New recognition of the heart-brain axis and its implication in the pathogenesis and treatment of PTSD.

Post-traumatic stress disorder (PTSD) is a complex psychological disorder provoked by distressing experiences, and it remains without highly effective intervention strategies. The exploration of PTSD's underlying mechanisms is crucial for advancing diagnostic and therapeutic approaches. Current studies primarily explore PTSD through the lens of the central nervous system, investigating concrete molecular alterations in the cerebral area and neural circuit irregularities. However, the body's response to external stressors, particularly the changes in cardiovascular function, is often pronounced, evidenced by notable cardiac dysfunction. Consequently, examining PTSD with a focus on cardiac function is vital for the early prevention and targeted management of the disorder. This review undertakes a comprehensive literature analysis to detail the alterations in brain and heart structures and functions associated with PTSD. It also synthesizes potential mechanisms of heart-brain axis interactions relevant to the development of PTSD. Ultimately, by considering cardiac function, this review proposes novel perspectives for PTSD's prophylaxis and therapy.

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

The clinical application value of 3.0T magnetic resonance T2 mapping imaging in evaluating the degree of acetabular cartilage degeneration in joint replacement surgery running title: MRI and acetabular cartilage degeneration.

BACKGROUND: To explore and compare the values of 3.0T magnetic resonance imaging (MRI) T2 mapping in evaluating the degree of acetabular cartilage degeneration in hip replacement surgery. METHODS: A total of 26 elderly patients with femoral neck fractures who were scanned in 3.0T MRI T2 mapping quantification technique were included. Basing on MRI images, the degree of acetabular cartilage degeneration was classified into Grade 0, 1, 2, 3 and 4, according to the International Cartilage Repair Society (ICRS) scores. In addition, 8 healthy volunteers were included for control group. RESULTS: By comparison with health population, T2 relaxation values in the anterior, superior, and posterior regions of acetabular cartilage in patients with femoral neck fracture were obviously increased (P < 0.001). Among the patients with femoral neck fractures, there were 16 hip joint with Grade 1-2 (mild degeneration subgroup) and 10 hip joints with Grade 3-4 (severe degeneration subgroup), accounting for 61.54% and 38.46%, respectively. Additionally, T2 relaxation values in the anterior and superior bands of articular cartilage were positively related to the MRI-based grading (P < 0.05); while there was no significant difference of T2 relaxation values in the posterior areas of articular cartilage between severe degeneration subgroup and mild degeneration subgroup (P > 0.05). Importantly, acetabular cartilage degeneration can be detected through signal changes of T2 mapping pseudo-color images. CONCLUSION: 3.0T MRI T2 mapping technology can be used to determine the degree of acetabular cartilage degeneration, which can effectively monitor the disease course.

Herpes Zoster and Post-Herpetic Neuralgia-Diagnosis, Treatment, and Vaccination Strategies.

INTRODUCTION: Herpes zoster is caused by the reactivation of latent varicella infection within the sensory ganglia, caused by the varicella-zoster virus (VZV). The disease is classically characterized by a painful unilateral vesicular eruption. Complications of the disease include herpes zoster ophthalmicus, Ramsay Hunt syndrome, acute retinal necrosis, and post-herpetic neuralgia. In this paper, we discuss the epidemiology, pathogenesis, clinical features, diagnosis, management, and vaccination strategies of herpes zoster and post-herpetic neuralgia. METHOD: This paper was developed with input from specialists from Singapore's public sectors-dermatologists, family physicians, and infectious diseases specialists. RESULTS: The diagnosis of herpes zoster is clinical and can be aided with laboratory investigations. Early initiation of antivirals, within 72 h of onset, can reduce the severity and duration of the condition and decrease the intensity of pain. In patients with a high risk of post-herpetic neuralgia, early initiation of anticonvulsants or tricyclic antidepressants can be considered. Herpes zoster is highly preventable, with the advent of the recombinant zoster vaccine (RZV) providing an overall vaccine efficacy of 97.2%. Procedures such as epidural blocks and subcutaneous or intracutaneous injections of local anesthetics and steroids can be considered for patients with a high risk of post-herpetic neuralgia to reduce its incidence. CONCLUSION: This article serves as a guideline for clinicians in the diagnosis, investigations, management, and prevention of herpes zoster. With the majority of adults in Singapore currently at risk of developing herpes zoster due to varicella immunization being only introduced in 2020, it is important for clinicians to recognize and manage herpes zoster appropriately.

Measurement error in hydrostatic leveling system due to temperature effect and their reduction method.

Temperature is a crucial factor influencing the accuracy of the hydrostatic leveling system (HLS), necessitating a temperature compensation test for HLS. This paper investigates HLS temperature compensation through theoretical correction and experimental verification. The influence of temperature on the accuracy of hydrostatic level products is determined through temperature tests on 34 hydrostatic level products. The optimal temperature compensation formula is derived using the non-linear curve fitting method. The HLS is enhanced with a temperature compensation algorithm and temperature sensor, resulting in a new, high-precision, and high-stability hydrostatic leveling product with temperature compensation. Experimental findings reveal that the stability of the improved hydrostatic leveling product exceeds 30% compared to products on the market and surpasses 70% compared to the original products.

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia.

BACKGROUND: Accumulating evidence suggests that the inflammatory cytokine interleukin-6 (IL-6) contributes to the pathophysiology of psychiatric disorders. However, there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia (EOS). AIM: To investigate the relationship between serum IL-6 concentration and the clinical features of EOS. METHODS: We measured serum IL-6 Levels from 74 patients with chronic schizophrenia, including 33 with age at onset < 21 years (EOS group) and 41 with onset ≥ 21 years in [adult-onset schizophrenia (AOS) group], and from 41 healthy controls. Symptom severities were evaluated using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls (F = 22.32, P < 0.01), but did not differ significantly between EOS and AOS groups (P > 0.05) after controlling for age, body mass index, and other covariates. Negative symptom scores were higher in the EOS group than the AOS group (F = 6.199, P = 0.015). Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score (r = -0.389, P = 0.032) and avolition/asociality subscore (r = -0.387, P = 0.026). CONCLUSION: Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness. IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.

Environmentally Relevant Levels of Antiepileptic Carbamazepine Altered Intestinal Microbial Composition and Metabolites in Amphibian Larvae.

There is growing concern about the potential ecological risks posed by pharmaceutical residues in the aquatic environment. However, our understanding of the toxic effects of antiepileptic pharmaceuticals, such as carbamazepine (CBZ), on aquatic animal larvae is still limited. In this study, the tadpoles of the black-spotted pond frog (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of CBZ (0.3 and 3.0 µg/L) for 30 days, and their growth, intestinal microbial composition, and metabolites were investigated to assess the potential toxic effects of CBZ in non-targeted aquatic organisms. Some tadpoles died during exposure, but there was no significant among-group difference in the survival and growth rates. CBZ exposure significantly altered the composition of tadpole intestinal microbiota. Relative abundances of some bacterial genera (e.g., Blautia, Prevotella, Bacillus, Microbacterium, etc.) decreased, while others (e.g., Paucibacter, etc.) increased in CBZ-exposed tadpoles. Interestingly, CBZ-induced alterations in some bacteria might not necessarily lead to adverse outcomes for animals. Meanwhile, small molecular intestinal metabolites related to energy metabolism, and antioxidant and anti-inflammatory activities were also altered after exposure. Taken together, environmentally relevant levels of CBZ might alter the metabolic and immune performances of amphibian larvae by modifying the abundance of some specific bacteria and the level of metabolites in their intestines, thereby potentially causing a long-term effect on their fitness.

Enhancing efficiency of protein language models with minimal wet-lab data through few-shot learning.

Accurately modeling the protein fitness landscapes holds great importance for protein engineering. Pre-trained protein language models have achieved state-of-the-art performance in predicting protein fitness without wet-lab experimental data, but their accuracy and interpretability remain limited. On the other hand, traditional supervised deep learning models require abundant labeled training examples for performance improvements, posing a practical barrier. In this work, we introduce FSFP, a training strategy that can effectively optimize protein language models under extreme data scarcity for fitness prediction. By combining meta-transfer learning, learning to rank, and parameter-efficient fine-tuning, FSFP can significantly boost the performance of various protein language models using merely tens of labeled single-site mutants from the target protein. In silico benchmarks across 87 deep mutational scanning datasets demonstrate FSFP's superiority over both unsupervised and supervised baselines. Furthermore, we successfully apply FSFP to engineer the Phi29 DNA polymerase through wet-lab experiments, achieving a 25% increase in the positive rate. These results underscore the potential of our approach in aiding AI-guided protein engineering.

Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19.

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls was performed, excluding patients previously treated with glucocorticoids. Several SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity of mineralocorticoids and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls, excluding those that affected adrenal function. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with those in SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with exacerbation of inflammation, differentiation and the presence of dual-ZG/ZF identity cells. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of adrenal axis and the corticosteroid sensitivity.

[Effects of reductive soil disinfestation and organic fertilizer application on microbial community stability in a facility vegetable soil]. / 强还原处理和施用有机肥对设施蔬菜地土壤微生物群落稳定性的影响.

Reductive soil disinfestation (RSD) is an effective method for remediating degraded facility vegetable soils. However, the effectiveness of RSD using green manure as a carbon source in the field has not yet been clarified. We investigated the effects of RSD and organic fertilizer application on soil microbial community composition, diversity, and stability in a degraded facility vegetable soil. There were six treatments, including no fertilization (CK), no fertilization and soil flooded and mulched with plastic film (FF), soil amended with chicken manure (OM), soil amended with chicken manure and flooded and mulched with plastic film (OMR), soil amended with Sesbania cannabina (TF), and soil amended with S. cannabina and flooded and mulched with plastic film (TR). The results showed that the OMR and TR treatments significantly decreased bacterial Chao1 index, altered bacterial and fungal community structure, and increased the relative abundances of Bacillus, Rhodococcus, Clostridium, and Penicillium. The TR treatment significantly reduced the relative abundance of Fusarium. Results of redundancy analysis and Mantel test analysis suggested that soil ammonium nitrogen and dissolved organic carbon contents were the key factors influencing bacterial community composition, and soil pH was the key factor affecting fungal community composition. Results of cohesion analysis showed that the OMR and TR treatments significantly improved bacterial community stability, and that there was no difference between OMR and TR treatments. The TR treatment enhanced fungal community stability, which was significantly higher than the OMR treatment. Therefore, the RSD with green manure as carbon source could be effective remediation practice to improve soil health.

Left atrial volume index and interleukin-6 as predictors for postoperative atrial fibrillation.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery. However, the predictive value of single indictor still remains controversial. This study aimed to assess the predictive value of combining preoperative left atrial volume index (LAVI) and postoperative interleukin-6 (IL-6) for POAF in the patients receiving cardiac surgery. METHODS: Patients who admitted to Nanjing First Hospital during the study period between December 2022 and June 2023, and underwent open-heart surgery without a history of atrial fibrillation (AF) were enrolled. The relationships between predictors and POAF were investigated using logistic regression analysis. We determined the combined predictive value of LAVI and IL-6 for POAF by measuring the changes in the area under the receiver operating characteristic curve (AUC) and calculating the net reclassification improvements (NRIs) and integrated discrimination improvement (IDIs). RESULTS: 102 patients were enrolled in this study, and 50 participants developed POAF (49.0%). Patients who experienced POAF had higher levels of preoperative LAVI and postoperative IL-6 than those who did not. Regression analysis revealed that larger LAVI and higher level of IL-6 were independently associated with increased risk of POAF. The combined addition of LAVI and IL-6 to the predictive model resulted in an evident increase in the AUC. Incorporating both LAVI and IL-6 increased IDIs in all models. CONCLUSION: Our results demonstrated that combined LAVI and IL-6 achieved a higher prediction performance for POAF.

Visualising cancer in 3D: 3-Dimensional Tissue Imaging for management of cutaneous basal cell carcinoma.

Surgical management of basal cell carcinoma (BCC) typically involves surgical excision with post-operative margin assessment using the bread-loafing technique; or gold-standard Mohs micrographic surgery (MMS), where margins are iteratively examined for residual cancer after tumour removal, with additional excisions performed upon detecting residual tumour at margins. There is limited sampling of resection margins with bread loafing, with detection of positive margins 44% of the time using 2 mm intervals. To resolve this, we have developed three-dimensional (3D) Tissue Imaging for: (1) complete examination of cancer margins and (2) detection of tumour proximity to nerves and blood vessels. 3D Tissue optical clearing with a light sheet imaging protocol was developed for margin assessment in two datasets assessed by two independent evaluators: (1) 48 samples from 29 patients with varied BCC subtypes, sizes and pigmentation levels; (2) 32 samples with matching Mohs' surgeon reading of tumour margins using two-dimensional haematoxylin & eosin-stained sections. The 3D Tissue Imaging protocol permits a complete examination of deeper and peripheral margins. Two independent evaluators achieved negative predictive values of 92.3% and 88.24% with 3D Tissue Imaging. Images obtained from 3D Tissue Imaging recapitulates histological features of BCC, such as nuclear crowding, palisading and retraction clefting and provides a 3D context for recognising normal skin adnexal structures. Concurrent immunofluorescence labelling of nerves and blood vessels allows visualisation of structures closer to tumour-positive regions, which may have a higher risk for neural and vascular infiltration. Together, this method provides more information in a 3D spatial context, enabling better cancer management by clinicians.

Temperature dependence of the rain-gas and snow-gas partition coefficients for nearly a thousand chemicals.

Compared to the particle-gas partition coefficients (KPG), the rain-gas (KRG) and snow-gas (KSG) partition coefficients are also essential in studying the environmental behavior and fate of chemicals in the atmosphere. While the temperature dependence for the KPG have been extensively studied, the study for KRG and KSG are still lacking. Adsorption coefficients between water surface-air (KIA) and snow surface-air (KJA), as well as partition coefficients between water-air (KWA) and octanol-air (KOA) are vital in calculating KRG and KSG. These four basic adsorption and partition coefficients are also temperature-dependent, given by the well-known two-parameters Antoine equation logKXY = AXY + BXY/T, where KXY is the adsorption or partition coefficients, AXY and BXY are Antoine parameters (XY stand for IA, JA, WA, and OA), and T is the temperature in Kelvin. In this study, the parameters AXY and BXY are calculated for 943 chemicals, and logKXY can be estimated at any ambient temperature for these chemicals using these Antoine parameters. The results are evaluated by comparing these data with published experimental and modeled data, and the results show reasonable accuracy. Based on these coefficients, temperature-dependence of logKRG and logKSG is studied. It is found that both logKRG and logKSG are linearly related to 1/T, and Antoine parameters for logKRG and logKSG are also estimated. Distributions of the 943 chemicals in the atmospheric phases (gas, particle, and rain/snow), are illustrated in a Chemical Space Map. The findings reveal that, at environmental temperatures and precipitation days, the dominant state for the majority of chemicals is the gaseous phase. All the AXY and BXY values for logKSG, logKRG, and basic adsorption and partition coefficients, both modeled by this study and collected from published work, are systematically organized into an accessible dataset for public utilization.

Unraveling the Mechanisms of Cannabidiol's Pharmacological Actions: A Comprehensive Research Overview.

Cannabis sativa has long been used for neurological and psychological healing. Recently, cannabidiol (CBD) extracted from cannabis sativa has gained prominence in the medical field due to its non-psychotropic therapeutic effects on the central and peripheral nervous systems. CBD, also acting as a potent antioxidant, displays diverse clinical properties such as anticancer, antiinflammatory, antidepressant, antioxidant, antiemetic, anxiolytic, antiepileptic, and antipsychotic effects. In this review, we summarized the structural activity relationship of CBD with different receptors by both experimental and computational techniques and investigated the mechanism of interaction between related receptors and CBD. The discovery of structural activity relationship between CBD and target receptors would provide a direction to optimize the scaffold of CBD and its derivatives, which would give potential medical applications on CBD-based therapies in various illnesses.

White Matter Microstructure Changes Revealed by Diffusion Kurtosis and Diffusion Tensor Imaging in Mutant Huntingtin Gene Carriers.

Background: Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington's disease (HD). Objective: To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD. Methods: 22 mutant huntingtin (mHTT) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage. Results: Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (r = -0.80 to -0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Index = 0.786), and discerning different phase of HD (Youden Index = 0.804). Conclusions: Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD.

Supplier selection in green supply chain management using correlation-based TOPSIS in a q-rung orthopair fuzzy soft environment.

Fuzzy hybrid models are efficient mathematical tools for managing unclear and vague data in real-world scenarios. This research explores the q-rung orthopair fuzzy soft set (q-ROFSS), which presents incomplete and ambiguous details in decision-making problems. The main intention of this study is to describe and evaluate the characteristics of the correlation coefficient (CC) and weighted correlation coefficient (WCC) for q-ROFSS. Also, the technique for order preference should be enhanced by similarity to the ideal solution (TOPSIS) with extended measures in q-ROFSS settings. Furthermore, we integrated mathematical formulations of correlation obstructions to confirm the consistency of the planned technique. It helps handle difficulties involving multi-attribute group decision-making (MAGDM). Moreover, a numerical illustration is presented to clarify how the advocated decision-making methodology can be implemented in evaluating suppliers in green supply chain management (GSCM). As a result, each alternative is assessed using multiple criteria, such as quality and reliability, capacity and scalability, compliance and certifications, and sustainability practices. The technique proposed in this study retains the selected research's specific structure more effectively than current techniques. A comparative analysis further substantiates the feasibility and effectiveness of the proposed approach over other decision-making techniques.

The potential of RNA therapeutics in dermatology.

Ribonucleic acid (RNA) therapeutics hold great potential for the advancement of dermatological treatments due to, among other reasons, the possibility of treating previously undruggable targets, high specificity with minimal side effects, and ability to include multiple RNA targets in a single product. Although there have been research relating to RNA therapeutics for decades, there have not been many products translated for clinical use until recently. This may be because of challenges to the application of RNA therapeutics, including the dearth of effective modes of delivery to the target, and rapid degradation of RNA in the human body and environment. This article aims to provide insight on (1) the wide-ranging possibilities of RNA therapeutics in the field of dermatology as well as (2) how key challenges can be addressed, so as to encourage the development of novel dermatological treatments. We also share our experience on how RNA therapeutics have been applied in the management of hypertrophic and keloid scars.

Insight into saffron associated microbiota from different origins and explore the endophytes for enhancement of bioactive compounds.

Crocus sativus L. is a perennial crop for its valuable active compounds. Plant-associated microbes impact on the quality and efficacy of medicinal herbs by promoting bioactive components accumulation. However, how microbes influence the accumulation of bioactive components in saffron have not been well studied. Here, the microbiome in C. sativus derived from 3 core production areas were deciphered by 16S rDNA sequencing and the relationship between endophytes and bioactive ingredients were further investigated. The main results are as follows: (1) Both Comamonadaceae and Burkholderiaceae were positively correlated with the content of bioactive components in the stigmas. (2) The synthesis of crocin was positively correlated with Xanthomonadaceae, negatively correlated with Lachnospiraceae and Prevotellaceae. Therefore, further investigation is required to determine whether Xanthomonadaceae plays an unknown function in the synthesis of crocin. These findings provide guidelines for disentangling the function of endophytes in the production of bioactive ingredients and thus for microbe-mediated breeding.

The MdNAC72-MdABI5 module acts as an interface integrating jasmonic acid and gibberellin signals and undergoes ubiquitination-dependent degradation regulated by MdSINA2 in apple.

Jasmonic acid (JA) and gibberellin (GA) coordinately regulate plant developmental programs and environmental cue responses. However, the fine regulatory network of the cross-interaction between JA and GA remains largely elusive. In this study, we demonstrate that MdNAC72 together with MdABI5 positively regulates anthocyanin biosynthesis through an exquisite MdNAC72-MdABI5-MdbHLH3 transcriptional cascade in apple. MdNAC72 interacts with MdABI5 to promote the transcriptional activation of MdABI5 on its target gene MdbHLH3 and directly activates the transcription of MdABI5. The MdNAC72-MdABI5 module regulates the integration of JA and GA signals in anthocyanin biosynthesis by combining with JA repressor MdJAZ2 and GA repressor MdRGL2a. MdJAZ2 disrupts the MdNAC72-MdABI5 interaction and attenuates the transcriptional activation of MdABI5 by MdNAC72. MdRGL2a sequesters MdJAZ2 from the MdJAZ2-MdNAC72 protein complex, leading to the release of MdNAC72. The E3 ubiquitin ligase MdSINA2 is responsive to JA and GA signals and promotes ubiquitination-dependent degradation of MdNAC72. The MdNAC72-MdABI5 interface fine-regulates the integration of JA and GA signals at the transcriptional and posttranslational levels by combining MdJAZ2, MdRGL2a, and MdSINA2. In summary, our findings elucidate the fine regulatory network connecting JA and GA signals with MdNAC72-MdABI5 as the core in apple.

RiboDiffusion: tertiary structure-based RNA inverse folding with generative diffusion models.

MOTIVATION: RNA design shows growing applications in synthetic biology and therapeutics, driven by the crucial role of RNA in various biological processes. A fundamental challenge is to find functional RNA sequences that satisfy given structural constraints, known as the inverse folding problem. Computational approaches have emerged to address this problem based on secondary structures. However, designing RNA sequences directly from 3D structures is still challenging, due to the scarcity of data, the nonunique structure-sequence mapping, and the flexibility of RNA conformation. RESULTS: In this study, we propose RiboDiffusion, a generative diffusion model for RNA inverse folding that can learn the conditional distribution of RNA sequences given 3D backbone structures. Our model consists of a graph neural network-based structure module and a Transformer-based sequence module, which iteratively transforms random sequences into desired sequences. By tuning the sampling weight, our model allows for a trade-off between sequence recovery and diversity to explore more candidates. We split test sets based on RNA clustering with different cut-offs for sequence or structure similarity. Our model outperforms baselines in sequence recovery, with an average relative improvement of 11% for sequence similarity splits and 16% for structure similarity splits. Moreover, RiboDiffusion performs consistently well across various RNA length categories and RNA types. We also apply in silico folding to validate whether the generated sequences can fold into the given 3D RNA backbones. Our method could be a powerful tool for RNA design that explores the vast sequence space and finds novel solutions to 3D structural constraints. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/ml4bio/RiboDiffusion.