[Structural design and evaluation of bone remodeling effect of fracture internal fixation implants with time-varying stiffness].

The stiffness of an ideal fracture internal fixation implant should have a time-varying performance, so that the fracture can generate reasonable mechanical stimulation at different healing stages, and biodegradable materials meet this performance. A topology optimization design method for composite structures of fracture internal fixation implants with time-varying stiffness is proposed, considering the time-dependent degradation process of materials. Using relative density and degradation residual rate to describe the distribution and degradation state of two materials with different degradation rates and elastic modulus, a coupled mathematical model of degradation simulation mechanical analysis was established. Biomaterial composite structures were designed based on variable density method to exhibit time-varying stiffness characteristics. Taking the bone plate used for the treatment of tibial fractures as an example, a composite structure bone plate with time-varying stiffness characteristics was designed using the proposed method. The optimization results showed that material 1 with high stiffness formed a columnar support structure, while material 2 with low stiffness was distributed at the degradation boundary and inside. Using a bone remodeling simulation model, the optimized bone plates were evaluated. After 11 months of remodeling, the average elastic modulus of callus using degradable time-varying stiffness plates, titanium alloy plates, and stainless steel plates were 8 634 MPa, 8 521 MPa, and 8 412 MPa, respectively, indicating that the use of degradable time-varying stiffness plates would result in better remodeling effects on the callus.

Topology optimization of embracing fixator considering bone remodeling to mitigate stress shielding effect.

The embracing fixator is one of the widely used internal fixation implants for bone fracture treatment. However, the stress shielding effect, a stress imbalance between the implant and bone caused by the mismatch in mechanical properties between them, is a significant and critical issue that may lead to treatment failure. Thus, it is of great importance to design the implant with an appropriate stiffness which can mitigate the stress shielding effect and provide the most favorable mechanical environment for bone healing and remodeling. To this end, a time-dependent topology optimization algorithm considering bone remodeling is proposed to optimize an embracing fixator used in the tibia fracture treatment. The change of callus density over time is simulated based on a bone remodeling model, and the callus density after a period of bone remodeling is selected to be the design objective to maximize. The design constraints include volume and the compliance of the whole fixation system. Meanwhile, the influence of the constraints on the regularity of material distribution of the optimized result is also studied. Besides, to test the effectiveness of the consideration of the bone remodeling in the embracing fixator design, a topology optimization concerning the minimization of the compliance of the entire system is also performed to make a comparison. Finally, the safety performance of optimized results considering bone remodeling is also verified by static analysis.

Strengthening E-cadherin adhesion via antibody-mediated binding stabilization.

E-cadherins (Ecads) are a crucial cell-cell adhesion protein with tumor suppression properties. Ecad adhesion can be enhanced by the monoclonal antibody 66E8, which has potential applications in inhibiting cancer metastasis. However, the biophysical mechanisms underlying 66E8-mediated adhesion strengthening are unknown. Here, we use molecular dynamics simulations, site-directed mutagenesis, and single-molecule atomic force microscopy experiments to demonstrate that 66E8 strengthens Ecad binding by stabilizing the primary Ecad adhesive conformation: the strand-swap dimer. By forming electrostatic interactions with Ecad, 66E8 stabilizes the swapped ß-strand and its hydrophobic pocket and impedes Ecad conformational changes, which are necessary for rupture of the strand-swap dimer. Our findings identify fundamental mechanistic principles for strengthening of Ecad binding using monoclonal antibodies.

Digging out the biology properties of tRNA-derived small RNA from black hole.

An unique subclass of functional non-coding RNAs generated by transfer RNA (tRNA) under stress circumstances is known as tRNA-derived small RNA (tsRNA). tsRNAs can be divided into tRNA halves and tRNA-derived fragments (tRFs) based on the different cleavage sites. Like microRNAs, tsRNAs can attach to Argonaute (AGO) proteins to target downstream mRNA in a base pairing manner, which plays a role in rRNA processing, gene silencing, protein expression and viral infection. Notably, tsRNAs can also directly bind to protein and exhibit functions in transcription, protein modification, gene expression, protein stabilization, and signaling pathways. tsRNAs can control the expression of tumor suppressor genes and participate in the initiation of cancer. It can also mediate the progression of diseases by regulating cell viability, migration ability, inflammatory factor content and autophagy ability. Precision medicine targeting tsRNAs and drug therapy of plant-derived tsRNAs are expected to be used in clinical practice. In addition, liquid biopsy technology based on tsRNAs indicates a new direction for the non-invasive diagnosis of diseases.

Strengthening E-cadherin adhesion via antibody mediated binding stabilization.

E-cadherins (Ecads) are a crucial cell-cell adhesion protein with tumor suppression properties. Ecad adhesion can be enhanced by the monoclonal antibody 66E8, which has potential applications in inhibiting cancer metastasis. However, the biophysical mechanisms underlying 66E8 mediated adhesion strengthening are unknown. Here, we use molecular dynamics simulations, site directed mutagenesis and single molecule atomic force microscopy experiments to demonstrate that 66E8 strengthens Ecad binding by stabilizing the primary Ecad adhesive conformation: the strand-swap dimer. By forming electrostatic interactions with Ecad, 66E8 stabilizes the swapped ß-strand and its hydrophobic pocket and impedes Ecad conformational changes, which are necessary for rupture of the strand-swap dimer. Our findings identify fundamental mechanistic principles for strengthening of Ecad binding using monoclonal antibodies.

Biomechanical evaluation of a healed acetabulum with internal fixators: finite element analysis.

BACKGROUND: Treatment of complicated acetabular fracture with internal fixation usually has high risk of failure because of unbefitting fixation. However, evaluation of the biomechanical effect of internal fixation under physiological loading for fracture healing is still generally rarely performed. The purpose of this study is to analyze the biomechanical characteristics of a healed acetabulum with designed internal fixators under gait and to explore the biomechanical relationship between the healed bone and the internal fixator. METHODS: A patient-specific finite element model of whole pelvis with designed internal fixators was constructed based on the tomographic digital images, in which the spring element was used to simulate the main ligaments of the pelvis. And the finite element analysis under both the combination loading of different phases and the individual loading of each phase during the gait cycle was carried out. The displacement, von Mises stress, and strain energy of both the healed bone and the fixation were calculated to evaluate the biomechanical characteristics of the healed pelvis. RESULTS: Under the combination loading of gait, the maximum difference of displacement between the left hip bone with serious injury and the right hip bone with minor injury is 0.122 mm, and the maximum stress of the left and right hemi-pelvis is 115.5 MPa and 124.28 MPa, respectively. Moreover, the differences of average stress between the bone and internal fixators are in the range of 2.3-13.7 MPa. During the eight phases of gait, the stress distribution of the left and right hip bone is similar. Meanwhile, based on the acetabular three-column theory, the strain energy ratio of the central column is relatively large in stance phases, while the anterior column and posterior column of the acetabular three-column increase in swing phases. CONCLUSIONS: The acetabular internal fixators designed by according to the anatomical feature of the acetabulum are integrated into the normal physiological stress conduction of the pelvis. The design and placement of the acetabular internal fixation conforming to the biomechanical characteristics of the bone is beneficial to the anatomical reduction and effective fixation of the fracture, especially for complex acetabular fracture.

Maternal Serum tRNA-Derived Fragments (tRFs) as Potential Candidates for Diagnosis of Fetal Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) is one of the most predominant birth defects that causes infant death worldwide. The timely and successful surgical treatment of CHD on newborns after delivery requires accurate detection and reliable diagnosis during pregnancy. However, there are no biomarkers that can serve as an early diagnostic factor for CHD patients. tRNA-derived fragments (tRFs) have been reported to play an important role in the occurrence and progression of numerous diseases, but their roles in CHD remains unknown. METHODS: High-throughput sequencing was performed on the peripheral blood of pregnant women with an abnormal fetal heart and a normal fetal heart, and 728 differentially expressed tRFs/tiRNAs were identified, among which the top 18 tRFs/tiRNAs were selected as predictive biomarkers of CHD. Then, a quantitative reverse transcriptase polymerase chain reaction verified the expression of tRFs/tiRNAs in more clinical samples, and the correlation between tRFs/tiRNAs abnormalities and CHD was analyzed. RESULTS: tRF-58:74-Gly-GCC-1 and tiRNA-1:35-Leu-CAG-1-M2 may be promising biomarkers. Through further bioinformatics analysis, we predicted that TRF-58:744-GLy-GCC-1 could induce CHD by influencing biological metabolic processes. CONCLUSIONS: Our results provide a theoretical basis for the abnormally expressed tRF-58:74-Gly-GCC-1 in maternal peripheral blood as a new potential biomarker for the accurate diagnosis of CHD during pregnancy.

Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity.

Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.

The optimal design of 3D-printed lattice bone plate by considering fracture healing mechanism.

The biomechanical stimulus is the most important factor for fracture healing and mainly determined by the structural stiffness of bone plate. Currently, the materials commonly used in bone plates are stainless steel and titanium, which often lead to stress shielding effects because of their higher elastic modulus compared with the bone. This article suggests an optimal design method of lattice bone plate based on fracture healing theory. First, the mechanical regulation model with deviatoric strain is established to simulate the tissue differentiation process during fracture healing process. The ratio of the average elastic modulus of callus at the 120th day to the elastic modulus of mature bone is used to characterize the fracture healing rate. Second, the optimal elastic modulus of the design domain is obtained by the optimization mathematical model with the maximum fracture healing rate. Then, the design domain is filled with microstructures, the porosity of which is adjusted to make it possible that the equivalent elastic modulus is equal to the optimized value. And the finite element analysis of the bone plate with microstructure is executed. Finally, the designed lattice bone plates are manufactured through 3D printing, and the mechanical test is carried out. The simulation results indicate that the fracture healing rate is maximum when the elastic modulus of material in design domain is 38 GPa under the constraints of fixation stability. And both the finite element analysis and experiment results show that the designed lattice bone plate meet the strength requirements of fracture internal fixation implants.

Altered glycolysis results in drug-resistant in clinical tumor therapy.

Cancer cells undergo metabolic reprogramming, including increased glucose metabolism, fatty acid synthesis and glutamine metabolic rates. These enhancements to three major metabolic pathways are closely associated with glycolysis, which is considered the central component of cancer cell metabolism. Increasing evidence suggests that dysfunctional glycolysis is commonly associated with drug resistance in cancer treatment, and aberrant glycolysis plays a significant role in drug-resistant cancer cells. Studies on the development of drugs targeting these abnormalities have led to improvements in the efficacy of tumor treatment. The present review discusses the changes in glycolysis targets that cause drug resistance in cancer cells, including hexokinase, pyruvate kinase, pyruvate dehydrogenase complex, glucose transporters, and lactate, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies. In addition, the association between increased oxidative phosphorylation and drug resistance is introduced, which is caused by metabolic plasticity. Given that aberrant glycolysis has been identified as a common metabolic feature of drug-resistant tumor cells, targeting glycolysis may be a novel strategy to develop new drugs to benefit patients with drug-resistance.

Impact of socioeconomic development on ecosystem services and its conservation strategies: a case study of Shandong Province, China.

Ecosystems and their components provide a lot of benefits for the welfare of human beings. Coupled with increasing socioeconomic development, most of the rapidly developing and transitional countries and regions have been experiencing dramatic land use changes. This has resulted in a large amount of forestland, grassland, and wetland being occupied as residential and industrial land or reclaimed for arable land, which in turn results in a sharp deterioration of ecosystem services around the world. Shandong Province, an economically powerful province of China, was chosen as a case study in order to capture the impact of socioeconomic development on ecosystem services. By way of the study, land uses and their changes were categorized between 1980 and 2006, and the ecosystem services capital and changes of 111 counties of Shandong Province in different phases were evaluated, as well as the total ecosystem services capital, followed by the zoning of ecosystem services function region of Shandong Province. We found that the counties in mountainous areas and wetlands, where generally the prefectural-level cities are located with a rapid socioeconomic development, experienced a successive deterioration of ecosystem services especially during the 2000s. Finally, three conservation strategies for managing and improving ecosystem services were proposed and discussed with the aim of achieving coordinate and sustainable development of the socioeconomy, environment, and ecosystems not only in Shandong Province but also in other provinces of China, as well as in other developing and transitional countries and regions.