Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders.

Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been identified as a promising oncogenic driver of several types of cancer and is considered to be a critical cancer therapeutic target. Several inhibitors of DYRK2 have been reported, but no degraders have been found yet. In this work, we designed and synthesized the first series of proteolysis-targeting chimeras (PROTACs) using curcumin and its analogs as warheads to target and degrade DYRK2. The results of degradation assays showed that the compound CP134 could effectively downregulate the intracellular DYRK2 level (DC50 = 1.607 µM). Further mechanism of action experiments revealed that CP134 induced DYRK2 degradation through the ubiquitin-proteasome system. Altogether, CP134 disclosed in this study is the first potent DYRK2 degrader, which could serve as a valuable chemical tool for further evaluation of its therapeutic potential, and our results broaden the substrate spectrum of PROTAC-based degraders for further therapeutic applications.

A bio-fabricated tesla valves and ultrasound waves-powered blood plasma viscometer.

Introduction: There is clinical evidence that the fresh blood viscosity is an important indicator in the development of vascular disorder and coagulation. However, existing clinical viscosity measurement techniques lack the ability to measure blood viscosity and replicate the in-vivo hemodynamics simultaneously. Methods: Here, we fabricate a novel digital device, called Tesla valves and ultrasound waves-powered blood plasma viscometer (TUBPV) which shows capacities in both viscosity measurement and coagulation monitoring. Results: Based on the Hagen-Poiseuille equation, viscosity analysis can be faithfully performed by a video microscopy. Tesla-like channel ensured unidirectional liquid motion with stable pressure driven that was triggered by the interaction of Tesla valve structure and ultrasound waves. In few seconds the TUBPV can generate an accurate viscosity profile on clinic fresh blood samples from the flow time evaluation. Besides, Tesla-inspired microchannels can be used in the real-time coagulation monitoring. Discussion: These results indicate that the TUBVP can serve as a point-of-care device in the ICU to evaluate the blood's viscosity and the anticoagulation treatment.

Deciphering the environmental adaptation and functional trait of core and noncore bacterial communities in impacted coral reef seawater.

Microorganisms play pivotal roles in different biogeochemical cycles within coral reef waters. Nevertheless, our comprehension of the microbially mediated processes following environmental perturbation is still limited. To gain a deeper insight into the environmental adaptation and nutrient cycling, particularly within core and noncore bacterial communities, it is crucial to understand reef ecosystem functioning. In this study, we delved into the microbial community structure and function of seawater in a coral reef under different degrees of anthropogenic disturbance. To achieve this, we harnessed the power of 16S rRNA gene high-throughput sequencing and metagenomics techniques. The results showed that a continuous temporal succession but little spatial heterogeneity in the bacterial communities of core and noncore taxa and functional profiles involved in nitrogen (N) and phosphorus (P) cycling. Eutrophication state (i.e., nutrient concentration and turbidity) and temperature played pivotal roles in shaping both the microbial community composition and functional traits of coral reef seawater. Within this context, the core subcommunity exhibited a remarkably broader habitat niche breadth, stronger phylogenetic signal and lower environmental sensitivity when compared to the noncore taxa. Null model analysis further revealed that the core subcommunity was governed primarily by stochastic processes, while deterministic processes played a more significant role in shaping the noncore subcommunity. Furthermore, our observations indicated that changes in function related to N cycling were correlated to the variations in noncore taxa, while core taxa played a more substantial role in critical processes such as P cycling. Collectively, these findings facilitated our knowledge about environmental adaptability of core and noncore bacterial taxa and shed light on their respective roles in maintaining diverse nutrient cycling within coral reef ecosystems.

Corrigendum: Genomic evolution of BA.5.2 and BF.7.14 derived lineages causing SARS-CoV-2 outbreak at the end of 2022 in China.

[This corrects the article DOI: 10.3389/fpubh.2023.1273745.].

CrnnCrispr: An Interpretable Deep Learning Method for CRISPR/Cas9 sgRNA On-Target Activity Prediction.

CRISPR/Cas9 is a powerful genome-editing tool in biology, but its wide applications are challenged by a lack of knowledge governing single-guide RNA (sgRNA) activity. Several deep-learning-based methods have been developed for the prediction of on-target activity. However, there is still room for improvement. Here, we proposed a hybrid neural network named CrnnCrispr, which integrates a convolutional neural network and a recurrent neural network for on-target activity prediction. We performed unbiased experiments with four mainstream methods on nine public datasets with varying sample sizes. Additionally, we incorporated a transfer learning strategy to boost the prediction power on small-scale datasets. Our results showed that CrnnCrispr outperformed existing methods in terms of accuracy and generalizability. Finally, we applied a visualization approach to investigate the generalizable nucleotide-position-dependent patterns of sgRNAs for on-target activity, which shows potential in terms of model interpretability and further helps in understanding the principles of sgRNA design.

Assessing health-related quality of life of Chinese population using CQ-11D.

PURPOSE: This study aimed to assess the health-related quality of life (HRQoL) of the Chinese population by using the Chinese medicine quality of life-11 dimensions (CQ-11D) questionnaire and to identify factors associated with HRQoL. METHODS: The data was derived from a survey conducted by the Institute of Pharmacoeconomics Evaluation at Beijing University of Chinese Medicine on the quality of life of the Chinese population. The sex and age of respondents were considered through quota sampling. Demographic, socioeconomic, and health indicators were collected using the structured questionnaire. We performed bivariate analyses first to examine the associations between the above factors and the HRQoL of respondents measured by the CQ-11D. Multivariate linear regression and ordinal logistic regression models were established to analyze the factors (demographic, socioeconomic, and health indicators) differences in HRQoL, as well as the risk of each group reporting problems across the 11 dimensions of CQ-11D. RESULTS: From February 2021 to November 2022, a total of 7,604 respondents were involved and 7,498 respondents were included. The sample approximated the general adult Chinese population in terms of age, sex, and district of residence, and each geographic distribution ranged from 9.71 to 25.54%. Of the respondents, 45.84% were male, and 89.82% were Han ethnicity. The mean utility score ranged from 0.796 to 0.921 as age increased. According to the respondents, most health problems were identified in the PL (fatigue) (70.16%) and SM (quality of sleep) (63.63%) dimensions. The CQ-11D index scores varied with the demographic and socioeconomic characteristics of respondents, except for ethnicity (p > 0.05) and income (p > 0.05). The multivariate analysis revealed significant negative associations between health utility scores and various factors. These factors include sex (female), age over 65, belonging to ethnic minorities, rural household registration, being widowed or divorced, having a primary school education or below, being a student or unemployed, having a low income of 0-1,300, engaging in smoking or drinking, limited participation in physical activities, experiencing changes in self-perceived health status compared to the previous year, and having chronic diseases. The odds of respondents reporting problems in 11 dimensions varied among different socio-demographic groups. CONCLUSIONS: This study reports the first Chinese population norms for the CQ-11D derived using a representative sample of the Chinese general population. Self-reported health status measured by the CQ-11D varies among different socio-economic groups. In addition to participation a physical activity and the presence of chronic disease, smoking and drinking also significantly influence HRQoL.

Enhanced resistance to heat and fungal infection in transgenic Trichoderma via over-expressing the HSP70 gene.

Heat stress is one of the major abiotic stresses affecting the growth, sporulation, colonization and survival of Trichoderma viride. This study aimed to gain a better insight into the underlying mechanism governing the heat stress response of T. viride Tv-1511. We analysed the transcriptomic changes of Tv-1511 under normal and heat stress conditions using RNA sequencing. We observed that Tv-1511 regulates the biosynthesis of secondary metabolites through a complex network of signalling pathways. Additionally, it significantly activates the anti-oxidant defence system, heat shock proteins and stress-response-related transcription factors in response to heat stress. TvHSP70 was identified as a key gene, and transgenic Tv-1511 overexpressing TvHSP70 (TvHSP70-OE) was generated. We conducted an integrated morphological, physiological and molecular analyses of the TvHSP70-OE and wild-type strains. We observed that TvHSP70 over-expression significantly triggered the growth, anti-oxidant capacity, anti-fungal activity and growth-promoting ability of Tv-1511. Regarding anti-oxidant capacity, TvHSP70 primarily up-regulated genes involved in enzymatic and non-enzymatic anti-oxidant systems. In terms of anti-fungal activity, TvHSP70 primarily activated genes involved in the synthesis of enediyne, anti-fungal and aminoglycoside antibiotics. This study provides a comparative analysis of the functional significance and molecular mechanisms of HSP70 in Trichoderma. These findings provide a valuable foundation for further analyses.

Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor.

Aurora kinase (AURK) and heat shock factor 1 (HSF1) are commonly overexpressed in non-small cell lung cancer (NSCLC), correlating with poor prognosis. This study aims to assess the therapeutic potential of combining the Danusertib (Danu, AURK inhibitor) and KRIBB11 (HSF1 inhibitor) for NSCLC treatment. The effects of this combination were investigated in A549 cells and a tumor xenograft mouse model. The findings demonstrate that concurrent administration of Danu and KRIBB11 effectively impedes cell proliferation, induces apoptosis, and triggers G2/M cell cycle arrest. Moreover, the combination treatment upregulates pro-apoptotic proteins (Cleaved-caspase3, Cleaved-PARP, and Bax) while downregulating anti-apoptotic proteins (Bcl-2), as well as G2/M-related proteins (CDC2 and cyclin B1). Additionally, the combination treatment elevates reactive oxygen species (ROS) levels, decreases mitochondrial membrane potential, and activates the DNA damage pathway. Interestingly, we discovered that the PI3K/AKT pathway is involved in mediating the effects of both Danu and KRIBB11. Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.

Ultrabroad bandwidth of quasi-parametric amplification beyond the phase-matching limit.

Quasi-parametric amplification (QPA), a variant of optical parametric amplification, can release the phase-matching requirement owing to the introduction of idler dissipation, and thus may support ultrabroad bandwidth. Here we establish the gain-dispersion equation for QPA, which reveals the interplay of signal gain, idler dissipation and phase mismatch. The idler dissipation dramatically enhances the gain bandwidth, which breaks the limit set by phase matching. We theoretically demonstrate that QPA with strong dissipation allows high-efficiency few-cycle pulse amplification in those nonlinear crystals without a magic phase-matching solution.

Cost-effectiveness analysis of Shexiang Baoxin Pill (MUSKARDIA) as the add-on treatment to standard therapy for stable coronary artery disease in China.

BACKGROUND: Recent evidence indicates that Shexiang Baoxin Pill (MUSKARDIA), as an add-on treatment to standard therapy for stable coronary artery disease (CAD), is effective. Nevertheless, the cost-effectiveness of introducing the Shexiang Baoxin Pill (Abbreviation SBP) to the current standard treatment for patients with CAD in China remains unknown. OBJECTIVE: The objective of this study was to assess the cost-effectiveness of introducing SBP into the current standard treatment in China for patients with CAD. METHOD: The effects of two treatment strategies-the SBP group (SBP combined with standard therapy) and the standard therapy group (placebo combined with standard therapy)-were simulated using a long-term Markov model. The simulation subjects might experience non-fatal MI and/or stroke or vascular or non-vascular death events. The study parameters were primarily derived from the MUSKARDIA trial, which was a multicenter, double-blind, placebo-controlled phase IV randomized clinical trial. Furthermore, age-related change, event costs, and event utilities were drawn from publicly available sources. Both costs and health outcomes were discounted at 5.0% per annum. One-way and probabilistic sensitivity analyses were conducted to verify the robustness of the model. Based on the MUSKARDIA trial results, the risk with the events of major adverse cardiovascular events (MACE) was decreased (P < 0.05) in the female subgroup treated with SBP therapy compared with standard therapy. Consequently, a scenario analysis based on subgroups of Chinese females was conducted for this study. Incremental cost-effectiveness ratios (ICERs) were assessed for each strategy for costs per quality-adjusted life-year (QALY) saved. RESULTS: After 30 years of simulation, the SBP group has added 0.32 QALYs, and the cost has been saved 841.00 CNY. Compared with the standard therapy, the ICER for the SBP therapy was -2628.13 CNY per QALY. Scenario analyses of Chinese females showed that, after 30 years of simulation, the SBP therapy has been increased by 0.82 QALYs, and the cost has been reduced by 19474.00 CNY. Compared with the standard therapy, the ICER for the SBP therapy was -26569.51 CNY per QALY. Similar results were obtained in various extensive sensitivity analyses. CONCLUSIONS: This is the first study to evaluate the cost-effectiveness of SBP in the treatment of CAD. In conclusion, SBP as an add-on treatment to standard therapy appears to be a cost-effective strategy for CAD in Chinese patients.

EphA2-specific microvesicles derived from tumor cells facilitate the targeted delivery of chemotherapeutic drugs for osteosarcoma therapy.

Despite advances in surgery and chemotherapy, the survival of patients with osteosarcoma (OS) has not been fundamentally improved over the last two decades. Microvesicles (MVs) have a high cargo-loading capacity and are emerging as a promising drug delivery nanoplatform. The aim of this study was to develop MVs as specifically designed vehicles to enable OS-specific targeting and efficient treatment of OS. Herein, we designed and constructed a nanoplatform (YSA-SPION-MV/MTX) consisting of methotrexate (MTX)-loaded MVs coated with surface-carboxyl Fe3O4 superparamagnetic nanoparticles (SPIONs) conjugated with ephrin alpha 2 (EphA2)-targeted peptides (YSAYPDSVPMMS, YSA). YSA-SPION-MV/MTX showed an effective targeting effect on OS cells, which was depended on the binding of the YSA peptide to EphA2. In the orthotopic OS mouse model, YSA-SPION-MV/MTX effectively delivered drugs to tumor sites with specific targeting, resulting in superior anti-tumor activity compared to MTX or MV/MTX. And YSA-SPION-MV/MTX also reduced the side effects of high-dose MTX. Taken together, this strategy opens up a new avenue for OS therapy. And we expect this MV-based therapy to serve as a promising platform for the next generation of precision cancer nanomedicines.

Multi-omics and gut microbiome: Unveiling the pathogenic mechanisms of early-life pesticide exposure.

The extensive application of pesticides in agricultural production has raised significant concerns about its impact on human health. Different pesticides, including fungicides, insecticides, and herbicides, cause environmental pollution and health problems for non-target organisms. Infants and young children are so vulnerable to the harmful effects of pesticide exposure that early-life exposure to pesticides deserves focused attention. Recent research lays emphasis on understanding the mechanism between negative health impacts and early-life exposure to various pesticides. Studies have explored the impacts of exposure to these pesticides on model organisms (zebrafish, rats, and mice), as well as the mechanism of negative health effects, based on advanced methodologies like gut microbiota and multi-omics. These methodologies help comprehend the pathogenic mechanisms associated with early-life pesticide exposure. In addition to presenting health problems stemming from early-life exposure to pesticides and their pathogenic mechanisms, this review proposes expectations for future research. These proposals include focusing on identifying biomarkers that indicate early-life pesticide exposure, investigating transgenerational effects, and seeking effective treatments for diseases arising from such exposure. This review emphasizes how to understand the pathogenic mechanisms of early-life pesticide exposure through gut microbiota and multi-omics, as well as the adverse health effects of such exposure.

[Morphological and biochemical characterization during seed development of Notopterygium incisum].

This study aimed to examine the morphological, physiological, and biochemical alterations occurring in Notopterygium incisum seeds throughout their developmental stages, with the objective of establishing a theoretical foundation for the cultivation of superior quality seeds. The experimental materials utilized in this study were the seeds of N. incisum at various stages of development following anthesis. Through the employment of morphological observation and plant physiology techniques, the external morphology, nutrients, enzyme activity, and endogenous hormones of the seeds were assessed. The results revealed a transition in seed coat color from light green to brown during the growth and development of N. incisum seeds. Additionally, as the seeds matured, a decrease in water content was observed. Conversely, starch content exhibited a progressive increase, while sucrose content displayed fluctuations. At 7 days after anthesis, the soluble sugar content attained its highest level of 4.52 mg·g~(-1), whereas the soluble protein content reached its maximum of 6.00 mg·g~(-1) at 14 days after anthesis and its minimum of 4.94 mg·g~(-1) at 42 days after anthesis. The activity of superoxide dismutase(SOD) exhibited an initial increase, followed by a decrease, and eventually reached a stable state. Conversely, the activities of catalase(CAT) and peroxidase(POD) demonstrated a decrease initially, followed by an increase, and then another decrease. The levels of the four endogenous hormones, namely gibberellin(GA_3), zeatin riboside(ZR), auxin(IAA), and abscisic acid(ABA), in the seeds displayed significant variations, with IAA and ABA exhibiting considerably higher levels compared to the other hormones. The levels of plant growth-promoting hormones, represented by IAA, generally displayed a pattern of initial increase followed by a subsequent decrease during seed development, while the plant growth-inhibiting hormone ABA showed the opposite trend. The findings indicate that the alterations in nutrient composition, antioxidant enzyme activity, and endogenous hormone levels vary throughout the maturation process of N. incisum seeds. These observations hold relevance for the cultivation of N. incisum seeds.

GCRV-II invades monocytes/macrophages and induces macrophage polarization and apoptosis in tissues to facilitate viral replication and dissemination.

Grass carp reovirus (GCRV), particularly the highly prevalent type II GCRV (GCRV-II), causes huge losses in the aquaculture industry. However, little is known about the mechanisms by which GCRV-II invades grass carp and further disseminates among tissues. In the present study, monocytes/macrophages (Mo/Mφs) were isolated from the peripheral blood of grass carp and infected with GCRV-II. The results of indirect immunofluorescent microscopy, transmission electron microscopy, real-time quantitative RT-PCR (qRT-PCR), western blot (WB), and flow cytometry analysis collectively demonstrated that GCRV-II invaded Mo/Mφs and replicated in them. Additionally, we observed that GCRV-II induced different types (M1 and M2) of polarization of Mo/Mφs in multiple tissues, especially in the brain, head kidney, and intestine. To assess the impact of different types of polarization on GCRV-II replication, we recombinantly expressed and purified the intact cytokines CiIFN-γ2, CiIL-4/13A, and CiIL-4/13B and successfully induced M1 and M2 type polarization of macrophages using these cytokines through in vitro experiments. qRT-PCR, WB, and flow cytometry analyses showed that M2 macrophages had higher susceptibility to GCRV-II infection than other types of Mo/Mφs. In addition, we found GCRV-II induced apoptosis of Mo/Mφs to facilitate virus replication and dissemination and also detected the presence of GCRV-II virus in plasma. Collectively, our findings indicated that GCRV-II could invade immune cells Mo/Mφs and induce apoptosis and polarization of Mo/Mφs for efficient infection and dissemination, emphasizing the crucial role of Mo/Mφs as a vector for GCRV-II infection.IMPORTANCEType II grass carp reovirus (GCRV) is a prevalent viral strain and causes huge losses in aquaculture. However, the related dissemination pathway and mechanism remain largely unclear. Here, our study focused on phagocytic immune cells, monocytes/macrophages (Mo/Mφs) in blood and tissues, and explored whether GCRV-II can invade Mo/Mφs and replicate and disseminate via Mo/Mφs with their differentiated type M1 and M2 macrophages. Our findings demonstrated that GCRV-II infected Mo/Mφs and replicated in them. Furthermore, GCRV-II infection induces an increased number of M1 and M2 macrophages in grass carp tissues and a higher viral load in M2 macrophages. Furthermore, GCRV-II induced Mo/Mφs apoptosis to release viruses, eventually infecting more cells. Our study identified Mo/Mφs as crucial components in the pathway of GCRV-II dissemination and provides a solid foundation for the development of treatment strategies for GCRV-II infection.

Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates.

The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. The targeted protein degradation (TPD) strategy has been studied in the treatment of NDs, but multitarget bifunctional molecules have been ignored. Herein, a series of effective dual PROTAC degraders were developed, which could degrade α-Syn aggregates and total tau simultaneously. The degradation effects were evaluated in vitro, and the results showed that T3 could significantly knockdown α-Syn aggregates and total tau in the degradation efficiency with DC50 of 1.57 ± 0.55 and 4.09 ± 0.90 µM, respectively. Further mechanistic exploration showed that the degradation effect was mediated by the ubiquitin-proteasome system (UPS). Additionally, the therapeutic efficacy of T3 was confirmed in an MPTP-induced PD mouse model. Our results suggest that these dual PROTACs may provide a potential therapeutic strategy for NDs.

Deciphering the influencing mechanism of hydraulic retention time on purification performance of a mixotrophic system from the perspective of reaction kinetics.

At present, eutrophication is increasingly serious, so it is necessary to effectively reduce nitrogen and phosphorus in water bodies. In this study, a pyrite/polycaprolactone-based mixotrophic denitrification (PPMD) system using pyrite and polycaprolactone (PCL) as electron donors was developed and compared with pyrite-based autotrophic denitrification (PAD) system and PCL-based heterotrophic denitrification (PHD) system through continuous flow experiment. The removal efficiency of NO3--N (NRE) and PO43--P (PRE) and the contribution proportion of PAD in the PPMD system were significantly increased by prolonging hydraulic retention time (HRT, from 1 to 48 h). When HRT was equal to 24 h, the PPMD system conformed to the zero-order kinetic model, so NRE and PRE were mainly limited by the PAD process. When HRT was equal to 48 h, the PPMD system met the first-order kinetic model with NRE and PRE reaching 98.9 ± 1.1% and 91.8 ± 4.5%, respectively. When HRT = 48 h, the NRE and PRE by PAD system were 82.7 ± 9.1% and 88.5 ± 4.7%, respectively, but the effluent SO42- concentration was as high as 152.1 ± 13.7 mg/L (the influent SO42- concentration was 49.2 ± 3.3 mg/L); the NRE by PHD system was 98.5 ± 1.7%, but the PO43--P could not be removed ideally. The concentrations of NO3--N, total nitrogen, PO43--P, and SO42- in the PPMD system also showed distinct changes along the reactor column. In addition, the microbial diversity analysis showed that prolonging HRT (from 24 to 48 h) increased the abundance of autotrophic denitrifying microorganisms in the PPMD system, ultimately increasing the contribution proportion of PAD.

The cytosolic aminotransferase VAS1 coordinates aromatic amino acid biosynthesis and metabolism.

The aromatic amino acids (AAAs) phenylalanine, tyrosine, and tryptophan are basic protein units and precursors of diverse specialized metabolites that are essential for plant growth. Despite their significance, the mechanisms that regulate AAA homeostasis remain elusive. Here, we identified a cytosolic aromatic aminotransferase, REVERSAL OF SAV3 PHENOTYPE 1 (VAS1), as a suppressor of arogenate dehydrogenase 2 (adh2) in Arabidopsis (Arabidopsis thaliana). Genetic and biochemical analyses determined that VAS1 uses AAAs as amino donors, leading to the formation of 3-carboxyphenylalanine and 3-carboxytyrosine. These pathways represent distinct routes for AAA metabolism that are unique to specific plant species. Furthermore, we show that VAS1 is responsible for cytosolic AAA biosynthesis, and its enzymatic activity can be inhibited by 3-carboxyphenylalanine. These findings provide valuable insights into the crucial role of VAS1 in producing 3-carboxy AAAs, notably via recycling of AAAs in the cytosol, which maintains AAA homeostasis and allows plants to effectively coordinate the complex metabolic and biosynthetic pathways of AAAs.

Anatomically Guided PET Image Reconstruction Using Conditional Weakly-Supervised Multi-Task Learning Integrating Self-Attention.

To address the lack of high-quality training labels in positron emission tomography (PET) imaging, weakly-supervised reconstruction methods that generate network-based mappings between prior images and noisy targets have been developed. However, the learned model has an intrinsic variance proportional to the average variance of the target image. To suppress noise and improve the accuracy and generalizability of the learned model, we propose a conditional weakly-supervised multi-task learning (MTL) strategy, in which an auxiliary task is introduced serving as an anatomical regularizer for the PET reconstruction main task. In the proposed MTL approach, we devise a novel multi-channel self-attention (MCSA) module that helps learn an optimal combination of shared and task-specific features by capturing both local and global channel-spatial dependencies. The proposed reconstruction method was evaluated on NEMA phantom PET datasets acquired at different positions in a PET/CT scanner and 26 clinical whole-body PET datasets. The phantom results demonstrate that our method outperforms state-of-the-art learning-free and weakly-supervised approaches obtaining the best noise/contrast tradeoff with a significant noise reduction of approximately 50.0% relative to the maximum likelihood (ML) reconstruction. The patient study results demonstrate that our method achieves the largest noise reductions of 67.3% and 35.5% in the liver and lung, respectively, as well as consistently small biases in 8 tumors with various volumes and intensities. In addition, network visualization reveals that adding the auxiliary task introduces more anatomical information into PET reconstruction than adding only the anatomical loss, and the developed MCSA can abstract features and retain PET image details.

Nano-selenium repaired the damage caused by fungicides on strawberry flavor quality and antioxidant capacity by regulating ABA biosynthesis and ripening-related transcription factors.

Recently, studies have shown that pesticides may have adverse effects on the flavor quality of the fruits, but there is still a lack of appropriate methods to repair the damage. This study investigated the effects and mechanism of applying the emerging material, nano­selenium, and two fungicides (Boscalid and Pydiflumetofen) alone or together on the flavor quality and antioxidant capacity of strawberries. The results showed that the two fungicides had a negative impact on strawberry color, flavor, antioxidant capacity and different enzymatic systems. The color damage was mainly attributed to the impact on anthocyanin content. Nano­selenium alleviated the quality losses by increasing sugar-acid ratio, volatiles, anthocyanin levels, enzyme activities and DPPH scavenging ability and reducing ROS levels. Results also showed that these damage and repair processes were related to the regulation of flavor and ripening related transcription factors (including FaRIF, FaSnRK1, FaMYB10, FaMYB1, FaSnRK2.6 and FaABI1), the upregulation of genes on sugar-acid, volatile, and anthocyanin synthesis pathways, as well as the increase of sucrose and ABA signaling molecules. In addition, the application of nano-Se supplemented the selenium content in fruits, and was harmless to human health. This information is crucial for revealing the mechanisms of flavor damage caused by pesticides to strawberry and the repaired of nano­selenium, and broadens the researching and applying of nano­selenium in repairing the damage caused by pesticides.

Interpretable CRISPR/Cas9 off-target activities with mismatches and indels prediction using BERT.

Off-target effects of CRISPR/Cas9 can lead to suboptimal genome editing outcomes. Numerous deep learning-based approaches have achieved excellent performance for off-target prediction; however, few can predict the off-target activities with both mismatches and indels between single guide RNA (sgRNA) and target DNA sequence pair. In addition, data imbalance is a common pitfall for off-target prediction. Moreover, due to the complexity of genomic contexts, generating an interpretable model also remains challenged. To address these issues, firstly we developed a BERT-based model called CRISPR-BERT for enhancing the prediction of off-target activities with both mismatches and indels. Secondly, we proposed an adaptive batch-wise class balancing strategy to combat the noise exists in imbalanced off-target data. Finally, we applied a visualization approach for investigating the generalizable nucleotide position-dependent patterns of sgRNA-DNA pair for off-target activity. In our comprehensive comparison to existing methods on five mismatches-only datasets and two mismatches-and-indels datasets, CRISPR-BERT achieved the best performance in terms of AUROC and PRAUC. Besides, the visualization analysis demonstrated how implicit knowledge learned by CRISPR-BERT facilitates off-target prediction, which shows potential in model interpretability. Collectively, CRISPR-BERT provides an accurate and interpretable framework for off-target prediction, further contributes to sgRNA optimization in practical use for improved target specificity in CRISPR/Cas9 genome editing. The source code is available at https://github.com/BrokenStringx/CRISPR-BERT.