Base editors: a powerful tool for generating animal models of human diseases

Myriads of genetic mutations, including base substitutions, deletions, and insertions as well as chromosome structural variations, have been detected in many human diseases. Although current combination of genomics and bioinformatics has contributed greatly to understanding the genetics of these disorders, it remains challenging to ensure the causal functions of each mutation, and then to further investigate the underlying mechanism and to develop therapeutic strategies. Animal models generated by genome engineering are the key to address these issues. In this review, we will first revisit the limitation of conventional gene editing tools and mouse models generated in the past. We will then introduce a novel tool, base editors (BEs), which present a new promising approach to establish pathogenically relevant animal models. Finally, we will discuss the application of BEs in non-human primates and share our perspectives on future development of base-editing techniques

Probing Dirac Neutrino Properties with Dilepton Signature

The neutrinophilic two Higgs doublet model is one of the simplest models to explain the origin of tiny Dirac neutrino masses. This model introduces a new Higgs doublet with eV scale VEV to naturally generate the tiny neutrino masses. Depending on the same Yukawa coupling, the neutrino oscillation patterns can be probed with the dilepton signature from the decay of charged scalar $H^\pm$. For example, the normal hierarchy predicts BR$(H^+\to e^+\nu)\ll$ BR$(H^+\to \mu^+\nu)\approx$ BR$(H^+\to \tau^+\nu)\simeq0.5$ when the lightest neutrino mass is below 0.01 eV, while the inverted hierarchy predicts BR$(H^+\to e^+\nu)/2\simeq$ BR$(H^+\to \mu^+\nu)\simeq$ BR$(H^+\to \tau^+\nu)\simeq0.25$. By precise measurement of BR$(H^+\to \ell^+\nu)$, we are hopefully to probe the lightest neutrino mass and the atmospheric mixing angle $\theta_{23}$. Through the detailed simulation of the dilepton signature and corresponding backgrounds, we find that the 3 TeV CLIC could discover $M_{H^+}\lesssim1220$ GeV for NH and $M_{H^+}\lesssim1280$ GeV for IH. Meanwhile, the future 100 TeV FCC-hh collider could probe $M_{H^+}\lesssim1810$ GeV for NH and $M_{H^+}\lesssim2060$ GeV for IH.Comment: 18 pages, 9 figure

Development of novel AMP-based absorbents for efficient CO2 capture with low energy consumption through modifying the electrostatic potential

The global deployment of aqueous amine absorbents for carbon dioxide (CO2) capture is hindered by their high energy consumption. A potential solution to this challenge lies in the utilization of non-aqueous amine systems, which offer energy-efficient alternatives. However, they are prone to form precipitation during CO2 absorption process, which limits their application. Combining experimental and theoretical studies, we found that the electrostatic potential of carbamate, instead of van der Waals force, is a major factor controlling the precipitation, and hydrogen bonds can effectively reduce the electrostatic potential of carbamate and prevent precipitation. Single solvent screening experiments have also demonstrated that the absorption rate is closely related to the viscosity of the organic solvent and the affinity of the functional group for CO2. The polar solvents (Dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), and N-Methylformamide (NMF)) exhibit higher absorption rates, but suffer from issues of precipitation. Hydroxyl group riched solvents (Ethylene glycol (EG) and Glycerol) exhibit lower absorption rate, but they don’t have the issue of precipitation. Based on these findings, several novel 2-Amino-2-methyl-1-propanol (AMP)-based non-aqueous absorbents have been developed aiming at reducing the energy penalty, and improving CO2 absorption and desorption performance. Among these absorbents, AMP-EG-DMF (4–3) exhibits maximum CO2 absorption rate and absorption capacity of 9.91 g-CO2/(kg-soln.·min.) and 122 g-CO2/(kg-soln.), respectively, which are 64.1% and 28.4% higher than those of 30 wt% AMP aqueous solution, respectively. Additionally, compared to 30 wt% MEA, the energy consumption of AMP-EG-DMF (4–3) shows 46.30% reduction. The addition of EG effectively improves the electrostatic solubility of AMP-carbamate by increasing the number and strength of hydrogen bonds, thus avoiding the generation of precipitation. The final product species and reaction mechanism were analysed by using 13C and 1H NMR, In-situ ATR-FTIR, and quantum chemical calculation. The combination of theoretical and experimental results indicates that bi-solvent AMP-based absorbents can serve as a promising alternative for low-energy CO2 capture

Scenario-based design and evaluation for capability

Scenarios are frequently used within techniques for planning and designing systems. They are an especially helpful means of visualizing and understanding the incorporation of new systems within systems of systems. If used as the basis for decisions about candidate designs, then it is important that such decisions can be rationalized and quantitative assessment is particularly important. In this paper, an approach for developing complex scenarios, which incorporates the phases of systems development and deployment, is presented and a quantitative method of comparison is described. This approach is based on the development of measures of merit and measures of performance. The techniques are illustrated using cases that are relevant to Network Enabled Capability

An energy-efficient cyclic amine system developed for carbon capture from both flue gas and air

High energy consumption is a major barrier to the large-scale deployment of carbon capture processes from flue gases or air (direct air capture, DAC). The non-aqueous amines reported in literature possess a high energy efficiency for CO2 capture from flue gases, they struggle with gas streams containing ultra-dilute CO2, like air, due to poor absorption kinetics. This study developed novel 2-PE (2-piperidineethanol)/APZ (Aminoethylpiperazine) based CO2 absorbents to address these problems. The experiments and MD simulation results showed that the 2-PE/APZ-based absorbents possessed a superior absorption performance both in flue gas and air. Among the developed absorbents, when 2-PE/APZ mixed with DMF (Dimethylformamide), the CO2 loading reached to 1.004 mol/mole, as the theoretical maximum. In DAC tests, 87.31 % CO2 from the air was captured in 24 h experiments. The regeneration heat duty of 2-PE/APZ/DMF decreased to 1.694 KJ/g CO2, a 55.89 % reduction compared to the benchmark 30 wt% MEA. The CO2 absorption/desorption mechanism was analysed by NMR, In-situ FT-IR, and DFT calculation. It indicated that this significant improvement in CO2 absorption performance and the reduction in energy consumption are due to the synergistic effect of 2-PE and APZ. During CO2 absorption, CO2 reacts with APZ forming APZ zwitterion rapidly, then deprotonation to the 2-PE. The formation of protonated 2-PEH+ ion pairs with APZCOO- reduces hydrogen bonds and van der Waals forces among the amine-CO2 complex, facilitating easy regeneration at mild conditions while maintaining high reactivity. The combination of theoretical and experimental results indicates that 2-PE/APZ-based absorbents can serve as a promising alternative for carbon capture from flue gas to air with low energy usage

Scenario-based design and evaluation for capability

Scenarios are frequently used within techniques for planning and designing systems. They are an especially helpful means of visualizing and understanding the incorporation of new systems within systems of systems. If used as the basis for decisions about candidate designs, then it is important that such decisions can be rationalized and quantitative assessment is particularly important. In this paper, an approach for developing complex scenarios, which incorporates the phases of systems development and deployment, is presented and a quantitative method of comparison is described. This approach is based on the development of measures of merit and measures of performance. The techniques are illustrated using cases that are relevant to Network Enabled Capability

Human Umbilical Cord Blood-Derived CD34+ Cells Reverse Osteoporosis in NOD/SCID Mice by Altering Osteoblastic and Osteoclastic Activities

Osteoporosis is a bone disorder associated with loss of bone mineral density and micro architecture. A balance of osteoblasts and osteoclasts activities maintains bone homeostasis. Increased bone loss due to increased osteoclast and decreased osteoblast activities is considered as an underlying cause of osteoporosis.The cures for osteoporosis are limited, consequently the potential of CD34+ cell therapies is currently being considered. We developed a nanofiber-based expansion technology to obtain adequate numbers of CD34(+) cells isolated from human umbilical cord blood, for therapeutic applications. Herein, we show that CD34(+) cells could be differentiated into osteoblastic lineage, in vitro. Systemically delivered CD34(+) cells home to the bone marrow and significantly improve bone deposition, bone mineral density and bone micro-architecture in osteoporotic mice. The elevated levels of osteocalcin, IL-10, GM-CSF, and decreased levels of MCP-1 in serum parallel the improvements in bone micro-architecture. Furthermore, CD34(+) cells improved osteoblast activity and concurrently impaired osteoclast differentiation, maturation and functionality.These findings demonstrate a novel approach utilizing nanofiber-expanded CD34(+) cells as a therapeutic application for the treatment of osteoporosis