Role and mechanism of KIAA1429 in regulating cellular ferroptosis and radioresistance in colorectal cancer.

Colorectal cancer (CRC) is one of the most common non-cutaneous malignancies, causing significant mortality and a substantial burden. This study aims to explore the role of KIAA1429 (also known as vir-like m6A methyltransferase associated [VIRMA]) protein in the radioresistance of CRC. CRC cells and a radioresistant cell line were cultured, and KIAA1429 expression was detected. After the down-regulation of KIAA1429, its effect on the radioresistance and ferroptosis of cancer cells was analyzed. The role of ferroptosis in radioresistance was verified. The binding relationship among long non-coding RNA endogenous Bornavirus-like nucleoprotein 3, pseudogene (lncRNA EBLN3P), microRNA (miR)-153-3p, and KIAA1429 was analyzed. KIAA1429 and lncRNA EBLN3P were highly expressed in CRC, while miR-153-3p was poorly expressed. KIAA1429 and lncRNA EBLN3P were further increased/decreased in the radioresistant cells. KIAA1429 knockdown decreased the survival rate of the radioresistant cell line after X-ray irradiation and increased gamma H2A histone family member X (γ-H2AX), ferroptosis, and oxidative stress. A ferroptosis inhibitor alleviated the inhibitory effect of KIAA1429 knockdown on radioresistance. KIAA1429-mediated m6A modification up-regulated lncRNA EBLN3P, and lncRNA EBLN3P increased KIAA1429 by competitively binding to miR-153-3p. miR-153-3p silencing or lncRNA EBLN3P overexpression attenuated the promotion of ferroptosis and the inhibition of radioresistance induced by KIAA1429 knockdown. Overall, KIAA1429-mediated m6A modification up-regulated lncRNA EBLN3P expression, and lncRNA EBLN3P increased KIAA1429 expression by competitively binding to miR-153-3p, thus reducing ferroptosis and increasing the radioresistance of CRC.

Large-Scale Synthesis of High-Loading Single Metallic Atom Catalysts by a Metal Coordination Route.

Single atom catalyst (SAC) is one of the most efficient and versatile catalysts with well-defined active sites. However, facile and large-scale preparation of single-atom catalysts, the prerequisite of industrial applications, has been very challenging. This dilemma suffers from the Gibbs-Thomson effect which renders it rather difficult to achieve high single atom loading rate that mostly is below 3 mol%. Further, most of the synthesizing procedures of SAC are rather complex which result in significant mass loss and thus low yields. Herein, a novel metal coordination route is developed to address these issues simultaneously, which is realized owing to the rapid complexation between ligands (e.g., biuret) and metal ions in aqueous solutions and subsequent in-situ polymerization of the formed complexes to synthesize SACs. The whole preparation process involves only one heating step operated in air without any special protecting atmospheres, which is generally applicable for diverse transition metals. Take Cu SACs for an example, a record yield of up to 3.565 kg in one pot and an ultrahigh metal loading 16.03 mol% on carbon nitride (Cu/CN) are both approached. The as-prepared Cu/CN SACs are demonstrated to possess high activity, outstanding selectivity and robust cyclicity for CO2 photoreduction to HCOOH. This research explores a robust route toward cost-effective, massive production of SACs for potential industrial applications. This article is protected by copyright. All rights reserved.

Integrative analyses identify opportunistic pathogens of patients with lower respiratory tract infections based on metagenomic next-generation sequencing.

Lower respiratory tract infections (LRTIs) represent some of the most globally prevalent and detrimental diseases. Metagenomic next-generation sequencing (mNGS) technology has effectively addressed the requirement for the diagnosis of clinical infectious diseases. This study aimed at identifying and classifying opportunistic pathogens from the respiratory tract-colonizing microflora in LRTI patients using data acquired from mNGS analyses. A retrospective study was performed employing the mNGS data pertaining to the respiratory samples derived from 394 LRTIs patients. Linear discriminant analysis effect size (LEfSe) analysis was conducted to discern the discriminant bacteria. Receiver operating characteristic curves (ROC) were established to demonstrate discriminant bacterial behavior to distinguish colonization from infection. A total of 443 discriminant bacteria were identified and segregated into three cohorts contingent upon their correlation profiles, detection frequency, and relative abundance in order to distinguish pathogens from colonizing microflora. Among them, 119 emerging opportunistic pathogens (cohort 2) occupied an average area under the curve (AUC) of 0.976 for exhibiting the most prominent predictability in distinguishing colonization from infection, 39 were colonizing bacteria (cohort 1, 0.961), and 285 were rare opportunistic pathogens (cohort 3, 0.887). The LTRIs patients appeared modular in the form of cohorts depicting complex microbial co-occurrence networks, reduced diversity, and a high degree of antagonistic interactions in the respiratory tract microbiome. The study findings indicate that therapeutic interventions should target interaction networks rather than individual microbes, providing an innovative perspective for comprehending and combating respiratory infections. Conclusively, this study reports a profile of LRTIs-associated bacterial colonization and opportunistic pathogens in a relatively large-scale cohort, which might serve as a reference panel for the interpretation of mNGS results in clinical practice.

Discovery of Novel p53-MDM2 Inhibitor (RG7388)-Conjugated PlatinumIV Complexes as Potent Antitumor Agents.

While a number of p53-MDM2 inhibitors have progressed into clinical trials for the treatment of cancer, their progression has been hampered by a variety of problems, including acquired drug resistance, dose-dependent toxicity, and limited clinical efficiency. To make more progress, we integrated the advantages of MDM2 inhibitors and platinum drugs to construct novel PtIV-RG7388 (a selective MDM2 inhibitor) complexes. Most complexes, especially 5a and 5b, displayed greatly improved antiproliferative activity against both wild-type and mutated p53 cancer cells. Remarkably, 5a exhibited potent in vivo tumor growth inhibition in the A549 xenograft model (66.5%) without apparent toxicity. It arrested the cell cycle at both the S phase and the G2/M phase and efficiently induced apoptosis via the synergistic effects of RG7388 and cisplatin. Altogether, PtIV-RG7388 complex 5a exhibited excellent in vitro and in vivo antitumor activities, highlighting the therapeutic potential of PtIV-RG7388 complexes as antitumor agents.

Strategic Lacunes Associated With Mild Cognitive Impairment in Rural Chinese Older Adults: A Population-Based Study.

BACKGROUND: Lacunes are associated with cognitive impairment. We sought to identify strategic lacune locations associated with mild cognitive impairment (MCI) and subtypes of MCI among older adults, and further to examine the role of white matter hyperintensities and perivascular spaces in the association. METHODS: This population-based cross-sectional study included 1230 dementia-free participants in the brain magnetic resonance imaging substudy (2018-2020) in MIND-China (Multimodal Interventions to Delay Dementia and Disability in Rural China). Lacunes were visually identified in frontal lobe, parieto-occipital lobe, temporal lobe, insula, basal ganglia, thalamus, cerebellum, and brainstem. MCI, amnestic MCI (aMCI), and nonamnestic MCI (naMCI) were defined following the Petersen's criteria. Data were analyzed using logistic regression models. RESULTS: Of the 1230 participants (age, ≥60 years; mean age, 69.40; SD, 4.30 years; 58.5% women), lacunes were detected in 357 people and MCI was defined in 286 individuals, including 243 with aMCI and 43 with naMCI. Lacunes in the supratentorial area, internal capsula, putamen/pallidum, and insula was significantly associated with increased odds ratio of MCI (multivariable-adjusted odds ratio ranged 1.40-3.21; P<0.05) and aMCI (multivariable-adjusted odds ratio ranged 1.46-3.36; P<0.05), whereas lacunes in the infratentorial area and brainstem were significantly associated with naMCI (multivariable-adjusted odds ratio ranged 2.68-3.46; P<0.01). Furthermore, the associations of lacunes in insula and internal capsula with MCI and aMCI, as well as the associations of lacunes in infratentorial area and brainstem with naMCI were present independent of white matter hyperintensities volume and perivascular spaces number. CONCLUSIONS: Lacunes in the internal capsula, putamen/pallidum, insula, and brainstem may represent the strategic lacunes that are independently associated with MCI, aMCI, or naMCI in Chinese older adults. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017758.

Associations of change in body fat percentage with baseline body composition and diabetes remission after bariatric surgery.

OBJECTIVE: The objective of this study was to determine the role of body fat percentage (BFP) changes in diabetes remission (DR) and the association between baseline body composition and its changes after bariatric surgery. METHODS: We analyzed 203 patients with type 2 diabetes who underwent Roux-en-Y gastric bypass. Body composition was measured using a gold-standard-derived predictive equation and magnetic resonance imaging. Body composition changes were calculated as 100 × (baseline value - follow-up value)/baseline value. We verified the results in a laparoscopic sleeve gastrectomy cohort with 311 patients. RESULTS: Compared with non-remission patients in the Roux-en-Y gastric bypass cohort, those who achieved DR showed a higher baseline fat-free mass index (FFMI) and experienced the most significant changes in BFP (p < 0.001). In comparative analyses, BFP changes were significantly better than BMI changes in identifying short- and long-term DR. Linear regression analysis identified FFMI as the most significant baseline variable correlated with BFP changes (p < 0.001). Baseline BMI was positively correlated with changes in BFP but negatively correlated with changes in FFMI. These findings were replicated in the laparoscopic sleeve gastrectomy cohort. CONCLUSIONS: BFP changes determine DR after bariatric surgery, and baseline FFMI is crucial for BFP changes. A low initial BMI is associated with a smaller BFP reduction and greater FFMI loss after bariatric surgery.

Nomogram for Predicting Remission of Metabolic Syndrome 1 Year after Sleeve Gastrectomy Surgery in Chinese Patients with Obesity.

PURPOSE: Sleeve gastrectomy (SG) is a widely used and effective treatment for patients with obesity and comorbid metabolic abnormalities. No specialized tool is available to predict metabolic syndrome (MS) remission after SG. We presented a nomogram that evaluated the probability of MS remission in obese patients 1 year after SG. MATERIALS AND METHODS: Patients with preoperative MS who underwent SG were enrolled in this retrospective study. They were divided into a training set and a validation set. Multivariate logistic regression analysis was performed to identify independent predictors of MS remission, and these predictors were included in the nomogram. Receiver operating characteristic curve was used to evaluate discrimination. Calibration was performed with the Hosmer-Lemeshow goodness-of-fit test. The net benefits of the nomogram were evaluated using decision curve analysis (DCA). RESULTS: Three hundred and eighteen patients with a median age of 34.0 years were analyzed. A training set and a validation set with 159 individuals each were established. A combination of age, preoperative high-density lipoprotein cholesterol, elevated triglycerides and glycated hemoglobin level independently and accurately predicted MS remission. The nomogram included these factors. The discriminative ability was moderate in training and validation sets (Area under curve 0.800 and 0.727, respectively). The Hosmer-Lemeshow X2 value of the nomogram was 8.477 (P = 0.388) for the training set and 5.361 (P = 0.718) for the validation set, indicating good calibration. DCA showed the nomogram had clinical benefits in both datasets. CONCLUSION: Our nomogram could accurately predict MS remission in Chinese patients with obesity 1 year after SG.

Generation of human induced pluripotent stem cell line (XWHNi004-A) from a male with APOE gene mutation.

Genetic polymorphism of apolipoprotein E (APOE) confers differential susceptibility to Alzheimer's disease (AD), and APOE ɛ4 variants is the most powerful risk factor for this disease. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line carrying the APOE ɛ4/ɛ4 genotype from peripheral blood mononuclear cells (PBMCs) isolated from a male with a family history of AD utilizing non-integrative Sendai virus vector. The iPSC maintains their original genotype, highly express endogenous pluripotency markers, displays a normal karyotype, and retains the ability to differentiate into cells representative of the three germ layers.

Multiple mediation of the association between childhood emotional abuse and adult obesity by anxiety and bulimia - a sample from bariatric surgery candidates and healthy controls.

Bulimia, which means a person has episodes of eating a very large amount of food (bingeing) during which the person feels a loss of control over their eating, is the most primitive reason for being overweight and obese. The extended literature has indicated that childhood emotional abuse has a close relationship with adverse mood states, bulimia, and obesity. To comprehensively understand the potential links among these factors, we evaluated a multiple mediation model in which anxiety/depression and bulimia were mediators between childhood emotional abuse and body mass index (BMI). A set of self-report questionnaires, including the Childhood Trauma Questionnaire (CTQ), Beck Anxiety Inventory, Beck Depression Inventory (BDI), and Eating Disorder Inventory (EDI), was sent out. Clinical data from 37 obese patients (age: 29.65 ± 5.35, body mass index (BMI): 37.59 ± 6.34) and 37 demographically well-matched healthy people with normal body weight (age: 31.35 ± 10.84, BMI: 22.16 ± 3.69) were included in the investigation. We first performed an independent t-test to compare all scales or subscale scores between the two groups. Then, we conducted Pearson correlation analysis to test every two variables' pairwise correlation. Finally, multiple mediation analysis was performed with BMI as the outcome variable, and childhood emotional abuse as the predictive variable. Pairs of anxiety, bulimia, and depression, bulimia were selected as the mediating variables in different multiple mediation models separately. The results show that the obese group reported higher childhood emotional abuse (t = 2.157, p = 0.034), worse mood state (anxiety: t = 5.466, p < 0.001; depression: t = 2.220, p = 0.030), and higher bulimia (t = 3.400, p = 0.001) than the healthy control group. Positive correlations were found in every pairwise combination of BMI, childhood emotional abuse, anxiety, and bulimia. Multiple mediation analyses indicate that childhood emotional abuse is positively linked to BMI (ß = 1.312, 95% CI = 0.482-2.141). The model using anxiety and bulimia as the multiple mediating variables is attested to play roles in the relationship between childhood emotional abuse and obesity (indirect effect = 0.739, 95% CI = 0.261-1.608, 56.33% of the total effect). These findings confirm that childhood emotional abuse contributes to adulthood obesity through the multiple mediating effects of anxiety and bulimia. The present study adds another potential model to facilitate our understanding of the eating psychopathology of obesity.

Exposure to different surface-modified polystyrene nanoparticles caused anxiety, depression, and social deficit in mice via damaging mitochondria in neurons.

Nanoplastics (NPs) are unavoidable hazardous materials that result from the human production and use of plastics. While there is evidence that NPs can bioaccumulate in the brain, no enough research regarding the pathways by which NPs reach the brain was conducted, and it is also urgently needed to evaluate the health threat to the nervous system. Here, we observed accumulation of polystyrene nanoplastics (PS-NPs) with different surface modifications (PS, PS-COOH, and PS-NH2) in mouse brains. Further studies showed that PS-NPs disrupted the tight junctions between endothelial cells and transport into endothelial cells via the endocytosis and macropinocytosis pathways. Additionally, NPs exposure induced a series of alternations in behavioral tests, including anxiety- and depression-like changes and impaired social interaction performance. Further results identified that NPs could be internalized into neurons and localized in the mitochondria, bringing about mitochondrial dysfunction and a concurrent decline of ATP production, which might be associated with abnormal animal behaviors. The findings provide novel insights into the neurotoxicity of NPs and provide a basis for the formulation of policy on plastic production and usage by relevant government agencies.

Negative enthalpy alloys and local chemical ordering: a concept and route leading to synergy of strength and ductility.

Solid solutions are ubiquitous in metals and alloys. Local chemical ordering (LCO) is a fundamental sub-nano/nanoscale process that occurs in many solid solutions and can be used as a microstructure to optimize strength and ductility. However, the formation of LCO has not been fully elucidated, let alone how to provide efficient routes for designing LCO to achieve synergistic effects on both superb strength and ductility. Herein, we propose the formation and control of LCO in negative enthalpy alloys. With engineering negative enthalpy in solid solutions, genetic LCO components are formed in negative enthalpy refractory high-entropy alloys (RHEAs). In contrast to conventional 'trial-and-error' approaches, the control of LCO by using engineering negative enthalpy in RHEAs is instructive and results in superior strength (1160 MPa) and uniform ductility (24.5%) under tension at ambient temperature, which are among the best reported so far. LCO can promote dislocation cross-slip, enhancing the interaction between dislocations and their accumulation at large tensile strains; sustainable strain hardening can thereby be attained to ensure high ductility of the alloy. This work paves the way for new research fields on negative enthalpy solid solutions and alloys for the synergy of strength and ductility as well as new functions.

Single-Atom Site SERS Chip for Rapid, Ultrasensitive, and Reproducible Direct-Monitoring of RNA Binding.

Ribonucleic acids (RNA) play active roles within cells or viruses by catalyzing biological reactions, controlling gene expression, and communicating responses to cellular signals. Rapid monitoring RNA variation has become extremely important for appropriate clinical decisions and frontier biological research. However, the most widely used method for RNA detection, nucleic acid amplification, is restricted by a mandatory temperature cycling period of ≈1 h required to reach target detection criteria. Herein, a direct detection approach via single-atom site integrated surface-enhanced Raman scattering (SERS) monitoring nucleic acid pairing reaction, can be completed within 3 min and reaches high sensitivity and extreme reproducibility for COVID-19 and two other influenza viruses' detection. The mechanism is that a single-atom site on SERS chip, enabled by positioning a single-atom oxide coordinated with a specific complementary RNA probe on chip nanostructure hotspots, can effectively bind target RNA analytes to enrich them at designed sites so that the binding reaction can be detected through Raman signal variation. This ultrafast, sensitive, and reproducible single-atom site SERS chip approach paves the route for an alternative technique of immediate RNA detection. Moreover, single-atom site SERS is a novel surface enrichment strategy for SERS active sites for other analytes at ultralow concentrations.

Embryonic exposure to aluminum chloride blocks the onset of spermatogenesis through disturbing the dynamics of testicular tight junctions via upregulating Slc25a5 in offspring.

Studies have revealed neurotoxicity, hepatotoxicity, and developmental and reproductive toxicity in mice exposed to aluminum. However, relatively few studies have been conducted to clarify the mechanism underlying the impact of embryonic exposure to aluminum on the development of the male reproductive system in offspring. Pregnant mice were administered aluminum chloride (AlCl3) by gavage from day 12.5 of gestation until birth. Our findings demonstrated that embryonic exposure to AlCl3 disrupted testicular development and spermatogenesis by impairing testicular architecture, reducing sperm count, and upregulating the expression of tight junction (TJ) protein between Sertoli cells (SCs). Further in vitro studies revealed that treatment with AlCl3 stabilized TJ proteins Occludin and ZO-1 expression by inhibiting ERK signaling pathway activation, thereby upregulating Slc25a5 expression which induced ATP production leading to disruption of cytoskeletal protein homeostasis. Therefore, the study provided a new mechanistic insight into how AlCl3 exposure interfered with testicular development and spermatogenesis while suggesting that Slc25a5 might be a target affected by AlCl3 influencing cell metabolism.

Correction to "Microstructure of Heavy Oil Components and Mechanism of Influence on Viscosity of Heavy Oil".

[This corrects the article DOI: 10.1021/acsomega.2c07713.].

Light-Induced Variation of Lithium Coordination Environment in g-C3N4 Nanosheet for Highly Efficient Oxygen Reduction Reactions.

The structure and electronic state of the active center in a single-atom catalyst undergo noticeable changes during a dynamic catalytic process. The metal atom active center is not well demonstrated in a dynamic manner. This study demonstrated that Li metal atoms, serving as active centers, can migrate on a C3N4 monolayer or between C3N4 monolayers when exposed to light irradiation. This migration alters the local coordination environment of Li in the C3N4 nanosheets, leading to a significant enhancement in photocatalytic activity. The photocatalytic H2O2 process could be maintained for 35 h with a 920 mmol/g record-high yield, corresponding to a 0.4% H2O2 concentration, which is far greater than the value (0.1%) of practical application for wastewater treatment. Density functional theory calculations indicated that dynamic Li-coordinated structures contributed to the superhigh photocatalytic activity.

Negative mixing enthalpy solid solutions deliver high strength and ductility.

Body-centred cubic refractory multi-principal element alloys (MPEAs), with several refractory metal elements as constituents and featuring a yield strength greater than one gigapascal, are promising materials to meet the demands of aggressive structural applications1-6. Their low-to-no tensile ductility at room temperature, however, limits their processability and scaled-up application7-10. Here we present a HfNbTiVAl10 alloy that shows remarkable tensile ductility (roughly 20%) and ultrahigh yield strength (roughly 1,390 megapascals). Notably, these are among the best synergies compared with other related alloys. Such superb synergies derive from the addition of aluminium to the HfNbTiV alloy, resulting in a negative mixing enthalpy solid solution, which promotes strength and favours the formation of hierarchical chemical fluctuations (HCFs). The HCFs span many length scales, ranging from submicrometre to atomic scale, and create a high density of diffusive boundaries that act as effective barriers for dislocation motion. Consequently, versatile dislocation configurations are sequentially stimulated, enabling the alloy to accommodate plastic deformation while fostering substantial interactions that give rise to two unusual strain-hardening rate upturns. Thus, plastic instability is significantly delayed, which expands the plastic regime as ultralarge tensile ductility. This study provides valuable insights into achieving a synergistic combination of ultrahigh strength and large tensile ductility in MPEAs.

Spatial targeting of fibrosis-promoting macrophages with nanoscale metal-organic frameworks for idiopathic pulmonary fibrosis therapy.

Targeted delivery of therapeutic drugs to fibrosis-promoting macrophages (FPMs) holds promise as a challenging yet effective approach for the treatment of idiopathic pulmonary fibrosis (IPF). Here, nanocarriers composed of Mn-curcumin metal-organic frameworks (MOFs) were utilized to deliver the immune inhibitor BLZ-945 to the lungs, with the goal of depleting fibrosis-promoting macrophages (FPMs) from fibrotic lung tissues. FPM targeting was achieved by functionalizing the nanocarrier surface with an M2-like FPM binding peptide (M2pep). As a result, significant therapeutic benefits were observed through the successful depletion of approximately 80 % of the M2-like macrophages (FPMs) in a bleomycin-induced fibrosis mouse model treated with the designed M2-like FPM-targeting nanoparticle (referred to as M2NP-BLZ@Mn-Cur). Importantly, the released Mn2+ and curcumin after the degradation of M2NP-BLZ@Mn-Cur accumulated in the fibrotic lung tissue, which can alleviate inflammation and oxidative stress reactions, thereby further improving IPF therapy. This study presents a novel strategy with promising prospects for molecular-targeted fibrosis therapy. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs)- based nanocarriers equipped with both fibrosis-promoting macrophage (FPM)-specific targeting ability and therapeutic drugs are appealing for pulmonary fibrosis treatment. Here, we prepared M2pep (an M2-like FPM binding peptide)-modified and BLZ945 (a small molecule inhibitor of CSF1/CSF-1R axis)-loaded Mn-curcumin MOF nanoparticles (M2NP-BLZ@Mn-Cur) for pulmonary fibrosis therapy. The functionalized M2NP-BLZ@Mn-Cur nanoparticles can be preferentially taken up by FPMs, resulting in their depletion from fibrotic lung tissues. In addition, Mn2+and curcumin released from the nanocarriers have anti-inflammation and immune regulation effects, which further enhance the antifibrotic effect of the nanoparticles.

The impact of metabolic surgery on natural conception rates in women with infertility, obesity and polycystic ovary syndrome: a retrospective study.

BACKGROUND: Women with obesity and polycystic ovary syndrome (OPOS) are at high risk for infertility. However, the reproductive effects of metabolic surgery on women with infertility and OPOS have not been fully elucidated. OBJECTIVES: We investigated the natural conception rates after metabolic surgery, and the variables associated with infertility in women with OPOS. SETTING: Shanghai Sixth People's Hospital, Shanghai, China. METHODS: This study included 72 women with infertility and OPOS who underwent metabolic surgery and were followed up for 4 years after surgery. Finally, 54 patients completed the study. Reproductive outcomes were assessed, along with changes in anthropometric parameters and metabolic indices before and 1 year after surgery (prepregnancy). Logistic regression analysis was used to identify variables influencing natural conception and delivery outcomes. RESULTS: After metabolic surgery, 35 patients (64.8%) became pregnant naturally, while 16 were still unable to conceive naturally. Preoperative body mass index (BMI) tended to be lower in the natural conception group than in the no natural conception group (38.9 ± 6.9 versus 43.6 ± 11.0 kg/m2, P = .070) and there were no significant differences in weight loss between the 2 groups after surgery. Logistic regression analysis showed that the BMI 1 year after surgery (prepregnancy) was an independent predictor of natural conception, and receiver operating characteristic analysis showed that a BMI of 27.0 kg/m2 was the optimal cutoff for predicting successful natural conception after surgery. CONCLUSIONS: Metabolic surgery can improve fertility in women with OPOS. Patients with a BMI < 27.0 kg/m2 1 year after surgery (prepregnancy) are more likely to become pregnant naturally and give birth.

Multimorbidity, cognitive phenotypes, and Alzheimer's disease plasma biomarkers in older adults: A population-based study.

INTRODUCTION: To examine the burden and clusters of multimorbidity in association with mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD)-related plasma biomarkers among older adults. METHODS: This population-based study included 5432 participants (age ≥60 years); of these, plasma amyloid beta (Aß), total tau, and neurofilament light chain (NfL) were measured in a subsample (n = 1412). We used hierarchical clustering to generate five multimorbidity clusters from 23 chronic diseases. We diagnosed dementia and MCI following international criteria. Data were analyzed using logistic and linear regression models. RESULTS: The number of chronic diseases was associated with dementia (multivariable-adjusted odds ratio = 1.22; 95% confidence interval [CI] = 1.11 to 1.33), AD (1.13; 1.01 to 1.26), vascular dementia (VaD) (1.44; 1.25 to 1.64), and non-amnestic MCI (1.25; 1.13 to 1.37). Metabolic cluster was associated with VaD and non-amnestic MCI, whereas degenerative ocular cluster was associated with AD (p < 0.05). The number of chronic diseases was associated with increased plasma Aß and NfL (p < 0.05). DISCUSSION: Multimorbidity burden and clusters are differentially associated with subtypes of dementia and MCI and AD-related plasma biomarkers in older adults. HIGHLIGHTS: We used hierarchical clustering to generate five clusters of multimorbidity. The presence and load of multimorbidity were associated with dementia and mild cognitive impairment. Multimorbidity clusters were differentially associated with subtypes of dementia and Alzheimer's disease plasma biomarkers.

Over-expression of microRNA-145 Elevating Autophagy Activities via Downregulating FRS2 Expression.

OBJECTIVES: Osteoarthritis (OA) is one of the most common chronic and progressive joint diseases characterized by cartilage degeneration and chondrocyte death. In this study, we aimed to identify the modulation effect of miR-145 on chondrocytes' autophagy during the development of OA. BACKGROUND: Osteoarthritis (OA) is one of the most prevalent types of chronic and progressive joint disorder with the symptoms of joint pain and stiffness, and it leads to disability at the end stage. In recent years, microRNA-145 (miR-145) has been found to activate autophagy in various cell types, including mesenchymal stem cells, cardiomyocytes, and osteosarcoma cells. However, it is unknown whether miR-145 regulates the progression of OA by influencing chondrocyte autophagy. METHODS: Before investigating the regulatory effect of miR-145 on the autophagic activity of chondrocytes, the expression of miR-145 in human joint samples was analyzed. The targeting relationship between miR-145 and FRS2 was detected by dual luciferase assay. The effect of FRS2 and miR-145 on the autophagic activity of chondrocytes was observed by bidirectional expression of FRS2 and miR-145. RESULTS: The miR-145 expression and LC3-II/LC3-I ratio were significantly decreased and the SQSTM1 expression was increased in OA patients. The miR-145 overexpression in C20A4 cells increased LC3-II/LC3-I ratio, decreased SQSTM1 expression, and was positively correlated with autophagic activity. Under oxidative stress, miR-145 overexpression significantly improved chondrocyte viability through autophagy stimulation. FRS2 is a potential target of miR-145 via a binding sequence within its 3' UTR. FRS2 acts as the downstream mediator of miR-145 to suppress autophagy through activating PI3K/Akt/mTOR pathways. CONCLUSION: The miR-145 acts as a protective factor against chondrocytes by regulating miRFRS2- autophagy axis. The decrease of miR-145 in articular synovial fluid may turn out to be an important marker for early diagnosis of OA, and modulation of miR-145 may represent a promising therapeutic strategy for OA.