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1.
J Transl Med ; 22(1): 860, 2024 Sep 27.
Article in English | MEDLINE | ID: mdl-39334418

ABSTRACT

BACKGROUND: There is currently a lack of comprehensive evidence regarding the correlation between Alternate Mediterranean Diet (AMED) and the survival of patients with ovarian cancer (OC). This prospective cohort study first assessed the association of AMED, not only pre-diagnosis and post-diagnosis but also the change from pre-diagnosis to post-diagnosis with OC survival. METHODS: A total of 560 OC patients were included in the study, and their dietary intake was assessed using a reliable 111-item food frequency questionnaire. The overall survival (OS) of the patients was monitored through active follow-up and review of medical records until February 16th, 2023. Cox proportional hazard regression models were utilized to compute the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). RESULTS: Out of the total 560 patients with OC, 211 (37.68%) succumbed during a median follow-up period of 44.40 months (interquartile range: 26.97-61.37). Comparative analysis indicated a significant association between the highest tertiles of pre-diagnosis (HR = 0.59; 95% CI 0.38-0.90; Ptrend < 0.05) and post-diagnosis (HR = 0.61; 95% CI 0.41-0.91; Ptrend < 0.05) AMED intake and improved OS as opposed to the lowest tertile. Additionally, a significant linear trend was observed for AMED and OC survival. Notably, decreased intake (more than 5% change) and significantly increased intake (more than 15% change) of AMED from pre-diagnosis to post-diagnosis were linked to worse and better OS, respectively, when compared to the stable intake group (change within 5%). Furthermore, patients displaying consistently higher AMED intake both before and after diagnosis experienced enhanced OS in comparison to those with consistently low AMED intake (HRHigh-High vs. Low-Low = 0.47; 95% CI 0.31-0.70). CONCLUSION: High pre-diagnosis and post-diagnosis AMED was associated with an improved OS in patients with OC, suggesting that maintaining a consistently high intake of AMED could potentially benefit the prognosis of OC.


Subject(s)
Diet, Mediterranean , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/mortality , Ovarian Neoplasms/diet therapy , Prospective Studies , Middle Aged , Proportional Hazards Models , Survival Analysis , Adult , Kaplan-Meier Estimate , Aged
2.
Biochem J ; 479(23): 2433-2447, 2022 Dec 09.
Article in English | MEDLINE | ID: mdl-36416748

ABSTRACT

The KEOPS complex is an evolutionarily conserved protein complex in all three domains of life (Bacteria, Archaea, and Eukarya). In budding yeast Saccharomyces cerevisiae, the KEOPS complex (ScKEOPS) consists of five subunits, which are Kae1, Bud32, Cgi121, Pcc1, and Gon7. The KEOPS complex is an ATPase and is required for tRNA N6-threonylcarbamoyladenosine modification, telomere length maintenance, and efficient DNA repair. Here, recombinant ScKEOPS full complex and Kae1-Pcc1-Gon7 and Bud32-Cgi121 subcomplexes were purified and their biochemical activities were examined. KEOPS was observed to have ATPase and GTPase activities, which are predominantly attributed to the Bud32 subunit, as catalytically dead Bud32, but not catalytically dead Kae1, largely eliminated the ATPase/GTPase activity of KEOPS. In addition, KEOPS could hydrolyze ADP to adenosine or GDP to guanosine, and produce PPi, indicating that KEOPS is an ADP/GDP nucleotidase. Further mutagenesis characterization of Bud32 and Kae1 subunits revealed that Kae1, but not Bud32, is responsible for the ADP/GDP nucleotidase activity. In addition, the Kae1V309D mutant exhibited decreased ADP/GDP nucleotidase activity in vitro and shortened telomeres in vivo, but showed only a limited defect in t6A modification, suggesting that the ADP/GDP nucleotidase activity of KEOPS contributes to telomere length regulation.


Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Adenosine Triphosphatases/metabolism , Adenosine Diphosphate/metabolism , GTP Phosphohydrolases/metabolism
3.
Inorg Chem ; 61(49): 20159-20168, 2022 Dec 12.
Article in English | MEDLINE | ID: mdl-36450105

ABSTRACT

Two coordination polymers (CPs), namely, [Mn3(L)2(4,4'-bipy)2(H2O)2]n (1) and [Ni(L1)(1,4-bib)(H2O)]n (2) (H3L = 5-(3-bromo-4-carboxyphenoxy)isophthalic acid, H2L1 = 5-(3-hydroxyphenoxy)isophthalic acid, 4,4'-bpy = 4,4'-bipyridine, and 1,4-bib = 1,4-bis(1H-imidazol-1-yl)benzene), were synthesized under hydrothermal conditions. Most notably, with the help of the bromine atom-inducing effect, ligand transformation was observed in the structure of complex 2, which was scrutinized thoroughly by single crystal X-ray crystallography and X-ray photoelectron spectroscopy (XPS). Strikingly, Ni(II) ions were utilized as both coordinated atoms and as a catalyst for in situ Br-OH exchange of H3L in the process, as a result of which the product would have preferred to form a one-dimensional chain. The same reaction cannot happen in 1, leading to form a two-dimensional structure. Moreover, Ni(II)-catalyzed and magnetic exchange mechanisms were well interpreted using density functional theory (DFT) calculations. Finally, complexes 1-2 show three-dimensional (3D) supramolecular structures because of intermolecular weak interactions (C-Br···π, C-H···π, C-H···O, and π···π stacking) and exhibit utterly different antiferrimagnetic coupling interactions.


Subject(s)
Phthalic Acids , Models, Molecular , Density Functional Theory , Magnetic Phenomena
4.
Nucleic Acids Res ; 48(22): 12792-12803, 2020 12 16.
Article in English | MEDLINE | ID: mdl-33270890

ABSTRACT

Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.


Subject(s)
Adenosine Triphosphatases/genetics , Histone Acetyltransferases/genetics , Saccharomyces cerevisiae Proteins/genetics , Telomere Homeostasis/genetics , Chromatin/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Fungal/genetics , Histones/genetics , Humans , Multiprotein Complexes/genetics , Saccharomyces cerevisiae/genetics , Telomerase/genetics , Telomere/genetics , Telomere-Binding Proteins/genetics
5.
Nucleic Acids Res ; 47(11): 5684-5697, 2019 06 20.
Article in English | MEDLINE | ID: mdl-30937455

ABSTRACT

KEOPS complex is one of the most conserved protein complexes in eukaryotes. It plays important roles in both telomere uncapping and tRNA N6-threonylcarbamoyladenosine (t6A) modification in budding yeast. But whether KEOPS complex plays any roles in DNA repair remains unknown. Here, we show that KEOPS complex plays positive roles in both DNA damage response and homologous recombination-mediated DNA repair independently of its t6A synthesis function. Additionally, KEOPS displays DNA binding activity in vitro, and is recruited to the chromatin at DNA breaks in vivo, suggesting a direct role of KEOPS in DSB repair. Mechanistically, KEOPS complex appears to promote DNA end resection through facilitating the association of Exo1 and Dna2 with DNA breaks. Interestingly, inactivation of both KEOPS and Mre11/Rad50/Xrs2 (MRX) complexes results in synergistic defect in DNA resection, revealing that KEOPS and MRX have some redundant functions in DNA resection. Thus we uncover a t6A-independent role of KEOPS complex in DNA resection, and propose that KEOPS might be a DSB sensor to assist cells in maintaining chromosome stability.


Subject(s)
DNA Helicases/physiology , DNA, Fungal , Exodeoxyribonucleases/physiology , Homologous Recombination , Recombinational DNA Repair , Saccharomyces cerevisiae Proteins/physiology , Binding, Competitive , Chromatin/chemistry , DNA/chemistry , DNA Breaks, Double-Stranded , DNA Repair , DNA-Binding Proteins/metabolism , Endodeoxyribonucleases/metabolism , Exodeoxyribonucleases/metabolism , Metalloendopeptidases/metabolism , Mutation , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/metabolism , Telomere/metabolism , Transcription Factors/metabolism
6.
J Arthroplasty ; 35(10): 2892-2898, 2020 10.
Article in English | MEDLINE | ID: mdl-32466996

ABSTRACT

BACKGROUND: Recently, the practice of ordering routine postoperative laboratory tests in primary total hip arthroplasty (THA) has been challenged. This study aimed to evaluate the utility of routine postoperative laboratory tests after primary elective THA in an Asian population and identify the risk factors associated with abnormal postoperative laboratory test-related intervention. METHODS: We retrospectively reviewed 395 consecutive patients who underwent primary elective THA at a single tertiary academic center. Patient clinical information and laboratory test results were collected for analysis. RESULTS: A total of 349 (88.4%) patients had abnormal postoperative laboratory test results; most patients had anemia and hypoalbuminemia. Twenty-seven (6.8%) patients received clinical intervention. Of the 307 (77.7%) patients with postoperative anemia, 7 patients received blood transfusion. Factors associated with transfusion were female gender, low body mass index, long operation time, and low preoperative hemoglobin levels. Of the 149 (37.7%) patients with postoperative hypoalbuminemia, 16 received albumin supplementation. Factors associated with albumin supplementation were female gender, long operation time, and low preoperative albumin levels. Although 36 patients had abnormal postoperative creatinine, only 1 patient required specialist consultation. For electrolyte abnormalities, hyponatremia was noted; however, no patient received sodium supplementation. Moreover, 14 patients developed hypokalemia, of which 6 required potassium supplementation; 163 patients had hypocalcemia, of which 2 received calcium supplementation. CONCLUSION: Routine laboratory tests after primary elective THA are unnecessary for most of the patients in modern clinical practice. However, for those with identified risk factors, postoperative laboratory tests still should be performed.


Subject(s)
Arthroplasty, Replacement, Hip , Diagnostic Tests, Routine , Arthroplasty, Replacement, Hip/adverse effects , Blood Transfusion , Clinical Laboratory Techniques , Female , Humans , Postoperative Period , Retrospective Studies , Risk Factors
7.
J Orthop Traumatol ; 21(1): 19, 2020 Nov 10.
Article in English | MEDLINE | ID: mdl-33170383

ABSTRACT

BACKGROUND: Recent studies suggest that routine postoperative laboratory tests are not necessary after primary elective total hip arthroplasty (THA). This study aims to evaluate the utility of routine postoperative laboratory tests in patients undergoing THA for hip fracture in a semi-urgent clinical setting. MATERIALS AND METHODS: This retrospective study included 213 consecutive patients who underwent primary unilateral THA for hip fractures. Patient demographics, clinical information, and laboratory tests were obtained from the electronic medical record system. Multivariate logistic regression analysis was performed to identify risk factors associated with abnormal laboratory test-related interventions. RESULTS: A total of 207 patients (97.18%) had abnormal postoperative laboratory results, which were mainly due to anemia (190/213, 89.20%) and hypoalbuminemia (154/213, 72.30%). Overall, 54 patients (25.35%) underwent a clinical intervention, 18 patients received blood transfusion, and 42 patients received albumin supplementation. Factors associated with blood transfusion were long operative time and low preoperative hemoglobin levels. Factors associated with albumin supplementation were long operative time and low preoperative albumin levels. Of the 33 patients with abnormal postoperative creatinine levels, 7 patients underwent a clinical intervention. For electrolyte abnormalities, sodium supplementation was not given for hyponatremia, three patients received potassium supplementation, and one patient received calcium supplementation. CONCLUSIONS: This study demonstrated a high incidence of abnormal postoperative laboratory tests and a significant clinical intervention rate in patients who underwent THA for hip fracture in a semi-urgent clinical setting, which indicates that routine laboratory tests after THA for hip fracture are still necessary for patients with certain risk factors. LEVEL OF EVIDENCE: Level III. Trial registration Clinical trial registry number ChiCTR1900020690.


Subject(s)
Arthroplasty, Replacement, Hip , Diagnostic Tests, Routine , Hip Fractures/surgery , Aged , Aged, 80 and over , Anemia/diagnosis , Anemia/etiology , Anemia/therapy , Arthroplasty, Replacement, Hip/adverse effects , Blood Transfusion , Emergencies , Female , Hip Fractures/blood , Hip Fractures/complications , Humans , Hypoalbuminemia/diagnosis , Hypoalbuminemia/etiology , Hypoalbuminemia/therapy , Male , Middle Aged , Postoperative Care , Postoperative Complications/diagnosis , Postoperative Complications/therapy , Postoperative Period , Retrospective Studies , Risk Factors
8.
Dalton Trans ; 53(2): 582-590, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38059743

ABSTRACT

Photodynamic therapy provides a promising solution for treating various cancer types. In this study, three distinct asymmetric porphyrin-cisplatin complex photosensitizers (ZnPt-P1, ZnPt-P2, and ZnPt-P3) were synthesized, each having unique side chains. Through a set of experiments involving singlet oxygen detection and density functional theory, ZnPt-P1 was demonstrated to have excellent efficacy, exceeding that of ZnPt-P2 and ZnPt-P3. Notably, ZnPt-1 showed significant phototoxicity while maintaining low dark toxicity when tested on HepG2 cells. Additionally, further examination revealed that ZnPt-P1 had the capability to generate reactive oxygen species within cancer cells when exposed to light irradiation. Taken together, these results highlight the potential of ZnPt-P1 as a photosensitizer for use in photodynamic therapy. This study contributes to enhancing cancer treatment methodologies and provides insights for the future development of innovative drugs for photosensitization.


Subject(s)
Photochemotherapy , Porphyrins , Photosensitizing Agents , Cisplatin/pharmacology , Porphyrins/chemistry , Singlet Oxygen/chemistry
9.
Int J Biol Macromol ; 273(Pt 2): 133162, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38878925

ABSTRACT

Calcium ß-hydroxy-ß-methylbutyrate (CaHMB), a functional calcium salt, is used to maintain and improve muscle health. Here, a new hydrogel material prepared from alginate (ALG) with three M/G ratios (1:1, 2:1, and 1:2) and CaHMB (0-2 mg/mL) was investigated. CaHMB regulates the formation and properties of ALG hydrogels through chelation and hydrogen bonding. When the M/G ratio was 2:1, the anionic groups of CaHMB containing carboxyl and hydroxyl groups formed hydrogen bonds with the polysaccharide chains, hindering the capture of Ca2+ by the G-residue fragments of ALG, which in turn retarded the gelation process. The noncalcium cross-linked polysaccharide chain structure of ALG and the anionic group of CaHMB also affected the water distribution in the hydrogel, especially when M residue content ≥G residue content. Lower M/G ratios and higher CaHMB concentrations could increase the number of "egg box" crosslinking junctions of calcium alginate, and the microstructure was denser in the gel pores, resulting in a stronger gel strength and more free water bound in the gel matrix. This study provides a theoretical and methodological basis for the design of novel hydrogels by studying the crosslinking features of ALG/CaHMB.


Subject(s)
Alginates , Calcium , Hydrogels , Alginates/chemistry , Hydrogels/chemistry , Calcium/chemistry , Valerates/chemistry , Ions/chemistry , Hydrogen Bonding , Water/chemistry
10.
Biomed Pharmacother ; 179: 117311, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39182322

ABSTRACT

The underlying mechanisms of diseases affecting the central nervous system (CNS) remain unclear, limiting the development of effective therapeutic strategies. Remarkably, cellular senescence, a biological phenomenon observed in cultured fibroblasts in vitro, is a crucial intrinsic mechanism that influences homeostasis of the brain microenvironment and contributes to the onset and progression of CNS diseases. Cellular senescence has been observed in disease models established in vitro and in vivo and in bodily fluids or tissue components from patients with CNS diseases. These findings highlight cellular senescence as a promising target for preventing and treating CNS diseases. Consequently, emerging novel therapies targeting senescent cells have exhibited promising therapeutic effects in preclinical and clinical studies on aging-related diseases. These innovative therapies can potentially delay brain cell loss and functional changes, improve the prognosis of CNS diseases, and provide alternative treatments for patients. In this study, we examined the relevant advancements in this field, particularly focusing on the targeting of senescent cells in the brain for the treatment of chronic neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis) and acute neurotraumatic insults (e.g., ischemic stroke, spinal cord injury, and traumatic brain injury).


Subject(s)
Cellular Senescence , Central Nervous System Diseases , Humans , Cellular Senescence/drug effects , Animals , Central Nervous System Diseases/pathology , Central Nervous System Diseases/drug therapy , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/pathology , Brain/pathology , Brain/drug effects , Brain/metabolism
11.
Biomaterials ; 311: 122664, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38889597

ABSTRACT

In order to guide the formulation of post-stroke treatment strategy in time, it is necessary to have real-time feedback on collateral circulation and revascularization. Currently used near-infrared II (NIR-II) probes have inherent binding with endogenous albumin, resulting in significant background signals and uncontrollable pharmacokinetics. Therefore, the albumin-escaping properties of the new probe, IR-808AC, was designed, which achieved timely excretion and low background signal, enabling the short-term repeatable injection for visualization of cerebral vessels and perfusion. We further achieved continuous observation of changes in collateral vessels and perfusion during the 7-d period in middle cerebral artery occlusion mice using IR-808AC in vivo. Furthermore, using IR-808AC, we confirmed that remote ischemic conditioning could promote collateral vessels and perfusion. Finally, we evaluated the revascularization after thrombolysis on time in embolic stroke mice using IR-808AC. Overall, our study introduces a novel methodology for safe, non-invasive, and repeatable assessment of collateral circulation and revascularization in real-time that is crucial for the optimization of treatment strategies.


Subject(s)
Disease Models, Animal , Stroke , Animals , Stroke/diagnostic imaging , Mice , Male , Perfusion Imaging/methods , Cerebral Arteries/diagnostic imaging , Mice, Inbred C57BL , Albumins/chemistry , Infarction, Middle Cerebral Artery/diagnostic imaging , Spectroscopy, Near-Infrared/methods , Collateral Circulation
12.
Cancers (Basel) ; 16(17)2024 Aug 23.
Article in English | MEDLINE | ID: mdl-39272801

ABSTRACT

BACKGROUND: Currently, prostate cancer (PCa) prebiopsy medical image diagnosis mainly relies on mpMRI and PI-RADS scores. However, PI-RADS has its limitations, such as inter- and intra-radiologist variability and the potential for imperceptible features. The primary objective of this study is to evaluate the effectiveness of a machine learning model based on radiomics analysis of MRI T2-weighted (T2w) images for predicting PCa in prebiopsy cases. METHOD: A retrospective analysis was conducted using 820 lesions (363 cases, 457 controls) from The Cancer Imaging Archive (TCIA) Database for model development and validation. An additional 83 lesions (30 cases, 53 controls) from Hong Kong Queen Mary Hospital were used for independent external validation. The MRI T2w images were preprocessed, and radiomic features were extracted. Feature selection was performed using Cross Validation Least Angle Regression (CV-LARS). Using three different machine learning algorithms, a total of 18 prediction models and 3 shape control models were developed. The performance of the models, including the area under the curve (AUC) and diagnostic values such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were compared to the PI-RADS scoring system for both internal and external validation. RESULTS: All the models showed significant differences compared to the shape control model (all p < 0.001, except SVM model PI-RADS+2 Features p = 0.004, SVM model PI-RADS+3 Features p = 0.002). In internal validation, the best model, based on the LR algorithm, incorporated 3 radiomic features (AUC = 0.838, sensitivity = 76.85%, specificity = 77.36%). In external validation, the LR (3 features) model outperformed PI-RADS in predictive value with AUC 0.870 vs. 0.658, sensitivity 56.67% vs. 46.67%, specificity 92.45% vs. 84.91%, PPV 80.95% vs. 63.64%, and NPV 79.03% vs. 73.77%. CONCLUSIONS: The machine learning model based on radiomics analysis of MRI T2w images, along with simulated biopsy, provides additional diagnostic value to the PI-RADS scoring system in predicting PCa.

13.
J Tissue Eng ; 15: 20417314241237052, 2024.
Article in English | MEDLINE | ID: mdl-38481708

ABSTRACT

The incidence of ischemic stroke (IS) is rising in tandem with the global aging population. There is an urgent need to delve deeper into the pathological mechanisms and develop new neuroprotective strategies. In the present review, we discuss the latest advancements and research on various nanodrug delivery systems (NDDSs) for targeting microglial polarization in IS treatment. Furthermore, we critically discuss the different strategies. NDDSs have demonstrated exceptional qualities to effectively permeate the blood-brain barrier, aggregate at the site of ischemic injury, and target specific cell types within the brain when appropriately modified. Consequently, NDDSs have considerable potential for reshaping the polarization phenotype of microglia and could be a prospective therapeutic strategy for IS. The treatment of IS remains a challenge. However, this review provides a new perspective on neuro-nanomedicine for IS therapies centered on microglial polarization, thereby inspiring new research ideas and directions.

14.
Food Funct ; 15(16): 8408-8417, 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39040017

ABSTRACT

Background: Previous studies on the association between diet quality and ovarian cancer (OC) survival are limited and inconsistent. We evaluated the relationship between pre- and post-diagnosis diet quality based on the Healthy Eating Index-2020 (HEI-2020), as well as their changes and OC survival. Methods: This prospective cohort study involved 1082 patients with OC aged 18-79 years, enrolled between 2015 and 2022. Detailed dietary intake before and after diagnosis was recorded using a validated food frequency questionnaire. Deaths were ascertained until February 16th, 2023 via medical records and active follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: We included 549 OC cases with a median follow-up of 44.9 months, representing 206 total deaths. Higher HEI scores were associated with better OS (pre-diagnosis: HRT3 vs. T1 0.66, 95%CI: 0.46-0.93, HR1-SD 0.84, 95%CI: 0.73-0.96; post-diagnosis: HRT3 vs. T1 0.68, 95%CI: 0.49-0.96, HR1-SD 0.80, 95%CI: 0.69-0.92). Compared to the stable group, the group with decreased HEI scores (>3%) from pre- to post-diagnosis had worse OS (HR 1.93, 95%CI: 1.26-2.97). Conclusion: High pre- and post-diagnosis diet quality was associated with improved OC survival, whereas deterioration in diet quality after diagnosis was associated with decreased OC survival.


Subject(s)
Diet, Healthy , Ovarian Neoplasms , Humans , Female , Middle Aged , Prospective Studies , Adult , Ovarian Neoplasms/mortality , Aged , Adolescent , Young Adult , Proportional Hazards Models
15.
J Hazard Mater ; 472: 134556, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38735187

ABSTRACT

BACKGROUND: Although evidence on the association between per- and polyfluoroalkyl substances (PFASs) and human health outcomes has grown exponentially, specific health outcomes and their potential associations with PFASs have not been conclusively evaluated. METHODS: We conducted a comprehensive search through the databases of PubMed, Embase, and Web of Science from inception to February 29, 2024, to identify systematic reviews with meta-analyses of observational studies examining the associations between the PFASs and multiple health outcomes. The quality of included studies was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool, and credibility of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The protocol of this umbrella review (UR) had been registered in PROSPERO (CRD 42023480817). RESULTS: The UR identified 157 meta-analyses from 29 articles. Using the AMSTAR measurement tool, all articles were categorized as of moderate-to-high quality. Based on the GRADE assessment, significant associations between specific types of PFASs and low birth weight, tetanus vaccine response, and triglyceride levels showed high certainty of evidence. Moreover, moderate certainty of evidence with statistical significance was observed between PFASs and health outcomes including lower BMI z-score in infancy, poor sperm progressive motility, and decreased risk of preterm birth as well as preeclampsia. Fifty-two (33%) associations (e.g., PFASs and gestational hypertension, cardiovascular disease, etc) presented low certainty evidence. Additionally, eighty-five (55%) associations (e.g., PFASs with infertility, lipid metabolism, etc) presented very low certainty evidence. CONCLUSION: High certainty of evidence supported that certain PFASs were associated with the incidence of low birth weight, low efficiency of the tetanus vaccine, and low triglyceride levels.


Subject(s)
Fluorocarbons , Systematic Reviews as Topic , Humans , Pregnancy , Observational Studies as Topic , Meta-Analysis as Topic , Infant, Low Birth Weight , Female , Environmental Pollutants , Tetanus Toxoid , Triglycerides/blood
16.
bioRxiv ; 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38979269

ABSTRACT

Genome editing is poised to revolutionize treatment of genetic diseases, but poor understanding and control of DNA repair outcomes hinders its therapeutic potential. DNA repair is especially understudied in nondividing cells like neurons, which must withstand decades of DNA damage without replicating. This lack of knowledge limits the efficiency and precision of genome editing in clinically relevant cells. To address this, we used induced pluripotent stem cells (iPSCs) and iPSC-derived neurons to examine how postmitotic human neurons repair Cas9-induced DNA damage. We discovered that neurons can take weeks to fully resolve this damage, compared to just days in isogenic iPSCs. Furthermore, Cas9-treated neurons upregulated unexpected DNA repair genes, including factors canonically associated with replication. Manipulating this response with chemical or genetic perturbations allowed us to direct neuronal repair toward desired editing outcomes. By studying DNA repair in postmitotic human cells, we uncovered unforeseen challenges and opportunities for precise therapeutic editing.

17.
Cell Res ; 34(10): 707-724, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39103524

ABSTRACT

The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.


Subject(s)
Chromatin , Histones , Nucleosomes , Nucleosomes/metabolism , Nucleosomes/ultrastructure , Nucleosomes/chemistry , Histones/metabolism , Histones/chemistry , Chromatin/metabolism , Chromatin/chemistry , Cryoelectron Microscopy , Protein Binding , Models, Molecular
18.
Radiology ; 266(1): 261-70, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23047839

ABSTRACT

PURPOSE: To investigate whether resting-state brain functional connectivity (FC) differed among cirrhotic patients without overt hepatic encephalopathy (HE) (OHE), those who currently had minimal HE (MHE), or those who had recovered from previous OHE and to investigate whether previous bouts of OHE rather than current MHE predominantly contributed to brain dysfunction in patients without current OHE. MATERIALS AND METHODS: This study was approved by the institutional ethics committee, and informed consent was obtained. Resting-state functional magnetic resonance (MR) data were compared between healthy controls and the following groups of cirrhotic patients: (a) patients without MHE and without previous OHE, (b) patients with current MHE and without previous OHE, and (c) patients with previous OHE. Independent component analysis was applied to identify the best-fit component for the default-mode network (DMN). One-way analysis of variance was performed to detect different FC among groups. Pearson correlation analyses were conducted to determine the relationships between FC and neurocognitive performance. RESULTS: Two important regions within the DMN, including the precuneus and posterior cingulate cortex and left medial frontal gyrus, showed significantly different FC among the four groups. A trend of gradually reduced FC in two regions was observed from controls, to patients without HE, and to patients with current MHE, while patients with previous OHE showed remarkably reduced FC in these two regions. Significant correlations were found between FC and neurocognitive performance in cirrhotic patients. CONCLUSION: The reduced resting-state FC within DMN was associated with neurocognitive impairments in MHE and after clinical resolution of OHE. Previous OHE rather than current MHE might be primarily related to brain dysfunction in patients with latent OHE. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120026/-/DC1.


Subject(s)
Brain Mapping/methods , Brain/physiopathology , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Hepatic Encephalopathy/complications , Hepatic Encephalopathy/physiopathology , Magnetic Resonance Imaging/methods , Brain/pathology , Cognition Disorders/diagnosis , Female , Hepatic Encephalopathy/diagnosis , Humans , Male , Middle Aged , Reproducibility of Results , Sensitivity and Specificity , Severity of Illness Index
19.
Acta Crystallogr C ; 69(Pt 4): 356-9, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23579705

ABSTRACT

A one-dimensional Ag(I) coordination complex, catena-poly[[silver(I)-µ-{2-[2-(pyridin-4-yl)-1H-benzimidazol-1-ylmethyl]phenol-κ(2)N(2):N(3)}] perchlorate monohydrate], {[Ag(C19H15N3O)]ClO4·H2O}n, was synthesized by the reaction of 2-[2-(pyridin-4-yl)-1H-benzimidazol-1-ylmethyl]phenol (L) with silver perchlorate. In the complex, the L ligands are arranged alternately and link Ag(I) cations through one benzimidazole N atom and the N atom of the pyridine ring, leading to an extended zigzag chain structure. In addition, the one-dimensional chains are extended into a three-dimensional supramolecular architecture via O-H···O hydrogen-bond interactions and π-π stacking interactions. The complex exhibits photoluminescence in acetonitrile solution, with an emission maximum at 390 nm, and investigation of the thermal stability reveals that the network structure is stable up to 650 K.


Subject(s)
Benzimidazoles/chemistry , Organometallic Compounds/chemistry , Pyridines/chemistry , Silver/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Ligands , Models, Molecular
20.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 3): m134, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23476484

ABSTRACT

In the title complex, [Cd(C13H8N5)2(C2H5OH)2], the Cd(II) cation is located on an inversion center and coordinated by two deprotonated 2-(1H-benzotriazol-1-yl)-1H-benzimid-azol-1-ide (L) ligands and two ethanol mol-ecules in a distorted N4O2 octa-hedral geometry. In the L ligand, the dihedral angle between benzoimidazole and benzotriazole ring systems is 10.8 (3)°. In the crystal, the complex mol-ecules are connected by O-H⋯N hydrogen bonds; inter-molecular π-π stacking is also observed [centroid-centroid distances of 3.668 (5) Šbetween triazole and benzene rings and 3.780 (5) Šbetween imidazole rings].

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