Human XPR1 structures reveal phosphate export mechanism.

Inorganic phosphate (Pi) is a fundamental macronutrient for all living organisms, the homeostasis of which is critical for numerous biological activities1-3. As the only known human Pi exporter to date, XPR1 has an indispensable role in cellular Pi homeostasis4,5. Dysfunction of XPR1 is associated with neurodegenerative disease6-8. However, the mechanisms underpinning XPR1-mediated Pi efflux and regulation by the intracellular inositol polyphosphate (InsPP) sensor SPX domain remain poorly understood. Here we present cryo-electron microscopy structures of human XPR1 in Pi-bound closed, open and InsP6-bound forms, revealing the structural basis for XPR1 gating and regulation by InsPPs. XPR1 consists of an N-terminal SPX domain, a dimer-formation core domain and a Pi transport domain. Within the transport domain, three basic clusters are responsible for Pi binding and transport, and a conserved W573 acts as a molecular switch for gating. In addition, the SPX domain binds to InsP6 and facilitates Pi efflux by liberating the C-terminal loop that limits Pi entry. This study provides a conceptual framework for the mechanistic understanding of Pi homeostasis by XPR1 homologues in fungi, plants and animals.

Global years lived with disability for musculoskeletal disorders in adults 70 Years and older from 1990 to 2019, and projections to 2040.

In this article, we provided a comprehensive overview and in-depth analysis of global patterns and temporal trends in years lived with disability (YLDs) for musculoskeletal (MSK) disorders in individuals aged ≥70. Data on YLDs for MSK disorders in individuals aged ≥70 were obtained from the Global Burden of Disease 2019. The average annual percentage change (AAPC) was calculated to assess the temporal trends in the YLDs rate of MSK disorders. A Bayesian Age-Period-Cohort model was used to predict the YLDs rate up to the year 2040. In 2019, the global rate of YLDs for MSK disorders in individuals aged ≥70 were 4819.81 (95 % UI: 3402.91 - 6550.77) per 100,000 persons. The YLDs rate of MSK disorders in female was 1.36 times higher than that in male, and was highest in high SDI regions. From 1990 to 2019, the global YLDs rate showed a slightly downward trend (AAPC = -0.04 %, 95 % CI: -0.06 % to -0.03 %), while it significantly increased in high, low-middle, low SDI regions. Tobacco and high body mass index were the primary risk factors worldwide, while in low SDI regions, occupational risks emerged as the predominant factors. Up to 2040, the global YLDs rate of MSK disorders are expected to increase by 1.78 %, with 36.39 %, 20.66 %, 18.96 % and 5.32 % growth in other MSK disorders, rheumatoid arthritis, neck pain and osteoarthritis. MSK disorders are a significant and continuously growing public health concern among older adults. Tailored interventions should be developed for older adults, taking into account the variations across distributions, trends, and risk factors in terms of sex and SDI levels.

Corrigendum to "WCN24-786 PHASE I DOSE ESCALATION STUDY OF SHR6508, A CALCIUM-SENSING RECEPTOR AGONIST, IN HEMODIALYSIS PATIENTS WITH SECONDARY HYPERPARATHYROIDISM" [Kidney International Reports Volume 9, Issue 4, Supplement, April 2024, Pages S368-S369].

[This corrects the article DOI: 10.1016/j.ekir.2024.02.771.].

A review of complex hormone regulation in thyroid cancer: novel insights beyond the hypothalamus-pituitary-thyroid axis.

Like the ovaries and prostate, the thyroid exhibits characteristic hormone secretion and regulation. Thyroid cancer (TC), especially differentiated thyroid carcinoma, has typical sex-specific and age-specific hormone-driven clinical features. Previous research has primarily focused on the effects of thyroid stimulating hormone, thyroid hormones, and estrogens on the onset and progression of TC, while the roles of growth hormone (GH), androgens, and glucocorticoids have largely been overlooked. Similarly, few studies have investigated the interactions between hormones and hormone systems. In fact, numerous studies of patients with acromegaly have shown that serum levels of GH and insulin-like growth factor-1 (IGF-1) may be associated with the onset and progression of TC, although the influences of age, sex, and other risk factors, such as obesity and stress, remain unclear. Sex hormones, the GH/IGF axis, and glucocorticoids are likely involved in the onset and progression of TC by regulating the tumor microenvironment and metabolism. The aim of this review was to clarify the roles of hormones and hormone systems in TC, especially papillary thyroid carcinoma, as references for further investigations.

Room temperature synthesis of a chiral covalent organic framework core-shell composite for high-performance liquid chromatography enantioseparation.

In this article, chiral covalent organic framework core-shell composite CCOF-TpPa-Py@SiO2 was facilely synthesized by induction at room temperature. The CCOF-TpPa-Py@SiO2 core-shell composite was used as a chiral stationary phase for the separation of the racemates by high-performance liquid chromatography, which exhibits good separation performance for chiral compounds including ketones, alcohols, esters, epoxides, carboxylic acids, amides, and amines. The effects of analyte injection mass on the enantioseparation were studied. The reproducibility and stability of the CCOF-TpPa-Py@SiO2 chiral column were explored. The intra-day (n = 5), inter-day (n = 5), and inter-column (n = 3) relative standard deviations for the migration times and resolution of benzoin were 0.32%-0.54%, 0.45%-0.61%, and 1.21%-1.53%, respectively. In addition, the chiral separation ability of the CCOF-TpPa-Py@SiO2 chiral column (column A) was compared with that of the MDI-ß-CD-Modified COF@SiO2 (column B) as well as a commercial chiral column (Chiralpak AD-H). The chiral recognition ability of column A is complementary to that of column B and AD-H column. The resolution mechanism of CCOF-TpPa-Py@SiO2 stationary phase towards chiral analyte was explored. Hence, the synthesis of CCOF-TpPa-Py@SiO2 core-shell composite by induction at room temperature as chiral stationary phases for chromatographic separation has important research potential and application prospects.

GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder.

Sleep disturbances, including rapid eye movement sleep behavior disorder (RBD), excessive daytime sleepiness, and insomnia, are common non-motor manifestations of Parkinson's disease (PD). Little is known about the underlying mechanisms, partly due to the inability of current rodent models to adequately mimic the human PD sleep phenotype. Clinically, increasing studies have reported that variants of the glucocerebrosidase gene (GBA) increase the risk of PD. Here, we developed a mouse model characterized by sleep-wakefulness by injecting α-synuclein preformed fibronectin (PFF) into the sublaterodorsal tegmental nucleus (SLD) of GBA L444P mutant mice and investigated the role of the GBA L444P variant in the transition from rapid eye movement sleep behavior disorder to PD. Initially, we analyzed spectral correlates of REM and NREM sleep in GBA L444P mutant mice. Importantly, EEG power spectral analysis revealed that GBA L444P mutation mice exhibited reduced delta power during non-rapid eye movement (NREM) sleep and increased theta power (8.2-10 Hz) in active rapid eye movement (REM) sleep phases. Our study revealed that GBA L444P-mutant mice, after receiving PFF injections, exhibited increased sleep fragmentation, significant motor and cognitive dysfunctions, and loss of dopaminergic neurons in the substantia nigra. Furthermore, the over-expression of GBA-AAV partially improved these sleep disturbances and motor and cognitive impairments. In conclusion, we present the initial evidence that the GBA L444P mutant mouse serves as an essential tool in understanding the complex sleep disturbances associated with PD. This model further provides insights into potential therapeutic approaches, particularly concerning α-synuclein accumulation and its subsequent pathological consequences.

Association between internet exclusion and depressive symptoms among older adults: panel data analysis of five longitudinal cohort studies.

Background: Internet exclusion and depressive symptoms are prevalent phenomena among older adults; however, the association between internet exclusion and depressive symptoms remains limited. This study aims to investigate the association between internet exclusion and depressive symptoms among older adults from high-income countries (HICs) and low- and middle-income countries (LMICs). Methods: We conducted a comprehensive longitudinal, cross-cultural analysis, and the participants were adults aged 60 years and older from 32 countries participating in five nationally representative longitudinal cohort studies: the Health and Retirement Study (HRS), the English Longitudinal Study of Ageing (ELSA), the Survey of Health, Ageing and Retirement in Europe (SHARE), the China Health and Retirement Longitudinal Study (CHARLS), and the Mexican Health and Ageing Study (MHAS). Internet exclusion was defined as the self-reported absence from internet use. Depressive symptoms were evaluated using the Centre for Epidemiologic Studies of Depression scale (CES-D) or the Euro-Depression scale (Euro-D). These five cohorts, being heterogeneous, were respectively conducted with panel data analysis. Logistic regression, implemented within the generalized estimating equations framework, was used to examine the association between internet exclusion and the likelihood of experiencing depressive symptoms, adjusting for the causal-directed-acyclic-graph (DAG) minimal sufficient adjustment set (MSAS), including gender, age, education, labour force status, household wealth level, marital status, co-residence with children, residence status, cognitive impairment, and functional ability. Findings: Our study included a total of 129,847 older adults during the period from 2010 to 2020, with a median follow-up of 5 (2, 7) years. The pooled proportion of internet exclusion was 46.0% in HRS, 32.6% in ELSA, 54.8% in SHARE, 92.3% in CHARLS, and 65.3% in MHAS. Internet exclusion was significantly associated with depressive symptoms across all cohort studies: HRS (OR = 1.13, 95% CI 1.07-1.20), ELSA (OR = 1.22, 95% CI 1.11-1.34), SHARE (OR = 1.55, 95% CI 1.47-1.62), CHARLS (OR = 1.49, 95% CI 1.26-1.77), and MHAS (OR = 1.48, 95% CI 1.39-1.58). Moreover, internet exclusion was found to be associated with all dimensions of depression in the SHARE, MHAS, and ELSA cohorts (except for sleep and felt sad) cohorts. Interpretation: A considerable proportion of older adults experienced internet exclusion, particularly those in LMICs. Internet exclusion among older adults, irrespective of their geographic location in HICs or LMICs, was associated with a higher likelihood of experiencing depressive symptoms, which demonstrated the importance of addressing barriers to internet access and promoting active participation in the internet society among older adults. Funding: National Key R&D Program of China (grant number 2022ZD0160704), the Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (grant number ZYCXTD2023005), the Collaborative Innovation Major Project of Zhengzhou (grant number 20XTZX08017), the Joint Project of Medical Science and Technology of Henan Province (grant number LHGJ20220428), and National Natural Science Foundation of China (grant number 82373341).

Architecture of native kinetochores revealed by structural studies utilizing a thermophilic yeast.

Eukaryotic chromosome segregation requires kinetochores, multi-megadalton protein machines that assemble on the centromeres of chromosomes and mediate attachments to dynamic spindle microtubules. Kinetochores are built from numerous complexes, and there has been progress in structural studies on recombinant subassemblies. However, there is limited structural information on native kinetochore architecture. To address this, we purified functional, native kinetochores from the thermophilic yeast Kluyveromyces marxianus and examined them by electron microscopy (EM), cryoelectron tomography (cryo-ET), and atomic force microscopy (AFM). The kinetochores are extremely large, flexible assemblies that exhibit features consistent with prior models. We assigned kinetochore polarity by visualizing their interactions with microtubules and locating the microtubule binder, Ndc80c. This work shows that isolated kinetochores are more dynamic and complex than what might be anticipated based on the known structures of recombinant subassemblies and provides the foundation to study the global architecture and functions of kinetochores at a structural level.

Individual suicide risk factors with resting-state brain functional connectivity patterns in bipolar disorder patients based on latent Dirichlet allocation model.

BACKGROUND: The widespread problem of suicide and its severe burden in bipolar disorder (BD) necessitate the development of objective risk markers, aiming to enhance individual suicide risk prediction in BD. METHODS: This study recruited 123 BD patients (61 patients with prior suicide attempted history (PSAs), 62 without (NSAs)) and 68 healthy controls (HEs). The Latent Dirichlet Allocation (LDA) model was used to decompose the resting state functional connectivity (RSFC) into multiple hyper/hypo-RSFC patterns. Thereafter, according to the quantitative results of individual heterogeneity over latent factor dimensions, the correlations were analyzed to test prediction ability. RESULTS: Model constructed without introducing suicide-related labels yielded three latent factors with dissociable hyper/hypo-RSFC patterns. In the subsequent analysis, significant differences in the factor distributions of PSAs and NSAs showed biases on the default-mode network (DMN) hyper-RSFC factor (factor 3) and the salience network (SN) and central executive network (CEN) hyper-RSFC factor (factor 1), indicating predictive value. Correlation analysis of the individuals' expressions with their Nurses' Global Assessment of Suicide Risk (NGASR) revealed factor 3 positively correlated (r = 0.4180, p < 0.0001) and factor 1 negatively correlated (r = - 0.2492, p = 0.0055) with suicide risk. Therefore, it could be speculated that patterns more associated with suicide reflected hyper-connectivity in DMN and hypo-connectivity in SN, CEN. CONCLUSIONS: This study provided individual suicide-associated risk factors that could reflect the abnormal RSFC patterns, and explored the suicide related brain mechanisms, which is expected to provide supports for clinical decision-making and timely screening and intervention for individuals at high risks of suicide.

Alisol C 23-acetate might be a lead compound of potential lipase inhibitor from Alismatis Rhizoma: Screening, identification and molecular dynamics simulation.

Alismatis Rhizoma (AR), a traditional Chinese medicine for treating obesity in traditional Chinese medicine clinic, is recognized as a promising source of lead compounds of lipase inhibitors. Ultrafiltration centrifugal combined with liquid chromatography-mass spectrometry (UF-LC-MS) was used for screening potential lipase inhibitors from AR, and the result indicated the binding capacity between compound 7 and lipase (92.3 ±â€¯1.28 %) was significantly higher than other triterpenoids, and was identified as alisol C 23-acetate. It exhibited a mixed-type inhibitory behavior with an IC50 value of 84.88 ±â€¯1.03 µM. Subsequently, the binding pockets of alisol C 23-acetate to lipase were predicted, and their binding mechanism was explored with molecular simulation. Pocket 1 (active center) and pocket 4 might be the orthosteric and allosteric binding sites of alisol C 23-acetate to lipase, respectively. The interaction between alisol C 23-acetate and lipase was identified to involve key amino acid residues such as GLY-77, PHE-78, TYR-115, LEU-154, PRO-181, PHE-216, LEU-264, ASP-278, GLN-306, ARG-313, and VAL-426. Meanwhile, alisol C 23-acetate remained stable during the intestinal digestive but degraded in the gastric digestion. Overall, alisol C 23-acetate is expected to be the lead compound of lipase inhibitors for treating obesity.

HR-MRI-based nomogram network calculator to predict stroke recurrence in high-risk non-disabling ischemic cerebrovascular events patients.

Background and objective: To investigate the use of high-resolution magnetic resonance imaging (HR-MRI) to identify the characteristics of culprit plaques in intracranial arteries, and to evaluate the predictive value of the characteristics of culprit plaques combined with the modified Essen score for the recurrence risk of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) patients. Methods: A retrospective analysis was conducted on 180 patients with HR-NICE at the First Affiliated Hospital of Xinxiang Medical University, including 128 patients with no recurrence (non-recurrence group) and 52 patients with recurrence (recurrence group). A total of 65 patients with HR-NICE were collected from the Sixth Affiliated Hospital of Shanghai Jiaotong University as a validation group, and their modified Essen scores, high-resolution magnetic resonance vessel wall images, and clinical data were collected. The culprit plaques were analyzed using VesselExplorer2 software. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for recurrence, and a nomogram was constructed using R software to evaluate the discrimination of the model. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was used to evaluate the model performance. Calibration curves and Decision Curve Analysis (DCA) were used to evaluate the model efficacy. Results: Intra-plaque hemorrhage (OR = 3.592, 95% CI = 1.474-9.104, p = 0.006), homocysteine (OR = 1.098, 95% CI = 1.025-1.179, p = 0.007), and normalized wall index (OR = 1.114, 95% CI = 1.027-1.222, p = 0.015) were significantly higher in the recurrent stroke group than in the non-recurrent stroke group, and were independent risk factors for recurrent stroke. The performance of the nomogram model (AUC = 0.830, 95% CI: 0.769-0.891; PR-AUC = 0.628) was better than that of the modified Essen scoring model (AUC = 0.660, 95% CI: 0.583-0.738) and the independent risk factor combination model (AUC = 0.827, 95% CI: 0.765-0.889). The nomogram model still had good model performance in the validation group (AUC = 0.785, 95% CI: 0.671-0.899), with a well-fitting calibration curve and a DCA curve indicating good net benefit efficacy for patients. Conclusion: High-resolution vessel wall imaging combined with a modified Essen score can effectively assess the recurrence risk of HR-NICE patients, and the nomogram model can provide a reference for identifying high-risk populations with good clinical application prospects.

Targeting the PI3K/AKT/mTOR pathway offer a promising therapeutic strategy for cholangiocarcinoma patients with high doublecortin-like kinase 1 expression.

BACKGROUND: Cholangiocarcinoma (CCA), characterized by high heterogeneity and extreme malignancy, has a poor prognosis. Doublecortin-like kinase 1 (DCLK1) promotes a variety of malignant cancers in their progression. Targeting DCLK1 or its associated regulatory pathways can prevent the generation and deterioration of several malignancies. However, the role of DCLK1 in CCA progression and its molecular mechanisms remain unknown. Therefore, we aimed to investigate whether and how DCLK1 contributes to CCA progression. METHODS: The expression of DCLK1 in CCA patients was detected using Immunohistochemistry (IHC). We established DCLK1 knockout and DCLK1 overexpression cell lines for Colony Formation Assay and Transwell experiments to explore the tumor-promoting role of DCLK1. RT-PCR, Western blot and multiple fluorescent staining were used to assess the association between DCLK1 and epithelial-mesenchymal transition (EMT) markers. RNA sequencing and bioinformatics analysis were performed to identify the underlying mechanisms by which DCLK1 regulates CCA progression and the EMT program. RESULTS: DCLK1 was overexpressed in CCA tissues and was associated with poor prognosis. DCLK1 overexpression facilitated CCA cell invasion, migration, and proliferation, whereas DCLK1 knockdown reversed the malignant tendencies of CCA cells, which had been confirmed both in vivo and in vitro. Furthermore, we demonstrated that DCLK1 was substantially linked to the advancement of the EMT program, which included the overexpression of mesenchymal markers and the downregulation of epithelial markers. For the underlying mechanism, we proposed that the PI3K/AKT/mTOR pathway is the key process for the role of DCLK1 in tumor progression and the occurrence of the EMT program. When administered with LY294002, an inhibitor of the PI3K/AKT/mTOR pathway, the tumor's ability to proliferate, migrate, and invade was greatly suppressed, and the EMT process was generally reversed. CONCLUSIONS: DCLK1 facilitates the malignant biological behavior of CCA cells through the PI3K/AKT/mTOR pathway. In individuals with cholangiocarcinoma who express DCLK1 at high levels, inhibitors of the PI3K/AKT/mTOR signaling pathway may be an effective therapeutic approach.

Increased stress from compound drought and heat events on vegetation.

Compound drought and heat events (CDHEs), which are frequently occurring compound extreme climate events, have garnered considerable attention because of their detrimental effects on ecosystems. However, the intricacies of the spatial and temporal distributions of different durations of compound events, along with the variability in vegetation responses remain unclear. Here, we delineated the CDHEs based on meteorological observation data and investigated the spatial and temporal characteristics of CDHEs from 1993 to 2020 using the Theil-Sen trend test and Mann-Kendall nonparametric test. Furthermore, we utilized sliding correlation analysis to evaluate the impacts of CDHEs on vegetation among different climatic regions and ecosystems. Our findings indicate significant increasing trends in both the frequency and persistence of CDHEs from 1993 to 2020. The average trend of CDHEs frequency across different duration periods amounted to 13.80 %/decade. The fractional contribution of CDHEs lasting more than three days exhibited a significant increase, with an average trend of 2.00 %/decade. We also observed that vegetation is most significantly affected by compound events lasting 5-9 days. During the study period, the geographical extent of vegetation significantly impacted by CDHEs expanded by 0.89 %, correlation strength increased by 0.02, and lag time decreased by 0.25 months. These insights highlight the growing impact of CDHEs on vegetation under climate change, improving our understanding of vegetation responses to these compound events.

Synthesis of highly sensitive and multi-response Eu-MOF, fluorescence sensing properties and anti-counterfeiting applications.

A new Europium metal-organic framework (Eu-MOF), namely [Eu(dpa) (H2O)]·0.5(bpy)·4H2O}n (H4dpa = 5-(3,4-dicarboxyphenoxy) isophenic acid, bpy = protonated 4,4'-bipyridine) was synthesized and structurally characterized by elemental analyses, infrared spectroscopy, and X-ray single-crystal diffraction analyses. Eu-MOF shows a three-dimensional network structure based on EuIII ions and (dpa)4- ligands via µ4: η1, η2, η2, η2 coordination mode. Fluorescence analysis shows that Eu-MOF has excellent fluorescence sensing characteristics, which can efficiently and sensitively detect various pollutants in water: the limit of detection (LOD) of ratiometric fluorescence detection of ANI in water was 42.9 nM, which was better than the single-peak detection limit. In addition, the peak detection limits of Eu-MOF for Flu, ORN and NB were 120 nM, 27 nM and 94 nM, respectively. In addition, XPS, LUMO orbital energy level, fluorescence lifetime, ultraviolet absorption and other principles are used to explore the mechanism of fluorescence quenching. Surprisingly, Eu-MOF not only has excellent anti- counterfeiting ability and stability, can be used as anti-counterfeiting material in life, but also has good selectivity to Flu. Eu-MOF has obvious fluorescence quenching effect on Flu on paper under ultraviolet light, which can be used for rapid in situ imaging test paper of pesticide residues.

Crystal-Rigidifying Strategy in Hybrid Manganese Halide to Achieve Narrow Green Emission and High Structural Stability.

Although organic-inorganic hybrid Mn2+ halides have advanced significantly, achieving high stability and narrow-band emission remains enormously challenging owing to the weak ionic nature and soft crystal lattice of the halide structure. To address these issues, we proposed a cationic engineering strategy of long-range cation π···π stacking and C-H···π interactions to simultaneously improve the crystal structural stability and rigidity. Herein, two organic zero-dimensional (0D) manganese halide hybrids of (BACQ)2MnX4 [BACQ = 4-(butylamino)-7-chloroquinolin-1-ium; X = Cl and Br] were synthesized. (BACQ)2MnX4 display strong green-light emissions with the narrowest full width at half-maximum (fwhm) of 39 nm, which is significantly smaller than those of commercial green phosphor ß-SiAlON:Eu2+ and most of reported manganese halides. Detailed Hirshfeld surface analyses demonstrate the rigid environment around the [MnX4]2- units originating from the interactions between [BACQ]+. The rigid crystal structure weakens the electron-phonon coupling and renders narrow fwhm of these manganese halides, which is further confirmed by temperature-dependent emission spectra. Remarkably, (BACQ)2MnX4 realizes outstanding structural and luminescence stabilities in various extreme environments. Benefiting from the excellent performance, these Mn2+ halides are used to assemble light-emitting diodes with a wide color gamut of 105% of the National Television System Committee 1931 standard, showcasing the advanced applications in liquid-crystal-display backlighting.

Characteristics and prognosis of elderly-onset antiphospholipid syndrome: An observational cohort study.

OBJECTIVE: Antiphospholipid syndrome (APS) is an autoimmune disease mainly affecting young individuals. Testing for antiphospholipid antibodies is recommended for young patients who are suspected to have APS. Yet, it is hard to differentiate APS from other acquired thrombophilia disorders in elderly-onset APS patients. This study aim to investigate the characteristics and prognosis of elderly-onset APS. METHODS: This is an observational cohort study. Thrombotic APS patients who underwent follow-ups between 2009 and 2022 were included. Elderly-onset APS patients (onset age ≥60 years) were compared to non-elderly-onset APS patients (onset age <60 years) and matched cases of elderly non-APS patients (age ≥60 years with thrombosis). RESULTS: A total of 161 APS patients were included in this study, 45 (28.0%) were elderly-onset APS. Stroke (35.6% vs. 18.1%, p = .018) was more common at disease onset in elderly-onset APS patients. Compared to non-elderly-onset patients, elderly-onset APS patients were associated with a higher number of cardiovascular risk factors. Elderly-onset APS patients showed significantly lower positive rate (51.1% vs. 71.6%, p = .014) and ratios [1.24 (1.01-1.38) vs. 1.37 (1.16-1.77), p = .004] of lupus anticoagulant. Elderly-onset APS patients had a significantly higher 10-years cumulative all-cause mortality (p < .001) and APS-related mortality than non-elderly-onset patients (p = .002) and elderly non-APS patients (p = .040). CONCLUSIONS: Elderly-onset APS patients have unique disease characteristics with higher 10-years cumulative all-cause mortality and APS-related mortality. Early recognition and control of comorbidities may reduce the recurrence of thrombosis and mortality in elderly-onset APS patients.

Distinct dynamics of parental 5-hydroxymethylcytosine during human preimplantation development regulate early lineage gene expression.

The conversion of DNA 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by TET enzymes represents a significant epigenetic modification, yet its role in early human embryos remains largely unknown. Here we showed that the early human embryo inherited a significant amount of 5hmCs from an oocyte, which unexpectedly underwent de novo hydroxymethylation during its growth. Furthermore, the generation of 5hmC in the paternal genome after fertilization roughly followed the maternal pattern, which was linked to DNA methylation dynamics and regions of sustained methylation. The 5hmCs persisted until the eight-cell stage and exhibited high enrichment at OTX2 binding sites, whereas knockdown of OTX2 in human embryos compromised the expression of early lineage genes. Specifically, the depletion of 5hmC affected the activation of embryonic genes, which was further evaluated by ectopically expressing mouse Tet3 in human early embryos. These findings revealed distinct dynamics of 5hmC and unravelled its multifaceted functions in early human embryonic development.

Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13.

The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin 13, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin 13 analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.

[Effects of iris xanthin on airway inflammation, airway remodeling, and the HMGB1/TLR4/NF-κB pathway in asthmatic young mice]. / é¸¢å°¾é»„ç´ å¯¹å“®å–˜å¹¼é¼ æ°”é“ç‚Žç—‡ã€æ°”é“é‡å¡‘åŠHMGB1/TLR4/NF-κB通路的影响.

OBJECTIVES: To explore the effects of iris xanthin on airway inflammation, airway remodeling, and the high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in asthmatic young mice. METHODS: Sixty male BALB/c young mice were randomly assigned into six groups: a blank group, a model group, a dexamethasone group, and low, medium, and high dose groups of iris xanthin, with ten mice per group. Asthma models were induced through intraperitoneal injections of a sensitizing agent [ovalbumin (OVA) 20 µg + aluminum hydroxide gel 2 mg], followed by 4% OVA aerosol inhalation. Lung function was measured using a pulmonary function tester to determine lung volume (LV), resting ventilation per minute (VE), and airway reactivity (Penh value). Hematoxylin-eosin (HE) staining was employed to examine and analyze airway remodeling. The contents of interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid were quantified using ELISA. Real-time fluorescence quantitative polymerase chain reaction and Western blot analysis were used to assess the expression of HMGB1/TLR4/NF-κB pathway-related mRNA and proteins in lung tissues. RESULTS: Compared to the model group, the dexamethasone and iris xanthin-treated groups (low, medium, and high doses) exhibited significant increases in LV and VE (P<0.05), with incremental dose-dependent increases observed in the iris xanthin groups. Additionally, Penh values, IL-1ß, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, and NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were all reduced (P<0.05) in a dose-dependent manner. When compared to the dexamethasone group, the low and medium dose iris xanthin groups showed decreases in LV and VE (P<0.05), whereas Penh values, IL-1ß, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were increased (P<0.05). No significant differences were noted in these indices between the high dose iris xanthin group and the dexamethasone group (P>0.05). CONCLUSIONS: Iris xanthin can effectively alleviates airway inflammation and inhibits airway remodeling in asthmatic young mice, possibly through the suppression of the HMGB1/TLR4/NF-κB pathway.

Serum YKL-40 and Serum Krebs von den Lungen-6 as Potential Predictive Biomarkers for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis (RA) and is associated with a poor prognosis. However, the role of blood biomarkers in RA-associated interstitial lung disease (RA-ILD) is ill-defined. We aim to evaluate the role of YKL-40 and Krebs von den Lungen-6 (KL-6) in the diagnosis and severity evaluation of RA-ILD. METHODS: 45 RA-non-ILD patients and 38 RA-ILD patients were included. The clinical data and the levels of YKL-40 and KL-6 were measured and collected for all patients. The risk factors for RA-ILD were analyzed and their correlation with relevant indicators and predictive value for RA-ILD was explored. RESULTS: The levels of YKL-40 and KL-6 in RA-ILD patients were higher than RA-non-ILD patients (p < .001). Both YKL-40 and KL-6 were correlated with the incidence of RA-ILD. The predictive power of combined KL-6 and YKL-40 for the presence of ILD was 0.789, with a sensitivity and specificity at 73.7% and 73.3%, respectively. In RA-ILD patients, both YKL-40 and KL-6 were positively correlated with the Scleroderma Lung Study (SLS) I score and negatively correlated with pulmonary function. CONCLUSIONS: KL-6 and YKL-40 might be a useful biomarker in the diagnosis and severity evaluation of RA-ILD.