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Stomata are epidermal openings that facilitate plant-atmosphere gas and water exchange during photosynthesis, respiration and water evaporation. SPEECHLESS (SPCH) is a master basic helix-loop-helix (bHLH) transcription factor that determines the initiation of stomatal development. It is known that blue light promotes stomatal development through the blue light photoreceptor cryptochromes (CRYs, CRY1 and CRY2). Whether CRYs regulate stomatal development through directly modulating SPCH is unknown. Here, we demonstrate by biochemical studies that CRY1 physically interacts with SPCH in a blue light-dependent manner. Genetic studies show that SPCH acts downstream of CRY1 to promote stomatal development in blue light. Furthermore, we show that CRY1 enhances the DNA-binding activity of SPCH and promotes the expression of its target genes in blue light. These results suggest that the mechanism by which CRY1 promotes stomatal development involves positive regulation of the DNA-binding activity of SPCH, which is likely mediated by blue light-induced CRY1-SPCH interaction. The precise regulation of SPCH DNA-binding activity by CRY1 may allow plants to optimize stomatal density and pattern according to ambient light conditions.

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Variant Porcine epidemic diarrhea virus (PEDV), which causes diarrhea and high mortality in piglets, has become a major pathogen, and co-epidemics of different subtypes of the virus have become a very thorny problem for the clinical prevention and control of PEDV. However, cross-protection between epidemic G2a and G2b subtype strains has not been observed, and there is currently no vaccine against both G2a and G2b strains. In this study, we demonstrate the low cross-protection between G2a and G2b strains with piglet immunization and challenge tests. The trimeric full-length S proteins of G2a and G2b variants were purified and a bivalent subunit vaccine against PEDV G2a/G2b-S was developed. In active and passive immune protection tests, the bivalent subunit vaccine produced high neutralizing antibody titers and S-specific immunoglobulin G (IgG) and IgA titers against both the G2a and G2b strains in piglets and sows. In the attack phase of the viruses, the clinical symptoms and microscopic lesions in the immunized groups were significantly alleviated. Importantly, the PEDV G2a/G2b-S bivalent subunit vaccine conferred effective passive immunity against PEDV G2a and G2b challenges in the form of colostrum-derived antibodies from the immunized sows. In conclusion, our data demonstrate the low cross-protection of PEDV epidemic G2a and G2b strains and show that the G2a/G2b-S bivalent subunit vaccine is protective against both G2a and G2b strains. It is therefore a candidate vaccine for PEDV prevention. IMPORTANCE: The detection rate of PEDV G2a subtype strains is currently increasing. Although commercial vaccines are available, most vaccines do not exert an ideal protective effect against these strains. Furthermore, there is no definitive research into the cross-protection between G2a and G2b strains, and no bivalent vaccine provides joint protection against both. Therefore, in this study, we investigated the cross-protection between PEDV G2a and G2b strains and designed a candidate bivalent subunit vaccine combining the trimeric S proteins of the G2a and G2b subtypes. We demonstrate that the cross-protection between strains G2a and G2b is poor and that this bivalent subunit vaccine protects piglets from viral attack by inducing both active and passive immunity. This study emphasizes the effectiveness of the PEDV G2a/G2b-S bivalent subunit vaccine and provides a feasible method for the development of efficient PEDV vaccines.

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BACKGROUND: Total knee arthroplasty (TKA) successfully alleviates pain from knee osteoarthritis, but muscle strength and function are reduced for a long period postoperatively. Postoperative active resistance exercise may play a relevant role. PURPOSE: To systematically evaluate effects of lower-limb active resistance exercise (ARE) on mobility, physical function, muscle strength and pain intensity in patients with TKA. METHODS: A search was conducted in PubMed, EMBASE, and Cochrane Library databases from inception to September 2023. Only randomized controlled trials (RCTs) that compared the effects of ARE and no intervention or other rehabilitation program without PRE were included. The outcome variables were mobility (Maximal walking speed [MWS]/6-Minute Walk Test[6MWT]), physical function (Stair Climb Test [SCT]/Timed Up and Go [TUG]), knee extension/ flexion power(KEP/KFP), joint range of motion (ROM) and pain. Standardized Mean Differences (SMD) or Mean Differences (MD) and 95% confidence intervals (CI) were calculated and combined in meta-analyses. The Cochrane Collaboration's Handbook were used for the methodological quality assessments. GRADE was used to assess the quality of evidence. The meta-analysis was performed using the RevMan 5.4 software. RESULTS: A total of 14 randomized controlled trials, involving 880 patients, were finally included. The lower-limb ARE exhibited significantly greater improvement in MWS (MD 0.13, 95%CI 0.08-0.18, P < 0.00001), TUG(MD -0.92, 95%CI -1.55- -0.28, P = 0.005), KEP (SMD 0.58, 95%CI 0.20-0.96, P = 0.003), KFP (SMD 0.38, 95%CI 0.13-0.63, P = 0.003), ROM-flexion (MD 2.74, 95%CI 1.82-3.67, P < 0.00001) and VAS (MD - 4.65, 95% CI - 7.86- -1.44, p = 0.005) compared to conventional exercise(CE) immediately post-intervention. However, there were no statistically significant differences between both groups in regard to 6MWT (MD 7.98, 95%CI -4.60-20.56, P = 0.21), SCT (MD -0.79, 95%CI -1.69-0.10, P = 0.08) and ROM-extension (MD -0.60, 95%CI -1.23-0.03, P = 0.06). CONCLUSIONS: According to the results of meta-analysis, patients undergoing TKA who receive the lower extremity ARE show better clinical effects in terms of pain relief, strength recovery and knee ROM. Simultaneously, it may be beneficial to improve mobility and physical function of patients after TKA.

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Cow milk possesses high nutritional value due to its rich array of beneficial fatty acids. It is important to understand the mechanisms involved in lipid metabolism in dairy cows. These mechanisms are driven by a complex molecular regulatory network. In addition, there are many regulatory factors involved in the process of fatty acid metabolism, including transcription factors and non-coding RNAs, amongst others. MicroRNAs (miRNAs) can regulate the expression of target genes and modulate various biological processes, including lipid metabolism. Specifically, miR-206 has been reported to impair lipid accumulation in nonruminant hepatocytes. However, the effects and regulatory mechanisms of miR-206 on lipid metabolism in bovine mammary cells remain unclear. In the present study, we investigated the effects of miR-206 on lipid-related genes and TAG accumulation. The direct downstream gene of miR-206 was subsequently determined via a dual-luciferase assay. Finally, the fatty acid content of bovine mammary epithelial cells (BMECs) upon ELOVL6 inhibition was examined. The results revealed that miR-206 overexpression significantly decreased triacylglycerol (TAG) concentration and abundances of the following: acetyl-coenzyme A carboxylase alpha (ACACA); fatty acid synthase (FASN); sterol regulatory element binding transcription factor 1 (SREBF1); diacylglycerol acyltransferase 1 (DGAT1); 1-acylglycerol-3-phosphate O-acyltransferase 6 (AGPAT6); lipin 1 (LPIN1); and fatty acid elongase 6 (ELOVL6). Overexpression of miR-206 was also associated with an increase in patatin-like phospholipase domain-containing 2 (PNPLA2), while inhibition of miR-206 promoted milk fat metabolism in vitro. In addition, we found that ELOVL6 is a direct target gene of miR-206 through mutation of the binding site. Furthermore, ELOVL6 intervention significantly decreased the TAG levels and elongation indexes of C16:0 and C16:1n-7 in BMECs. Finally, ELOVL6 siRNA partially alleviated the increased TAG accumulation caused by miR-206 inhibition. In summary, we found that miR-206 inhibits milk fatty acid synthesis and lipid accumulation by targeting ELOVL6 in BMECs. The results presented in this paper may contribute to the development of strategies for enhancing the quality of cow milk and its beneficial fatty acids, from the perspective of miRNA-mRNA networks.

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Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus that has been the main cause of diarrhea in piglets since 2010 in China. The aim of this study was to investigate sequence variation and recombination events in the spike (S) gene of PEDV isolates from China. Thirty complete S gene sequences were obtained from PEDV-positive samples collected in six provinces in China from 2020 to 2023. Phylogenetic analysis showed that 10% (3/30) belonged to subtype GII-a, 6.67% (2/30) were categorized as subtype GII-b, 66.67% (20/30) were categorized as subtype GII-c, and 16.66% (5/30) were clustered with the S-INDEL strains. Amino acid sequence alignments showed that, when compared to strains of other subtypes, the GII-c strains had two characteristic amino acid substitutions (N139D and I289M). Five S-INDEL subtype strains had a single amino acid deletion (139N) and four amino acid substitutions (N118G, T137S, A138S, and D141G). Recombination analysis allowed six putative recombination events to be identified, one involving recombination between GII-c strains, two involving GII-c and GII-b strains, two involving GII-c and GI-a strains, and one involving GII-a and GI-b strains. These results suggest that recombination between PEDV strains has been common and complex in recent years and is one of the main reasons for the continuous variation of PEDV strains.

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia with a poor prognosis and a pathogenesis that has not been fully elucidated. Oxidative stress is closely associated with IPF. In this research, we aimed to identify reliable diagnostic biomarkers associated with the oxidative stress through bioinformatics techniques. The gene expression profile data from the GSE70866 dataset was retrieved from the gene expression omnibus (GEO) database. We extracted 437 oxidative stress-related genes (ORGs) from gene set enrichment analysis (GSEA). The GSE141939 dataset was used for single-cell RNA-seq analysis to identify the expression of diagnostic genes in different cell clusters. A total of 10 differentially expressed oxidative stress-related genes (DE-ORGs) were screened. Subsequently, SOD3, CD36, ACOX2, RBM11, CYP1B1, SNCA, and MPO from the 10 DE-ORGs were identified as diagnostic genes based on random forest algorithm with randomized least absolute shrinkage and selection operator (LASSO) regression. A nomogram was constructed to evaluate the risk of disease. The decision curve analysis (DCA) and clinical impact curves indicated that the nomogram based on these seven biomarkers had extraordinary predictive power. Immune cell infiltration analysis results revealed that DE-ORGs were closely related to various immune cells, especially CYP1B1 was in positive correlation with monocytes and negative correlation with macrophages M1. Single-cell RNA-seq analysis showed that CYP1B1 was mainly associated with macrophages, and SNCA was mainly associated with basal cells. CYP1B1 and SNCA were diagnostic genes associated with oxidative stress in IPF.

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Developing selective CDK7 inhibitors has emerged as a promising approach for cancer treatment owing to the critical role of CDK7 in cancer progression. Starting from BTX-A51, a CK1α inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors. The representative compound, 22, displayed significant enzymatic inhibitory activity and demonstrated a remarkable selectivity profile against a panel of kinases, including seven CDK subtypes. Modeling studies and molecular dynamics simulations revealed that the sulfone group of 22 significantly enhanced the binding affinity, while the acetyl group contributed to the increased selectivity of CDK7 against CDK9. Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.

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Diarrhea is a common issue in domestic yaks (Bos grunniens) that can occur with pasture alterations and significantly impacts growth performance. Previous research has examined the microbiota of diarrhetic yaks; however, the structural changes in gut bacterial community and microbial interactions in yaks with grassland alteration-induced diarrhea remain poorly understood. To explore variations in gut microbiota homeostasis among yaks suffering from diarrhea, fecal microbiota diversity and composition were analyzed using 16 S rRNA amplicon sequencing. Gut fecal microbiota diversity was lower in diarrhetic yaks than in non-diarrhetic yaks. Furthermore, the bacterial community composition (including that of Proteobacteria and Actinobacteria) in the feces of diarrhetic yaks displayed significant alterations. Co-occurrence network analysis further underscored the compromised intestinal flora stability in yaks with diarrhea relative to that in non-diarrhetic yaks. Interestingly, the abundance of beneficial bacteria, such as Lachnospiraceae_AC2044_group and Lachnospiraceae_NK4A136_group, were decreased in yaks with diarrhea, and the reductions were negatively correlated with the fecal water content. Collectively, these findings indicate that diminished microbial stability and increased abundance of certain bacteria in the gut may contribute to diarrhea occurrence in yaks.

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Geopolymers, as a novel cementitious material, exhibit typical brittle failure characteristics under stress. To mitigate this brittleness, fibers can be incorporated to enhance toughness. This study investigates the effects of varying polypropylene fiber (PPF) content and fiber length on the flowability, mechanical properties, and flexural toughness of coal gangue-based geopolymers. Microstructural changes and porosity variations within the Fiber-Reinforced Geopolymer Mortar(GMPF) matrix were observed using scanning electron microscope (SEM) and Low field NMR(LF-NMR) to elucidate the toughening mechanism of PPF-reinforced geopolymers. The introduction of fibers into the geopolymer matrix demonstrated an initial bridging effect in the viscous geopolymer slurry, with a 3.0 vol% fiber content reducing fluidity by 5.6%. Early mechanical properties of GMPF were enhanced with fiber addition; at 1.5 vol% fiber content and 15 mm length, the 3-day flexural and compressive strengths increased by 30.81% and 17.4%, respectively. Furthermore, polypropylene fibers significantly improved the matrix's flexural toughness, which showed an increasing trend with higher fiber content. At a 3.0 vol% fiber content, the flexural toughness index increased by 198.35%. The data indicated that a fiber length of 12 mm yielded the best toughening effect, with an 84.03% increase in the flexural toughness index. SEM observations revealed a strong interfacial bond between fibers and the matrix, with noticeable damage on the fiber surface due to frictional forces, and fiber pull-out being the predominant failure mode. Porosity testing results indicated that fiber incorporation substantially improved the internal pore structure of the matrix, reducing the median pore diameter of mesopores and converting mesopores to micropores. Additionally, the number of harmless and less harmful pores increased by 23.01%, while the number of more harmful pores decreased by 30.43%.

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In this study, based on the principles of bionics, we fabricated a bionic non-smooth concave pit structure on the shoulders of friction stir welding tools and detected the thermal cycling curve, downforce, and torque of the tool in the welding process. We tested the wear loss weight and analyzed the surface morphology of the shoulder surfaces after welding for 200 m. This study found that as the distance between the concave pits decreased and the number of concave pits increased, the maximum downforce, torque, and temperature in the welding process showed a decreasing trend. As the speed increased, no matter how the tool structure changed, the downforce and torque decreased, while the peak thermal cycle temperature increased. The experimental welding results show that the wear loss weight of the non-smooth structure tool significantly reduced. The lowest wear loss weight of the tool with a concave pit interval of 1.125 mm was only 0.1529 g, which is 27% lower than that of the conventional tool. Our observations of the surface morphology of the tool shoulder after welding showed that the amount of aluminum swarf on the tool shoulder of the welding tool gradually declined with the increasing density of the uneven pits. The lowest number of aluminum chips adhered to a welding tool with a pit distance of 1.125 mm. Therefore, friction stir welding tools with biomimetic structures have better wear resistance and adhesion resistance.

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Cigarette smoking is the acknowledged major cause of cancers of the lung and oral cavity and is an established important risk factor for multiple other cancers. DNA addition products (DNA adducts) caused by cigarette smoking are critical factors in its mechanism of carcinogenesis. However, most DNA adducts detected to date in humans cannot be specifically ascribed to smoking but rather have multiple exogenous and endogenous sources. In the study reported here, we prepared [13C]-labeled tobacco to address this problem. We report for the first time the successful growth from seeds to flowering under hydroponic conditions of highly [13C]-labeled tobacco in a controlled 13CO2 environment. The standard growth procedure with optimized conditions is described in detail. The [13C]-enrichment rate was assessed by quantifying nicotine and sugars and their [13C]-isotopologues in this tobacco using high-resolution mass spectrometry, reaching >94% in the tobacco leaves. The [13C]-labeled leaves after curing will be used to make cigarettes, allowing investigation of the specific contributions of tobacco smoke carcinogens to identified DNA adducts in smokers.

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The 5' UTR, a regulatory region at the beginning of an mRNA molecule, plays a crucial role in regulating the translation process and impacts the protein expression level. Language models have showcased their effectiveness in decoding the functions of protein and genome sequences. Here, we introduced a language model for 5' UTR, which we refer to as the UTR-LM. The UTR-LM is pre-trained on endogenous 5' UTRs from multiple species and is further augmented with supervised information including secondary structure and minimum free energy. We fine-tuned the UTR-LM in a variety of downstream tasks. The model outperformed the best known benchmark by up to 5% for predicting the Mean Ribosome Loading, and by up to 8% for predicting the Translation Efficiency and the mRNA Expression Level. The model also applies to identifying unannotated Internal Ribosome Entry Sites within the untranslated region and improves the AUPR from 0.37 to 0.52 compared to the best baseline. Further, we designed a library of 211 novel 5' UTRs with high predicted values of translation efficiency and evaluated them via a wet-lab assay. Experiment results confirmed that our top designs achieved a 32.5% increase in protein production level relative to well-established 5' UTR optimized for therapeutics.

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The geographical variation and domestication of tree species are an important part of the theory of forest introduction, and the tracing of the germplasm is the theoretical basis for the establishment of high-quality plantations. Chinese pine (Pinus tabuliformis Carr.) is an important native timber tree species widely distributed in northern China, but it is unclear exactly where germplasm of the main Chinese pine plantation populations originated. Here, using two mtDNA markers, we analyzed 796 individuals representing 35 populations (matR marker), and 873 individuals representing 38 populations (nad5-1 marker) of the major natural and artificial populations in northern China, respectively (Shanxi, Hebei and Liaoning provinces). The results confirmed that the core position of natural SX* populations ("*" means natural population) in the Chinese pine populations of northern China, the genetic diversity of HB and LN plantations was higher than that of natural SX* populations, and there was a large difference in genetic background within the groups of SX* and LN, HB showed the opposite. More importantly, we completed the "point by point" tracing of the HB and LN plantings. The results indicated that almost all HB populations originated from SX* (GDS*, ZTS*, GCS*, and THS*), which resulted in homogeneity of the genetic background of HB populations. Most of germplasm of the LN plantations originated from LN* (ZJS* and WF*), and the other part originated from GDS* (SX*), resulting in the large differences in the genetic background within the LN group. Our results provided a reliable theoretical basis for the scientific allocation, management, and utilization of Chinese pine populations in northern China, and for promoting the high-quality establishment of Chinese pine plantations.

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BACKGROUND: Social media has become an increasingly popular and critical tool for users to digest diverse information and express their perceptions and attitudes. While most studies endeavor to delineate the emotional responses of social media users, there is limited research exploring the factors associated with the emergence of emotions, particularly negative ones, during news consumption. OBJECTIVE: We aim to first depict the web coverage by news organizations on social media and then explore the crucial elements of news coverage that trigger the public's negative emotions. Our findings can act as a reference for responsible parties and news organizations in times of crisis. METHODS: We collected 23,705 Facebook posts with 1,019,317 comments from the public pages of representative news organizations in Hong Kong. We used text mining techniques, such as topic models and Bidirectional Encoder Representations from Transformers, to analyze news components and public reactions. Beyond descriptive analysis, we used regression models to shed light on how news coverage on social media is associated with the public's negative emotional responses. RESULTS: Our results suggest that occurrences of issues regarding pandemic situations, antipandemic measures, and supportive actions are likely to reduce the public's negative emotions, while comments on the posts mentioning the central government and the Government of Hong Kong reveal more negativeness. Negative and neutral media tones can alleviate the rage and interact with the subjects and issues in the news to affect users' negative emotions. Post length is found to have a curvilinear relationship with users' negative emotions. CONCLUSIONS: This study sheds light on the impacts of various components of news coverage (issues, subjects, media tone, and length) on social media on the public's negative emotions (anger, fear, and sadness). Our comprehensive analysis provides a reference framework for efficient crisis communication for similar pandemics at present or in the future. This research, although first extending the analysis between the components of news coverage and negative user emotions to the scenario of social media, echoes previous studies drawn from traditional media and its derivatives, such as web newspapers. Although the era of COVID-19 pandemic gradually brings down the curtain, the commonality of this research and previous studies also contributes to establishing a clearer territory in the field of health crises.

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BimC family proteins are bipolar motor proteins belonging to the kinesin superfamily which promote mitosis by crosslinking and sliding apart antiparallel microtubules. Understanding the binding mechanism between the kinesin and the microtubule is crucial for researchers to make advances in the treatment of cancer and other malignancies. Experimental research has shown that the ion concentration affects the function of BimC significantly. But the insights of the ion-dependent function of BimC remain unclear. By combining molecular dynamics (MD) simulations with a series of computational approaches, we studied the electrostatic interactions at the binding interfaces of BimC and the microtubule under different KCl concentrations. We found the electrostatic interaction between BimC and microtubule is stronger at 0 mM KCl compared to 150 mM KCl, which is consistent with experimental conclusions. Furthermore, important salt bridges and residues at the binding interfaces of the complex were identified, which illustrates the details of the BimC-microtubule interactions. Molecular dynamics analyses of salt bridges identified that the important residues on the binding interface of BimC are positively charged, while those residues on the binding interface of the tubulin heterodimer are negatively charged. The finding in this work reveals some important mechanisms of kinesin-microtubule binding, which helps the future drug design for cancer therapy.

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Cryptochromes (CRYs) are blue light (BL) photoreceptors to regulate a variety of physiological processes including DNA double-strand break (DSB) repair. SUPPRESSOR OF GAMMA RADIATION 1 (SOG1) acts as the central transcription factor of DNA damage response (DDR) to induce the transcription of downstream genes, including DSB repair-related genes BRCA1 and RAD51. Whether CRYs regulate DSB repair by directly modulating SOG1 is unknown. Here, we demonstrate that CRYs physically interact with SOG1. Disruption of CRYs and SOG1 leads to increased sensitivity to DSBs and reduced DSB repair-related genes' expression under BL. Moreover, we found that CRY1 enhances SOG1's transcription activation of DSB repair-related gene BRCA1. These results suggest that the mechanism by which CRYs promote DSB repair involves positive regulation of SOG1's transcription of its target genes, which is likely mediated by CRYs-SOG1 interaction.

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Cryptochromes (CRYs) act as blue light photoreceptors to regulate various plant physiological processes including photomorphogenesis and repair of DNA double strand breaks (DSBs). ADA2b is a conserved transcription co-activator that is involved in multiple plant developmental processes. It is known that ADA2b interacts with CRYs to mediate blue light-promoted DSBs repair. Whether ADA2b may participate in CRYs-mediated photomorphogenesis is unknown. Here we show that ADA2b acts to inhibit hypocotyl elongation and hypocotyl cell elongation in blue light. We found that the SWIRM domain-containing C-terminus mediates the blue light-dependent interaction of ADA2b with CRYs in blue light. Moreover, ADA2b and CRYs act to co-regulate the expression of hypocotyl elongation-related genes in blue light. Based on previous studies and these results, we propose that ADA2b plays dual functions in blue light-mediated DNA damage repair and photomorphogenesis.

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Background: Extracorporeal life support (ECLS) therapy for refractory postcardiotomy cardiogenic shock (rPCS) is associated with high early mortality rates. This study aimed to identify negative predictors of mid-term survival and to assess health-related quality of life (HRQoL) and recovery of the survivors. Methods: Between 2017 and 2020, 142 consecutive patients received ECLS therapy following cardiac surgery. The median age was 66.0 [57.0-73.0] years, 67.6% were male and the median EuroSCORE II was 10.5% [4.2-21.3]. In 48 patients, HRQoL was examined using the 36-Item Short Form Survey (SF-36) and the modified Rankin-Scale (mRS) at a median follow-up time of 2.2 [1.9-3.2] years. Results: Estimated survival rates at 3, 12, 24 and 36 months were 47%, 46%, 43% and 43% (SE: 4%). Multivariable Cox Proportional Hazard regression analysis revealed preoperative EuroSCORE II (p = 0.013), impaired renal function (p = 0.010), cardiopulmonary bypass duration (p = 0.015) and pre-ECLS lactate levels (p = 0.004) as independent predictors of mid-term mortality. At the time of follow-up, 83.3% of the survivors were free of moderate to severe disability (mRS < 3). SF-36 analysis showed a physical component summary of 45.5 ± 10.2 and a mental component summary of 50.6 ± 12.5. Conclusions: Considering the disease to be treated, ECLS for rPCS is associated with acceptable mid-term survival, health-related quality of life and functional status. Preoperative EuroSCORE II, impaired renal function, cardiopulmonary bypass duration and lactate levels prior to ECLS implantation were identified as negative predictors and should be included in the decision-making process.

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OBJECTIVES: Ascending aortic aneurysms pose a different risk to each patient. We aim to provide personalized risk stratification for such patients based on sex, age, body surface area and aneurysm location (root versus ascending). METHODS: Root and ascending diameters, and adverse aortic events (dissection, rupture, death) of ascending thoracic aortic aneurysm patients were analysed. Aortic diameter was placed in context vis-a-vis the normal distribution in the general population with similar sex, age and body surface area, by conversion to z scores. These were correlated of major adverse aortic events, producing risk curves with 'hinge points' of steep risk, constructed separately for the aortic root and mid-ascending aorta. RESULTS: A total of 1162 patients were included. Risk curves unveiled generalized thresholds of z = 4 for the aortic root and z = 5 for the mid-ascending aorta. These correspond to individualized thresholds of less than the standard criterion of 5.5 cm in the vast majority of patients. Indicative results include a 75-year-old typical male with 2.1 m2 body surface area, who was found to be at increased risk of adverse events if root diameter exceeds 5.15 cm, or mid ascending exceeds 5.27 cm. An automated calculator is presented, which identifies patients at high risk of adverse events based on sex, age, height, weight, and root and ascending size. CONCLUSIONS: This analysis exploits a large sample of aneurysmal patients, demographic features of the general population, pre-dissection diameter, discrimination of root and supracoronary segments, and statistical tools to extract thresholds of increased risk tailor-made for each patient.

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DNA adducting drugs, including alkylating agents and platinum-containing drugs, are prominent in cancer chemotherapy. Their mechanisms of action involve direct interaction with DNA, resulting in the formation of DNA addition products known as DNA adducts. While these adducts are well-accepted to induce cancer cell death, understanding of their specific chemotypes and their role in drug therapy response remain limited. This perspective aims to address this gap by investigating the metabolic activation and chemical characterization of DNA adducts formed by the U.S. FDA-approved drugs. Moreover, clinical studies on DNA adducts as potential biomarkers for predicting patient responses to drug efficacy are examined. The overarching goal is to engage the interest of medicinal chemists and stimulate further research into the use of DNA adducts as biomarkers for guiding personalized cancer treatment.

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