (ß - 0.09, 95% CI - 0.13, - 0.04, P < 0.05). CONCLUSION: Our findings suggest that dietary fiber, high-quality carbohydrate, plant protein, and ω-3 PUFA intake may have a protective effect against AA, while low-quality carbohydrate and long-chain SFA intake may increase AA. Therefore, dietary interventions aimed at modifying macronutrient intakes may be useful in preventing or delaying age-related disease and improving overall health.

Facile synthesis of dual-ligand europium-metal organic gels for ratiometric electrochemiluminescence detecting I27L gene.

Metal organic gels (MOGs) are a new kind of intelligent soft materials with excellent luminescence properties. However, MOGs with dual electrochemiluminescence (ECL) properties have not been reported. In this study, using Eu3+ as metal node, 4'-(4-carboxyphenyl)-2,2':6',2″-terpyridine (Hcptpy) and Luminol as organic ligands, a novel dual-ligand Europium-organic gels (Eu-L-H MOGs) were prepared by simple mixing at room temperature. On the one hand, Eu-L-H MOGs could exhibit strong and stable anodic ECL signals in the phosphate buffered saline (PBS) without the addition of co-reactants, which came from the blue emission of Luminol. On the other hand, using K2S2O8 as a cathodic co-reactant, Eu-L-H MOGs produced cathodic signals, which were derived from the red emission of Eu sensitized by Hcptpy through the antenna effect. Based on the independent dual ECL signals of Eu-L-H MOGs, we selected Alexa Flour 430 as the receptor and anodic ECL emission of Eu-L-H MOGs as the donor to construct the ECL resonance energy transfer (ECL-RET) ratio biosensor, which utilized exonuclease III assisted DNA cycle amplification to achieve ultrasensitive detection of the I27L gene. The detection linearity of I27L ranged from 1 fM to 10 nM, with a detection limit as low as 284 aM. This study developed a straightforward technique for obtaining a single luminescent material with dual signals, and further broadened the analytical application of MOGs in the realm of ECL.

Ratiometric Electrochemiluminescence of Zirconium Metal-Organic Framework as a Single Luminophore for Sensitive Detection of HPV-16 DNA.

This study developed a new zirconium metal-organic framework (MOF) luminophore named Zr-DPA@TCPP with dual-emission electrochemiluminescence (ECL) characteristics at a resolved potential. First, Zr-DPA@TCPP with a core-shell structure was effectively synthesized through the self-assembly of 9,10-di(p-carboxyphenyl)anthracene (DPA) and 5,10,15,20-tetra(4-carboxyphenyl)porphyrin (TCPP) as the respective organic ligands and the Zr cluster as the metal node. The reasonable integration of the two organic ligands DPA and TCPP with ECL properties into a single monomer, Zr-DPA@TCPP, successfully exhibited synchronous anodic and cathodic ECL signals. Besides, due to the impressively unique property of ferrocene (Fc), which can quench the anodic ECL but cannot affect the cathodic ECL signal, the ratiometric ECL biosensor was cleverly designed by using the cathode signal as an internal reference. Thus, combined with DNA recycle amplification reactions, the ECL biosensor realized sensitive ratiometric detection of HPV-16 DNA with the linear range of 1 fM-100 pM and the limit of detection (LOD) of 596 aM. The distinctive dual-emission properties of Zr-DPA@TCPP provided a new idea for the development of ECL luminophores and opened up an innovative avenue of fabricating the ratiometric ECL platform.

Nannies Go Rogue? A Call for Research into Nanny-Induced Elderly Abuse in China.

Older people often face varied and vicious abuse from care workers. Situations are often more pronounced for older people who live with additional cognitive or physical difficulties, such as dementia and disabilities, the prevalence of which has been on the rise in China and elsewhere. Recent discoveries of elderly abuse in China, which span from alarming levels of verbal, physical, psychological, financial, to sexual abuse, are all caused by nannies or "bao mu". Different from Western countries, the word nanny is often used to refer to people who offer caregiving help in residential settings at large, regardless of the age of the care recipients. What is also different is the lack of regulations or even rigorous training and evaluation processes for nannies in China: almost anyone could become a nanny-even though a background check is often required for nannies, this process is often highly variable and dependent on the specific labour agencies that nannies are registered with. Yet without structured studies and systematic data, little is known about the extent and severity of nanny-induced elderly abuse in China. To this end, this paper aims to discuss the unique elderly care environment-such as the "721 Rule"-in China, particularly in the post-COVID era, and highlight the critical need for timely and rigorous studies on the potential prevalence and severity of nannies' abuse and neglect of older people.

Inhibition of α2,6-sialyltransferase relieves symptoms of ulcerative colitis by regulating Th17 cells polarization.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease that affects human intestines. Immune imbalance is one of the important factors inducing UC. After the activation of CD4+ T cells, pro-inflammatory cytokines are produced to induce colonic inflammation. α2,6-Sialylation, catalyzed by α2,6-sialyltransferase (ST6GAL1), affects the proliferation, activation, and T cell receptor (TCR) signaling of CD4+ T cells, but its role in CD4+ T cell polarization, regulation of Th17 / Treg balance, and its role in UC are still unclear. We found the number of CD4+ T and Th17 cells increased in colonic tissue with UC. The level of α2,6-sialylation of CD4+ T cells in patients with UC was significantly increased. De-α2,6-sialylation significantly reduced the symptoms of UC in rats. ST6GAL1 gene knockout inhibited the polarization of CD4+ T cells to Th17 cells, and promoted the polarization of CD4+ T cells to Treg cells. ST6GAL1 knockout significantly inhibited the IL-17 signaling pathway in CD4+ T cells and inhibited the secretion of pro-inflammatory cytokine IL-17a. ST6GAL1 and IL-17a are highly expressed in patients with UC, and there is a positive correlation between them. In conclusion, reduced α2,6-sialylation inhibits the polarization of CD4+ T cells to Th17 cells, inhibits IL-17a signaling pathway and reduces the level of pro-inflammatory cytokine IL-17a to alleviate the symptoms of UC, which is a potential novel target for the clinical treatment of UC.

TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting the M2 polarization of tumor-associated macrophages.

BACKGROUND: The endoplasmic reticulum (ER) regulates critical processes, including lipid synthesis, which are affected by transmembrane proteins localized in the ER membrane. One such protein, transmembrane protein 147 (TMEM147), has recently been implicated for its role in hepatocellular carcinoma (HCC) tumorigenesis; however, the mechanisms remain unclear. We investigated the role of TMEM147 in HCC and the underlying mechanisms. METHODS: TMEM147 expression was examined in human HCC cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of TMEM147 on the progression of HCC. Proteins interacting with TMEM147 were identified via RNA-seq, immunoprecipitation, and mass spectrometry analyses. Lipidomic analysis and enzyme-linked immunosorbent assay (ELISA) were employed to determine and analyze cholesterol and 27-hydroxycholesterol (27HC) contents. Extensive experimental techniques were used to study ferroptosis in HCC cells. The fatty acid content of macrophages affected by TMEM147 was quantified using ELISA. Macrophage phenotypes were determined using immunofluorescence assay and flow cytometric analysis. RESULTS: TMEM147 mRNA and protein levels were increased in HCC cells, and the increased TMEM147 expression was associated with a poor survival. TMEM147 promoted tumor cell proliferation and metastases in vitro and in vivo. The protein was found to interact with the key enzyme 7-dehydrocholesterol reductase (DHCR7), which affected cellular cholesterol homeostasis and increased the extracellular levels of 27HC in HCC cells. TMEM147 also promoted the expression of DHCR7 by enhancing the activity of signal transducer and activator of transcription 2. 27HC expression upregulated glutathione peroxidase 4 in HCC, leading to ferroptosis resistance and promotion of HCC proliferation. HCC cell-derived 27HC expression increased the lipid metabolism in macrophages and activated peroxisome proliferator-activated receptor-γ signaling, thereby activating M2 macrophage polarization and promoting HCC cell invasion and migration. CONCLUSIONS: Our results indicate that TMEM147 confers ferroptosis resistance and M2 macrophage polarization, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27HC secretion, leading to cancer growth and metastasis. These findings suggest that the TMEM147/STAT2/DHCR7/27HC axis in the tumor microenvironment may serve as a promising therapeutic target for HCC.

Development and validation of frailty and malnutrition knowledge assessment scale for community-dwelling older adults.

There is a lack of reliable tools to assess the knowledge of frailty and malnutrition in community-dwelling older adults. To develop and validate reliable frailty and malnutrition knowledge assessment scales for this population, two scales were developed and validated through five phases. Phase 1: the item pools were constructed through a literature review and research panel based on the symptom interpretation model. Phase 2: the expert consultation was performed to select the items. Phase 3: a pilot survey was conducted to assess the clarity of the items and further revise the scales. Phase 4: 242 older adults were surveyed to finalize the items. Phase 5: 241 older adults were surveyed to test the psychometric properties. The two scales each comprise 3 dimensions (symptoms, risk factors, and management strategies) and 11 items. They had good construct validity, with all indicators of correlation analysis and confirmatory factor analysis meeting their specific criteria. The reliability of the frailty and malnutrition knowledge assessment scales was good, with composite reliability coefficients all >0.60, Cronbach's alpha being 0.81 and 0.83, and the Spearman-Brown coefficient being 0.74 and 0.80, respectively. Their acceptability was good, with both having a completion rate of 92.18% and an average completion time of 3 min. The two scales are reliable tools to assess the knowledge of frailty and malnutrition among community-dwelling older adults, especially for large-scale surveys. They can help identify knowledge gaps in older adults and provide a basis for developing targeted educational interventions.