The HEAT repeat protein HPO-27 is a lysosome fission factor.

Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing1. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission2,3. Little is known about the molecular basis of fission. Here we identify HPO-27, a conserved HEAT repeat protein, as a lysosome scission factor in Caenorhabditis elegans. Loss of HPO-27 impairs lysosome fission and leads to an excessive tubular network that ultimately collapses. HPO-27 and its human homologue MROH1 are recruited to lysosomes by RAB-7 and enriched at scission sites. Super-resolution imaging, negative-staining electron microscopy and in vitro reconstitution assays reveal that HPO-27 and MROH1 self-assemble to mediate the constriction and scission of lysosomal tubules in worms and mammalian cells, respectively, and assemble to sever supported membrane tubes in vitro. Loss of HPO-27 affects lysosomal morphology, integrity and degradation activity, which impairs animal development and longevity. Thus, HPO-27 and MROH1 act as self-assembling scission factors to maintain lysosomal homeostasis and function.

Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.

BACKGROUND: Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. Apart from Parkin, little is known about additional Ub (ubiquitin) ligases that mediate mitochondrial ubiquitination and turnover, particularly in highly metabolically active organs such as the heart. METHODS: In this study, we have combined in silico analysis and biochemical assay to identify CRL (cullin-RING ligase) 5 as a mitochondrial Ub ligase. We generated cardiomyocytes and mice lacking RBX2 (RING-box protein 2; also known as SAG [sensitive to apoptosis gene]), a catalytic subunit of CRL5, to understand the effects of RBX2 depletion on mitochondrial ubiquitination, mitophagy, and cardiac function. We also performed proteomics analysis and RNA-sequencing analysis to define the impact of loss of RBX2 on the proteome and transcriptome. RESULTS: RBX2 and CUL (cullin) 5, 2 core components of CRL5, localize to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, increased cardiomyocyte cell death, and has a global impact on the mitochondrial proteome. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to the rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. The action of RBX2 in mitochondria is not dependent on Parkin, and Parkin gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 (PTEN-induced kinase 1) in mitochondria. CONCLUSIONS: These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that regulates mitophagy and cardiac homeostasis in a Parkin-independent, PINK1-dependent manner.

Conformational dynamics of CasX (Cas12e) in mediating DNA cleavage revealed by single-molecule FRET.

CasX (also known as Cas12e), a Class 2 CRISPR-Cas system, shows promise in genome editing due to its smaller size compared to the widely used Cas9 and Cas12a. Although the structures of CasX-sgRNA-DNA ternary complexes have been resolved and uncover a distinctive NTSB domain, the dynamic behaviors of CasX are not well characterized. In this study, we employed single-molecule and biochemical assays to investigate the conformational dynamics of two CasX homologs, DpbCasX and PlmCasX, from DNA binding to target cleavage and fragment release. Our results indicate that CasX cleaves the non-target strand and the target strand sequentially with relative irreversible dynamics. The two CasX homologs exhibited different cleavage patterns and specificities. The dynamic characterization of CasX also reveals a PAM-proximal seed region, providing guidance for CasX-based effector design. Further studies elucidate the mechanistic basis for why modification of sgRNA and the NTSB domain can affect its activity. Interestingly, CasX has less effective target search efficiency than Cas9 and Cas12a, potentially accounting for its lower genome editing efficiency. This observation opens a new avenue for future protein engineering.

Zinc-finger protein CXXC5 promotes breast carcinogenesis by regulating the TSC1/mTOR signaling pathway.

CXXC5, a member of the CXXC family of zinc-finger proteins, is associated with numerous pathological processes. However, the pathophysiological function of CXXC5 has not been clearly established. Herein, we found that CXXC5 interacts with the CRL4B and NuRD complexes. Screening of transcriptional targets downstream of the CXXC5-CRL4B-NuRD complex by next-generation sequencing (chromatin immunoprecipitation sequencing) revealed that the complex regulates the transcriptional repression process of a cohort of genes, including TSC1 (tuberous sclerosis complex subunit 1), which play important roles in cell growth and mammalian target of rapamycin signaling pathway regulation, and whose abnormal regulation results in the activation of programmed cell death-ligand protein 1 (PD-L1). Intriguingly, CXXC5 expression increased after stimulation with vitamin B2 but decreased after vitamin D treatment. We also found that the CXXC5-CRL4B-NuRD complex promotes the proliferation of tumor cells in vitro and accelerates the growth of breast cancer in vivo. The expression of CXXC5, CUL4B, and MTA1 increased during the occurrence and development of breast cancer, and correspondingly, TSC1 expression decreased. Meanwhile, a high expression of CXXC5 was positively correlated with the histological grade of high malignancy and poor survival of patients. In conclusion, our study revealed that CXXC5-mediated TSC1 suppression activates the mammalian target of rapamycin pathway, reduces autophagic cell death, induces PD-L1-mediated immune suppression, and results in tumor development, shedding light on the mechanism of the pathophysiological function of CXXC5.

Non-diabetes status after diagnosis of impaired glucose tolerance and risk of long-term death and vascular complications: A post hoc analysis of the Da Qing Diabetes Prevention Outcome Study.

BACKGROUND: The association between years of non-diabetes status after diagnosis of impaired glucose tolerance (IGT) and the risk of long-term death and cardiovascular outcomes needed to be clarified. METHODS AND FINDINGS: In this post hoc analysis, we included 540 individuals with IGT who participated in the original Da Qing Diabetes Prevention Study (DQDPS). In the DQDPS, all participants were diagnosed with IGT by a 75 g oral glucose tolerance test and randomized to intervention or control groups with a 6-year lifestyle intervention trial. After the completion of the trial, death, cardiovascular events, and microvascular complications were monitored over a 30-year follow-up. In this post hoc analysis, the Cox analysis assessed the extended risk of these outcomes in individuals who either remained non-diabetes status or progressed to diabetes at the end of 2, 4, and 6 years after diagnosis of IGT. In all participants, the difference in the cumulative incidence rate of the outcomes between the diabetes and non-diabetes group gradually increased over 30 years. Compared with the diabetes group, a significantly lower risk of all-cause death (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.57 to 0.97, p = 0.026), cardiovascular events (HR: 0.63; 95% CI: 0.49 to 0.82, p < 0.001), and microvascular complications (HR: 0.62; 95% CI: 0.45 to 0.86, p = 0.004) first emerged in individuals who remained non-diabetes at the 4 years visit, whereas the significant risk reduction in cardiovascular death was first observed at the end of 6 years (HR: 0.56; 95% CI: 0.39 to 0.81, p = 0.002) after adjustment for age, sex, smoking status, BMI, systolic blood pressure, blood glucose, total cholesterol, intervention, and medications (including insulin plus oral hypoglycaemics, antihypertensives, and lipid-lowering agents). The results in the original intervention group alone were similar to the whole group. The main limitations of our study are the limited number of participants and the sole ethnicity of the Chinese population. CONCLUSIONS: In this study, we observed that maintaining several years of non-diabetes status after IGT diagnosis was associated with a significant reduction in long-term risk of death and vascular complications, and for most of these outcomes, maintaining at least 4 years of non-diabetes status may be needed to achieve a significant risk reduction.

Integrated analysis of DNA methylome and transcriptome revealing epigenetic regulation of CRIR1-promoted cold tolerance.

BACKGROUND: DNA methylation contributes to the epigenetic regulation of nuclear gene expression, and is associated with plant growth, development, and stress responses. Compelling evidence has emerged that long non-coding RNA (lncRNA) regulates DNA methylation. Previous genetic and physiological evidence indicates that lncRNA-CRIR1 plays a positive role in the responses of cassava plants to cold stress. However, it is unclear whether global DNA methylation changes with CRIR1-promoted cold tolerance. RESULTS: In this study, a comprehensive comparative analysis of DNA methylation and transcriptome profiles was performed to reveal the gene expression and epigenetic dynamics after CRIR1 overexpression. Compared with the wild-type plants, CRIR1-overexpressing plants present gained DNA methylation in over 37,000 genomic regions and lost DNA methylation in about 16,000 genomic regions, indicating a global decrease in DNA methylation after CRIR1 overexpression. Declining DNA methylation is not correlated with decreased/increased expression of the DNA methylase/demethylase genes, but is associated with increased transcripts of a few transcription factors, chlorophyll metabolism and photosynthesis-related genes, which could contribute to the CRIR1-promoted cold tolerance. CONCLUSIONS: In summary, a first set of transcriptome and epigenome data was integrated in this study to reveal the gene expression and epigenetic dynamics after CRIR1 overexpression, with the identification of several TFs, chlorophyll metabolism and photosynthesis-related genes that may be involved in CRIR1-promoted cold tolerance. Therefore, our study has provided valuable data for the systematic study of molecular insights for plant cold stress response.

Solution-Processable Route for Large-Area Uniform 2D Semiconductor Nanofilms.

The semiconductor thin film engineering technique plays a key role in the development of advanced electronics. Printing uniform nanofilms on freeform surfaces with high efficiency and low cost is significant for actual industrialization in electronics. Herein, a high-throughput colloidal printing (HTCP) strategy is reported for fabricating large-area and uniform semiconductor nanofilms on freeform surfaces. High-throughput and uniform printing rely on the balance of atomization and evaporation, as well as the introduced thermal Marangoni flows of colloidal dispersion, that suppresses outward capillary flows. Colloidal printing with in situ heating enables the fast fabrication of large-area semiconductor nanofilms on freeform surfaces, such as SiO2/Si, Al2O3, quartz glass, poly(ethylene terephthalate) (PET), Al foil, plastic tube, and Ni foam, expanding their technological applications where substrates are essential. The printed SnS2 nanofilms are integrated into thin-film semiconductor gas sensors with one of the fastest responses (8 s) while maintaining the highest sensitivity (Rg/Ra = 21) (toward 10 ppm NO2), as well as an ultralow limit of detection (LOD) of 46 ppt. The ability to print uniform semiconductor nanofilms on freeform surfaces with high-throughput promises the development of next-generation electronics with low cost and high efficiency.

Degarelix limits the survival of mycobacteria and granuloma formation.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, is a serious health hazard, characterized by tuberculous granuloma formation, which may facilitate bacterial survival. At the same time, the identification of multidrug-resistant and extremely drug-resistant Mtb strains, and the progressive accumulation of mutations in biological targets of frontline antimicrobials, has made TB treatments more difficult. Therefore, new and rapid drug development for TB is warranted. Recently, drug repurposing has received considerable attention. In this study, we applied the anticancer drug degarelix to anti-TB research and found that it inhibits mycobacteria survival and pathological damage in Mycobacterium marinum-infected zebrafish and Mtb-infected mice. Supplementation of degarelix matched the bactericidal activities of rifampicin (RFP) toward M. marinum in zebrafish. Mechanistically, degarelix significantly increased interferon (IFN)-γ levels in M. marinum-infected zebrafish. Degarelix had no direct anti-mycobacterial activity in vitro but significantly reduced the survival of H37Rv in macrophages. The effect of degarelix could be reversed by 3-methyladenine (3-MA), which inhibits the class III phosphatidylinositol (PI) 3 kinase required for autophagy initiation. However, no effect on later steps in autophagy could be detected. Our findings demonstrate the potential of degarelix on limiting mycobacterial survival and granuloma formation, which may generate novel TB therapeutics.

Mechanistic Investigation on the Regioselectivity of Electrochemical Co(II)-Catalyzed [2 + 2 + 2] Cycloaddition of Terminal Acetylenes.

In this paper, the regioselectivity of electrochemical Co(II)-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes was investigated using density functional theory. We explored in detail the energy profiles for both 1,2,4- and 1,3,5-regioselectivity pathways and revealed the origin of the regioselectivity. Two kinds of conformational isomers derived from the different coordination modes of alkynes with cobaltacyclopentadiene have been found, which were formed through electrochemically mediated redox processes. The regioselectivity of the reaction depends on the two coordination modes. When the Co(II) center attacks α-C of the third alkyne, while ß2-C in cyclopentadiene bonds to ß-C of the alkyne, the reaction favors the formation of 1,2,4-products. In contrast, when the Co(II) center connects to ß-C of the alkyne, it forms only the 1,3,5-products via [4 + 2] cycloaddition because of the steric repulsion between the bulky ligand on Co(II) and the phenyl group in the alkyne.

Selective identification of p-nitroaniline by bromine-mediated polarization of carbon dots.

A fluorometric method based on boron, bromide-codoped carbon dots (BBCNs) was developed for the first time for the highly selective detection of p-nitroaniline (PNA) in wastewater samples. It should be noted that the introduction of bromine greatly increases the molecular polarizability of the probe, which can regulate the energy level matching between the probe and PNA, resulting in the interaction between BBCNs and PNA. In the presence of PNA, the fluorescence of BBCNs is obviously quenched and accompanied by a red shift of the fluorescence band, which might be attributed to the formation of aggregates caused by the polar adsorption of BBCNs and PNA. It is beneficial for constructing a highly selective sensing platform for PNA determination compared to its isomers (o-nitroaniline and m-nitroaniline) through atomic bromine-mediated polarization of the BBCNs. With the help of this mechanism, an excellent linear range of 0.5-300 µM with a low detection limit of 0.24 µM toward PNA was obtained. This work further confirms that there is a significant relationship between the nature of doping elements and the optical and physicochemical properties of fluorescent materials.

Neurotransmitter Metabolism in Arsenic Exposure-Induced Cognitive Impairment: Emerging Insights and Predictive Implications.

Scholars have long been interested in the association between arsenic (As) exposure and neurological disorders; however, existing systematic epidemiological investigations are insufficient and lack the inclusion of diagnostic or predictive biological markers. This study sought to evaluate the association between As exposure and cognitive impairment and identify potential biomarkers by developing predictive models. Here, we found that logarithm (Ln)-transformed urinary As concentrations were negatively linearly related to the mini-mental state examination (MMSE) score exposure-response curves. Subsequently, we identified a unique plasma neurometabolite profile in subjects exposed to As compared with the reference group. Further analyses showed that tryptophan, tyrosine, dopamine, epinephrine, and homovanillic acid were all significantly associated with both urinary As concentrations and MMSE scores. Notably, the association between As exposure and MMSE scores was partly mediated by tryptophan, tyrosine, dopamine, and epinephrine. Importantly, an unprecedented prediction model utilizing neurotransmitters was established to assess the risk of cognitive impairment due to As exposure. A 91.1% consistency rate was found between the predicted and the actual probabilities. Additionally, machine learning models also produced highly accurate predictions. Overall, this study revealed a dose-dependent cognitive decline in As-exposed adults accompanied by a disturbance in the signature of neurotransmitter metabolites, offering new predictive insights.

A Dual-Signal Sensing for the Visual and Luminescent Detection of p-Phenylenediamine Based on Cerium-Nitrogen-Co-Doped Carbon Dots.

Herein, a visual and luminescent dual-mode (colorimetric and fluorometric) method for the detection of P-phenylenediamine (PPD) in hair dye was successfully established based on cerium-nitrogen co-doped carbon dots (Ce, N-CDs) that displayed remarkable luminescence and peroxidase activity. Ce, N-CDs catalyzed H2O2 to produce superoxide anion, which then oxidized the colorless 3,3,5,5-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB), capable of quenching the fluorescence through fluorescence resonance energy transfer (FRET) between Ce, N-CDs and oxTMB. The reducing properties of PPD could reduce oxTMB back to TMB, leading to a decrease in the absorption intensity of oxTMB and a fluorescence recovery of Ce, N-CDs. As a result, the quantitative detection of PPD could be achieved by measuring the absorption values of oxTMB and the fluorescence signal of Ce, N-CDs. The detection limits for PPD were calculated as 0.36 µM and 0.10 µM for colorimetry and fluorimetry, respectively. Furthermore, smartphone application (ColorPicker) capable of measuring the RGB value of the color was utilized in the detection system, facilitating on-site quantitative detection. This approach effectively shortens the detection time and simplifies the operation, offering a powerful and convenient tool for real-time monitoring of PPD.

Value of endoscopic grading of gastroesophageal flap valve in gastroesophageal reflux disease.

OBJECTIVE: To investigate the significance of endoscopic grading (Hill's classification) of gastroesophageal flap valve (GEFV) in the examination of patients with gastroesophageal reflux disease (GERD). METHODS: One hundred and sixty-two patients undergoing gastroscopy in the Department of Gastroenterology, Xingyi People's Hospital between Apr. 2022 and Sept. 2022 were selected by convenient sampling, and data such as GEFV grade, and findings of esophageal high-resolution manometry (HRM) and esophageal 24-h pH/impedance reflux monitoring, and Los Angeles (LA) classification of reflux esophagitis (RE) were collected and compared. RESULTS: Statistically significant differences in age (F = 9.711, P < 0.001) and hiatal hernia (χ = 35.729, P < 0.001) were observed in patients with different GEFV grades. The resting LES pressures were 12.12 ± 2.79, 10.73 ± 2.68, 9.70 ± 2.29, and 8.20 ± 2.77 mmHg (F = 4.571, P < 0.001) and LES lengths were 3.30 ± 0.70, 3.16 ± 0.68, 2.35 ± 0.83, and 2.45 ± 0.62 (F = 3.789, P = 0.011), respectively, in patients with GEFV grades I-IV. DeMeester score (Z = 5.452, P < 0.001), AET4 (Z = 5.614, P < 0.001), acid reflux score (upright) (Z = 7.452, P < 0.001), weak acid reflux score (upright) (Z = 3.121, P = 0.038), liquid reflux score (upright) (Z = 3.321, P = 0.031), acid reflux score (supine) (Z = 6.462, P < 0.001), mixed reflux score (supine) (Z = 3.324, P = 0.031), gas reflux score (supine) (Z = 3.521, P = 0.024) were different in patients with different GEFV grades, with statistically significant differences. Pearson correlation analysis revealed a positive correlation between RE grade and LA classification of GERD (r = 0.662, P < 0.001), and the severity of RE increased gradually with the increase of the Hill grades of GEFV. CONCLUSION: The Hill grade of GEFV is related to age, hiatal hernia, LES pressure, and the consequent development and severity of acid reflux and RE. Evaluation of esophageal motility and reflux based on the Hill grade of GEFV is of significance for the diagnosis and treatment of GERD.

Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury.

Mesenchymal stem cells (MSCs) exert beneficial therapeutic effects in acute kidney injury (AKI), while the detailed repair mechanism remains unclear. Herein, we probed the underlying mechanisms of MSC therapy in AKI by performing unbiased single-cell RNA sequencing in IRI model with/without MSC treatment. Our analyses uncovered the tubular epithelial cells (TECs) and immune cells transcriptomic diversity and highlighted a repair trajectory involving renal stem/progenitor cell differentiation. Our findings also suggested that profibrotic TECs expressing pro-fibrotic factors such as Zeb2 and Pdgfb promoted the recruitment of inflammatory monocytes and Th17 cells to injured kidney tissue, inducing TGF-ß1 secretion and renal fibrosis. Finally, in addition to activating the repair properties of renal progenitor/stem cells, we uncovered a role for MSC-derived miR-26a-5p in mediating the therapeutic effects of MSCs by inhibiting Zeb2 expression and suppressing pro-fibrotic TECs and its subsequent recruitment of immune cell subpopulations. These findings may help to optimize future AKI treatment strategies.

Sleep timing and the prevalence of hypertension in middle-aged and older populations: the sleep heart health study.

OBJECTIVES: Sleep characteristics such as duration, continuity, and irregularity are associated with the risk of hypertension. This study aimed to investigate the association between sleep timing (including bedtime, wake-up time, and sleep midpoint) and the prevalence of hypertension. METHODS: Participants were selected from the Sleep Heart Health Study (n = 5504). Bedtime and wake-up times were assessed using sleep habit questionnaires. The sleep midpoint was calculated as the halfway point between the bedtime and wake-up time. Restricted cubic splines and logistic regression analyses were performed to explore the association between sleep timing and hypertension. RESULTS: A significant nonlinear association was observed between bedtime (Poverall<0.001; Pnonlinear<0.001), wake-up time (Poverall=0.024; Pnonlinear=0.076), sleep midpoint (Poverall=0.002; Pnonlinear=0.005), and the prevalence of hypertension after adjusting for potential confounders. Multivariable logistic regression showed that both late (> 12:00AM and 23:01PM to 12:00AM) and early (≤ 22:00PM) bedtimes were associated with an increased risk of hypertension compared to bedtimes between 22:01PM and 23:00PM. In addition, individuals with late (> 7:00AM) and early (≤ 5:00AM) wake-up times had a higher prevalence of hypertension than those with wake-up times ranging between 5:01AM and 6:00AM. Delaying the sleep midpoint (> 3:00AM) was also associated with an increased risk of hypertension. Furthermore, no significant interaction effect was found in the subgroup analyses stratified by age, sex, or apnea-hypopnea index. CONCLUSIONS: Our findings identified a nonlinear association between sleep timing and hypertension. Individuals with both early and late sleep timing had a high prevalence of hypertension.

Effects of decision making and impulsivity on the addictive features of non-suicidal self-injury behaviors in adolescents with depressive disorder.

BACKGROUND: Non-suicidal self-injury (NSSI) behaviors pose a significant threat to the physical and psychological well-being of adolescents. Recent research suggests that persistent, uncontrollable and repetitive NSSI can be conceptualized as a behavioral addiction. The addictive feature of NSSI behavior can be assessed using Ottawa self-injury inventory (OSI), the higher addiction score indicates the more serious NSSI behavior. This study aims to explore the relationship of impulsivity and decision-making on the addictive features of NSSI in adolescents with depressive disorder, to explore the influencing factors of behavioral addictive features of NSSI and to predict the addictive features of NSSI. METHODS: Using a cross-sectional design, a total of 126 adolescent outpatients and inpatients with a mean age of 15.49 years old (M = 15.49, SD = 1.56), male students (n = 28, 22.2%) and female students (n = 98, 77.8%) diagnosed with depressive disorders were recruited according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and clinical interviews were completed by two psychiatrists. NSSI addictive features according to the OSI's addictive features items. The final group was categorized into three groups: depression without NSSI (n = 42), depression with NSSI without addictive features (n = 44), and depression with NSSI and addictive features (n = 40). The present study employed the Hamilton Depression Scale (HAMD-24), Chinese Revised Barratt Impulsiveness Scale Version 11 (BIS-11), OSI, and the Adolescent Non-Suicidal Self-Injury Questionnaire (ANSSIQ). Cognitive decision-making abilities were assessed using the Iowa Gambling Task (IGT). RESULTS: The depression with NSSI addictive features group had significantly lower total net scores and net scores of block3, block4, and block5 in the IGT than the depression without NSSI group, whereas there was no statistically significant difference between the two in net scores of block1 and block2. Lower scores mean more unfavorable decisions and strategy adjustments. The addictive features of NSSI behaviors were significantly and positively correlated with the severity of NSSI behaviors, depression, and cognitive impulsiveness, and significantly and negatively correlated with the total net score of the IGT. The severity of NSSI behaviors, severity of depression, cognitive impulsiveness positively predicts the addictive features of NSSI behaviors, the total net score of the IGT negatively predicted the addictive features of NSSI behaviors. CONCLUSION: Adolescents with depressive disorders with NSSI behavioral addictive features had higher severity of depression, exhibited higher cognitive impulsivity, and made more unfavorable decisions when making choices.

Prediction of gestational diabetes mellitus by multiple biomarkers at early gestation.

BACKGROUND: It remains unclear which early gestational biomarkers can be used in predicting later development of gestational diabetes mellitus (GDM). We sought to identify the optimal combination of early gestational biomarkers in predicting GDM in machine learning (ML) models. METHODS: This was a nested case-control study including 100 pairs of GDM and euglycemic (control) pregnancies in the Early Life Plan cohort in Shanghai, China. High sensitivity C reactive protein, sex hormone binding globulin, insulin-like growth factor I, IGF binding protein 2 (IGFBP-2), total and high molecular weight adiponectin and glycosylated fibronectin concentrations were measured in serum samples at 11-14 weeks of gestation. Routine first-trimester blood test biomarkers included fasting plasma glucose (FPG), serum lipids and thyroid hormones. Five ML models [stepwise logistic regression, least absolute shrinkage and selection operator (LASSO), random forest, support vector machine and k-nearest neighbor] were employed to predict GDM. The study subjects were randomly split into two sets for model development (training set, n = 70 GDM/control pairs) and validation (testing set: n = 30 GDM/control pairs). Model performance was evaluated by the area under the curve (AUC) in receiver operating characteristics. RESULTS: FPG and IGFBP-2 were consistently selected as predictors of GDM in all ML models. The random forest model including FPG and IGFBP-2 performed the best (AUC 0.80, accuracy 0.72, sensitivity 0.87, specificity 0.57). Adding more predictors did not improve the discriminant power. CONCLUSION: The combination of FPG and IGFBP-2 at early gestation (11-14 weeks) could predict later development of GDM with moderate discriminant power. Further validation studies are warranted to assess the utility of this simple combination model in other independent cohorts.

Glutathione-depleting Liposome Adjuvant for Augmenting the Efficacy of a Glutathione Covalent Inhibitor Oridonin for Acute Myeloid Leukemia Therapy.

BACKGROUND: Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH. METHODS: We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets. RESULTS: We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells. CONCLUSION: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.

Predicting the impact of femtosecond-assisted arcuate keratotomy combined with tri-planar clear corneal incisions on astigmatism in implantable collamer lens surgery: one-year follow-up.

PURPOSE: To investigate the factors associated with and impact on the femtosecond-assisted (FS-assisted) limbal relaxing incision (LRI) combined with the steep-meridian tri-planar clear corneal incision (TCCI) to reduce astigmatism in patients undergoing Implantable Collamer Lens (ICL) surgery. METHODS: Retrospective case series. The study reviewed patients with ICL surgery combined with FS-assisted LRIs paired with steep-meridian TCCIs. Correlation analysis examined the relationship between independent variables, including preoperative characteristics (intraocular pressure, corneal thickness, axial length, et al.), TCCI, and LRI surgical parameters. The predictors of surgically induced astigmatism (SIA) were determined using individual-level analysis and accounting for inter-eye correlation with the generalized estimating equation (GEE). RESULTS: The study enrolled 69 patients, with 114 eyes (55 right and 59 left). The mean spherical equivalent (SEQ) was - 10.29 ± 2.99D and - 9.99 ± 2.72D for the right and left eye, respectively, while the mean preoperative corneal astigmatism was - 1.54 ± 0.47D and - 1.54 ± 0.46D for the right and left eyes, respectively. After 12 months of follow-up, univariate analysis revealed significant correlations between SIA and intraocular pressure (IOP), astigmatism type, TCCI position (degree), peripheral corneal thickness (PCT), LRI arc incision diameter, post depth (%), and angle, respectively (P = 0.046, 0.016, 0.039, 0.040, 0.009, 0.000, 0.000). Multivariate analysis using GEE demonstrated that axial length (AL), astigmatism type, LRI arc diameter, and angle were independent predictors of SIA (P = 0.000, 0.005, 0.029, 0.000). CONCLUSIONS: The type of astigmatism and axial length were independent factors that affected SIA when modifying the LRI arc diameter and angle through FS-assisted steep-meridian TCCI paired with LRI in ICL surgery.

Effect of leisure activity on frailty trajectories among Chinese older adults: a 16-year longitudinal study.

BACKGROUND: While the significant association between leisure activities and frailty risk among older adults is well-established, the impact of integrated leisure activity scores and different categories of them on frailty trajectories over time remains unclear. METHODS: This study utilized longitudinal data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), which enrolled participants aged 65 years and older between 2002 and 2018. Frailty trajectories were derived using group-based trajectory modelling, and based on these trajectories, subjects were classified into various categories. Leisure activity was measured by integrated scores as well as three distinct categories: physically, cognitively, and socially stimulating activity. The effect of leisure activity on frailty trajectories was examined using multinomial logistic regression. RESULTS: By analysing data from 2,299 older adults, three frailty trajectories were identified: non-frail, moderate progressive, and high progressive. The results indicated that an increase in the score of integrated leisure activity was associated with 11% (odds ratio [OR] 0.89; 95% Confidence Interval [CI] 0.85-0.93) and 14% (OR 0.86; 95% CI 0.80-0.91) decrease in the likelihood of being in the moderate and high progressive frailty trajectories, respectively. Engaging in physically stimulating activity lowered the odds of belonging to the moderate and high progressive trajectory by 43% (OR 0.57; 95% CI 0.40-0.81; OR 0.57; 95% CI 0.36-0.92, respectively). Participation in socially stimulating activity showed a lower odd of being in the moderate progressive trajectory (OR 0.68; 95% CI 0.49-0.93) and the high progressive trajectory (OR, 0.61; 95% CI, 0.39-0.95). The effects of leisure activities on frailty trajectories were observed not to vary by age, education level and retirement status. CONCLUSIONS: This study suggests that older adults should be encouraged to increase both the amount and variety of their leisure activities. Physically stimulating activities should be considered the primary choice, followed by socially and cognitively stimulating activities.