The evolution and diversification of oakleaf butterflies.

Oakleaf butterflies in the genus Kallima have a polymorphic wing phenotype, enabling these insects to masquerade as dead leaves. This iconic example of protective resemblance provides an interesting evolutionary paradigm that can be employed to study biodiversity. We integrated multi-omic data analyses and functional validation to infer the evolutionary history of Kallima species and investigate the genetic basis of their variable leaf wing patterns. We find that Kallima butterflies diversified in the eastern Himalayas and dispersed to East and Southeast Asia. Moreover, we find that leaf wing polymorphism is controlled by the wing patterning gene cortex, which has been maintained in Kallima by long-term balancing selection. Our results provide macroevolutionary and microevolutionary insights into a model species originating from a mountain ecosystem.

Application Potential of Extracellular Vesicles Derived From Mesenchymal Stem Cells in Renal Diseases.

The high prevalence and complex etiology of renal diseases already impose a heavy disease burden on patients and society. In certain kidney diseases such as acute kidney injury and chronic kidney disease, current treatments are limited to slowing rather than stabilizing or reversing disease progression. Therefore, it is crucial to study the pathological mechanisms of kidney disease and discover new therapeutic targets and effective therapeutic drugs. As cell-free therapeutic strategies are continually being developed, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have emerged as a hot topic for research in the field of renal diseases. Studies have demonstrated that MSC-EVs not only reproduce the therapeutic effects of MSCs but also localize to damaged kidney tissue. Compared to MSCs, MSC-EVs have several advantages, including ease of preservation, low immunogenicity, an inability to directly form tumors, and ease of artificial modification. Exploring the detailed mechanisms of MSC-EVs by developing standardized culture, isolation, purification, and drug delivery strategies will help facilitate their clinical application in kidney diseases. Here, we provide a comprehensive overview of studies about MSC-EVs in kidney diseases and discuss their limitations at the human nephrology level.

HDAC6 deacetylates IDH1 to promote the homeostasis of hematopoietic stem and progenitor cells.

Hematopoietic stem and progenitor cells (HSPCs) are cells mainly present in the bone marrow and capable of forming mature blood cells. However, the epigenetic mechanisms governing the homeostasis of HSPCs remain elusive. Here, we demonstrate an important role for histone deacetylase 6 (HDAC6) in regulating this process. Our data show that the percentage of HSPCs in Hdac6 knockout mice is lower than in wild-type mice due to decreased HSPC proliferation. HDAC6 interacts with isocitrate dehydrogenase 1 (IDH1) and deacetylates IDH1 at lysine 233. The deacetylation of IDH1 inhibits its catalytic activity and thereby decreases the 5-hydroxymethylcytosine level of ten-eleven translocation 2 (TET2) target genes, changing gene expression patterns to promote the proliferation of HSPCs. These findings uncover a role for HDAC6 and IDH1 in regulating the homeostasis of HSPCs and may have implications for the treatment of hematological diseases.

Chemical genetic screening identifies nalacin as an inhibitor of GH3 amido synthetase for auxin conjugation.

Auxin inactivation is critical for plant growth and development. To develop plant growth regulators functioning in auxin inactivation pathway, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that partially mimicked the effects of auxin. Genetic, pharmacological, and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.

Combined analysis of the effects of hypoxia and oxidative stress on DNA methylation and the transcriptome in HTR-8/SVneo trophoblast cells.

The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for pregnancy-related disorders. However, the exact mechanism is still not fully understood. In this study, we established models of hypoxia (H group) and oxidative stress (HR group) using HTR-8/SVneo trophoblast cells and performed combined analysis of genome-wide DNA methylation changes using reduced representation bisulphite sequencing and transcriptome expression changes using RNA sequencing. Our findings revealed that the H group exhibited a higher number of differentially methylated genes and differentially expressed genes than the HR group. In the H group, only 0.90% of all differentially expressed genes displayed simultaneous changes in DNA methylation and transcriptome expression. After the threshold was expanded, this number increased to 6.29% in the HR group. Notably, both the H group and HR group exhibited concurrent alterations in DNA methylation and transcriptome expression within Axon guidance and MAPK signalling pathway. Among the top 25 differentially methylated KEGG pathways in the promoter region, 11 pathways were commonly enriched in H group and HR group, accounting for 44.00%. Among the top 25 KEGG pathways in transcriptome with significant differences between the H group and HR group, 10 pathways were consistent, accounting for 40.00%. By integrating our previous data on DNA methylation from preeclamptic placental tissues, we identified that the ANKRD37 and PFKFB3 genes may contribute to the pathogenesis of preeclampsia through DNA methylation-mediated transcriptome expression under hypoxic conditions.

Arabidopsis EIN2 represses ABA responses during germination and early seedling growth by inactivating HLS1 protein independently of the canonical ethylene pathway.

The signaling pathways for the phytohormones ethylene and abscisic acid (ABA) have antagonistic effects on seed germination and early seedling establishment. However, the underlying molecular mechanisms remain unclear. In Arabidopsis thaliana, ETHYLENE INSENSITIVE 2 (EIN2) localizes to the endoplasmic reticulum (ER); although its biochemical function is unknown, it connects the ethylene signal with the key transcription factors EIN3 and EIN3-LIKE 1 (EIL1), leading to the transcriptional activation of ethylene-responsive genes. In this study, we uncovered an EIN3/EIL1-independent role for EIN2 in regulating the ABA response. Epistasis analysis demonstrated that this distinct role of EIN2 in the ABA response depends on HOOKLESS 1 (HLS1), the putative histone acetyltransferase acting as a positive regulator of ABA responses. Protein interaction assays supported a direct physical interaction between EIN2 and HLS1 in vitro and in vivo. Loss of EIN2 function resulted in an alteration of HLS1-mediated histone acetylation at the ABA-INSENSITIVE 3 (ABI3) and ABI5 loci, which promotes gene expression and the ABA response during seed germination and early seedling growth, indicating that the EIN2-HLS1 module contributes to ABA responses. Our study thus revealed that EIN2 modulates ABA responses by repressing HLS1 function, independently of the canonical ethylene pathway. These findings shed light on the intricate regulatory mechanisms underling the antagonistic interactions between ethylene and ABA signaling, with significant implications for our understanding of plant growth and development.

A Robust Anti-Thermal-Quenching Phosphor Based on Zero-Dimensional Metal Halide Rb3InCl6:xSb3.

High-power phosphor-converted white light-emitting diodes (hp-WLEDs) have been widely involved in modern society as outdoor lighting sources. In these devices, due to the Joule effect, the high applied currents cause high operation temperatures (>500 K). Under these conditions, most phosphors lose their emission, an effect known as thermal quenching (TQ). Here, we introduce a zero-dimensional (0D) metal halide, Rb3InCl6:xSb3+, as a suitable anti-TQ phosphor offering robust anti-TQ behavior up to 500 K. We ascribe this behavior of the metal halide to two factors: (1) a compensation process via thermally activated energy transfer from structural defects to emissive centers and (2) an intrinsic structural rigidity of the isolated octahedra in the 0D structure. The anti-TQ phosphor-based WLEDs can stably work at a current of 2000 mA. The low synthesis cost and nontoxic composition reported here can herald a new generation of anti-TQ phosphors for hp-WLED.

RNA-binding protein NOVA1 promotes acute T-lymphocyte leukemia progression by stabilizing USP44 mRNA.

Acute T-lymphocyte leukemia (T-ALL) is a malignant tumor disease. RNA-binding protein neotumor ventral antigen-1 (NOVA1) is highly expressed in bone marrow mononuclear cells of T-ALL patients, while the role of NOVA1 in T-ALL progression remains unknown. The gain- and loss-of-function studies for NOVA1 were performed in Jurkat and CCRF-CEM cells. NOVA1 overexpression promoted cell proliferation and cell cycle progression. NOVA1 knockdown increased the apoptosis rate of T-ALL cells. Ubiquitin-specific protease 44 (USP44), a nuclear protein with deubiquitinase catalytic activity, has been reported to play an oncogene role in human T-cell leukemia. USP44 expression was positively associated with NOVA1, and RNA immunoprecipitation assay verified the binding of NOVA1 to the mRNA of USP44. USP44 knockdown partially abolished NOVA1-induced cell proliferation and inhibition of apoptosis. The in vivo xenograft experiment was performed by injection of T-ALL tumor cells into the tail vein of NOD/SCID mice. The knockdown of NOVA1 had lower tumorigenicity. NOVA1 knockdown alleviated pathological changes in lung and spleen tissues, and increased the overall survival period and the weight of T-ALL mice. Thus, NOVA1 acts as an accelerator in T-ALL, and its function might be achieved by binding to and stabilizing USP44 mRNA.

Impact of baseline cardiovascular risk on the outcomes of intensive blood pressure intervention: a post hoc analysis of the China rural hypertension control project.

BACKGROUND: The 2018/2023 ESC/ESH Guidelines underlined a gap how baseline cardiovascular disease (CVD) risk predicted blood pressure (BP) lowering benefits. Further, 2017 ACC/AHA Guideline and 2021 WHO Guideline recommended implementation studies about intensive BP control. Now, to bridge these guideline gaps, we conducted a post hoc analysis to validate whether the baseline CVD risk influences the effectiveness of the intensive BP control strategy, which was designed by China Rural Hypertension Control Project (CRHCP). METHODS: This is a post hoc analysis of CRHCP, among which participants were enrolled except those having CVD history, over 80 years old, or missing data. Subjects were stratified into quartiles by baseline estimated CVD risk and then grouped into intervention and usual care group according to original assignment in CRHCP. Participants in the intervention group received an integrated, multi-faceted treatment strategy, executed by trained non-physician community health-care providers, aiming to achieve a BP target of < 130/80 mmHg. Cox proportional-hazards models were used to estimate the hazard ratios of outcomes for intervention in each quartile, while interaction effect between intervention and estimated CVD risk quartiles was additionally assessed. The primary outcome comprised myocardial infarction, stroke, hospitalization for heart failure, or CVD deaths. RESULTS: Significant lower rates of primary outcomes for intervention group compared with usual care for each estimated CVD risk quartile were reported. The hazard ratios (95% confidence interval) in the four quartiles (from Q1 to Q4) were 0.59 (0.40, 0.87), 0.54 (0.40, 0.72), 0.72 (0.57, 0.91) and 0.65 (0.53, 0.80), respectively (all Ps < 0.01). There's no significant difference of hazard ratios by intervention across risk quartiles (P for interaction = 0.370). Only the relative risk of hypotension, not symptomatic hypotension, was elevated in the intervention group among upper three quartiles. CONCLUSIONS: Intensive BP lowering strategy designed by CRHCP group was effective and safe in preventing cardiovascular events independent of baseline CVD risk. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov, NCT03527719.

Honeycomb-Structured MoSe2 /rGO Composites as High-Performance Anode Materials for Sodium-Ion Batteries.

Sodium-ion batteries are a promising substitute for lithium batteries due to the abundant resources and low cost of sodium. Herein, honeycomb-shaped MoSe2 /reduced graphene oxide (rGO) composite materials are synthesized from graphene oxide (GO) and MoSe2 through a one-step solvothermal process. Experiments show that the 3D honeycomb structure provides excellent electrolyte penetration while alleviating the volume change during electrochemical cycling. An anode prepared with MoSe2 /rGO composites exhibits significantly improved sodium-ion storage properties, where a large reversible capacity of 215 mAh g-1 is obtained after 2700 cycles at the current density of 30.0 A g-1 or after 5900 cycles at 8.0 A g-1 . When such an anode is paired with Na3 V2 (PO4 )3 to form a full cell, a reversible specific capacity of 107.5 mAh g-1 can be retained after 1000 cycles at the current of 1.0 A g-1 . Transmission electron microscopy, X-ray photoelectron spectroscopy and in situ X-ray diffraction (XRD) characterization reveal the reversible storage reaction of Na ions in the MoSe2 /rGO composites. The significantly enhanced sodium storage capacity is attributed to the unique honeycomb microstructure and the use of ether-based electrolytes. This study illustrates that combining rGO with ether-based electrolytes has tremendous potential in constructing high-performance sodium-ion batteries.

A novel immunogenic cell death-related classification indicates the immune landscape and predicts clinical outcome and treatment response in acute myeloid leukemia.

BACKGROUND: Immunogenic cell death (ICD) is closely related to anti-tumor therapy and regulates the tumor microenvironment (TME). This study aims to explore the molecular characteristics of ICD in acute myeloid leukemia (AML) and to analyze the value of ICD-related biomarkers in TME indication, prognosis prediction, and treatment response evaluation in AML. METHODS: Single-sample gene set enrichment analysis was used to calculate the ICD score. LASSO regression was used to construct a prognostic risk score model. We also analyzed differences in clinical characteristics, immune landscape, immunotherapy response, and chemotherapy sensitivity between high-risk and low-risk patients. RESULTS: This study identified two ICD-related subtypes and found significant heterogeneity in clinical prognosis, TME, and immune landscape between different ICD subtypes. Subsequently, a novel ICD-related prognostic risk score model was developed, which accurately predicted the prognosis of AML patients and was validated in nine AML cohorts. Moreover, there were significant correlations between risk scores and clinicopathological factors, somatic mutations, TME characteristics, immune cell infiltration, immunotherapy response, and chemosensitivity. We further validated the model gene expression in a clinically real-world cohort. CONCLUSIONS: The novel ICD-related signatures identified and validated by us can serve as promising biomarkers for predicting clinical outcomes, chemotherapy sensitivity, and immunotherapy response in AML patients, guiding the establishment of personalized and accurate treatment strategies for AML.

Unravelling the Metabolic Underpinnings of Gestational Diabetes Mellitus: A Comprehensive Mendelian Randomisation Analysis Identifying Causal Metabolites and Biological Pathways.

BACKGROUND: Gestational diabetes mellitus (GDM) has a strong genetic predisposition. Integrating metabolomics with Mendelian randomisation (MR) analysis offers a potent method to uncover the metabolic factors causally linked to GDM pathogenesis. OBJECTIVES: This study aims to identify specific metabolites and metabolic pathways causally associated with GDM susceptibility through a comprehensive MR analysis. Additionally, it seeks to explore the potential of these identified metabolites as circulating biomarkers for early GDM detection and risk assessment. Furthermore, it aims to evaluate the implicated metabolic pathways as potential therapeutic targets for preventive or interventional strategies against GDM. METHODS: A two-sample MR study was conducted using summary statistics from a metabolite genome-wide association study (GWAS) of 8299 individuals and a GDM GWAS comprising 13,039 cases and 197,831 controls. Rigorous criteria were applied to select robust genetic instruments for 850 metabolites. RESULTS: MR analysis revealed 47 metabolites exhibiting putative causal associations with GDM risk. Among these, five metabolites demonstrated statistically significant associations after multiple-testing correction: Beta-citrylglutamate, Isobutyrylcarnitine (c4), 1,2-dilinoleoyl-GPC (18:2/18:2), Alliin and Cis-3,4-methyleneheptanoylcarnitine. Importantly, all these metabolites exhibited protective effects against GDM development. Additionally, metabolic pathway enrichment analysis implicated the methionine metabolism and spermidine and spermine biosynthesis pathways in the pathogenesis of GDM. CONCLUSION: This comprehensive MR study has robustly identified specific metabolites and metabolic pathways with causal links to GDM susceptibility. These findings provide novel insights into the metabolic underpinnings of GDM aetiology and offer promising translational implications. The identified metabolites could serve as potential circulating biomarkers for early detection and risk stratification, while the implicated metabolic pathways may represent therapeutic targets for preventive or interventional strategies against GDM.

Allelic phenotype prediction of phenylketonuria based on the machine learning method.

BACKGROUND: Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Our study aimed to predict the phenotype using the allelic genotype. METHODS: A total of 1291 PKU patients with 623 various variants were used as the training dataset for predicting allelic phenotypes. We designed a common machine learning framework to predict allelic genotypes associated with the phenotype. RESULTS: We identified 235 different mutations and 623 various allelic genotypes. The features extracted from the structure of mutations and graph properties of the PKU network to predict the phenotype of PKU were named PPML (PKU phenotype predicted by machine learning). The phenotype of PKU was classified into three different categories: classical PKU (cPKU), mild PKU (mPKU) and mild hyperphenylalaninemia (MHP). Three hub nodes (c.728G>A for cPKU, c.721 for mPKU and c.158G>A for HPA) were used as each classification center, and 5 node attributes were extracted from the network graph for machine learning training features. The area under the ROC curve was AUC = 0.832 for cPKU, AUC = 0.678 for mPKU and AUC = 0.874 for MHP. This suggests that PPML is a powerful method to predict allelic phenotypes in PKU and can be used for genetic counseling of PKU families. CONCLUSIONS: The web version of PPML predicts PKU allele classification supported by applicable real cases and prediction results. It is an online database that can be used for PKU phenotype prediction http://www.bioinfogenetics.info/PPML/ .

Clinical epidemiology of adenovirus pneumonia among Chinese hospitalized children.

Adenovirus pneumonia is a prevalent form of community-acquired pneumonia among children. Research on the epidemiology and economic burden of this disease is crucial for public health, yet comprehensive data remains scarce, making it crucial to highlight on this topic. In this study, the data were extracted from the face sheet of discharge medical records collected from 26 tertiary children's hospitals from January 2016 to December 2021. In total, 1854 children with laboratory-confirmed adenovirus pneumonia were hospitalized, accounting for 0.13% of the total number of hospitalized for pneumonia in the database during the period. In addition, this figure represents a meager 0.027% when compared to the total number of hospitalized children. The male-to-female ratio was 1.78:1. The 1-3-year age group had the highest number of inpatients for adenoviral pneumonia and the largest proportion of the total hospitalizations in the same age group. Overall, winter is the primary season for the prevalence of adenovirus pneumonia, however, in southern China, there are two peak seasons, winter and summer. Although patients with 3/4 adenovirus pneumonia had no significant complications, some patients had complications such as respiratory failure, diarrhea, and myocardial damage. The median length of stay of adenovirus pneumonia was 8 d [interquartile range (IQR) 6-11], and the median hospitalization cost was 1293.83 United States dollars (IQR 811.81-2472.51). These valuable epidemiological insights into adenovirus pneumonia in Chinese children can help direct the development of targeted prevention and control strategies and surveillance measures for HAdV infections in this demographic.

Immunization with a low dose of zymosan A confers resistance to depression-like behavior and neuroinflammatory responses in chronically stressed mice.

Stimulation of the innate immune system prior to stress exposure is a possible strategy to prevent depression under stressful conditions. Based on the innate immune system stimulating activities of zymosan A, we hypothesize that zymosan A may prevent the development of chronic stress-induced depression-like behavior. Our results showed that a single injection of zymosan A 1 day before stress exposure at a dose of 2 or 4 mg/kg, but not at a dose of 1 mg/kg, prevented the development of depression-like behaviors in mice treated with chronic social defeat stress (CSDS). The prophylactic effect of a single zymosan A injection (2 mg/kg) on CSDS-induced depression-like behaviors disappeared when the time interval between zymosan A and stress exposure was extended from 1 day or 5 days to 10 days, which was rescued by a second zymosan A injection 10 days after the first zymosan A injection and 4 days (4×, once daily) of zymosan A injections 10 days before stress exposure. Further analysis showed that a single zymosan A injection (2 mg/kg) 1 day before stress exposure could prevent the CSDS-induced increase in pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Inhibition of the innate immune system by pretreatment with minocycline (40 mg/kg) abolished the preventive effect of zymosan A on CSDS-induced depression-like behaviors and CSDS-induced increase in pro-inflammatory cytokines in the brain. These results suggest that activation of the innate immune system triggered by zymosan A prevents the depression-like behaviors and neuroinflammatory responses in the brain induced by chronic stress.

Investigating the causal relationship between immune cell and Alzheimer's disease: a mendelian randomization analysis.

BACKGROUND: Complex interactions between the immune system and the brain may affect neural development, survival, and function, with etiological and therapeutic implications for neurodegenerative diseases. However, previous studies investigating the association between immune inflammation and Alzheimer's disease (AD) have yielded inconsistent results. METHODS: We applied Mendelian randomization (MR) to examine the causal relationship between immune cell traits and AD risk using genetic variants as instrumental variables. MR is an epidemiological study design based on genetic information that reduces the effects of confounding and reverse causation. We analyzed the causal associations between 731 immune cell traits and AD risk based on publicly available genetic data. RESULTS: We observed that 5 immune cell traits conferred protection against AD, while 7 immune cell traits increased the risk of AD. These immune cell traits mainly involved T cell regulation, monocyte activation and B cell differentiation. Our findings suggest that immune regulation may influence the development of AD and provide new insights into potential targets for AD prevention and treatment. We also conducted various sensitivity analyses to test the validity and robustness of our results, which revealed no evidence of pleiotropy or heterogeneity. CONCLUSION: Our research shows that immune regulation is important for AD and provides new information on potential targets for AD prevention and treatment. However, this study has limitations, including the possibility of reverse causality, lack of validation in independent cohorts, and potential confounding by population stratification. Further research is needed to validate and amplify these results and to elucidate the potential mechanisms of the immune cell-AD association.

Capture and Utilization of CO2 with Morpholine for Effective Photocatalytic N-Formylmorpholine Production.

Converting into high-value-added products represents the most optimal approach to CO2 utilization. The substitution of CO with CO2 as a potential critical material for formamide production is widely regarded as an ideal pathway and has garnered significant attention. However, high temperatures and pressures remain essential for the reaction, exerting a substantial influence on the utilization process. Herein, N-formylmorpholine was creatively synthesized by integrating the capture and solar-driven utilization of CO2 with morpholine. Notably, a remarkable N-formylmorpholine yield of 11433.3 µmol·h-1·g-1 was obtained, surpassing pure MoO3 by an astounding factor of 89.1 with a N-formylmorpholine yield of 63.8 µmol in 6 h, which is an astonishing increase of 57.5 times compared to MoO3. Both experimental results and density functional theory calculations suggest that the inclusion of Fe can effectively reduce the formation energy barrier while facilitating the desorption process of N-formylmorpholine, thereby optimizing the overall performance.

Recent contributions of pyridazine as a privileged scaffold of anticancer agents in medicinal chemistry: An updated review.

Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.

Multimodal contrastive representation learning for drug-target binding affinity prediction.

In the biomedical field, the efficacy of most drugs is demonstrated by their interactions with targets, meanwhile, accurate prediction of the strength of drug-target binding is extremely important for drug development efforts. Traditional bioassay-based drug-target binding affinity (DTA) prediction methods cannot meet the needs of drug R&D in the era of big data. Recent years we have witnessed significant success on deep learning-based models for drug-target binding affinity prediction task. However, these models only considered a single modality of drug and target information, and some valuable information was not fully utilized. In fact, the information of different modalities of drug and target can complement each other, and more valuable information can be obtained by fusing the information of different modalities. In this paper, we introduce a multimodal information fusion model for DTA prediction that is called FMDTA, which fully considers drug/target information in both string and graph modalities and balances the feature representations of different modalities by a contrastive learning approach. In addition, we exploited the alignment information of drug atoms and target residues to capture the positional information of string patterns, which can extract more useful feature information in SMILES and target sequences. Experimental results on two benchmark datasets show that FMDTA outperforms the state-of-the-art model, demonstrating the feasibility and excellent feature capture capability of FMDTA. The code of FMDTA and the data are available at: https://github.com/bestdoubleLin/FMDTA.

SIRT6 deficiency results in developmental retardation in cynomolgus monkeys.

SIRT6 acts as a longevity protein in rodents1,2. However, its biological function in primates remains largely unknown. Here we generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model using a CRISPR-Cas9-based approach. SIRT6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. SIRT6 loss delays neuronal differentiation by transcriptionally activating the long non-coding RNA H19 (a developmental repressor), and we were able to recapitulate this process in a human neural progenitor cell differentiation system. SIRT6 deficiency results in histone hyperacetylation at the imprinting control region of H19, CTCF recruitment and upregulation of H19. Our results suggest that SIRT6 is involved in regulating development in non-human primates, and may provide mechanistic insight into human perinatal lethality syndrome.