Proprotein convertase subtilisin/kexin type 9 deficiency in extrahepatic tissues: emerging considerations.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily secreted by hepatocytes. PCSK9 is critical in liver low-density lipoprotein receptors (LDLRs) metabolism. In addition to its hepatocellular presence, PCSK9 has also been detected in cardiac, cerebral, islet, renal, adipose, and other tissues. Once perceived primarily as a "harmful factor," PCSK9 has been a focal point for the targeted inhibition of both systemic circulation and localized tissues to treat diseases. However, PCSK9 also contributes to the maintenance of normal physiological functions in numerous extrahepatic tissues, encompassing both LDLR-dependent and -independent pathways. Consequently, PCSK9 deficiency may harm extrahepatic tissues in close association with several pathophysiological processes, such as lipid accumulation, mitochondrial impairment, insulin resistance, and abnormal neural differentiation. This review encapsulates the beneficial effects of PCSK9 on the physiological processes and potential disorders arising from PCSK9 deficiency in extrahepatic tissues. This review also provides a comprehensive analysis of the disparities between experimental and clinical research findings regarding the potential harm associated with PCSK9 deficiency. The aim is to improve the current understanding of the diverse effects of PCSK9 inhibition.

Computational analysis of the biomechanical stability of internal fixation of the lateral tibial plateau fracture: A mechanical stability study.

The selection of internal fixation as the primary fixation modality for the patient is one of the challenges for the surgeon treating the patient in question. A model of the lateral tibial plateau fracture was established. Three different configurations of internal fixators namely L bone plate, T bone plate, and screw-washer were analyzed. Three stages after surgery were simulated to assess the displacement of bone plates, screws, washers, and the stress shielding ratio in the fracture area.At three stages after surgery, the T bone plate showed better stability for patients during rehabilitation compared with the remaining two schemes, and the screw-washer scheme was the least stable due to the larger internal fixation displacement and stress shielding ratio in the fracture area. In contrast, the L bone plate scheme showed better stability in the early stages after surgery but was second only to the screw-washer scheme in the middle and late stages after surgery. The T bone plate showed better stability and became a new selection for surgeons to treat related patients. At three stages after surgery, the T bone plate has better biomechanical stability compared to the L bone plate and screw-washer schemes.

Finite element model with realistic bone geometries for the optimal design of internal fixation during the fibula healing process.

A finite element model with realistic bone geometries is developed to design optimal internal fixation during the fibula healing process in this study. The effect of bone plate parameters on fibula fracture healing is studied. The relationship between differences in plate length, thickness and working length, and bone healing performance is focused. The optimal combination form of the bone plate parameters was selected by the orthogonal experimental design and fracture block strain to achieve bone healing maximize the performance. The model results show that the maximum equivalent force of the bone plate was below the material yield limit; the higher mean contact stresses in the bone fragments indicate that the bone plate is prone to higher contact stresses when they are long. The working length of the bone plate has a greater effect on callus healing than the thickness and length of the bone plate. The optimal internal fixation option for distal fibula fractures is achieved when it provides the stability required for internal fixation during bone healing. It ensures lower contact stresses in the fibula as well as maximum Young's modulus during callus healing process.

Generation of a FLNA knockout hESC line (WAe009-A-P) to model cardiac valvular dysplasia using CRISPR/Cas9.

The FLNA gene encodes the cytoskeletal protein filamin A which plays a key role in the structure and function of the cardiac valves. Truncating FLNA mutations are associated with cardiac valvular dysplasia. To further understand the exact role of FLNA in this disease, we have generated a human FLNA knockout cell line from H9 using CRISPR/Cas9 technology in this study. This cell line WAe009-A-P has a 2 bp deletion in the exon 2 of FLNA gene which resulted in a frameshift in the translation of FLNA and no FLNA protein was detected in this cell line. Moreover, WAe009-A-P also expressed pluripotency markers, had a normal female karyotype (46XX) and maintained the ability to differentiate into the three germ layers in vitro.

The association between circulatory, local pancreatic PCSK9 and type 2 diabetes mellitus: The effects of antidiabetic drugs on PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent modulator of cholesterol metabolism and plays a crucial role in the normal functioning of pancreatic islets and the progression of diabetes. Islet autocrine PCSK9 deficiency can lead to the enrichment of low-density lipoprotein (LDL) receptor (LDLR) and excessive LDL cholesterol (LDL-C) uptake, subsequently impairing the insulin secretion in ß-cells. Circulatory PCSK9 levels are primarily attributed to hepatocyte secretion. Notably, anti-PCSK9 strategies proposed for individuals with hypercholesterolemia chiefly target liver-derived PCSK9; however, these anti-PCSK9 strategies have been associated with the risk of new-onset diabetes mellitus (NODM). In the current review, we highlight a new direction in PCSK9 inhibition therapy strategies: screening candidates for anti-PCSK9 from the drugs used in type 2 diabetes mellitus (T2DM) treatment. We explored the association between circulating, local pancreatic PCSK9 and T2DM, as well as the relationship between PCSK9 monoclonal antibodies and NODM. We discussed the emergence of artificial and natural drugs in recent years, exhibiting dual benefits of antidiabetic activity and PCSK9 reduction, confirming that the diverse effects of these drugs may potentially impact the progression of diabetes and associated disorders, thereby introducing novel avenues and methodologies to enhance disease prognosis.

Flexible pillared graphene-paper electrodes for high-performance electrochemical supercapacitors.

Flexible graphene paper (GP) pillared by carbon black (CB) nanoparticles using a simple vacuum filtration method is developed as a high-performance electrode material for supercapacitors. Through the introduction of CB nanoparticles as spacers, the self-restacking of graphene sheets during the filtration process is mitigated to a great extent. The pillared GP-based supercapacitors exhibit excellent electrochemical performances and cyclic stabilities compared with GP without the addition of CB nanoparticles. At a scan rate of 10 mV s(-1) , the specific capacitance of the pillared GP is 138 F g(-1) and 83.2 F g(-1) with negligible 3.85% and 4.35% capacitance degradation after 2000 cycles in aqueous and organic electrolytes, respectively. At an extremely fast scan rate of 500 mV s (-1) , the specific capacitance can reach 80 F g(-1) in aqueous electrolyte. No binder is needed for assembling the supercapacitor cells and the pillared GP itself may serve as a current collector due to its intrinsic high electrical conductivity. The pillared GP has great potential in the development of promising flexible and ultralight-weight supercapacitors for electrochemical energy storage.

Amorphization of nanocrystalline monoclinic ZrO2 by swift heavy ion irradiation.

Bulk ZrO(2) polymorphs generally have an extremely high amorphization tolerance upon low energy ion and swift heavy ion irradiation in which ballistic interaction and ionization radiation dominate the ion-solid interaction, respectively. However, under very high-energy irradiation by 1.33 GeV U-238, nanocrystalline (40-50 nm) monoclinic ZrO(2) can be amorphized. A computational simulation based on a thermal spike model reveals that the strong ionizing radiation from swift heavy ions with a very high electronic energy loss of 52.2 keV nm(-1) can induce transient zones with temperatures well above the ZrO(2) melting point. The extreme electronic energy loss, coupled with the high energy state of the nanostructured materials and a high thermal confinement due to the less effective heat transport within the transient hot zone, may eventually be responsible for the ionizing radiation-induced amorphization without transforming to the tetragonal polymorph. The amorphization of nanocrystalline zirconia was also confirmed by 1.69 GeV Au ion irradiation with the electronic energy loss of 40 keV nm(-1). These results suggest that highly radiation tolerant materials in bulk forms, such as ZrO(2), may be radiation sensitive with the reduced length scale down to the nano-metered regime upon irradiation above a threshold value of electronic energy loss.

[Relationship among areca nut, intracellular reactive oxygen species, and autophagy].

The relationship between areca nut as a primary carcinogen and oral cancer has been widely concerned. Areca can change the levels of reactive oxygen species (ROS) and autophagy in cells, and the levels of ROS and autophagy are closely related to the occurrence and development of tumors. This paper reviewed the relationships among areca nut, intracellular ROS, and autophagy.

Ion beam-induced amorphous-to-tetragonal phase transformation and grain growth of nanocrystalline zirconia.

Nanocrystalline zirconia has recently attracted extensive research interest due to its unique mechanical, thermal and electrical properties as compared with bulk zirconia counterparts, and it is of particular importance for controlling the phase stability of different polymorphs (amorphous, cubic, tetragonal and monoclinic phases) in different size regimes. In this work, we performed ion beam bombardments on bilayers (amorphous and cubic) of nano-zirconia using 1 MeV Kr2+ irradiation. Transmission electron microscopy (TEM) analysis reveals that amorphous zirconia transforms to a tetragonal structure under irradiation at room temperature, suggesting that the tetragonal phase is more energetically favorable under these conditions. The final grain size of the tetragonal zirconia can be controlled by irradiation conditions. A slower kinetics in the grain growth from cubic nanocrystalline zirconia was found as compared with that for the tetragonal grains recrystallized from the amorphous layer. The radiation-induced nanograins of tetragonal ZrO2 are stable at ambient conditions and maintain their physical integrity over a long period of time after irradiation. These results demonstrated that ion beam methods provide the means to control the phase stability and structure of zirconia polymorphs.

Advanced phase change composite by thermally annealed defect-free graphene for thermal energy storage.

Organic phase change materials (PCMs) have been utilized as latent heat energy storage and release media for effective thermal management. A major challenge exists for organic PCMs in which their low thermal conductivity leads to a slow transient temperature response and reduced heat transfer efficiency. In this work, 2D thermally annealed defect-free graphene sheets (GSs) can be obtained upon high temperature annealing in removing defects and oxygen functional groups. As a result of greatly reduced phonon scattering centers for thermal transport, the incorporation of ultralight weight and defect free graphene applied as nanoscale additives into a phase change composite (PCC) drastically improve thermal conductivity and meanwhile minimize the reduction of heat of fusion. A high thermal conductivity of the defect-free graphene-PCC can be achieved up to 3.55 W/(m K) at a 10 wt % graphene loading. This represents an enhancement of over 600% as compared to pristine graphene-PCC without annealing at a comparable loading, and a 16-fold enhancement than the pure PCM (1-octadecanol). The defect-free graphene-PCC displays rapid temperature response and superior heat transfer capability as compared to the pristine graphene-PCC or pure PCM, enabling transformational thermal energy storage and management.

[Exploring the relationship between secreted frizzled-related protein 1 and chronic periodontitis].

OBJECTIVE: This study detects the expression of secreted frizzled-related protein 1 (SFRP1) in healthy patients and patients with chronic periodontitis (CP) and explores the relationship between SFRP1 and the occurrence and development of CP. METHODS: First, 28 patients forming the CP group were further divided into mild, moderate, and severe CP subgroups according to clinical attachment loss (CAL) data. Ten healthy volunteers were recruited in the control group. Gingival crevicular fluid (GCF) was collected from all of the patients, and the concentration of SFRP1 in the GCF samples was detected using enzyme-linked immunosorbent assay. Next, gingival lesions were obtained from 22 patients in the CP group and healthy gingival tissues were obtained from the 10 healthy patients in the control group. Immunohistochemical analysis for SFRP1 was used to analyze the correlation between the expression of SFRP1 and the severity of CP based on staining intensities. RESULTS: The concentration of SFRP1 in GCF samples taken from of the CP group (281.07 ng x L(-1) +/- 33.37 ng x L(-1)) was significantly higher than that in samples taken from the control group (245.30 ng x L(-1) +/- 35.69 ng x L(-1)) (P < 0.05). A significant positive correlation was observed between the concentration of SFRP1 in GCF and CAL (r = 0.651, P < 0.001). Furthermore, the SFRP1 scores in the CP groups (4.500 +/- 0.913) were significantly higher than those in the control group (2.800 +/- 1.135) (P < 0.001). SFRP1 scores did not vary significantly among the CP subgroups (P > 0.05). CONCLUSION: SFRP1 expression in the CP groups was significantly higher than that in the control group. Thus, SFRP1 may play a significant role in the development of CP.

Unique role of ionic liquid in microwave-assisted synthesis of monodisperse magnetite nanoparticles.

A small amount of ionic liquid [bmim][BF(4)] was found to be an efficient aid for microwave heating of nonpolar dibenzyl ether in high temperature solution-phase synthesis of monodisperse magnetite nanoparticles. It was found to act as both microwave absorber and assistant stabilizer in the reactive process and was recovered and reused in successive reactions.