Genetic Removal of the CH1 Exon Enables the Production of Heavy Chain-Only IgG in Mice

Nano-antibodies possess great potential in many applications. However, they are naturally derived from heavy chain-only antibodies (HcAbs), which lack light chains and the CH1 domain, and are only found in camelids and sharks. In this study, we investigated whether the precise genetic removal of the CH1 exon of the γ1 gene enabled the production of a functional heavy chain-only IgG1 in mice. IgG1 heavy chain dimers lacking associated light chains were detected in the sera of the genetically modified mice. However, the genetic modification led to decreased expression of IgG1 but increased expression of other IgG subclasses. The genetically modified mice showed a weaker immune response to specific antigens compared with wild type mice. Using a phage-display approach, antigen-specific, single domain VH antibodies could be screened from the mice but exhibited much weaker antigen binding affinity than the conventional monoclonal antibodies. Although the strategy was only partially successful, this study confirms the feasibility of producing desirable nano-bodies with appropriate genetic modifications in mice

Prevalence, Predictors and Mechanisms of Steam Pops in Ablation Index-Guided High-Power Pulmonary Vein Isolation

Despite the good cooling effect of the contact-force porous catheter, the risk of steam pops (SP) remains one of the major concerns in high-power circumferential pulmonary vein isolation (CPVI). This study aimed to investigate the prevalence, predictors and possible mechanisms of SPs in CPVI. Patients experiencing SPs in de novo high-power CPVI were 1:3 matched by non-SP patients with gender, age (±5 years) and left atrial diameter (LAD) (±5 mm) to compare the ablation parameters of SP and non-SP lesions. Catheter tip displacement (Tipdisp) was compared between “edge-of-ridge” and “PV-side-of-ridge” placement at anterior and roof segments of the left pulmonary vein (PV). SPs occurred in 11 (1.57%) of 701 patients, including 6 at the antero-superior left PV, 2 at the roof, 1 at the postero-superior left PV, 1 at the bottom left PV and 1 at the antero-superior aspect of the right PV. There was significantly shorter RF delivery duration (13.9 ± 6.3 vs. 23.3 ± 6.0 s), greater Δimpedance (17.6 ± 6.7 vs. 6.7 ± 4.1 Ω) and lower ablation index (357.7 ± 68.8 vs. 430.2 ± 30.7) in SP patients than those in non-SP patients. Δimpedance >12 Ω during ablation could predict SP occurrence. Tipdisp was greater in “PV-side-of-ridge” than that in “edge-of -ridge” placement (3.2 ± 1.6 mm vs. 2.0 ± 0.8 mm) at antero-superior and roof segments of the left PV. The prevalence of SP was 1.57% in high-power CPVI procedures, with the most common site at the antero-superior segment of the left PV. Δimpedance was a significant predictor of SP occurrence. “PV-side-of-ridge” ablation at antero-superior and roof segments of left PV might predispose to SP occurrence due to excessive tissue coverage

Cyclophilin A Protects Cardiomyocytes against Hypoxia/Reoxygenation-Induced Apoptosis via the AKT/Nox2 Pathway

Hypoxia/reoxygenation (H/R) accelerates the process of cardiomyocyte apoptosis during ischemia-reperfusion. Excessive reactive oxygen species (ROS) are a critical driver of oxidative stress injury. Cyclophilin A (CyPA) is a major ROS-induced factor in atherosclerosis. There is a positive feedback mechanism between CyPA and ROS, which enables the oxidative stress response to continue and expand. However, it is unclear whether this positive feedback mechanism exists in cardiomyocytes. Through western blotting and flow cytometric assays and TUNEL assay, we found that CyPA inhibited the apoptosis of H9c2 cardiomyocytes under H/R conditions. By dihydroethidium (DHE) staining and electron spin resonance (ESR) assays, we demonstrated that CyPA reduced ROS production and suppressed O2- production dependent on reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. By western blotting, we showed that CyPA inhibited the expression of NADPH oxidase 2 (Nox2) protein by the AKT pathway. Through confocal microscopy assay, we found that CyPA reduced the expression of Nox2 membrane-bound subunits. The current study shows that a positive feedback mechanism does not exist in H9c2 cardiomyoblasts. CyPA protects H9c2 cardiomyoblasts against H/R-induced apoptosis via the AKT/Nox2 pathway. This could be a potential target for ischemia-reperfusion injury therapy

Numerical Analysis and Optimization of Flow Rate for Vanadium Flow Battery Incorporating Temperature Effect

The vanadium flow batteries that employ the vanadium element as active couples for both half-cells, thus avoiding cross-contamination, are promising large-scale energy storage devices. In this work, the flow rate is optimized by incorporating the temperature effects, attempting to realize a more accurate flow control and subsequently enhance the performance of vanadium flow batteries. This work starts with the development of a comprehensive dynamic model on the basis of mass conservation, followed by a modeling validation and a thorough investigation of the temperature effects on electrolyte viscosity and internal resistance. After that, the flow rate is optimized to incorporate such effects. It is found that the flow rate strategy needs to be regulated with the variation of temperature due to the variations of electrolyte viscosity and internal resistance. Moreover, a relatively low flow rate is preferable for low-temperature applications, while for the high-temperature use, a relatively high flow rate is encouraged. Such in-depth investigation can not only provide a cost-effective method to optimize the flow rate and predict the behaviors of vanadium flow batteries, but can also be of great benefit to the management, application, and promotion of vanadium flow batteries

Lateral Power Mosfet For Megahertz-Frequency, High-Density Dc/Dc Converters

DC/DC converters to power future CPU cores mandate low-voltage power metal-oxide semiconductor field-effect transistors (MOSFETs) with ultra low on-resistance and gate charge. Conventional vertical trench MOSFETs cannot meet the challenge. In this paper, we introduce an alternative device solution, the large-area lateral power MOSFET with a unique metal interconnect scheme and a chip-scale package. We have designed and fabricated a family of lateral power MOSFETs including a sub-10 V class power MOSFET with a record-low R DS(ON) of 1 mΩ at a gate voltage of 6 V, approximately 50% of the lowest RDS(ON) previously reported. The new device has a total gate charge Qg of 22 nC at 4.5 V and a performance figures of merit of less than 30 mΩ - nC, a 3 × improvement over the state of the art trench MOSFETs. This new MOSFET was used in a 100-W dc/dc converter as the synchronous rectifiers to achieve a 3.5-MHz pulse-width modulation switching frequency, 97%-99% efficiency, and a power density of 970 W/in3. The new lateral MOSEFT technology offers a viable solution for the next-generation, multimegahertz, high-density dc/dc converters for future CPU cores and many other high-performance power management applications. © 2006 IEEE

Corrosion Behavior of As-Cast Ti–10Mo–6Zr–4Sn–3Nb and Ti–6Al–4V in Hank’s Solution: A Comparison Investigation

Newly developed Ti–10Mo–6Zr–4Sn–3Nb has fascinating mechanical properties to be used as a biomedical material. However, there is still a lack of investigation focusing on the corrosion behavior of Ti–10Mo–6Zr–4Sn–3Nb. In this work, the microstructure and corrosion behavior of as-cast Ti–10Mo–6Zr–4Sn–3Nb was investigated by optical microscopy, X-ray diffraction, and electrochemical measurements. Hank’s solution was used as the electrolyte. A classical as-cast Ti–6Al–4V was used as reference. The results showed that Ti–10Mo–6Zr–4Sn–3Nb has a higher corrosion potential and a lower corrosion current density compared with Ti–6Al–4V, indicating better corrosion resistance. However, after applying anodic potentials, Ti–10Mo–6Zr–4Sn–3Nb shows larger passivation current density in both potentiodynamic polarization and potentiostatic polarization tests. This is because more alloying elements contained in Ti–10Mo–6Zr–4Sn–3Nb trigger the production of a larger number of oxygen vacancies, resulting in a higher flux of oxygen vacancy. This finding illustrates that the passive film on Ti–10Mo–6Zr–4Sn–3Nb is less protective compared with that on Ti–6Al–4V when applying an anodic potential in their passivation range

Pulmonary vein perforation into the respiratory tract with systemic air embolism: a rare complication of left atrial appendage closure

Abstract Background Pulmonary vein perforation is an uncommon complication during cardiac intervention. We present a rare case of pulmonary vein perforation into the respiratory tract with systemic air embolism during left atrial appendage closure (LAAC). Case presentation A 77-year-old man with persistent nonvalvular atrial fibrillation was referred for percutaneous LAAC under local anaesthesia (CHA2DS2-VASc score of 4, HAS-BLED score of 3, and prior ischaemic stroke). During the procedure, after delivering a super-stiff guidewire into the left superior pulmonary vein (LSPV), the patient suddenly developed a severe cough with haemoptysis upon advancement of a delivery sheath along the guidewire. Fluoroscopy showed signs of blood entering the left main bronchus, and fast transthoracic echocardiography revealed bubbles in the left heart without pericardial effusion. The procedure was terminated because of a major complication indicated by the repeated haemoptysis and headache, and haemostatic drugs were immediately administered. Subsequent chest computed tomography angiography (CTA) revealed a filling defect in the LSPV branches and bubbles in the aorta. The patient was transferred to the critical care unit for haemostasis and antibacterial treatment. Transthoracic echocardiography later that day showed no bubbles in the heart. The headache and haemoptysis significantly abated the following day. The bubbles in the aorta disappeared on chest CTA 7 days later. Conclusions Interventional cardiologists should pay attention to anatomical variations of the pulmonary vein, which are associated with a high risk of complications of pulmonary vein perforation during LAAC. Preoperative CTA examination and intraoperative transoesophageal echocardiography might be helpful to avoid this complication

Precipitation Behavior and Microstructural Evolution of α Phase during Hot Deformation in a Novel β-Air-Cooled Metastable β-Type Ti-B12 Alloy

The precipitation behavior and microstructural evolution of α phase in a novel metastable β-type Ti alloy, Ti-10Mo-6Zr-4Sn-3Nb (wt.%), during isothermal compression are investigated in this study through the use of SEM (scanning electron microscope), TEM (transmission electron microscope) (HRTEM) (high-resolution transmission electron microscopy) and EBSD techniques. The results show that some finer α precipitates are randomly distributed within the β matrix during hot deformation. The morphological characteristics of α precipitates are distinctly different from those of α precipitates during the same solution-plus-aging treatment. The volume fraction of α precipitate gradually increases with increased true strain. A large proportion of precipitated α phases are prone to be precipitated at HAGBs (high-angle grain boundaries) and LAGBs (low-angle grain boundaries) during isothermal deformation. On the contrary, only a small amount of spherical α phases is precipitated within the β grain. The crystallographic orientation relationships for most spherical α precipitates formed at LAGBs and within the β grains are similar, whereas the crystallographic orientation relationships for α precipitates at grain boundaries are significantly different. The precipitation behavior of α phase in the Ti-B12 alloy during hot compression is considerably influenced by the density of dislocations

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Ameliorate Aging-Induced BTB Impairment in Porcine Testes by Activating Autophagy and Inhibiting ROS/NLRP3 Inflammasomes via the AMPK/mTOR Signaling Pathway

As a pivotal player in spermatogenesis, the blood-testis barrier (BTB) made from junction apparatus coexisting in Sertoli cells (SCs) is impaired with an increase in age and ultimately induces spermatogenic dysfunction or even infertility. It has been corroborated that bone marrow mesenchymal stem cell (BMSC) transplantation can efficiently repair and regenerate the testicular function. As vital mediators of cell-to-cell communication, MSC-derived exosomes (Exos) can directly serve as therapeutic agents for tissue repair and regeneration. However, the therapeutic value of BMSC-Exos in aging-induced BTB damage remains to be confirmed. In this study, we explored that the old porcine testes had defective autophagy, which aggravated BTB disruption in SCs. BMSC-Exos could decrease ROS production and NLRP3 inflammasome activation but enhanced autophagy and tight junction (TJ) function in D-gal-triggered aging porcine SCs and mouse model testes, according to in vitro and in vivo experiments. Furthermore, rapamycin, NAC, MCC950, and IL-1Ra restored the TJ function in D-gal-stimulated aging porcine SCs, while BMSC-Exos’ stimulatory effect on TJ function was inhibited by chloroquine. Moreover, the treatment with BMSC-Exos enhanced autophagy in D-gal-induced aging porcine SCs by means of the AMPK/mTOR signal transduction pathway. These findings uncovered through the present study that BMSC-Exos can enhance the BTB function in aging testes by improving autophagy via the AMPK/mTOR signaling pathway, thereby suppressing ROS production and NLRP3 inflammasome activation