Effect of Clomethiazole Vs. Clorazepate on Hepatic Fat and Serum Transaminase Activities in Alcohol-Associated Liver Disease: Results from a Randomized, Controlled Phase II Clinical Trial.

AIMS: Alcohol-associated liver disease (ALD) is a global health problem caused, among other factors, by oxidative stress from the formation of reactive oxygen species (ROS). One important source of ROS is microsomal ethanol metabolism catalyzed by cytochrome P450 2E1 (CYP2E1), which is induced by chronic ethanol consumption. Inhibition of CYP2E1 by clomethiazole (CMZ) decreases oxidative stress in cell cultures and improves ALD in animal studies. Our study aimed to assess the benefits of a CYP2E1 inhibitor (clomethiazole) in detoxification of patients with ALD. METHODS: Open label, randomized controlled clinical trial to study whether CYP2E1 inhibition improves ALD in the patients with alcohol use disorders admitted for alcohol detoxification therapy (ADT). Patients had to have a serum aspartate aminotransferase (AST) activity exceeding twice the upper normal limit at time of admission and be non-cirrhotic defined by fibroscan value <12 kPa. Sixty patients were randomly assigned to ADT with either CMZ or clorazepate (CZP) for 7-10 days in a 1:1 ratio. The chlorzoxazone test of CYP2E1 activity was performed at enrolment and at 2 points during the study. RESULTS: ADT improved hepatic steatosis (controlled attenuation parameter) in both groups significantly. A trend towards a greater improvement in hepatic fat content during ADT (-21.5%) was observed in the CMZ group (252 ± 48 dB/m vs. 321 ± 38 dB/m; P < 0.0001) compared with the CZP group (-13.9%; 273 ± 38 dB/m vs. 317 ± 39 dB/m; P < 0.0001). As already reported, serum AST (P < 0.004) and alanine aminotransferase (ALT) activities (P < 0.0006) significantly decreased in CMZ patients as compared with patients on CZP by the end of hospitalization. A significant correlation was found between AST (P = 0.023), ALT (P = 0.009), GGT (P = 0.039) and CAP. CONCLUSION: This study demonstrates that CMZ improves clinical biomarkers for ALD in humans most likely due to its inhibitory effect on CYP2E1. Because of its addictive potential, CMZ can only be given for a short period of time and therefore other CYP2E1 inhibitors to treat ALD are needed.

A Simple Screening and Optimization Bioprocess for Long-Chain Peptide Catalysts Applied to Asymmetric Aldol Reaction.

Peptides have demonstrated their efficacy as catalysts in asymmetric aldol reactions. But the constraints inherent in chemical synthesis have imposed limitations on the viability of long-chain peptide catalysts. A noticeable dearth of tools has impeded the swift and effective screening of peptide catalysts using biological methods. To address this, we introduce a straightforward bioprocess for the screening of peptide catalysts for asymmetric aldol reactions. We synthesized several peptides through this method and obtained a 15-amino acid peptide. This peptide exhibited asymmetric aldol catalytic activity, achieving 77% ee in DMSO solvent and 63% ee with over an 80.8% yield in DMSO mixed with a pH 9.0 buffer solution. The successful application of our innovative approach not only represents an advancement but also paves the way for currently unexplored research avenues.

Evaluation of the Therapeutic Effect of Bi-Maxillary Osteotomy Using the Stress Distribution on the Temporomandibular Joint When Doing Anterior Teeth Occlusion.

The purpose of this study was to investigate how sagittal split ramus osteotomy (SSRO) and Le Fort 1 osteotomy affected the stress distribution of the temporomandibular joint (TMJ) during an anterior teeth bite using the three-dimensional (3D) finite element (FE) method. Fourteen orthognathic surgery patients were examined with mandibular prognathism, facial asymmetry, and mandibular retraction. They underwent Le Fort 1 osteotomy in conjunction with SSRO. In addition, ten asymptomatic subjects were recruited as the control group. The 3D models of the mandible, disc, and maxilla were reconstructed according to cone-beam computed tomography (CBCT). Contact was used to simulate the interaction of the disc-condyle, disc-temporal bone, and upper-lower dentition. Muscle forces and boundary conditions corresponding to the anterior occlusions were applied on the models. The stresses on the articular disc and condyle in the pre-operative group were significantly higher than normal. The contact stress and minimum principal stress in TMJ for patients with temporomandibular disorder (TMD) were abnormally higher. The peak stresses of the TMJ of the patients under anterior occlusions decreased after bimaxillary osteotomy. No postoperative TMD symptoms were found. Maxillofacial deformity led to excessive stress on the TMJ. Bimaxillary osteotomy can partially improve the stress distributions of the TMJ and relieve the symptoms of TMD.

The biomechanical effects of bilateral sagittal split ramus osteotomy and bimaxillary osteotomies to the patients with maxillofacial deformities under incisal clenching.

OBJECTIVE: Bilateral sagittal split ramus osteotomy (BSSRO) and bimaxillary osteotomies (BSSRO plus Lefort1 osteotomy) are widely used to solve maxillofacial deformities. The effect of the surgeries on the temporomandibular joint (TMJ) is still not clear. The purpose of this study was to investigate the preoperative and postoperative stress environment of the patients and to compare the biomechanical differences of the two surgeries. METHODS: Ten patients were performed BSSRO and fourteen underwent bimaxillary osteotomies. Eleven asymptomatic subjects were recruited to be the control group. The muscle forces of incisal clenching were applied on the finite element models. And contact was used to simulate the interactions within the TMJs. RESULTS: two kinds of surgeries could not completely eliminate the negative biomechanical distribution within the TMJs. CONCLUSION: Compared to BSSRO only, the bimaxillary osteotomies could better repair the biomechanical environment of the TMJs under incisal clenching. And the TMD symptoms were strongly related to the stress distributions of the TMJs.

Biomechanical study of temporomandibular joints of patients with temporomandibular disorders under incisal clenching: A finite element analysis.

Temporomandibular disorders (TMD) encompass a collection of pathologies. Within the multitude of etiological factors contributing to TMD, mechanical factors hold significant importance. The aim of this investigation was to assess the magnitude and distribution of stresses encountered by the temporomandibular joints (TMJs) during incisal clenching among TMD patients while also elucidating the mechanical pathogenesis underlying TMD. Ten asymptomatic subjects and ten TMD patients were recruited. The Control, Bilateral, and Unilateral groups were set. The contact stress, maximum principal stress, and minimum principal stresses of TMJ structures among the groups were compared. In addition, comparisons of the contact stress distribution among the groups were adopted. In the Control and Bilateral groups, the magnitudes of stresses (contact stress, maximum and minimum principal stresses) between the right and left sides showed no significant difference (P > 0.05). For unilateral TMD patients,the minimum principal stress on the condyle in the Uni-N group (the normal side) was significantly greater than thatin the Uni-T group (the TMD side)(P = 0.016, mean difference 9.99 MPa [95 %CI: 3.11 to 16.87]). Furthermore, stresses on the condyle and fossa of the patients were significantly greater than those of asymptomatic subjects (P < 0.05). The contact stress distributions were concentrated in the Control group while irregular in the TMD groups. In conclusion, asymmetrical contact stress distributions were observed in unilateral TMD, with excessive stresses on the healthy side. The protection of the healthy TMJ during treatment is recommended for patients with unilateral TMD.

Influence of internal angle and shape of the lining on residual stress of Class II molar restorations.

Polymerization shrinkage is a major side effect of resin composite materials that affects the success and longevity of caries restorations. This study was to analyze the effect of the internal angle and shape of the lining on the shrinkage residual stress of dental restorations in Class II mesio-occlusal-distal (MOD) cavities through finite element analysis (FEA). A 3D reconstructed model of a human mandibular first molar was created from micro-CT images, and then the tooth was prepared as a Class II MOD cavity. 3D models of four regular internal corner shapes of Class II MOD cavities with different internal angles of lining and one 90° filleted corner model were created. The thermal expansion technique was applied to approximate the shrinkage impact of composite resin polymerization in the FE software ABAQUS. Von Mises stress was taken as a metric. The results showed that the level of residual stresses in the Class II MOD cavities was greatly dependent on the internal angle of the lining. The maximum von Mises stress in tooth tissue decreased as the internal angle of the lining increased. The internal shapes of the lining had no obvious effect on the stress, and the filleted corner model had less stress. This lining strategy is appropriate for Class II MOD cavities with serious loss of tooth tissue.

The biomechanical effects of bimaxillary osteotomies to the patients with mandibular retraction under incisal clenching.

The purpose of this study is to investigate the biomechanical effect of bimaxillary osteotomies on patients with mandibular retraction. Mandibular retraction, as a typical maxillofacial deformity, and has great adverse effects on TMJ. Bimaxillary osteotomies are widely used to correct symptoms of mandibular retraction. It is necessary to understand the effect of surgery on temporomandibular disc (TMJ). Five patients with mandibular retraction and 10 asymptomatic subjects were involved in this study. Finite element models of preoperative, postoperative and control group were constructed based on the CT data. Nine sets of concentrated forces were used to simulate the muscle effect and contact method was used to simulate the interaction within the TMJs and dentitions. The results showed that bimaxillary osteotomies could effectively improve the maxillofacial morphology and alleviate the overload in TMJ. The facial asymmetry and right chewing side preference could cause imbalanced stress distributions in the TMJs and interfere the surgical treatment.

In vivo biomechanical dynamic simulation of a healthy knee during the single-leg lunge and its experiment validation.

Biomechanical modeling of the knee during motion is a pivotal component in disease treatment, implant designs, and rehabilitation strategies. Historically, dynamic simulations of the knee have been scant. This study uniquely integrates a dual fluoroscopic imaging system (DFIS) to investigate the in vivo dynamic behavior of the meniscus during functional activities using a finite element (FE) model. The model was subsequently validated through experiments. Motion capture of a single-leg lunge was executed by DFIS. The motion model was reconstructed using 2D-to-3D registration in conjunction with computed tomography (CT) scans. Both CT and magnetic resonance imaging (MRI) data facilitated the development of the knee FE model. In vivo knee displacements and rotations were utilized as driving conditions for the FE model. Moreover, a 3D-printed model, accompanied with digital imaging correlation (DIC), was used to evaluate the accuracy of the FE model. To a better inner view of knees during the DIC analysis, tibia and femur were crafted by transparent resin. The availability of the FE model was guaranteed by the similar strain distribution of the DIC and FE simulation. Subsequent modeling revealed that the compressive stress distribution between the medial and lateral menisci was balanced in the standing posture. As the flexion angle increased, the medial meniscus bore the primary compressive load, with peak stresses occurring between 60 and 80° of flexion. The simulation of a healthy knee provides a critical theoretical foundation for addressing knee pathologies and advancing prosthetic designs.

Enhancing the Thermostability and Catalytic Activity of the Lipase from Rhizopus oryzae via Introducing N-Glycosylation.

Lipase from Rhizopus oryzae (ROL) exhibits remarkable sn-1,3 stereoselectivity and catalytic activity, but its poor thermostability limits its applications in the production of 1,3-dioleoyl-2-palmitoyl glycerol (OPO, a high-quality substitute for human milk fat). In this work, a semirational method was proposed to engineer the thermostability and catalytic activity of 4M (ROL mutant in our previous study). First, a computer-aided design is performed using 4M as a template, and N-glycosylation mutants are then recombinantly expressed and screened in Pichia pastoris, the optimal mutant N227 exhibited a half-life of 298.8 h at 45 °C, which is 7.23-folds longer than that of 4M. Its catalytic activity also reached 1043.80 ± 61.98 U/mg, representing a 29.2% increase compared to 4M (808.02 ± 47.02 U/mg). Molecular dynamics simulations of N227 suggested that the introduction of glycan enhanced the protein rigidity, while the strong hydrogen bonds formed between the glycan and the protein stabilized the lipase structure, thereby improving its thermostability. The acidolysis reaction between oleic acid (OA) and glycerol tripalmitate (PPP) was successfully carried out using immobilized N227, achieving a molar conversion rate of 90.2% for PPP. This engineering strategy guides the modification of lipases, while the glycomutants obtained in this study have potential applications in the biosynthesis of OPO.

Rationally introducing non-canonical amino acids to enhance catalytic activity of LmrR for Henry reaction.

The use of enzymes to catalyze Henry reaction has advantages of mild reaction conditions and low contamination, but low enzyme activity of promiscuous catalysis limits its application. Here, rational design was first performed to identify the key amino acid residues in Henry reaction catalyzed by Lactococcal multidrug resistance Regulator (LmrR). Further, non-canonical amino acids were introduced into LmrR, successfully obtaining variants that enhanced the catalytic activity of LmrR. The best variant, V15CNF, showed a 184% increase in enzyme activity compared to the wild type, and was 1.92 times more effective than the optimal natural amino acid variant, V15F. Additionally, this variant had a broad substrate spectrum, capable of catalyzing reactions between various aromatic aldehydes and nitromethane, with product yielded ranging from 55 to 99%. This study improved enzymatic catalytic activity by enhancing affinity between the enzyme and substrates, while breaking limited types of natural amino acid residues by introducing non-canonical amino acids into the enzyme, providing strategies for molecular modifications.

Effect of bimaxillary surgery on the stress distributions in patients with mandibular retrognathia under unilateral molar clenching.

To investigate the effect of bimaxillary surgery on the stress distribution of the temporomandibular joint (TMJ) in patients with mandibular retrognathia under unilateral molar clenching (UMC). Five patients with mandibular retrognathia (preoperative group) and ten asymptomatic subjects (control group) were recruited. In addition, patients treated with bimaxillary surgery were considered as the postoperative group. The muscle forces corresponding to UMC were applied. The results showed that the discal stresses in the postoperative group were significantly greater than those in the preoperative and control groups. Bimaxillary surgery plus UMC had a detrimental effect on the TMJ.

Effects of bilateral sagittal split ramus osteotomy and bimaxillary osteotomies on stress distribution of temporomandibular joints in patients with maxillofacial deformity under asymmetric occlusions.

Bilateral sagittal split ramus osteotomy (BSSRO) and bimaxillary osteotomies (BSSRO plus Lefort1 osteotomy) are representative surgeries to solve maxillofacial deformity. It is important to understand the biomechanical impact of the surgeries on the temporomandibular joint (TMJ). The purpose of this study is to compare the stress variations of the patients before and after the two surgeries. Twenty-four patients with maxillofacial deformities and 14 asymptomatic subjects were recruited to be the preoperative group and control group in this study. Ten patients were performed BSSRO and other 14 underwent bimaxillary osteotomies. Finite element models of the preoperative, postoperative, and control groups were established according to the CBCT data of the subjects. The muscle forces of the left and right unilateral occlusion were applied on the models. And the contact was used to simulate the interaction within the TMJs and between the maxillary and mandibular teeth. Under the asymmetric occlusion, bimaxillary osteotomies were found to be superior to BSSRO in the stress distributions of the TMJs. The magnitude of the asymmetric stresses was strongly correlated with the TMD symptoms in the patients. And the stress variation of the postoperative TMJs was the cause of the improvement or aggravation of the TMD symptoms.

Effect of pre-stress on dynamic finite element analysis of the temporomandibular joint.

The pre-stress of the temporomandibular joint (TMJ) at the intercuspal position (ICP) was often neglected, which would cause errors in the finite element analysis. The purpose of this study was to investigate the effect of pre-stress on dynamic finite element analysis of the TMJs. One healthy female adult was recruited for medical imaging and motion data acquisition of the reference position (RP) to the ICP and the clicking teeth. The three-dimensional maxillofacial model including the maxilla, mandible, articular cartilages, discs, and discal attachments was reconstructed. Motion from the RP to the ICP was simulated to obtain pre-stress at the ICP. Two groups of the clicking teeth were simulated: (1) the group without pre-stress (GWoP); (2) the group with pre-stress (GwP). Significant differences were found between the two groups at the initial moment of movement, during the open-mouth phase, and during the collision phase between the upper and lower teeth. The maximum difference in the discal contact stress between both groups was even more than double. The relaxation of the TMJ at the beginning of the mouth opening was simulated in the GwP. In addition, an increase in the TMJ stress during teeth tapping was simulated in the GwP. These were not reflected in the GWoP. If pre-stress at the ICP was not considered, part of the true results would be lost. It is necessary to consider pre-stress in the dynamic finite element analysis of the TMJ.

Biomechanical comparison of the effect of bilateral sagittal split ramus osteotomy with or without Le Fort I osteotomy on the temporomandibular joints of the patients with maxillofacial deformities under centric occlusion.

Mandibular deformities negatively affect the daily activities of the patients and may cause temporomandibular disorders (TMD). Bilateral sagittal split ramus osteotomy (BSSRO) and Le Fort I osteotomy are effective treatments to correct the mandibular deformities. The aim of this study was to investigate and compare the effects of the BSSRO with or without Le Fort I on the stress distributions of the temporomandibular joints (TMJs) of the patients with mandibular deformities under centric occlusion based on finite element (FE) method. Preoperative and postoperative cone-beam computed tomography (CBCT) images of twenty-four patients diagnosed with mandibular prognathism, including ten patients with BSSRO and another 14 patients with bimaxillary osteotomy (BSSRO with Le Fort I), were used to construct maxillofacial models. Ten asymptomatic individuals were also performed CBCT scanning and defined as the control group. In addition, the muscle forces and boundary conditions corresponding to centric occlusions were applied on each model. For the preoperative groups with both the BSSRO and bimaxillary osteotomies, the average peak contact stresses of the TMJs were both greater than those of the control group. After the surgeries, the contact stresses of the discs and temporal bones of both groups considerably decreased. However, the contact stresses on the condyles slightly increased after BSSRO but decreased after bimaxillary osteotomy. The TMJs of the patients with maxillofacial deformities suffered abnormal tensile and compressive stresses compared with the asymptomatic subjects under centric occlusion. Both of the BSSRO and bimaxillary osteotomy could improve the risk stress distributions of the TMJs.

The pressure in the temporomandibular joint in the patients with maxillofacial deformities.

BACKGROUND: Temporomandibular disorder (TMD) symptoms were found to be common in the patients with maxillofacial deformities. The mandibular structure was in relation with the stress within temporomandibular joint (TMJ). However, the current studies on the TMJ stresses in the patients with different maxillofacial deformities are not comprehensive enough. PURPOSE: The aim of this study was to investigate the compression and morphology of the TMJ in the patients with different maxillofacial deformities under central occlusion. METHODS: 24 patients and 10 asymptomatic individuals were included in this study and divided into patient groups and control group. The 3D models were reconstructed. Muscle forces and boundary conditions corresponding to the central occlusion were applied. Nine morphological parameters of mandible were evaluated. RESULTS: The minimum principal stresses in the articular disc and condyle were significantly greater than those of the control group (P<0.05). For the articular disc, the compression on the non-deviation side was greater than those on the deviation side in patients with asymmetrical mandibles. There was difference between both sides in the mandibular prognathism and retrusion groups. The joint space of patients was significantly lower than that of the control group (P<0.05). CONCLUSIONS: Maxillofacial deformities might change the condylar position within the articular fossa, which decreased the joint space and increased the compression within TMJ. The patients with asymmetry mandible suffered greater pressure within TMJ on the non-deviation side. The bilaterally over-developed and under-developed mandible in patients might also increase the compression within TMJ.

Finite element contact stress analysis of the temporomandibular joints of patients with temporomandibular disorders under mastication.

BACKGROUND AND OBJECTIVES: Temporomandibular disorders (TMD) represent a group of diseases occurred in the temporomandibular joint (TMJ) and its surrounding tissues. In epidemiological studies, up to 75% of adults have shown at least one sign of temporomandibular disorders during their examinations. The incongruous biomechanical environment in the TMJ is the main pathogenic factor of TMD. This study attempts to determine the mechanical differences in different groups of TMD patients through biomechanics and to explain the mechanical pathogenesis of TMD according to various cases. METHODS: Eleven control subjects and eleven TMD patients were selected and divided into three groups: the control group, bilateral TMD group, and unilateral TMD group. The contact stresses of the articular discs, condyles and temporal bones were analyzed using finite element method and statistical analysis of variance. RESULTS: The results indicated that the contact stresses in the joints with TMD were significantly greater in the Bi-Group (Bilateral TMD patients) compared to the Control-Group. The TMD side always exhibited greater stresses in the Uni-Group [Unilateral TMD patients) under various conditions (clenching on the TMD side or asymptomatic side). The greatest stress of all the groups occurred at the contralateral side with TMD when clenching on the asymptomatic side. CONCLUSIONS: Excessive protection would lead to greater stress on the affected side and increased TMD risk on the asymptomatic side. Clinically, the abnormal stress distributions of the disc represented poor buffering and articular clicking. The asymmetric distributions of the articular fossa manifested the deviation of mouth opening or inconsistent TMJ loading.

High resolution mapping of Cia3: a common arthritis quantitative trait loci in different species.

Murine collagen induced arthritis (CIA) is a widely used model of rheumatoid arthritis (RA). Identification of CIA susceptibility genes will aid in the understanding of RA pathogenesis and development of therapeutic targets. This study aims to identify and refine quantitative trait loci (QTL) controlling CIA. Major CIA clinical traits were evaluated in both (DBA/1xFVB/N) F(2) and advanced intercross line (AIL) mice; QTLs were confirmed and refined in AIL. To search for candidate genes, we applied multiple approaches, including gene expression profiling, identification of nonsynonymous polymorphism, and comparative genomic mapping. We identified six suggestive QTLs controlling CIA clinical traits in the F(2) progeny; one of these was confirmed and refined in AIL. This QTL is located on chromosome 6 and overlaps with Cia3, which was identified previously. We refined the 2-log support interval of Cia3 into a 5.6 Mb genomic region; 15 of 77 genes are differentially expressed or carry nonsynonymous polymorphisms between two parental strains. The counterpart genomic region of Cia3 on the rat and human genomes are linked to RA. Twenty-nine of 77 genes are located in the arthritis-linked genomic regions of all three species. Five of those 29 genes are differentially expressed or carry nonsynonymous polymorphisms between parental strains: Timp4, Tmem40, Mbd4, Cacna1c, and Lrtm2. Taken together, we refined Cia3 into a 5.6 Mb genomic region on mouse chromosome 6 and identified candidate genes. This will aid in the search for susceptibility gene(s) controlling arthritis development within Cia3 and its counterpart regions in rat and human genomes.

[Three-dimensional morphological changes in the temporomandibular joints of patients with anterior disc displacement with reduction].

OBJECTIVES: To investigate the differences in the temporomandibular joints (TMJs) between patients with anterior disc displacement with reduction (ADDwR) and asymptomatic subjects by using 3D morphometric measurements. METHODS: A total of 15 patients with ADDwR and 10 asymptomatic subjects were enrolled. Then, 3D models of the maxilla and mandible were reconstructed using MIMICS 20.0. Nine morphologic parameters of TMJs on both sides were measured on the 3D solid model. The differences in the parameters were analyzed between the patients and the asymptomatic subjects and between the left and right sides of each group. RESULTS: The horizontal and coronal condylar angles on the ipsilateral side of the patients were significantly greater than those of the asymptomatic subjects (P<0.01). Meanwhile, the sagittal ramus angle (SRA), medial joint space, lateral joint space, superior joint space, anterior joint space, and posterior joint space in the patients were significantly lower than those in the asymptomatic subjects (P<0.01). CONCLUSIONS: ADDwR will increase the condylar angles to be significantly greater than the normal level and decrease SRA and articular spaces to be significantly smaller than the normal level. The condyles will be displaced upward, closer to the fossa.

Three-dimensional finite element analysis of temporomandibular joints in patients with jaw deformity during unilateral molar clenching before and after orthognathic surgery.

ABSTRACT: To analyze the effects of orthognathic surgery on stress distributions in the temporomandibular joint (TMJ) of patients with jaw deformity during unilateral molar clenching (UMC) by using three-dimensional (3D) finite element method.Nine patients with jaw deformity (preoperative group, 26.1 ±â€Š5.6 years old) and 9 asymptomatic subjects (control group, 22.0 ±â€Š6.0 years old) were selected. Furthermore, the patients with jaw deformity were also considered as the postoperative group after undergoing orthognathic surgery. Finite element models for the mandible, articular disc, and maxilla were developed through cone beam computed tomography. Contact was used to simulate the interaction of the articular disc, condyle, fossa, and upper and lower dentition. The muscle forces and boundary conditions corresponding to the UMC were applied on the models.The stresses on both TMJs of the control group were significantly different, whereas there was no significant difference on both sides for the preoperative group. All the stresses of the preoperative group were greater than those of the control and postoperative groups, except the minimum principal stress on the ipsilateral fossa.Orthognathic surgery is beneficial for alleviating the abnormal stress distributions on TMJ.