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1.
J Am Chem Soc ; 146(15): 10381-10392, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38573229

RESUMO

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.


Assuntos
Adenina/análogos & derivados , Dioxigenases , Ácidos Cetoglutáricos , Humanos , Dioxigenases/metabolismo , DNA/química , Reparo do DNA , Compostos Ferrosos , Adutos de DNA , Homólogo AlkB 2 da Dioxigenase Dependente de alfa-Cetoglutarato/metabolismo
2.
Inorg Chem ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38598777

RESUMO

Lamellar metal-organic frameworks (MOFs) have attracted significant attention in the field of electrochemical sensing due to their abundant open active sites and specific electron conductivity. Herein, by employing a bottom-up synthesis strategy, rhombic lamellar heterometallic CoNi-MOFs with varying thicknesses are constructed. This is achieved by using 4-methylpyridine as a capping agent based on the (4,6)-linked Co2(azpy)2(bptc) (azpy = 4,4'-azopyridine, bptc = 3,3',5,5'-biphenyltetracarboxylic acid) structure with a fsc topology and by introducing Ni species simultaneously. To mitigate sulfur deposition on electrodes, the triple pulse amperometry (TPA) method is employed. Among the synthesized lamellar CoNi-MOFs, lamellar CoNi-MOF-3 with the minimum thickness exhibits an optimal electrochemical sensing performance toward hydrogen sulfide, with a sensitivity of 119.3 µA·mM-1·cm-2 in the linear range of 2-2000 µM. This study pioneers a new approach to the controlled construction and electrochemical activity modification of lamellar MOF materials.

3.
Heart Rhythm ; 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38588992

RESUMO

BACKGROUND: The aorta-mitral annulus conjunction (AMC) is uncommon site of origin of focal atrial tachycardias (AT). Hence, the electrophysiological and ablation target characteristics are poorly described. OBJECTIVE: To describe the characteristics of AMC AT in detail. METHODS: The study enrolled 650 patients with AT, 21 (3.2%) of whom had AT originating from AMC. A comprehensive evaluation, including electrocardiography, electrophysiologic study, CT scan, and intracardiac echocardiography (ICE) was performed. RESULTS: The majority (90.5%) of ATs occurred spontaneously. The average age of this group was 48.9±21.6 years, with 12 females (57.1%). Seventeen patients had a typical biphasic P wave with a prominent positive component. The earliest activation site in the right atrium was near the His bundle with average activation -10.3±6.0 ms preceding the P wave. The successful ablation targets were distributed as follows: 1 case at 9 o'clock, 6 cases at 10 o'clock, 7 cases at 11 o'clock, 6 cases at 12 o'clock, and 1 case in the left coronary cusp (LCC). The local AMC potential differed from the commonly perceived annular potential, and was characterized by a large A and a small V (A/V ratio >1). The angle of encroachment on the LA anterior wall, compressed by the LCC, was significantly smaller in the AMC-AT group compared to the control group, which may have contributed to the arrhythmia substrate (141.7°±11.5° vs. 155.2°±13.9°, p = 0.026). CONCLUSION: A new strategy for mapping AMC ATs has been introduced. The ablation target should have an A/V ratio greater than 1.

4.
Nat Methods ; 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589516

RESUMO

Single-cell Hi-C (scHi-C) technologies allow for probing of genome-wide cell-to-cell variability in three-dimensional (3D) genome organization from individual cells. Computational methods have been developed to reveal single-cell 3D genome features based on scHi-C, including A/B compartments, topologically associating domains and chromatin loops. However, no method exists for annotating single-cell subcompartments, which is important for understanding chromosome spatial localization in single cells. Here we present scGHOST, a single-cell subcompartment annotation method using graph embedding with constrained random walk sampling. Applications of scGHOST to scHi-C data and contact maps derived from single-cell 3D genome imaging demonstrate reliable identification of single-cell subcompartments, offering insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from complex tissues, scGHOST identifies cell-type-specific or allele-specific subcompartments linked to gene transcription across various cell types and developmental stages, suggesting functional implications of single-cell subcompartments. scGHOST is an effective method for annotating single-cell 3D genome subcompartments in a broad range of biological contexts.

5.
Sci Rep ; 14(1): 8195, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589564

RESUMO

Large floating raft vibration isolation systems (FRVISs) based on high-static-low-dynamic stiffness (HSLDS) technology offer excellent low frequency vibration isolation performance with broad application prospects. However, the design process for these complex high-dimensional coupled nonlinear systems remains poorly developed, particularly when applied for ocean-going vessels that experience rolling and pitching motions. The present work addresses this issue by establishing a six-degree-of-freedom HSLDS vibration isolation model for FRVISs composed of eight isolators, and the model is applied to fully analyze the swing stability and multidimensional vibration isolation performance of these systems. The influence of nonlinearity on the mechanical properties of the vibration isolators is analyzed more clearly by assuming that each vibration isolator realizes nonlinear HSLDS characteristics in the z direction and linear characteristics in the x and y directions. The results demonstrate that the swing displacement responses of the system are greatly reduced under weak nonlinearity, which reflects the high static stiffness and high static stability characteristics of an HSLDS system. The multidimensional vibration isolation performance of the system is evaluated according to the impacts of nonlinearity, the installation height Hz of the isolators, and the relative position Dr of the two middle isolators. The results of analysis demonstrate that applying a value of Hz = 0 produces the best vibration isolation performance overall under strong nonlinearity by avoiding unnecessary secondary peaks in the force transmission rate under harmonic mechanical excitation and ensuring a maximum high-frequency vibration isolation effect. However, applying a weak nonlinearity is better than a strong nonlinearity if Hz is not zero. In contrast, Dr has little effect on the vibration isolation effect of the raft in the x, y, and z directions. Therefore, an equidistant installation with Dr = 0.5 would be considered ideal from the standpoint of installation stability.

6.
Nat Commun ; 15(1): 2951, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580660

RESUMO

Hepatitis B virus is a globally distributed pathogen and the history of HBV infection in humans predates 10000 years. However, long-term evolutionary history of HBV in Eastern Eurasia remains elusive. We present 34 ancient HBV genomes dating between approximately 5000 to 400 years ago sourced from 17 sites across Eastern Eurasia. Ten sequences have full coverage, and only two sequences have less than 50% coverage. Our results suggest a potential origin of genotypes B and D in Eastern Asia. We observed a higher level of HBV diversity within Eastern Eurasia compared to Western Eurasia between 5000 and 3000 years ago, characterized by the presence of five different genotypes (A, B, C, D, WENBA), underscoring the significance of human migrations and interactions in the spread of HBV. Our results suggest the possibility of a transition from non-recombinant subgenotypes (B1, B5) to recombinant subgenotypes (B2 - B4). This suggests a shift in epidemiological dynamics within Eastern Eurasia over time. Here, our study elucidates the regional origins of prevalent genotypes and shifts in viral subgenotypes over centuries.


Assuntos
Vírus da Hepatite B , Migração Humana , Humanos , Vírus da Hepatite B/genética , Filogenia , Genótipo , Evolução Biológica , DNA Viral/genética
8.
Cell Death Dis ; 15(4): 242, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565547

RESUMO

Endometrial cancer (EC) cells exhibit abnormal glucose metabolism, characterized by increased aerobic glycolysis and decreased oxidative phosphorylation. Targeting cellular glucose metabolism in these cells could be an effective therapeutic approach for EC. This study aimed to assess the roles of LIN28B, PCAT5, and IGF2BP3 in the glucose metabolism, proliferation, migration, and invasion of EC cells. LIN28B highly expressed in EC, binds and stabilizes PCAT5. PCAT5, overexpressed in EC, and its 1485-2288nt region can bind to the KH1-2 domain of IGF2BP3 to prevent MKRN2 from binding to the K294 ubiquitination site of IGF2BP3, thus stabilizing IGF2BP3. Finally, IGF2BP3 promotes the aerobic glycolysis, proliferation, migration and invasion of EC cells by stabilizing the key enzymes of glucose metabolism HK2 and PKM2. Taken together, our data reveal that the LIN28B/PCAT5/IGF2BP3 axis is critical for glucose reprogramming and malignant biological behavior in EC cells. Therefore, targeting this axis may contribute to the development of a novel therapeutic strategy for EC metabolism.


Assuntos
Neoplasias do Endométrio , Glicólise , Feminino , Humanos , Linhagem Celular Tumoral , Glicólise/genética , Neoplasias do Endométrio/genética , Fosforilação Oxidativa , Glucose/metabolismo , Proliferação de Células/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
9.
New Phytol ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600023

RESUMO

Iron (Fe) needs to be delivered to different organs and tissues of above-ground parts for playing its multiple physiological functions once it is taken up by the roots. However, the mechanisms underlying Fe distribution are poorly understood. We functionally characterized OsOPT7, a member of oligo peptide transporter family in terms of expression patterns, localization, transport activity and phenotypic analysis of knockdown lines. OsOPT7 was highly expressed in the nodes, especially in the uppermost node I, and its expression was upregulated by Fe-deficiency. OsOPT7 transports ferrous iron into the cells coupled with proton. Immunostaining revealed that OsOPT7 is mainly localized in the xylem parenchyma cells of the enlarged vascular bundles in the nodes and vascular tissues in the leaves. Knockdown of OsOPT7 did not affect the Fe uptake, but altered Fe distribution; less Fe was distributed to the new leaf, upper nodes and developing panicle, but more Fe was distributed to the old leaves. Furthermore, knockdown of OsOPT7 also resulted in less Fe distribution to the leaf sheath, but more Fe to the leaf blade. Taken together, OsOPT7 is involved in the xylem unloading of Fe for both long-distance distribution to the developing organs and local distribution within the leaf in rice.

10.
J Neuroinflammation ; 21(1): 81, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566081

RESUMO

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.


Assuntos
Metformina , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Astrócitos/metabolismo , Neurônios Dopaminérgicos , Nucleotidiltransferases/metabolismo , Mitocôndrias/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , GTP Fosfo-Hidrolases/farmacologia
11.
ChemistryOpen ; : e202400008, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38511871

RESUMO

Solid state nanochannels provide significant practical advantages in many fields due to their interesting properties, such as controllable shape and size, robustness, ion selectivity. But their complex preparation processes severely limit their application. In this study, a simple cost-effective method to fabricate single nanochannel by embedding a single polyethylene oxide (PEO) nanofiber is presented. Firstly, PEO nanofibers are prepared by electrospinning, and then a single PEO nanofiber are precisely transferred to the target sample using a micromanipulation platform. Then, PDMS is used for embedding, and finally, the PEO nanofiber is dissolved to obtain a single nanochannel. Unlike other methods of preparing nanochannels by embedding nanofibers, this method can prepare single nanochannel. The diameter of nanochannel can be as fine as 100 nm, and the length can reach several micrometers. The power generation between two potassium chloride solutions with various combinations of concentrations was investigated using the nanochannel. This low-cost flexible nanochannel can also be used in various applications, including DNA sequencing and biomimetic ion channel.

12.
Andrology ; 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38506240

RESUMO

BACKGROUND: Like the coronavirus disease 2019, the hepatitis B virus is also wreaking havoc worldwide, which has infected over 2 billion people globally. Using an experimental animal model, our previous research observed that the hepatitis B virus genes integrated into human spermatozoa can replicate and express after being transmitted to embryos. However, as of now, this phenomenon has not been confirmed in clinical data from patients. OBJECTIVES: To explore the integration of the hepatitis B virus into patients' sperm genome and its potential clinical risks. MATERIALS AND METHODS: Forty-eight patients with chronic hepatitis B virus infection were categorized into two groups: Test Group-1 comprised 23 patients without integration of hepatitis B virus DNA within the sperm genome. Test Group-2 comprised 25 patients with integration of hepatitis B virus DNA within the sperm genome. Forty-eight healthy male donors were included as control. The standard semen parameter analysis, real-time polymerase chain reaction, quantitative real-time polymerase chain reaction, sperm chromatin structure assay, fluorescence in situ hybridization, and immunofluorescence assays were utilized. RESULTS: The difference in the median copy number of hepatitis B virus DNA per mL of sera between Test Group-1 and Group-2 was not statistically significant. In Test Group-2, the integration rate of hepatitis B virus DNA was 0.109%, which showed a significant correlation with the median copy number of hepatitis B virus DNA in motile spermatozoa (1.18 × 103 /mL). Abnormal semen parameters were found in almost all these 25 patients. The integrated hepatitis B virus S, C, X, and P genes were detected to be introduced into sperm-derived embryos through fertilization and retained their function in replication, transcription, and translation. CONCLUSION: Our findings suggest that hepatitis B virus infection can lead to sperm quality deterioration and reduced fertilization capacity. Furthermore, viral integration causes instability in the sperm genome, increasing the potential risk of termination, miscarriage, and stillbirth. This study identified an unconventional mode of hepatitis B virus transmission through genes rather than virions. The presence of viral sequences in the embryonic genome poses a risk of liver inflammation and cancer.

13.
Nat Commun ; 15(1): 2408, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499590

RESUMO

Despite the dominance of lead-based piezoelectric materials with ultrahigh electric-field-induced strain in actuating applications, seeking eco-friendly substitutes with an equivalent performance remains an urgent demand. Here, a strategy of regulating the irreversible non-180° domain via phase engineering is introduced to optimize the available strain (the difference between the maximum strain and the remnant strain in a unipolar strain curve) in the lead-free potassium-sodium niobate-based piezoelectric ceramics. In situ synchrotron X-ray diffraction and Rayleigh analysis reveal the contribution of the non-180° domain to available strain in the tetragonal-orthorhombic-rhombohedral phase boundary. The reducing orthorhombic phase and increasing rhombohedral/tetragonal phase accompanied by the reduced irreversible non-180° domain are obtained with increasing doping of Sb5+, resulting in an enlarged available strain due to the significantly lowered remnant strain. This optimization is mainly attributed to the reduced irreversible non-180° domain wall motion and the increased lattice distortion, which are beneficial to decrease extrinsic contribution and enhance intrinsic contribution. The mesoscopic structure of miniaturized nanosized domain with facilitated domain switching also contributes to the enhancement of available strain due to the improved random field and decreased energy barrier. The study will shed light on the design of lead-free high-performance piezoelectric ceramics for actuator applications.

14.
JACS Au ; 4(2): 816-827, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38425893

RESUMO

Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder their widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, and limited membrane permeability. Nonetheless, while peptide stapling has successfully stabilized α-helical peptides, it has shown limited applicability for most ß-sheet peptide motifs. In this study, we present the design of a novel double-stapled peptide capable of simultaneously stabilizing both α-helix and ß-sheet structures. Our designed double-stapled peptide, named DSARTC, specifically targets the androgen receptor (AR) DNA binding domain and MDM2 as E3 ligase. Serving as a peptide-based PROTAC (proteolysis-targeting chimera), DSARTC exhibits the ability to degrade both the full-length AR and AR-V7. Molecular dynamics simulations and circular dichroism analysis validate the successful constraint of both secondary structures, demonstrating that DSARTC is a "first-in-class" heterogeneous-conformational double-stapled peptide drug candidate. Compared to its linear counterpart, DSARTC displays enhanced stability and an improved cell penetration ability. In an enzalutamide-resistant prostate cancer animal model, DSARTC effectively inhibits tumor growth and reduces the levels of both AR and AR-V7 proteins. These results highlight the potential of DSARTC as a more potent and specific peptide PROTAC for AR-V7. Furthermore, our findings provide a promising strategy for expanding the design of staple peptide-based PROTAC drugs, targeting a wide range of "undruggable" transcription factors.

15.
Pediatr Res ; 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438553

RESUMO

BACKGROUND: To facilitate the identification of less common clinical phenotypes of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in children. METHODS: We retrospectively reviewed medical records of 236 patients with MOGAD. The following phenotypes were considered to be typical for MOGAD: ADEM, ON, TM, and NMOSD. Less common onset clinical phenotypes were screened out; their clinical and magnetic resonance imaging (MRI), diagnosis, treatment, and prognosis were summarized and analyzed. RESULTS: 16 cases (6.8%) presented as cortical encephalitis, with convulsions, headache, and fever as the main symptoms. 15 cases were misdiagnosed in the early period. 13 cases (5.5%) showed the overlapping syndrome of MOGAD and anti-N-methyl-D aspartate receptor encephalitis (MNOS), with seizures (92.3%) being the most common clinical symptom. 11 cases (84.6%) showed relapses. The cerebral leukodystrophy-like phenotype was present in seven cases (3.0%), with a recurrence rate of 50%. Isolated seizures without any findings on MRI phenotype was present in three cases (1.3%), with the only clinical symptom being seizures of focal origin. Three cases (1.3%) of aseptic meningitis phenotype presented with prolonged fever. CONCLUSION: 40/236 (16.9%) of children with MOGAD had less common phenotypes. Less common clinical phenotypes of pediatric MOGAD are susceptible to misdiagnosis and deserve more attention. IMPACT: This is the first comprehensive analysis and summary of all less commonl clinical phenotypes of MOGAD in children, while previous studies have only focused on a specific phenotype or case reports. We analyzed the characteristics of MOGAD in children and further revealed the reasons why these less common clinical phenotypes are prone to misdiagnosis and deserve more attention. Our research on treatment has shown that early detection of MOG antibodies and early treatment are of great significance for improving the prognosis of these patients.

16.
World J Gastroenterol ; 30(7): 728-741, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515944

RESUMO

BACKGROUND: Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP via binding to αvß3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy. AIM: To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux. METHODS: SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 µg/kg cerulein plus lipopolysaccharide. mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvß3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8. RESULTS: The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8's beneficial effects in SAP-induced liver injury. CONCLUSION: MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVß3/5.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Ferroptose , Glicolipídeos , Glicoproteínas , Gotículas Lipídicas , Pancreatite , Camundongos , Animais , Fator VIII , Pancreatite/induzido quimicamente , Pancreatite/complicações , Doença Aguda , Hepatócitos/metabolismo , Autofagia , Família de Proteínas EGF , Proteínas do Leite/metabolismo , Proteínas do Leite/farmacologia
17.
Clin Oral Investig ; 28(4): 221, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38499908

RESUMO

OBJECTIVES: To establish a three-dimensional finite element model of the upper palate, pharyngeal cavity, and levator veli palatini muscle in patients with unilateral complete cleft palate, simulate two surgical procedures that the two-flap method and Furlow reverse double Z method, observe the stress distribution of the upper palate soft tissue and changes in pharyngeal cavity area after different surgical methods, and verify the accuracy of the model by reconstructing and measuring the levator veli palatini muscle. MATERIALS AND METHODS: Mimics, Geomagic, Ansys, and Hypermesh were applied to establish three-dimensional finite element models of the pharyngeal cavity, upper palate, and levator veli palatini muscle in patients with unilateral complete cleft palate. The parameters including length, angle, and cross-sectional area of the levator veli palatini muscle etc. were measured in Mimics, and two surgical procedures that two-flap method and Furlow reverse double Z method were simulated in Ansys, and the area of pharyngeal cavity was measured by hypermesh. RESULTS: A three-dimensional finite element model of the upper palate, pharyngeal cavity, and bilateral levator veli palatini muscle was established in patients with unilateral complete cleft palate ; The concept of horizontal projection characteristics of the palatal dome was applied to the finite element simulation of cleft palate surgery, vividly simulating the displacement and elastic stretching of the two flap method and Furlow reverse double Z method during the surgical process; The areas with the highest stress in the two-flap method and Furlow reverse double Z method both occur in the hard soft palate junction area; In resting state, as measured, the two flap method can narrow the pharyngeal cavity area by 50.9%, while the Furlow reverse double Z method can narrow the pharyngeal cavity area by 65.4%; The measurement results of the levator veli palatini muscle showed no significant difference compared to previous studies, confirming the accuracy of the model. CONCLUSIONS: The finite element method was used to establish a model to simulate the surgical procedure, which is effective and reliable. The area with the highest postoperative stress for both methods is the hard soft palate junction area, and the stress of the Furlow reverse double Z method is lower than that of the two-flap method. The anatomical conditions of pharyngeal cavity of Furlow reverse double Z method are better than that of two-flap method in the resting state. CLINICAL RELEVANCE: This article uses three-dimensional finite element method to simulate the commonly used two-flap method and Furlow reverse double Z method in clinical cleft palate surgery, and analyzes the stress distribution characteristics and changes in pharyngeal cavity area of the two surgical methods, in order to provide a theoretical basis for the surgeon to choose the surgical method and reduce the occurrence of complications.


Assuntos
Fissura Palatina , Insuficiência Velofaríngea , Humanos , Fissura Palatina/cirurgia , Fissura Palatina/complicações , Análise de Elementos Finitos , Insuficiência Velofaríngea/complicações , Insuficiência Velofaríngea/cirurgia , Músculos Palatinos/cirurgia , Palato Mole/cirurgia , Palato Duro
18.
Clin Rheumatol ; 43(4): 1299-1310, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38433147

RESUMO

OBJECTIVE: To explore the association of geriatric nutrition risk index (GNRI), a traditional albumin-body weight calculation, with myopenia in patients with rheumatoid arthritis (RA) and compare its ability to identify myopenia with protein indicators. METHODS: This cross-sectional study was carried out based on a Chinese RA cohort. Clinical data and protein indicators (including albumin, globulin, albumin to globulin ratio, prealbumin, hemoglobin) were collected. GNRI was estimated by serum albumin and body weight. Myopenia was indicated as muscle mass loss measured by bioelectric impedance analysis. RESULTS: There were 789 RA patients included with mean age 52.6 ± 12.6 years and 77.6% female. There were 41.3%, 18.0%, 27.5%, 13.2% patients with no (GNRI > 98), low (GNRI 92 to ≤ 98), moderate (GNRI 82 to < 92), and major nutrition-related risk (GNRI < 82). There were 406 (51.5%) RA patients with myopenia, RA patients with major nutrition-related risk had the highest prevalence of myopenia (87.5% vs. 73.3% vs. 50.0% vs. 26.1%). Multivariate logistic analysis showed that compared with no risk, RA patients with low (OR = 3.23, 95% CI: 1.86-5.61), moderate (OR = 9.56, 95% CI: 5.70-16.01), and major nutrition-related risk (OR = 28.91, 95% CI: 13.54-61.71) were associated with higher prevalence of myopenia. Receiver operating characteristic curves showed that GNRI (AUC = 0.79) performed a better identifiable ability toward myopenia than serum albumin (AUC = 0.66) or others indicators (AUC range 0.59 to 0.65), respectively. CONCLUSION: GNRI, an objective and convenient albumin-weight index, may be preferable for identifying myopenia in RA patients. Key Points • We firstly elucidated the association of GNRI with muscle mass loss among RA patients, and compared its ability to identify muscle mass loss with serum albumin or other protein indicators. • Major nutrition-related risk identified by GNRI showed the highest risk of muscle mass loss, GNRI demonstrated a greater ability to identify myopenia in RA patients. which indicated GNRI was an objective and convenient albumin-weight index to identify myopenia in RA patients.


Assuntos
Artrite Reumatoide , Globulinas , Humanos , Feminino , Idoso , Adulto , Pessoa de Meia-Idade , Masculino , Avaliação Nutricional , Estudos Transversais , Estado Nutricional , Artrite Reumatoide/complicações , Atrofia Muscular , Albumina Sérica , Peso Corporal , Músculos , Fatores de Risco
19.
Mol Metab ; 82: 101905, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38431218

RESUMO

OBJECTIVE: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. METHODS: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. RESULTS: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. CONCLUSIONS: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Doenças não Transmissíveis , Serpinas , Humanos , Camundongos , Animais , Glucose/metabolismo , Resistência à Insulina/fisiologia , Serpinas/genética , Sobrepeso , Insulina/metabolismo , Obesidade/metabolismo , Camundongos Transgênicos , Dieta Hiperlipídica/efeitos adversos , Homeostase , Redução de Peso , RNA Mensageiro/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-38437117

RESUMO

360° images, with a field-of-view (FoV) of 180° ×360°, provide immersive and realistic environments for emerging virtual reality (VR) applications, such as virtual tourism, where users desire to create diverse panoramic scenes from a narrow FoV photo they take from a viewpoint via portable devices. It thus brings us to a technical challenge: 'How to allow the users to freely create diverse and immersive virtual scenes from a narrow FoV image with a specified viewport?' To this end, we propose a transformer-based 360° image outpainting framework called Dream360, which can generate diverse, high-fidelity, and high-resolution panoramas from user-selected viewports, considering the spherical properties of 360° images. Compared with existing methods, e.g., [3], which primarily focus on inputs with rectangular masks and central locations while overlooking the spherical property of 360° images, our Dream360 offers higher outpainting flexibility and fidelity based on the spherical representation. Dream360 comprises two key learning stages: (I) codebook-based panorama outpainting via Spherical-VQGAN (S-VQGAN), and (II) frequency-aware refinement with a novel frequency-aware consistency loss. Specifically, S-VQGAN learns a sphere-specific codebook from spherical harmonic (SH) values, providing a better representation of spherical data distribution for scene modeling. The frequency-aware refinement matches the resolution and further improves the semantic consistency and visual fidelity of the generated results. Our Dream360 achieves significantly lower Frechet Inception Distance (FID) scores and better visual fidelity than existing methods. We also conducted a user study involving 15 participants to interactively evaluate the quality of the generated results in VR, demonstrating the flexibility and superiority of our Dream360 framework.

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