In situ correction of various β-thalassemia mutations in human hematopoietic stem cells

β-thalassemia (β-thal) is the most common monogenic disorder caused by various mutations in the human hemoglobin β (HBB) gene and affecting millions of people worldwide. Electroporation of Cas9 and single-guide RNA (sgRNA)–ribonucleoprotein (RNP) complex-mediated gene targeting in patient-derived hematopoietic stem cells (HSCs), followed by autologous transplantation, holds the promise to cure patients lacking a compatible bone marrow donor. In this study, a universal gene correction method was devised to achieve in situ correction of most types of HBB mutations by using validated CRISPR/sgRNA–RNP complexes and recombinant adeno-associated viral 6 (rAAV6) donor-mediated homology-directed repair (HDR) in HSCs. The gene-edited HSCs exhibited multi-lineage formation abilities, and the expression of β-globin transcripts was restored in differentiated erythroid cells. The method was applied to efficiently correct different mutations in β-thal patient-derived HSCs, and the edited HSCs retained the ability to engraft into the bone marrow of immunodeficient NOD-scid-IL2Rg−/− (NSI) mice. This study provides an efficient and safe approach for targeting HSCs by HDR at the HBB locus, which provides a potential therapeutic approach for treating other types of monogenic diseases in patient-specific HSCs

Electronically phase separated nano-network in antiferromagnetic insulating LaMnO3/PrMnO3/CaMnO3 tricolor superlattice

Strongly correlated materials often exhibit an electronic phase separation (EPS) phenomena whose domain pattern is random in nature. The ability to control the spatial arrangement of the electronic phases at microscopic scales is highly desirable for tailoring their macroscopic properties and/or designing novel electronic devices. Here we report the formation of EPS nanoscale network in a mono-atomically stacked LaMnO3/CaMnO3/PrMnO3 superlattice grown on SrTiO3 (STO) (001) substrate, which is known to have an antiferromagnetic (AFM) insulating ground state. The EPS nano-network is a consequence of an internal strain relaxation triggered by the structural domain formation of the underlying STO substrate at low temperatures. The same nanoscale network pattern can be reproduced upon temperature cycling allowing us to employ different local imaging techniques to directly compare the magnetic and transport state of a single EPS domain. Our results confirm the one-to-one correspondence between ferromagnetic (AFM) to metallic (insulating) state in manganite. It also represents a significant step in a paradigm shift from passively characterizing EPS in strongly correlated systems to actively engaging in its manipulation

Enhancement of PRMT6 binding to a novel germline <i>GATA1</i> mutation associated with congenital anemia

Mutations in the master hematopoietic transcription factor GATA1 are often associated with functional defects in erythropoiesis and megakaryopoiesis. In this study, we identified a novel GATA1 germline mutation (c.1162delGG, p.Leu387Leufs*62) in a patient with congenital anemia and occasional thrombocytopenia. The C-terminal GATA1, a rarely studied mutational region, undergoes frameshifting translation as a consequence of this double-base deletion mutation. To investigate the specific function and pathogenic mechanism of this mutant, in vitro mutant models of stable re-expression cells were generated. The mutation was subsequently validated to cause diminished transcriptional activity of GATA1 and defective differentiation of erythroid and megakaryocytes. Using proximity labeling and mass spectrometry, we identified selective alterations in the proximal protein networks of the mutant, revealing decreased binding to a set of normal GATA1-interaction proteins, including the essential co-factor FOG1. Notably, our findings further demonstrated enhanced recruitment of the protein arginine methyltransferase PRMT6, which mediates histone modification at H3R2me2a and represses transcription activity. We also found an enhanced binding of this mutant GATA1/PRMT6 complex to the transcriptional regulatory elements of GATA1’s target genes. Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function and the broader role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis

Derivative Markets in China: Guest Editors' Introduction

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Reversible Addition-Fragmentation Chain Transfer Polymerization of Acrylonitrile under Irradiation of Blue LED Light

Compared to unhealthy UV or γ-ray and high-energy-consumption thermal external stimuli, the promising light emitting diode (LED) external stimulus has some outstanding technological merits such as narrow wavelength distribution, low heat generation and energy consumption, and safety for human beings. In this work, a novel reversible addition-fragmentation transfer (RAFT) polymerization system for acrylonitrile (AN) was developed under the irradiation of blue LED light at room temperature, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a novel radical initiator and 2-cyanoprop-2-yl-1-dithionaphthalate (CPDN) as the typical chain transfer agent. Well-defined polyacrylonitrile (PAN) with a controlled molecular weight and narrow molecular weight distribution was successfully synthesized. This strategy may provide another effective method for scientific researchers or the industrial community to synthesize a PAN-based precursor of carbon fibers

Regional differences and determinants of built-up area expansion in China

Based on remote sensing data on land use provided by the Chinese Academy of Sciences and socioeconomic data collected by the authors, this paper analyzes the trends and regional differences in built-up area (BUA) expansion in China from the late 1980s to 2000, and empirically estimates the major determinants of BUA expansion in different regions in 1996-2000. In 1989-2000, although China's overall BUA expansion accelerated, the trends differed significantly among regions. BUA expansion in the central and western regions accelerated significantly, but it slowed down considerably in the eastern region. The estimation results from our econometric analysis reveal that BUA expansion in the eastern region reached a period when economic growth had no further significant impact on per capita BUA, the land utilization in this region has become more intensive with further expansion of the economy. In the central and western regions, the BUA has expanded remarkably due to the relatively more flexible land development policies and the relatively cheap land prices. Therefore, as the economy continues to grow rapidly, policies relating to BUA expansion and cultivated land reductions may face more serious challenges in the central and western regions

A green route to synthesize low-cost and high-performance hard carbon as promising sodium-ion battery anodes from sorghum stalk waste

Sodium-ion batteries (SIBs) have been considered to be potential candidates for next-generation low-cost energy storage systems due to the low-cost and abundance of Na resources. However, it is a big challenge to find suitable anode materials with low-cost and good performance for the application of SIBs. Hard carbon could be a promising anode material due to high capacity and expectable low-cost if originating from biomass. Herein, we report a hard carbon material derived from abundant and abandoned biomass of sorghum stalk through a simple carbonization method. The effects of carbonization temperature on microstructure and electrochemical performance are investigated. The hard carbon carbonized at 1300 °C delivers the best rate capability (172 mAh gâ1 at 200 mA gâ1) and good cycling performance (245 mAh gâ1 after 50 cycles at 20 mA gâ1, 96% capacity retention). This contribution provides a green route for transforming sorghum stalk waste into âtreasureâ of promising low-cost anode material for SIBs. Keywords: Sorghum stalk, Hard carbon, Anode, Sodium-ion battery, Carbonizatio