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Mine flooding accidents have occurred frequently in recent years, and the predicting of mine water inflow is one of the most crucial flood warning indicators. Further, the mine water inflow is characterized by non-linearity and instability, making it difficult to predict. Accordingly, we propose a time series prediction model based on the fusion of the Transformer algorithm, which relies on self-attention, and the LSTM algorithm, which captures long-term dependencies. In this paper, Baotailong mine water inflow in Heilongjiang Province is used as sample data, and the sample data is divided into different ratios of the training set and test set in order to obtain optimal prediction results. In this study, we demonstrate that the LSTM-Transformer model exhibits the highest training accuracy when the ratio is 7:3. To improve the efficiency of search, the combination of random search and Bayesian optimization is used to determine the network model parameters and regularization parameters. Finally, in order to verify the accuracy of the LSTM-Transformer model, the LSTM-Transformer model is compared with LSTM, CNN, Transformer and CNN–LSTM models. The results prove that LSTM-Transformer has the highest prediction accuracy, and all the indicators of its model are well improved.

High-performance n-type organic electrochemical transistors (OECTs) are essential for logic circuits and sensors. However, the performances of n-type OECTs lag far behind that of p-type ones. Conventional wisdom posits that the LUMO energy level dictates the n-type performance. Herein, we show that engineering the doped state is more critical for n-type OECT polymers. By balancing more charges to the donor moiety, we could effectively switch a p-type polymer to high-performance n-type material. Based on this concept, the polymer, P(gTDPP2FT), exhibits a record high n-type OECT performance with μC * of 54.8 F cm −1 V −1 s −1 , mobility of 0.35 cm 2 V −1 s −1 , and response speed of τ on / τ off  = 1.75/0.15 ms. Calculations and comparison studies show that the conversion is primarily due to the more uniform charges, stabilized negative polaron, enhanced conformation, and backbone planarity at negatively charged states. Our work highlights the critical role of understanding and engineering polymers’ doped states. Conventional strategies to obtain n-type organic electrochemical transistors are based on lowering the lowest unoccupied molecular orbital. Here Lei et al., engineer the polymer doped states to fabricate high-performance n-type organic electrochemical transistors.

The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers. Verma et al. report that ALC1 loss confers PARP inhibitor hypersensitivity in homologous recombination-deficient cells through reducing chromatin accessibility.

Cellulose-based materials can be used as chemical sensors for efficiently detecting metal ions in environmental applications because of their low price, excellent biodegradability and biocompatibility. Metal-ions poisoning have potential threats to human life and health. Therefore, it is of great significance to detect metal ions. In this review, we introduce the merits and drawbacks of using instruments and other materials and cover the recent progress of cellulose-based materials for the detection of metal-ions. We anticipate that the review supplies some guidances to cellulose-based materials for metal-ions detection. Moreover, the challenges and opportunities of the future development of cellulose-based sensors are also prospected.Graphic abstract

CRISPR-based genetic screening has revolutionized cancer drug target discovery, yet reliable, multiplex gene editing to reveal synergies between gene targets remains a major challenge. Here, we present a simple and robust CRISPR-Cas12a-based approach for combinatorial genetic screening in cancer cells. By engineering the CRISPR-AsCas12a system with key modifications to the Cas protein and its CRISPR RNA (crRNA), we can achieve high efficiency combinatorial genetic screening. We demonstrate the performance of our optimized AsCas12a (opAsCas12a) through double knockout screening against epigenetic regulators. This screen reveals synthetic sick interactions between Brd9 & Jmjd6 , Kat6a & Jmjd6 , and Brpf1 & Jmjd6 in leukemia cells. Reliable, multiplexed gene editing to uncover synergies between targets remains challenging. Here, the authors engineer AsCas12a and the crRNA to improve double knockout for synthetic sick/lethal interaction genetic screening.

Cancer drug targets are identified by CRISPR-based screens that knock out functional protein domains. CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9–induced mutations to the 5′ exons of candidate genes 1 , 2 , 3 , 4 , 5 , but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.

Background WRKY transcription factors are involved in plant responses to both biotic and abiotic stresses. Arabidopsis WRKY18, WRKY40, and WRKY60 transcription factors interact both physically and functionally in plant defense responses. However, their role in plant abiotic stress response has not been directly analyzed. Results We report that the three WRKYs are involved in plant responses to abscisic acid (ABA) and abiotic stress. Through analysis of single, double, and triple mutants and overexpression lines for the WRKY genes, we have shown that WRKY18 and WRKY60 have a positive effect on plant ABA sensitivity for inhibition of seed germination and root growth. The same two WRKY genes also enhance plant sensitivity to salt and osmotic stress. WRKY40 , on the other hand, antagonizes WRKY18 and WRKY60 in the effect on plant sensitivity to ABA and abiotic stress in germination and growth assays. Both WRKY18 and WRKY40 are rapidly induced by ABA, while induction of WRKY60 by ABA is delayed. ABA-inducible expression of WRKY60 is almost completely abolished in the wrky18 and wrky40 mutants. WRKY18 and WRKY40 recognize a cluster of W-box sequences in the WRKY60 promoter and activate WRKY60 expression in protoplasts. Thus, WRKY60 might be a direct target gene of WRKY18 and WRKY40 in ABA signaling. Using a stable transgenic reporter/effector system, we have shown that both WRKY18 and WRKY60 act as weak transcriptional activators while WRKY40 is a transcriptional repressor in plant cells. Conclusions We propose that the three related WRKY transcription factors form a highly interacting regulatory network that modulates gene expression in both plant defense and stress responses by acting as either transcription activator or repressor.

During chronic infection and cancer, a self-renewing CD8 + T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8 + T cells diverge from other CD8 + subsets early after chronic viral infection. However, pathways guarding stem-like CD8 + T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8 + T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8 + T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8 + T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8 + lineage and prevents an alternative terminally exhausted cell fate. Tuoqi Wu and colleagues show that the transcriptional repressor BACH2 is required early after chronic viral infection to enforce a stem-like fate in activated CD8 + T cells. BACH2 acts to suppress genes that lead to the exhausted cell state.

Hemoglobin in red blood cells (RBCs) carries oxygen to the tissues. Sickle cell disease is an inherited condition that involves abnormal hemoglobin. Current treatments entail modulating the level of fetal hemoglobin expression. Grevet et al. performed a CRISPR-Cas9 screen for regulators of fetal hemoglobin in RBCs and identified heme-regulated eIF2α kinase (HRI). Depleting the kinase in RBCs led to an increase in fetal hemoglobin levels and reduced sickling of cultured human RBCs. Thus, HRI may be a therapeutic target for sickle cell disease and other hemoglobin disorders. Science , this issue p. 285 HRI kinase represses expression of fetal hemoglobin and provides a potential target for sickle cell disease treatment. Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of β-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain–focused CRISPR-Cas9–based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.

Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.