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Known fetal hemoglobin (HbF) silencers have potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here, through transcription factor (TF) CRISPR screening, we identify zinc-finger protein (ZNF) 410 as an HbF repressor. ZNF410 does not bind directly to the genes encoding γ-globins, but rather its chromatin occupancy is concentrated solely at CHD4, encoding the NuRD nucleosome remodeler, which is itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for the effects of ZNF410 on fetal globin repression. Knockout of ZNF410 or its mouse homolog Zfp410 reduces CHD4 levels by 60%, enough to substantially de-repress HbF while eluding cellular or organismal toxicity. These studies suggest a potential target for HbF induction for β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved TF with singular devotion to regulation of a chromatin subcomplex.

During the 29th Chinese National Antarctic Research Expedition, spatial variations in nitrogen isotopic composition of particulate nitrogen (δ15NPN) and their controlling factors were examined in detail with regard to nitrate drawdown by phytoplankton and particulate nitrogen (PN) remineralization in the Prydz Bay and its adjacent areas. To better constrain the nitrogen transformations, the physical and chemical parameters, including temperature, salinity, nutrients, PN and δ15NPN in seawater column were measured from surface to bottom. In addition, the nitrogen isotopic fractionation factor of nitrate assimilation by phytoplankton in the mixed layer, and the nitrogen isotopic fractionation factor of PN remineralization below the mixed layer were estimated using Rayleigh model and Steady State model, respectively. Our results showed that suspended particles had its lowest δ15NPN in the surface layer, which was due to the preferential assimilation of 14N in nitrate by phytoplankton. The δ15NPN in the mixed layer of the Prydz Bay and its adjacent areas decreased from the inner shelf to the outer basin, ascribing to the effect of isotope fractionation during phytoplankton assimilation. In mixed layer, the spatial distribution of δ15NPN associated with particulate organic matter (POM) production can be well interpreted according to Rayleigh model and Steady State model. The nitrogen isotope fractionation factor during phytoplankton assimilating nitrate was estimated as 10.0%o by Steady State model, which was more reasonable than that calculated by Rayleigh model. These results validate the previous reports of fractionation factor during nitrate assimilation by phytoplankton. Increasing δ15NPN with depth below the euphotic zone correlated with the decreasing PN contents, and it was attributed to preferential remineralization of 14N in PN by bacteria. In subsurface and deep layer, the δ15NPN distributions also conformed to Rayleigh model and Steady State model during PN remineralization, with a fractionation factor of about 3.6% and 3.2%, respectively. It is the first time to estimate the fractionation factor during POM production and remineralization in the Prydz Bay and its adjacent areas. Such fractionation may provide a useful tool for the follow-up study of the nitrogen dynamics in the Southern Ocean.

Microbe-assisted phytoremediation provides an eco-friendly and cost-effective approach to reclaim Cd- and Pb-contaminated soils. In this work, incubation and pot experiments were established to investigate the effect of Streptomyces pactum (Act12) combined with compost on soil physicochemical properties, enzymatic activities, and thereby acted on phytoextraction of Cd and Pb by using potherb mustard (Brassica juncea Coss.). The addition of Act12 and compost increased EC (7.2%), available phosphorus (P) (14.9%), available potassium (K) (17.0 folds), DOC (37.7%), OM (2.8 folds), urease (49.8%), dehydrogenase (2.2 folds), and alkaline phosphatase (23.0 folds) of soil, while reduced pH (7.7%) compared with control. Significant decrease of available Cd and Pb uptake was observed after adding compost and Act12 by 29.1% and 32.2%. Presence of compost and Act12 enhanced the biomass by 3.98 folds and 1.83 folds in shoots and roots of plant. Results showed the assimilation of Cd and Pb in shoots was increased by 103.8% and 48.7% due to the increased of biomass. Meanwhile, the rhizosphere effect of soil microorganisms increased the uptake of Cd (60.4%) and Pb (19.2%) in roots. These findings suggested that Act12 joined with compost-strengthened potherb mustard phytoremediation of Cd- and Pb-polluted soils, which may provide new insights into the clean-up of mining-contaminated soils in field practice.

Base editing by nucleotide deaminases linked to programmable DNA-binding proteins represents a promising approach to permanently remedy blood disorders, although its application in engrafting hematopoietic stem cells (HSCs) remains unexplored. In this study, we purified A3A (N57Q)-BE3 base editor for ribonucleoprotein (RNP) electroporation of human-peripheral-blood-mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs). We observed frequent on-target cytosine base edits at the BCL11A erythroid enhancer at +58 with few indels. Fetal hemoglobin (HbF) induction in erythroid progeny after base editing or nuclease editing was similar. A single therapeutic base edit of the BCL11A enhancer prevented sickling and ameliorated globin chain imbalance in erythroid progeny from sickle cell disease and β-thalassemia patient-derived HSPCs, respectively. Moreover, efficient multiplex editing could be achieved with combined disruption of the BCL11A erythroid enhancer and correction of the HBB −28A>G promoter mutation. Finally, base edits could be produced in multilineage-repopulating self-renewing human HSCs with high frequency as assayed in primary and secondary recipient animals resulting in potent HbF induction in vivo. Together, these results demonstrate the potential of RNP base editing of human HSPCs as a feasible alternative to nuclease editing for HSC-targeted therapeutic genome modification. A single therapeutic base edit of the BCL11A enhancer in human HSPCs can ameliorate cellular defects associated with sickle cell disease and β-thalassemia in vitro and efficiently induce fetal hemoglobin expression upon engraftment in mice in vivo.

Soil potentially toxic metals (PTMs) pollution caused by anthropogenic activities has become serious concern with respect to the crop safety production. In this study, an emerging biochar derived from kiwi pruning branches waste was employed as amendment aiming to evaluate its remediation potential on smelter- and mining-contaminated soils. The effect of biochar on the soil physicochemical properties, leachability, and chemical fractions acted on stabilization practice of PTMs in soil was investigated. The results showed that the addition of biochar increased the soil pH, cation exchange capacity, organic matter, and enzymatic activities (dehydrogenase, urease, and sucrase) but reduced the extraction toxicity of PTMs in both smelter (Fengxian, FX) and mining (Tongguan, TG) soils. The fraction analysis showed that the maximum reduction of exchangeable fraction of Cd, Zn, and Pb in the 4% biochar amended soils decreased by 11.1, 13.3, and 24.7% in FX soil and 7.67, 22.8, and 7.89% in TG soil, respectively, in comparison with to control (no biochar added). Additionally, the residual fraction of Cd, Zn, and Pb increased by 55.9, 7.14, and 11.0% in FX soil and 23.7, 5.86, and 10.0% in TG soil, respectively. The further greenhouse experiment showed that the Indian mustard (Brassica juncea) production increased with the increasing application dosages of biochar, while the PTMs uptakes in plant notably decreased after amendments. Conversion of kiwi pruning branches waste into emerging biochar benefits the agricultural waste recycling utilization and enhances PTMs-contaminated soil remediation in practice. Graphical abstract.

CRISPR-Cas systems not only play key roles in prokaryotic acquired immunity, but can also be adapted as powerful genome editing tools. Understanding the native role of CRISPR-Cas systems in providing adaptive immunity can lead to new CRISPR-based technologies. Here, we develop CRISPRminer, a knowledge base and web server to comprehensively collect and investigate the knowledge of CRISPR-Cas systems and generate instructive annotations, including CRISPR arrays and Cas protein annotation, CRISPR-Cas system classification, self-targeting events detection, microbe–phage interaction inference, and anti-CRISPR annotation. CRISPRminer is user-friendly and freely available at http://www.microbiome-bigdata.com/CRISPRminer., Fan Zhang et al. present CRISPRminer, a comprehensive database for exploring CRISPR-Cas systems in more than 3500 microbial species and a web-server for in-depth data mining. CRISPRminer allows researchers to predict CRISPR-Cas systems and investigate self-targeting CRISPRs, microbe-phage interaction networks, and anti-CRISPR features.

A series of Sr3AlO4F:A (A = Tb3+, Sm3+) phosphors were prepared by solid-state reaction process. The optical properties of Tb3+ and Sm3+ single-doped or co-doped Sr3AlO4F phosphors were researched by means of X-ray diffraction and photoluminescence spectra. Under the excitation of 250–400 nm, all samples exhibited their characteristic emissions of Sr3AlO4F:Tb3+ (5D3 → 7F5, blue and 5D4 → 7F5, green), Sr3AlO4F:Sm3+ (4G5/2 → 6H7/2, red). The concentration dependent luminescence intensity of Sr3AlO4F:A (A = Tb3+, Sm3+) phosphors have been investigated in detail. Besides, the energy transfer from Tb3+ to Sm3+ ion has been researched in the Sr3AlO4F host, and the energy transfer mechanism was demonstrated to be a resonant type, through a dipole–quadrupole mechanism on the basis of experimental and theoretical analysis. In addition, white/tunable light can be prepared by changed the doping concentration of Sm3+ from 0.03 to 0.12 mol in Sr3AlO4F:0.5 % Tb3+ under excitation of deep-UV. It is the first time to produce white light emission through Tb3+ and Sm3+ co-doped Sr3AlO4F phosphor.