Search

CRISPR/Cas9 is a popular genome editing technology, yet its clinical application is hindered by off-target effects. Many deep learning-based methods are available for off-target prediction. However, few can predict off-target activities with insertions or deletions (indels) between single guide RNA and DNA sequence pairs. Additionally, the analysis of off-target data is challenged due to a data imbalance issue. Moreover, the prediction accuracy and interpretability remain to be improved. Here, we introduce a deep learning-based framework, named Crispr-SGRU, to predict off-target activities with mismatches and indels. This model is based on Inception and stacked BiGRU. It adopts a dice loss function to solve the inherent imbalance issue. Experimental results show our model outperforms existing methods for off-target prediction in terms of accuracy and robustness. Finally, we study the interpretability of this model through Deep SHAP and teacher–student-based knowledge distillation, and find it can provide meaningful explanations for sequence patterns regarding off-target activity. [ABSTRACT FROM AUTHOR]

CRISPR/Cas9 has been applied to edit the genome of various organisms, but our understanding of editing outcomes at specific sites after Cas9-mediated DNA cleavage is still limited. Several deep learning-based methods have been proposed for repair outcome prediction; however, there is still room for improvement in terms of performance regarding frameshifts and model interpretability. Here, we present DeepIndel, an end-to-end multi-label regression model for predicting repair outcomes based on the BERT-base module. We demonstrate that our model outperforms existing methods in terms of accuracy and generalizability across various metrics. Furthermore, we utilized Deep SHAP to visualize the importance of nucleotides at various positions for DNA sequence and found that mononucleotides and trinucleotides in DNA sequences surrounding the cut site play a significant role in repair outcome prediction. [ABSTRACT FROM AUTHOR]

ABSTRACT Subduction zones are the primary locations of material exchange between the crust and mantle, and thus, arc igneous rocks are extensively examined to explore crust–mantle interactions during oceanic subduction. In this study, the Sr‐Nd‐Hf isotopic compositions and elemental characteristics of the Yinwaxia mafic dykes from the Shibanshan–Huaniushan arc in the southern Beishan Orogen were investigated to determine their petrogenesis and explore crust–mantle interactions during the subduction of the Liuyuan Ocean. The dykes were subdivided into two groups based on their geochemical composition and spatial distribution. Group I dykes in the northern Yinwaxia area possess depleted light rare earth elements and slightly enriched large‐ion lithophile elements, indicated by relatively high ratios of Rb/Nb (1.4–82), Ba/Nb (6–408), and Cs/Nb (0.13–2.74), and low ratios of Th/Yb (0.03–0.39), Th/Nb (0.10–0.83), and (La/Yb)N (0.33–1.36). Further isotopic composition study revealed that low values of (87Sr/86Sr)i (0.7028–0.7052), and high values of εNd(t) (4.9–9.1) and εHf(t) (13.2–24.0), which suggests that the mantle source of Group I dykes was metasomatized by aqueous fluids. In Group II dykes located in the southern Yinwaxia area, enrichment of light rare‐earth elements and large‐ion lithophile elements was observed, featuring lower ratios of Rb/Nb (0.5–16.7), Ba/Nb (13–51), and Cs/Nb (0.15–1.56), but higher ratios of Th/Yb (0.25–2.64), Th/Nb (0.19–1.49), and (La/Yb)N (1.09–2.98) compared to Group I. Furthermore, Group II dykes exhibited higher values of (87Sr/86Sr)i (0.7051–0.7077) and lower εNd(t) (−1.7 to +3.8) and εHf(t) (3.7–9.4) isotopic compositions, which suggests that the slab fluids involved in their mantle source were dominated by sediment‐derived melts. The difference between the mafic dykes from Groups I and II suggests the addition of steadily increasing amounts of sediment‐derived melt in their mantle source; moreover, the increased (La/Yb)N ratio and decreased εNd(t) with increasing distance from the Liuyuan mélange are records of the spatial evolution of the composition of the slab fluids during the oceanic subduction of Liuyuan Ocean in the early Permian. [ABSTRACT FROM AUTHOR]

Permian mafic dikes crop out widely within Beishan area in the southernmost Central Asian Orogenic Belt (CAOB). These mantle-derived products provide important clues for elucidating the genesis and geodynamic setting of Permian magmatism. The mafic dikes within the Beishan area display zircons U–Pb ages of 281 ± 4 Ma. Characterized by low SiO2 (44.88–47.73 wt.%) and high Mg# values (62.2–68.6), the type 1 dikes are relatively depleted in light rare earth elements (LREEs; (La/Yb)n = 0.72–1.43) but enriched in large ion lithophile elements (LILEs). They show high positive εNd(t) values (6.6–8.5) with a range of (87Sr/86Sr)i (0.703477–0.705789) ratios. In contrast, the type 2 dikes have higher SiO2 content (47.47–51.13 wt.%) and lower Mg# (40.9–63.0). They are enriched in LREEs ((La/Yb)n = 1.79–5.02) and LILEs, and have lower εNd(t) values (3.8–7.4) with a variable range of (87Sr/86Sr)i (0.702873–0.706949) ratios. Thus, the type 1 dikes resulted from lower degrees of fractional crystallization and contamination than the type 2 dikes. Considering the LILEs and Pb enrichments, high field strength elements depletions, and high Ba/Th (86–460) ratios, the mantle source was metasomatized by subduction-related fluids. These dikes should be derived from high degrees (>20%) of partial melting of a Sr–Nd isotope-depleted, phlogopite-bearing spinel lherzolite lithospheric mantle according to their high Rb/Sr (0.04–0.24), low Ba/Rb (0.9–3.3), low La/Sm, and constant Sm/Yb ratios in addition to Sr–Nd depletion. Combined with the coeval evidence of regional geology and novel tectonic discriminate diagrams, we suggest that the mafic dikes in Beishan area formed in arc-related setting rather than intracontinental setting during the Permian. The metasomatized lithospheric mantle by subduction-related fluids were heated by upwelling asthenosphere mantle triggered by the slab roll-back, resulting in the formation of the parental magma of the mafic dikes. [ABSTRACT FROM AUTHOR]

MicroRNA exerts an important regulatory role in almost all the biological process, including hair follicle development in Liaoning Cashmere goat. In order to improve the Cashmere performance of goat, the regulatory role of microRNA in hair follicle cycle has drawn hotspot attention. However, the molecular mechanisms of miRNA-1-3p involved in hair follicle development are poorly understood. In this study, we found that miRNA-1-3p was less expressed in anagen stage of hair follicle cycle of Cashmere goat than that in telogen stage by using RT-qPCR and immunoblotting analysis, in contrast to the expression pattern of FGF14. The Dual-Luciferase reporter assay was employed to verify the relationship between miRNA-1-3p and FGF14. The results showed that miRNA-1-3p specifically binds to the 3′UTR of FGF14 mRNA, and FGF14 is the target gene of miR-1-3p. In conclusion, this study shows that miRNA-1-3p may regulate hair follicle development in Liaoning Cashmere goats by targeting FGF14. [ABSTRACT FROM AUTHOR]