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1.
J Clin Invest ; 2024 May 14.
Article in English | MEDLINE | ID: mdl-38743486

ABSTRACT

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high L-2HG kidney cancers demonstrates reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.

2.
Transl Stroke Res ; 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38558011

ABSTRACT

Intracerebral hemorrhage (ICH) is the most serious form of stroke and has limited available therapeutic options. As knowledge on ICH rapidly develops, cutting-edge techniques in the fields of surgical robots, regenerative medicine, and neurorehabilitation may revolutionize ICH treatment. However, these new advances still must be translated into clinical practice. In this review, we examined several emerging therapeutic strategies and their major challenges in managing ICH, with a particular focus on innovative therapies involving robot-assisted minimally invasive surgery, stem cell transplantation, in situ neuronal reprogramming, and brain-computer interfaces. Despite the limited expansion of the drug armamentarium for ICH over the past few decades, the judicious selection of more efficacious therapeutic modalities and the exploration of multimodal combination therapies represent opportunities to improve patient prognoses after ICH.

3.
J Dent Sci ; 19(2): 1087-1095, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38618132

ABSTRACT

Background/purpose: Healthy states of human microbiota depend on a stable community of symbiotic microbes irrespective of external challenges from the environment. Thus, long-term stability of the oral microbiota is of importance, particularly for older patient populations. Materials and methods: We used next-generation sequencing (NGS) to examine the tongue microbiota of 18 individuals receiving long-term care over a 10-month period. Results: Beta diversity analysis demonstrated temporal stability of the tongue microbiota, as microbial compositions from all time points were indistinguishable from each other (P = 0.0887). However, significant individual variation in microbial composition (P = 0.0001) was observed, underscoring the presence of a unique microbial profile for each patient. Conclusion: The temporal dynamics of tongue microbiota exhibit long-term stability, providing diagnostic implications for oral diseases within older patient populations.

4.
Article in English | MEDLINE | ID: mdl-38651245

ABSTRACT

Zinpentraxin alfa is a recombinant form of the human pentraxin-2 that was studied in idiopathic pulmonary fibrosis (IPF). To improve the purity and yield of the drug material, a 2nd-generation drug product was developed. To characterize and compare the pharmacokinetic (PK) properties of the 1st- and 2nd-generation zinpentraxin alfa, PK studies were conducted in healthy volunteers (HVs). In a phase 1 randomized, double-blind, 2-sequence crossover, sequential 2-stage study (ISRCTN59409907), single intravenous (IV) doses of 1st- and 2nd-generation zinpentraxin alfa at 10 mg/kg were studied with a blinded interim analysis (IA) at the end of stage 1. Bioequivalence (BE) was achieved for the maximum observed plasma concentration (Cmax), but the overall exposure was higher for the 2nd- compared to the 1st-generation zinpentraxin alfa. The study was stopped after stage 1 as the gating criteria were met based on the result of the blinded IA. Safety profiles were similar for the 1st- and 2nd-generation drug products, and antidrug antibody (ADA) was not observed in this study.

5.
Int J Biol Macromol ; 267(Pt 2): 131665, 2024 May.
Article in English | MEDLINE | ID: mdl-38636758

ABSTRACT

Micropolymorphism significantly shapes the peptide-binding characteristics of major histocompatibility complex class I (MHC-I) molecules, affecting the host's resistance to pathogens, which is particularly pronounced in avian species displaying the "minimal essential MHC" expression pattern. In this study, we compared two duck MHC-I alleles, Anpl-UAA*77 and Anpl-UAA*78, that exhibit markedly different peptide binding properties despite their high sequence homology. Through mutagenesis experiments and crystallographic analysis of complexes with the influenza virus-derived peptide AEAIIVAMV (AEV9), we identified a critical role for the residue at position 62 in regulating hydrogen-bonding interactions between the peptide backbone and the peptide-binding groove. This modulation affects the characteristics of the B pocket and the stability of the loop region between the 310 helix and the α1 helix, leading to significant changes in the structure and stability of the peptide-MHC-I complex (pMHC-I). Moreover, the proportion of different residues at position 62 among Anpl-UAAs may reflect the correlation between pAnpl-UAA stability and duck body temperature. This research not only advances our understanding of the Anpl-UAA structure but also deepens our insight into the impact of MHC-I micropolymorphism on peptide binding.


Subject(s)
Ducks , Histocompatibility Antigens Class I , Animals , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/metabolism , Peptides/chemistry , Peptides/genetics , Polymorphism, Genetic , Protein Stability , Amino Acid Sequence , Protein Binding , Alleles , Antigen Presentation , Models, Molecular
6.
Org Lett ; 26(18): 3997-4001, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38687048

ABSTRACT

The radical decarboxylative azidation of structurally diverse uronic acids has been established as an efficient approach to reverse glycosyl azides and rare sugar-derived glycosyl azides under the action of Ag2CO3, 3-pyridinesulfonyl azide, and K2S2O8. The power of this method has been highlighted by the divergent synthesis of 4'-C-azidonucleosides using Vorbrüggen glycosylation of nucleobases with 4-C-azidofuranosyl acetates. The antiviral assessment of the resulting nucleosides revealed one compound as a potential inhibitor of covalently closed circular DNA.


Subject(s)
Antiviral Agents , Azides , Nucleosides , Azides/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Molecular Structure , Nucleosides/chemistry , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Glycosylation
7.
Brain Sci ; 14(4)2024 Mar 30.
Article in English | MEDLINE | ID: mdl-38671995

ABSTRACT

Emotion recognition using the electroencephalogram (EEG) has garnered significant attention within the realm of human-computer interaction due to the wealth of genuine emotional data stored in EEG signals. However, traditional emotion recognition methods are deficient in mining the connection between multi-domain features and fitting their advantages. In this paper, we propose a novel capsule Transformer network based on a multi-domain feature for EEG-based emotion recognition, referred to as MES-CTNet. The model's core consists of a multichannel capsule neural network(CapsNet) embedded with ECA (Efficient Channel Attention) and SE (Squeeze and Excitation) blocks and a Transformer-based temporal coding layer. Firstly, a multi-domain feature map is constructed by combining the space-frequency-time characteristics of the multi-domain features as inputs to the model. Then, the local emotion features are extracted from the multi-domain feature maps by the improved CapsNet. Finally, the Transformer-based temporal coding layer is utilized to globally perceive the emotion feature information of the continuous time slices to obtain a final emotion state. The paper fully experimented on two standard datasets with different emotion labels, the DEAP and SEED datasets. On the DEAP dataset, MES-CTNet achieved an average accuracy of 98.31% in the valence dimension and 98.28% in the arousal dimension; it achieved 94.91% for the cross-session task on the SEED dataset, demonstrating superior performance compared to traditional EEG emotion recognition methods. The MES-CTNet method, utilizing a multi-domain feature map as proposed herein, offers a broader observation perspective for EEG-based emotion recognition. It significantly enhances the classification recognition rate, thereby holding considerable theoretical and practical value in the EEG emotion recognition domain.

8.
J Am Chem Soc ; 146(17): 11811-11822, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38635880

ABSTRACT

The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.


Subject(s)
Anti-Inflammatory Agents , Glycosides , Steroids , Glycosides/chemistry , Glycosides/chemical synthesis , Glycosides/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Steroids/chemistry , Steroids/pharmacology , Steroids/chemical synthesis , Mice , Animals , Humans , Density Functional Theory , Molecular Structure , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Macrophages/drug effects
9.
Front Immunol ; 15: 1295305, 2024.
Article in English | MEDLINE | ID: mdl-38481990

ABSTRACT

Introduction: Ubiquitination is a crucial biological mechanism in humans, essential for regulating vital biological processes, and has been recognized as a promising focus for cancer therapy. Our objective in this research was to discover potential enzymes associated with ubiquitination that may serve as therapeutic targets for individuals with esophageal carcinoma (ESCA). Methods: To identify genes linked to the prognosis of ESCA, we examined mRNA sequencing data from patients with ESCA in the TCGA database. Further investigation into the role of the candidate gene in ESCA was conducted through bioinformatic analyses. Subsequently, we carried out biological assays to assess its impact on ESCA development. Results: Through univariate Cox regression analysis, we identified Ubiquitin Conjugating Enzyme E2 B (UBE2B) as a potential gene associated with the prognosis of ESCA. UBE2B exhibited significant upregulation and was found to be correlated with survival outcomes in ESCA as well as other cancer types. Additionally, UBE2B was observed to be involved in various biological pathways linked to the development of ESCA, including TNF-a signaling via NF-κB, epithelial-mesenchymal transition, inflammatory response, and hypoxia. Moreover, immune-related pathways like B cell activation (GO: 0042113), B cell receptor signaling pathway (GO: 0050853) and B cell mediated immunity (GO:0019724) were also involved. It was found that high expression of UBE2B was correlated with the increase of several kinds of T cells (CD8 T cells, Th1 cells) and macrophages, while effector memory T cell (Tem) and Th17 cells decreased. Furthermore, UBE2B showed potential as a prognostic biomarker for ESCA, displaying high sensitivity and specificity. Notably, proliferation and migration in ESCA cells were effectively suppressed when the expression of UBE2B was knocked down. Conclusions: To summarize, this study has made a discovery regarding the importance of gaining new insights into the role of UBE2B in ESCA. UBE2B might be an oncogene with good ability in predicting and diagnosing ESCA. Consequently, this discovery highlights the feasibility of targeting UBE2B as a viable approach for treating patients with ESCA.


Subject(s)
Carcinoma , Esophageal Neoplasms , Humans , Prognosis , Oncogenes , B-Lymphocytes , Esophageal Neoplasms/genetics , Biomarkers , Ubiquitin-Conjugating Enzymes/genetics
10.
J Am Chem Soc ; 146(11): 7400-7407, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38456799

ABSTRACT

Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assembly. Existing TGase inhibitors like moenomycin and Lipid II analogues always occupy the TGase active sites; other strategies to interfere with proper PG elongation have not been widely exploited. Inspired by the natural 1,6-anhydro-MurNAc termini that mark the ends of PG strands in bacteria, we hypothesized that the incorporation of an anhydromuramyl-containing glycosyl acceptor by TGase into the growing PG may effectively inhibit PG elongation. To explore this possibility, we synthesized 4-O-(N-acetyl-ß-d-glucosaminyl)-1,6-anhydro-N-acetyl-ß-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, and demonstrated that this anhydromuropeptide and its analogue lacking the peptide, 1-deAA, were both utilized by bacterial TGase as noncanonical anhydro glycosyl acceptors in vitro. The incorporation of an anhydromuramyl moiety into PG strands by TGases afforded efficient termination of glycan chain extension. Moreover, the preliminary in vitro studies of 1-deAA against Staphylococcus aureus showed that 1-deAA served as a reasonable antimicrobial adjunct of vancomycin. These insights imply the potential application of such anhydromuropeptides as novel classes of PG-terminating inhibitors, pointing toward novel strategies in antibacterial agent development.


Subject(s)
Anti-Bacterial Agents , Peptidoglycan , Peptidoglycan/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/metabolism , Glycosyltransferases/metabolism
11.
BMC Med Educ ; 24(1): 289, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38491384

ABSTRACT

BACKGROUND: Practicing and assessment of selective caries removal techniques in dental students remain challenges in many dental schools. The aim of this study was to utilize a 3D assessment technique, within a designated acceptable range of deviation, to evaluate the tendency of dental students in performing selective caries removal (SCR). The correlation between 3D assessment results and the conventional rubric rated by an instructor was also determined. METHODS: Fifth-year dental students (n = 61) performed the SCR task on 3D-printed teeth containing simulated deep caries lesions in occlusal and proximal surfaces. One instructor assessed the results using a conventional analytic rubric. The excavated teeth were additionally evaluated using 3D analysis software with the designated acceptable range of deviations (± 0.5 mm) from the standard cavities. The average root mean square (RMS) value, representing the deviation between student-prepared cavities and the predefined standard cavities, was recorded. A tendency towards over-excavation was defined for RMS values > 0.5 mm, and towards under-excavation for RMS values < 0.5 mm. RESULTS: The mean (min-max) of RMS was 0.27 (0.18-0.40) for occlusal and 0.29 (0.20-0.57)for proximal cavities. A tendency of dental students toward over-excavation was observed in both occlusal (74%) and proximal cavities (87%). There was a moderate negative correlation between the RMS values and the traditional rubric scores for both occlusal (R2 = 0.148, P = 0.002) and proximal cavities (R2 = 0.107, P = 0.010). CONCLUSIONS: The 3D evaluation technique effectively revealed specific tendencies in dental students' caries removal skills. The integration of computerized assessments with traditional methods could potentially assist the instructors in delivering more objective and specific feedback to students. Further research is encouraged to investigate the impact of this assessment technique on improving student performance in selective caries removal skills.


Subject(s)
Dental Caries Susceptibility , Students, Dental , Humans , Pilot Projects , Software
12.
Chem Sci ; 15(10): 3711-3720, 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38455029

ABSTRACT

We herein present a strain-release glycosylation method employing a rationally designed ortho-2,2-dimethoxycarbonylcyclopropylbenzyl (CCPB) thioglycoside donor. The donor is activated through the nucleophilic ring-opening of a remotely activable donor-acceptor cyclopropane (DAC) catalyzed by mild Sc(OTf)3. Our new glycosylation method efficiently synthesizes O-, N-, and S-glycosides, providing facile chemical access to the challenging S-glycosides. Because the activation conditions of conventional glycosyl donors and our CCPB thioglycoside are orthogonal, our novel donor is amenable to controlled one-pot glycosylation reactions with conventional donors for expeditious access to complex glycans. The strain-release glycosylation is applied to the assembly of a tetrasaccharide of O-polysaccharide of Escherichia coli O-33 in one pot and the synthesis of a 1,1'-S-linked glycoside oral galectin-3 (Gal-3) inhibitor, TD139, to demonstrate the versatility and effectiveness of the novel method for constructing both O- and S-glycosides.

13.
bioRxiv ; 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38352483

ABSTRACT

Pseudouridylation is a prevalent post-transcriptional RNA modification that impacts many aspects of RNA biology and function. The conversion of uridine to pseudouridine (Ψ) is catalyzed by the family of pseudouridine synthases (PUSs). Development of robust methods to determine PUS-dependent regulation of Ψ location and stoichiometry in low abundant mRNA is essential for biological and functional understanding of pseudouridylation. Here, we present a framework, NanoPsiPy, for identifying Ψ sites and quantify their levels in poly-A RNA at single-nucleotide resolution using direct RNA long-read Nanopore sequencing, based on the observation that Ψ can cause characteristic U-to-C basecalling errors in Nanopore direct RNA sequencing data. Our method was able to detect low and high stoichiometric Ψ sites in human mRNA. We validated our method by transcriptome-wide quantitative profiling of PUS7-dependent Ψ sites in poly-A RNA from a MYCN -amplified neuroblastoma cell line. We identified 8,625 PUS7-dependent Ψ sites in 1,246 mRNAs that encode proteins involved primarily in ribosome biogenesis, translation, and mitochondrial energy metabolism. Our work provides the first example of using direct RNA long-read Nanopore sequencing for transcriptome-wide quantitative profiling of mRNA pseudouridylation regulated by a PUS. We envision that our method will facilitate functional interrogation of PUSs in biological and pathological processes.

14.
J Neurosurg ; : 1-11, 2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38364227

ABSTRACT

OBJECTIVE: The authors performed a further in-depth study of the lateral compartment of the cavernous sinus (LCCS) by the endoscopic endonasal approach to improve the safety and efficacy of the lateral approach for the removal of Knosp grade 4 pituitary adenomas (KG4PAs). METHODS: Twenty-three cadaveric specimens were used for endoscopic endonasal dissection, and the LCCS was exposed to observe the neurovascular and fibrous structures within. A subclassification of the lateral approach based on further knowledge of the LCCS was proposed and used to resect 86 KG4PAs, and the surgical outcomes of these cases were reviewed. Type A KG4PAs represent tumor that was mainly distributed in the posterosuperior and superolateral compartments, type B KG4PAs represent tumor that was mainly distributed in the anteroinferior compartments, and type AB KG4PAs represent tumor that extended into each compartment with characteristics of types 4A and 4B. RESULTS: The authors identified multiple fibers that anchored the horizontal segment of the internal carotid artery (ICA) to the abducens nerve. The fibers, the sympathetic nerve, and the inferior lateral trunk form a partition-like structure in the LCCS named the abducens nerve-ICA complex (AIC), and the LCCS can be divided into the superolateral and inferolateral compartments by the AIC. Accordingly, the lateral approach was subclassified into the lateral superior (LS) approach and the anterior inferior (AI) approach. The LS approach was mainly used to resect type A KG4PAs, whereas the AI approach was used to resect type B KG4PAs, and a combination of the two was used to resect type AB KG4PAs. The gross-total, subtotal, and partial resection rates were 81.4%, 12.8%, and 5.8%, respectively. The numbers of cases of postoperative transient cranial nerve palsy, postoperative permanent cranial nerve palsy, ICA injury, and CSF leakage were 6 (6.9%), 2 (2.3%), 1 (1.2%), and 1 (1.2%), respectively. CONCLUSIONS: This study revealed that the LCCS is divided by the AIC into the superolateral and inferolateral compartments, avoiding the misconception that the LCCS has vertical communication. Therefore, the lateral approach was subclassified into the LS approach and the AI approach for the resection of KG4PAs, which allowed a high gross-total resection rate with acceptable safety in the surgical treatment of KG4PAs.

15.
Sci Rep ; 14(1): 3214, 2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38332171

ABSTRACT

In recent decades, rising air temperatures (AT) and apparent temperatures (AP) have posed growing health risks. In the context of China's rapid urbanization and global climate change, it is crucial to understand the impact of urban land use/land cover (LULC) changes on AP. This study investigates the spatial distribution and long-term variation patterns of AT and AP, using data from 834 meteorological stations across China from 1996 to 2020. It also explores the relationship between AT, AP, and LULC in the urban core areas of 30 major cities. Study reveals that AT and AP exhibit overall high spatial similarity, albeit with greater spatial variance in AP. Notably, regions with significant disparities between the two have been identified. Furthermore, it's observed that the spatial range of high AP change rates is wider than that of AT. Moreover, the study suggests a potential bivariate quadratic function relationship between ΔT (the difference between AT and AP) and Wa_ratio and Ar_ratio, indicating the presence of a Least Suitable Curve (LSC), [Formula: see text]. Urban LULC planning should carefully avoid intersecting with this curve. These findings can provide valuable insights for urban LULC planning, ultimately enhancing the thermal comfort of urban residents.

16.
Nat Commun ; 15(1): 1491, 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38374180

ABSTRACT

Mimicking living creatures, soft robots exhibit incomparable adaptability and various attractive new features. However, untethered insect-scale soft robots are often plagued with inferior controllability and low kinetic performance. Systematically inspired by the swift swingable abdomen, conducting canals for secretion transport, and body setae of Stenus comma, together with magnetic-induced fast-transformed postures, herein, we present a swift, agile untethered millimetre-scale soft propulsor propelling on water. The demonstrated propulsor, with a body length (BL) of 3.6 mm, achieved a recorded specific speed of ~201 BL/s and acceleration of ~8,372 BL/s2. The comprehensive kinetic performance of this propulsor surpasses those of previous ones at similar scales by several orders. Notably, we discovered momentum-transfer-induced over-biological on-demand braking (deceleration ~-5,010 BL/s2) and elucidated the underlying hydrodynamics. This work offers new insights into systematically bio-inspired artificial insect-scale soft robots, enabling them to push boundaries in performance, and potentially revolutionizing robot design, optimization, and control paradigms.


Subject(s)
Coleoptera , Animals , Insecta , Birds , Acceleration , Hydrodynamics
17.
J Pharmacokinet Pharmacodyn ; 51(2): 141-153, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37864000

ABSTRACT

Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration-time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified.


Subject(s)
C-Reactive Protein , Inflammatory Bowel Diseases , Humans , Body Weight , Models, Biological
18.
J Interpers Violence ; 39(1-2): 393-413, 2024 01.
Article in English | MEDLINE | ID: mdl-37698135

ABSTRACT

Child maltreatment (CM) is a major global public health issue, and a strong association exists between CM and aggression. However, the underlying mechanism of this association has not been understood to date. The objective of this study was to explore the mediating role of irritability in the association between CM and aggression in Chinese early adolescents. A cross-sectional study was conducted using a self-report questionnaire to evaluate the levels of CM, aggression, and irritability in 5,724 middle school students from the Anhui Province, China. Structural equation modeling was used to test the hypothesis of the mediating effect of irritability on the relationship between CM and aggression. We further investigated gender differences in this association using multiple group analyses. CM was positively related to both irritability and aggression, and irritability was positively associated with aggression (p < .01). The mediating effects of irritability between CM and aggression were significant (ß = .107, 95% confidence intervals [CI]: 0.077-0.133, p < .05). Males had a higher indirect effect size of the pathway from CM to aggression via irritability compared with females. Overall, irritability was a crucial mediator in the relationship between CM and aggression in Chinese adolescents, and males were more prone to engage in aggression compared with females through the pathway of irritability. Therefore, early irritability characteristics should be carefully monitored in adolescents, and they should be provided adequate support to acquire critical emotion regulation skills.


Subject(s)
Aggression , Child Abuse , Male , Child , Female , Humans , Adolescent , Aggression/psychology , Cross-Sectional Studies , Surveys and Questionnaires , China
19.
J Agric Food Chem ; 72(1): 245-258, 2024 Jan 10.
Article in English | MEDLINE | ID: mdl-38148374

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) has become a major global health problem with no approved pharmacological treatment for this disease. Thus, it is urgent to develop effective therapeutic targets for clinical intervention. Here, we show for the first time that ZFP30, a member of the KRAB-ZFP family, is significantly increased in NAFLD models. ZFP30 silencing ameliorates free fatty acid (FFA)-induced lipid accumulation; in contrast, the ZFP30 overexpression exacerbates the triglyceride accumulation and steatosis in hepatocytes. Further investigation revealed that the effects of ZFP30 on hepatic lipid accumulation were mainly attributed to the PPARα downregulation in the NAFLD model. Mechanistically, ZFP30 directly binded to the promoter of PPARα and recruited KAP1 to suppress its transcription. Moreover, chlorogenic acid (CGA) reversed the upregulation of ZFP30 in NAFLD, promoting the PPARα expression, resulting in enhanced fatty acid oxidation and alleviated hepatic steatosis. Collectively, our study indicates ZFP30 as a potential target for NAFLD treatment.


Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Animals , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Chlorogenic Acid/pharmacology , Chlorogenic Acid/metabolism , PPAR alpha/genetics , PPAR alpha/metabolism , Liver/metabolism , Lipid Metabolism , Fatty Acids, Nonesterified/metabolism , Mice, Inbred C57BL , Diet, High-Fat
20.
Arch Gerontol Geriatr ; 117: 105277, 2024 02.
Article in English | MEDLINE | ID: mdl-37995647

ABSTRACT

BACKGROUND & PURPOSE: Oral health education helps older adults optimize their oral health. However, traditional lecture-based oral health education has limitations, exacerbated by the COVID-19 pandemic. Mobile augmented reality (MAR) has emerged as an alternative educational method. This study compared the effectiveness of MAR-integrated oral health education with that of lecture-based education and no education. METHODS: This parallel, randomized controlled, open-label trial enrolled 75 older adults from six activity centers. The participants were randomly assigned, by a random number table technique, to the lecture-based, MAR, or control group. Data on oral healthcare-related knowledge, self-efficacy, and oral health status were collected through questionnaires and oral examinations at baseline, immediately after the intervention, and at a 2-week follow-up. The MAR system's usability was assessed. Statistical analyses, comprising descriptive statistics and inferential tests, were performed. RESULTS: Data from 61 participants were analyzed, 22 in the lecture-based group, 20 in the MAR group, and 19 in the control group. Both lectures and MAR education significantly improved oral health status. However, changes in knowledge and self-efficacy scores were significantly different only for the MAR versus control group (p = .002 and .001, respectively). The MAR group demonstrated better knowledge and self-efficacy retention than did the lecture-based group, without significant difference. Usability assessment revealed potential for improvement in the MAR system. CONCLUSIONS: MAR-integrated oral health education enhanced the knowledge, self-efficacy, and oral health status of community-dwelling older adults. However, addressing technology adoption and usability challenges is vital. Longer-term evaluations and broader geographical studies are recommended.


Subject(s)
Augmented Reality , Independent Living , Humans , Aged , Pandemics , User-Computer Interface , Health Education
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