Although base editors are useful tools for precise genome editing, current base editors can only convert either adenines or cytosines. We developed a dual adenine and cytosine base editor (A&C-BEmax) ...by fusing both deaminases with a Cas9 nickase to achieve C-to-T and A-to-G conversions at the same target site. Compared to single base editors, A&C-BEmax's activity on adenines is slightly reduced, whereas activity on cytosines is higher and RNA off-target activity is substantially decreased.
Studying the evolution history of the southwest summer monsoon (SSM) throughout geological time, particularly during its strongest period in the Holocene, can improve our understanding of its ...variation and driving mechanisms, and even help predict future climate changes, due to its significant social and economic implications. Here, we reconstructed the history of chemical weathering intensity since the Last Glacial Maximum (LGM) based on clay mineral proxies (illite/smectite)/(illite + chlorite) and illite crystallinity obtained from Qionghai Lake sediments and examined its response to paleoclimate and SSM. Our findings indicate that the intensity of chemical weathering generally aligned with changes in paleoclimate, exhibiting strong chemical weathering intensity during warm and humid climate conditions. In addition, the intensity of chemical weathering basically tracks the evolution of the SSM since the LGM. Our results support the view that the highest SSM intensity occurred during the early‐middle Holocene, followed by gradual weakening during the late Holocene, with Northern Hemisphere summer insolation being the primary driver of the SSM evolution. The variations of the SSM and the corresponding intensity of chemical weathering were also influenced by the cumulative effects of glacier boundary conditions, North Atlantic climate fluctuations, and Intertropical Convergence Zone migrations.
Key Points
Clay minerals can effectively reflect regional chemical weathering intensity
Chemical weathering intensity was following the monsoon variability
The strongest southwest summer monsoon occurred in the early‐middle Holocene
The Indian summer monsoon (ISM) significantly influences the climate of southwestern China; however, continuous quantitative temperature reconstructions since the Last Glacial Maximum are rare, which ...limits our understanding of ISM evolution. In this study, we analyzed the branched glycerol dialkyl glycerol tetraethers (brGDGTs) from a lacustrine sediment core from Qionghai Lake to reconstruct the paleoclimatology of southwestern subtropical China over the past 27.7 kyr. Our results suggest that the brGDGTs in Qionghai Lake sediments were probably sourced from catchment soils, with some contributions from in situ lacustrine production. We found that the temperature of the Last Glacial Maximum and Holocene Climatic Optimum was ~3 °C cooler and ~ 2.5 °C warmer than present-day conditions, respectively, based on brGDGTs-reconstructed mean annual air temperatures (MATs). Generally, temperature and precipitation showed synchronous paleovariability in ISM regions. Moreover, Northern Hemisphere summer insolation was the dominant control on climate variability in ISM regions on the precessional scale, while Atlantic Meridional Overturning Circulation activity, Intertropical Convergence Zone positioning, and glacial boundary conditions (ice sheet extent and sea surface temperature) contributed to climate shifts on millennial timescales.
•LGM was about 3 °C cooler and HCO about 2.5 °C warmer than the present day.•Broadly synchronous variation of temperature and precipitation occurred in the ISM area.•AMOC, ITCZ and glacial boundary conditions are important factors regulating paleoclimates.
Knowledge of the chemical weathering history under the subtropical monsoonal climate will help to resolve the discrepancies regarding how climate conditions constrain chemical weathering. Major ...element and rare earth element (REE) compositions of the Qionghai Lake sediments in Sichuan Province, southwestern China were analyzed, aiming to provide information on sediment source discrimination and history of chemical weathering intensities and its responses to variations of Indian summer monsoon (ISM) and paleoclimate conditions. As revealed by the A-CN-K diagram and other provenance proxies including TiO2/Zr ratio, Th/Sc vs. Zr/Sc and La/Th vs. Hf diagrams, as well as the REE characteristics, the source of Qionghai Lake sediments was felsic rocks. Additionally, these sediments were subjected to small changes in provenance, sedimentary sorting and recycling, and weak diagenesis after deposition and/or metasomatism, indicating original signals were maintained on the intensity of chemical weathering of source area. The chemical weathering intensities inferred from CIA (chemical index of alteration) values have significantly fluctuated over the past 28 kyr, reflecting three stages of paleoclimate evolution, which is consistent with grain size characteristics, carbonate contents, low-frequency magnetic susceptibilities, TOC and biomarker proxy (Paq). The CIA values changed significantly during the typical warm and cold climate events including the Last Glacial Maximum, Heinrich 1 cold event, Younger Dryas and Holocene Climatic Optimum, and generally exhibited an increasing trend in amplitude correspondingly, in concert with the climate shifting from cold and dry to warm and humid conditions. Generally warm and humid climate conditions suggest enhanced chemical weathering intensity, whereas weak chemical weathering denotes cold and dry climate in the ISM region. In addition, sequential variations of the CIA values during the past 28 kyr may reflect changing chemical weathering processes, in responses to the varying intensities of Indian summer monsoon and the climate conditions forced by the Northern Hemisphere solar insolation.
•Weak degree of changes in provenance, sedimentary sorting and recycling, and diagenesis in Qionghai Lake sediments.•Sequential variations of CIA in typical climate events increased as temperature and humidity increased progressively.•Chemical weathering intensities regulated by monsoonal climate.
The climate reconstruction of the Tibetan Plateau, which was called the Third Pole Environment, has been a research hotspot in recent years. However, there are few studies on C3 and C4 plants ...evolution and it is an area of active debate on whether there are C4 plants existing on the Tibetan Plateau. In this study, the paleoclimate of the Hurleg Lake on the northeastern Tibetan Plateau is reconstructed based on n‐alkane‐induced indicators, while the C4 plant evolution history is established by compound‐specific isotope of long‐chain n‐alkanes since 14.1 cal kyr BP. The response of C4 plant evolution history to climate change on the northeastern margin of the Tibetan Plateau demonstrated that C3 and C4 plants were sensitive to local and global climate change. Solar radiation in summer, insolation‐affected East Asian monsoon, and seasonal climate (including seasonal variation of the solar radiation, temperature, and precipitation) had significant effects on the long‐term growth of C4. On the other hand, factors such as temperature, precipitation, and other potential factors affected the detailed variation of C4 plants in a relatively short‐term. Our finding maintained the existence of C4 plants in the high‐altitude region and indicated that the abundance of C4 plants might increase significantly and the ecological pattern of vegetation on the Tibetan Plateau will change distinctly in the coming warmer climate conditions.
Key Points
Paleoclimate and C4 plant evolution on the northeastern Tibetan Plateau since the Last Deglacial were revealed
C4 plants on the northeastern Tibetan Plateau were relatively abundant during the Younger Dryas period
Insolation, temperature, East Asian monsoon, and seasonal differences play significant roles in the evolution of C4 plants
The CRISPR-Cas RNA-guided system has versatile uses in many organisms and allows modification of multiple target sites simultaneously. Generating novel genetically modified mouse and rat models is ...one valuable application of this system. Through the injection of Cas9 protein instead of mRNA into embryos, we observed fewer off-target effects of Cas9 and increased point mutation knock-in efficiency. Large genomic DNA fragment (up to 95 kb) deletion mice were generated for in vivo study of lncRNAs and gene clusters. Site-specific insertion of a 2.7 kb CreERT2 cassette into the mouse Nfatc1 locus allowed labeling and tracing of hair follicle stem cells. In addition, we combined the Cre-Loxp system with a gene-trap strategy to insert a GFP reporter in the reverse orientation into the rat Lgr5 locus, which was later inverted by Cre-mediated recombination, yielding a conditional knockout/reporter strategy suitable for mosaic mutation analysis.
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific ...engineering. Multidrug resistance 1 MDR1 (also known as P-glycoprotein) is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (
) double-knockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of
(-/-) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new
(-/-) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation.
Cancers have always been the most difficult to fight, the treatment of cancer is still not considered. Thus, exploring new anticancer drugs is still imminent. Traditional Chinese medicine has played ...an important role in the treatment of cancer. Polyphenol oxidase (PPO) extracted from
has many related reports on its characteristics, but its role in cancer treatment is still unclear. This study aims to investigate the effects of PPO extracted from
on the proliferation, migration, invasion, and apoptosis of cancer cells in vitro and explore the therapeutic effects of PPO on tumors in vivo. A cell counting kit-8 (CCK8) assay was used to detect the effect of PPO on the proliferation of cancer cells. The effect of PPO on cancer cell migration ability was detected by scratch test. The effect of PPO on the invasion ability of cancer cells was detected by a transwell assay. The effect of PPO on the apoptosis of cancer cells was detected by flow cytometry. Female BALB/c mice (18-25 g, 6-8 weeks) were used for in vivo experiments. The experiments were divided into control group, model group, low-dose group (25 mg/kg), and high-dose group (50 mg/kg). In vitro, PPO extracted from
significantly inhibited the proliferation, migration, and invasion capability of breast cancer cell 4T1, lung cancer cell A549, and prostate cancer cell C4-2, and significantly promoted the apoptosis of 4T1, A549, and C4-2. In vivo experiments showed PPO inhibitory effect on tumor growth. Collectively, the edible fungus extract PPO could play an effective role in treating various cancers, and it may potentially be a promising agent for treating cancers.
SETDB2 is a H3K9 histone methyltransferase required for accurate chromosome segregation. Its H3K9 histone methyltransferase activity was reported to be associated with chromosomes during metaphase. ...Here, we confirm that SETDB2 is required for mitosis and accurate chromosome segregation. However, these functions are independent of its histone methyltransferase activity. Further analysis showed that SETDB2 can interact with BUBR1, and is required for CDC20 binding to BUBR1 and APC/C complex and CYCLIN B1 degradation. The ability of SETDB2 to regulate the binding of CDC20 to BUBR1 or APC/C complex, and stabilization of CYCLIN B1 are also independent of its histone methyltransferase activity. These results suggest that SETDB2 interacts with BUBR1 to promote binding of CDC20 to BUBR1 and APC3, then degrades CYCLIN B1 to ensure accurate chromosome segregation and mitosis, independently of its histone methyltransferase activity.
The histone methyltransferase SETDB2 interacts with BUBR1 and is required for binding of CDC20 to BUBR1 and APC, thereby mediating degradation of CYCLIN B1 to guarantee accurate chromosome segregation and mitosis exit. This occurs independently of SETDB2's histone methyltransferase activity.
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•There is a continuous paleoclimatic records since 29 Ma in the Linxia Basin.•The evolution of microbes is used to demonstrate fast stepwise drying of the Linxia Basin at around ...8 Ma.•Microbial community could serve as a potential indicator of paleoclimate reconstruction.
The Linxia Basin on the north-eastern Tibetan Plateau in northwest China bears continuous and thick lacustrine-fluvial sediments with environmental significance to central Asian aridification. However, limited efforts have been made on investigating the microbial community evolution, even though lipid biomarkers have been successfully employed to reconstruct paleoenvironmental conditions in this area. This study used the ancient DNA and n-alkanes preserved in the lacustrine-fluvial sediments from the Linxia Basin, and employed high throughput sequencing and geochemical analyses to understand the climatic conditions spanning the past 29 million years. The characteristics of n-alkanes indicate that the organic matter was derived from mixed sources (bacteria, algae, and higher plants), and a series of n-alkane proxies (ACL, n-C21−/n-C22+, Paq, and Pwax) established that the climate shifted to arid conditions at approximately 8 Ma. It is noteworthy that the relative abundance trends of two classes of microbes (Proteobacteria and Firmicutes) were negatively correlated. Furthermore, the increasing Firmicutes and the relatively decreasing Proteobacteria at approximately 8 Ma also corroborated this arid event. In addition, during this period, there was an extremely low abundance of archaea, which might correspond to severe climatic conditions around 8 Ma. Therefore, this study suggests that the microbial communities could serve as a potential tool for the reconstruction of paleoenvironments.
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