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YTHDC2, a unique YTH-domain-containing protein that recognizes N6-methyladenosine (m 6 A) on RNA, plays critical roles in diverse pathological processes and represents a promising therapeutic target. Despite its potential, no potent small-molecule inhibitors have been reported to date. To bridge this gap, we develop EPMolGen, a deep learning-based molecular generative model that explicitly incorporates the electrostatic features of receptor proteins. The model achieves state-of-the-art performance in dry-lab validations. Using EPMolGen, we identify H3 , a YTHDC2 inhibitor with an IC 50 of 16.84 μM. Subsequent structural optimization of H3 yields DC2-C1 , a highly potent compound with an IC 50 of 0.168 μM against YTHDC2 and selectivity over other YTH-domain proteins. In cellular assays, DC2-C1 effectively targets YTHDC2. Notably, DC2-C1 treatment substantially reduces the expression levels of multiple target mRNAs of YTHDC2, leading to phenotypic suppression of related cells. Overall, this study highlights the great potential of deep learning in drug discovery and provides a promising lead compound for drug development targeting YTHDC2. YTHDC2 is a promising therapeutic target, but lacks potent inhibitors. Yang et al. develop a deep learning-based molecule generator EPMolGen. Using this model, they discover a potent, selective, and cell-active small molecule inhibitor of YTHDC2.

Luzhou-flavor liquor is one of the most popular liquors in China, produced by the distillation of Zaopei, a mixture of fermented and fresh cereals. The quality and flavor of Luzhou-flavor liquor are closely related to the multitudinous bacteria in Zaopei. Little is known about the effect of brewing seasons, a main operating parameter, on the bacterial diversity of Zaopei. In this study Illumina Miseq sequencing platform was first applied to study the bacterial succession in Zaopei during liquor fermentation processes in winter and summer. The research results showed that 10 phyla and 13 families were detected in Zaopei. Differences in bacterial communities of summer and winter Zaopei were apparent. Proteobacteria was the most abundant phylum in winter Zaopei. However, bacteria belonging to Firmicutes were most frequently detected in summer Zaopei. The diverse genera decreased sharply at the first half of the 40-day fermentation stage, and then bacterial population were mainly represented by Acetobacter and Lactobacillus both in winter and summer Zaopei. Interestingly, the summer Zaopei contained significantly higher proportions of LAB and lower proportions of Acetobacter than winter Zaopei. Clustering analysis also revealed that bacterial community structure was distinct between the Zaopei fermented in the two seasons. Thermoactinomycetaceae , Prevotella , Alcaligenes , and Gluconacetobacter not previously identified in Zaopei were revealed in this study by high-throughput sequencing. This study might be helpful in achieving better control over the quality of Luzhou-flavor liquor brewed in different seasons.

To assess the viability and effectiveness of bioretention cell in enhancing rainwater resource utilization within sponge cities, this study employs field monitoring, laboratory testing, and statistical analysis to evaluate the water purification capabilities of bioretention cell. Findings indicate a marked purification impact on surface runoff, with removal efficiencies of 59.81% for suspended solids (SS), 39.01% for chemical oxygen demand (COD), 37.53% for ammonia nitrogen (NH3-N), and 30.49% for total phosphorus (TP). The treated water largely complies with rainwater reuse guidelines and tertiary sewage discharge standards. Notably, while previous research in China has emphasized water volume control in sponge city infrastructures, less attention has been given to the qualitative aspects and field-based evaluations. This research not only fills that gap but also offers valuable insights and practical implications for bioretention cell integration into sponge city development. Moreover, the methodology and outcomes of this study serve as a benchmark for future sponge city project assessments, offering guidance to relevant authorities.

Evolution may drive homologous proteins to be functionally nonexchangeable in different organisms. However, much is unknown about the mechanisms underlying this phenomenon beyond amino acid substitutions. LysR-type transcriptional regulators (LTTRs), which function in diverse biological processes in prokaryotes, are composed of a conserved structure with an N-terminal DNA-binding domain (DBD) and a C-terminal signal-sensing regulatory domain (RD). LTTRs that sense and respond to the same signal are often functionally exchangeable in bacterial species across wide phyla, but this phenomenon has not been demonstrated for the H 2 O 2 -sensing and -responding OxyRs. Here, we systematically examined the biochemical and structural determinants differentiating activator-only OxyRs from dual-activity ones by comparing OxyRs from two Gammaproteobacteria , Escherichia coli and Shewanella oneidensis . Our data show that Ec OxyR could function as neither an activator nor a repressor in S. oneidensis . Using So OxyR-based OxyR chimeras and mutants, we demonstrated that residues 283 to 289, which form the first half of the last C-terminal α-helix (α10), are critical for the proper function of So OxyR and cannot be replaced with the Ec OxyR counterpart. Crystal structural analysis reveals that α10 is important for the oligomerization of So OxyR, which, unlike Ec OxyR, forms several high-order oligomers upon DNA binding. As the mechanisms of OxyR oligomerization vary substantially among bacterial species, our findings underscore the importance of subtle structural features in determining regulatory activities of structurally similar proteins descending from a common ancestor. IMPORTANCE Evolution may drive homologous proteins to be functionally nonexchangeable in different organisms. However, much is unknown about the mechanisms underlying this phenomenon beyond amino acid substitutions. Here, we systematically examined the biochemical and structural determinants differentiating functionally nonexchangeable OxyRs, H 2 O 2 -responding transcriptional regulators from two Gammaproteobacteria , Escherichia coli and Shewanella oneidensis . Using So OxyR-based OxyR chimeras and mutants, we demonstrated that residues 283 to 289, which form the first half of the last C-terminal α-helix (α10), are critical for the proper function of So OxyR and cannot be replaced with the Ec OxyR counterpart. Crystal structural analysis reveals that this last helix is critical for formation of high-order oligomers upon DNA binding, a phenomenon not observed with Ec OxyR. Our findings provide a new dimension to differences in sequence and structural features among bacterial species in determining regulatory activities of homologous regulators.

The tonoplast intrinsic proteins TIP3;1 and TIP3;2 are specifically expressed during seed maturation and localized to the seed protein storage vacuole membrane. However, the function and physiological roles of TIP3s are still largely unknown. The seed performance of TIP3 knockdown mutants was analysed using the controlled deterioration test. The tip3;1/tip3;2 double mutant was affected in seed longevity and accumulated high levels of hydrogen peroxide compared with the wild type, suggesting that TIP3s function in seed longevity. The transcription factor ABSCISIC ACID INSENSITIVE 3 (ABI3) is known to be involved in seed desiccation tolerance and seed longevity. TIP3 transcript and protein levels were significantly reduced in abi3-6 mutant seeds. TIP3;1 and TIP3;2 promoters could be activated by ABI3 in the presence of abscisic acid (ABA) in Arabidopsis protoplasts. TIP3 proteins were detected in the protoplasts transiently expressing ABI3 and in ABI3-overexpressing seedlings when treated with ABA. Furthermore, ABI3 directly binds to the RY motif of the TIP3 promoters. Therefore, seed-specific TIP3s may help maintain seed longevity under the expressional control of ABI3 during seed maturation and are members of the ABI3-mediated seed longevity pathway together with small heat shock proteins and late embryo abundant proteins.

Cytochromes c (cyts c ), essential for respiration and photosynthesis in eukaryotes, confer bacteria respiratory versatility for survival and growth in natural environments. In bacteria having a cyt c maturation (CCM) system, DsbD is required to mediate electron transport from the cytoplasm to CcmG of the Ccm apparatus. Here with cyt c -rich Shewanella oneidensis as the research model, we identify NapB, a cyt c per se, that suppresses the CCM defect of a dsbD mutant during anaerobiosis, when NapB is produced at elevated levels, a result of activation by cAMP-Crp. Data are then presented to suggest that NapB reduces CcmG, leading to the suppression. We further show that NapB proteins capable of rescuing CCM in the dsbD mutant form a small distinct clade. The study sheds light on multifunctionality of cyts c , and more importantly, unravels a self-salvation strategy through which bacteria have evolved to better adjust to the natural world. The DsbD protein is normally required for cytochrome c maturation (Ccm) in bacteria. With cytochrome c -rich Shewanella oneidensis as the research model, NapB, the small subunit of the nitrate reductase which is a cytochrome c per se, was found to suppress the Ccm defect resulting from DsbD loss under anaerobic conditions.

The highly conserved eukaryotic WD40 repeat protein, Receptor for Activated C Kinase 1 (RACK1), is involved in the abscisic acid (ABA) response in Arabidopsis . However, the regulation of RACK1 and the proteins with which it interacts are poorly understood. Here, we show that RACK1B is sumoylated at four residues, Lys50, Lys276, Lys281 and Lys291. Sumoylation increases RACK1B stability and its tolerance to ubiquitination-mediated degradation in ABA response. As a result, sumoylation leads to enhanced interaction between RACK1B and RAP2.6, an AP2/ERF family transcription factor. RACK1B binds directly to the AP2 domain of RAP2.6, which alters the affinity of RAP2.6 for CE1 and GCC cis -acting regulatory elements. Taken together, our findings illustrate that protein stability controlled by dynamic post-transcriptional modification is a critical regulatory mechanism for RACK1B, which functions as scaffold protein for RAP2.6 in ABA signaling.

With the continuous expansion of the scale of the network, modeling the complex graph structure is a major challenge for the recommendation task. There are conflicts between these complex information, which will directly affect the recommendation results. For this reason, a graph neural network recommendation method based on multi-branch decision is proposed. The algorithm models the social network graph and the user project graph through the neural network, connects the two graphs intrinsically, and learns the feature vectors of the target users in the social space and the project space. Then two feature vectors are connected in series by MLP to extract the potential feature vector of the user. Finally, the prediction score is generated by integrating the probability matrix decomposition model. In this method, the graph neural network is used to model the program data and dependence graph, and the effective program features are automatically extracted from the source code, and then the extracted features are input into the downstream model for loop vectorization parameter prediction. Finally, the attention mechanism is used for information fusion to get the final session representation and predict the next interactive item. Comparative experiments are carried out under the two scenarios of e-commerce and civil aviation respectively. The experimental results show that, compared with the optimal benchmark model, the improvement of MGSP model on each index of e-commerce data set is more than 1%, and that of civil aviation data set is about 3%, which verifies the effectiveness of MGSP model. On the LLVM cyclic vector test set, the proposed method achieves a speedup of 2.08 times and improves the performance by 12% compared with the existing methods. In order to solve the problem that the existing deep learning model considers the program code as a serial sequence and misses a large performance optimization space, a new program heuristic method based on depth map network is proposed to achieve optimization.

YTHDC2, a unique YTH-domain-containing protein that recognizes N6-methyladenosine (m A) on RNA, plays critical roles in diverse pathological processes and represents a promising therapeutic target. Despite its potential, no potent small-molecule inhibitors have been reported to date. To bridge this gap, we develop EPMolGen, a deep learning-based molecular generative model that explicitly incorporates the electrostatic features of receptor proteins. The model achieves state-of-the-art performance in dry-lab validations. Using EPMolGen, we identify H3, a YTHDC2 inhibitor with an IC of 16.84 μM. Subsequent structural optimization of H3 yields DC2-C1, a highly potent compound with an IC of 0.168 μM against YTHDC2 and selectivity over other YTH-domain proteins. In cellular assays, DC2-C1 effectively targets YTHDC2. Notably, DC2-C1 treatment substantially reduces the expression levels of multiple target mRNAs of YTHDC2, leading to phenotypic suppression of related cells. Overall, this study highlights the great potential of deep learning in drug discovery and provides a promising lead compound for drug development targeting YTHDC2.

Due to gravitational stimulation, the lower part of a shoot base grows faster than the upper part, leading the shoot to curve upward. Though much research has been done on the mechanism of plant gravitropism, it still requires extensive elucidation. Recently, functional genomic strategies have been applied to study this mechanism in plants. The present study carried out a proteomic analysis to gain a better understanding of gravity stimulation in rice. Three-week-old rice seedlings were gravitropically stimulated and samples were harvested at 4 different time points: 0.5, 3, 6, and 9 h. Then, the total crude proteins were extracted from the lower and upper parts of the shoot base, separated by 2-DE, and silver stained. At each time point, proteins in the lower and upper parts were compared, and the differently expressed proteins were identified using MALDI TOF or ESI-MS/MS. After gravity stimulation, proteins involved in nine different functional categories were either up-regulated or down-regulated. Sugar metabolism, glycolysis, the tricarboxylic acid (TCA/citric) cycle, pyruvate metabolism, and transcription regulation-related proteins were regulated. Although the initiation of defense reactions mainly occurred in roots, some different defense mechanisms were also evoked in the aerial tissues. Interestingly, the abundance of some proteins changed drastically at only 0.5 h after reorientation: inosine monophosphate dehydrogenase (up to 6.49-fold higher in lower flanks at 0.5 h), ATP synthase D (4.25-fold), and ribulose-1,5 -bisphosphate carboxylase oxygenase (3.62-fold). These findings may aid in understanding the mechanism of the gravitropism.