Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes.

The clinical treatment of human acute myeloid leukemia (AML) is rapidly progressing from chemotherapy to targeted therapies led by the BCL-2 inhibitor venetoclax (VEN). Despite its unprecedented success, VEN still encounters clinical resistance. Thus, uncovering the biological vulnerability of VEN-resistant AML disease and identifying effective therapies to treat them are urgently needed. We have previously demonstrated that iron oxide nanozymes (IONE) are capable of overcoming chemoresistance in AML. The current study reports a new activity of IONE in overcoming VEN resistance. Specifically, we revealed an aberrant redox balance with excessive intracellular reactive oxygen species (ROS) in VEN-resistant monocytic AML. Treatment with IONE potently induced ROS-dependent cell death in monocytic AML in both cell lines and primary AML models. In primary AML with developmental heterogeneity containing primitive and monocytic subpopulations, IONE selectively eradicated the VEN-resistant ROS-high monocytic subpopulation, successfully resolving the challenge of developmental heterogeneity faced by VEN. Overall, our study revealed an aberrant redox balance as a therapeutic target for monocytic AML and identified a candidate IONE that could selectively and potently eradicate VEN-resistant monocytic disease.

In Silico Prediction of Skin Sensitization for Compounds via Flexible Evidence Combination Based on Machine Learning and Dempster-Shafer Theory.

Skin sensitization is increasingly becoming a significant concern in the development of drugs and cosmetics due to consumer safety and occupational health problems. In silico methods have emerged as alternatives to traditional in vivo animal testing due to ethical and economic considerations. In this study, machine learning methods were used to build quantitative structure-activity relationship (QSAR) models on five skin sensitization data sets (GPMT, LLNA, DPRA, KeratinoSens, and h-CLAT), achieving effective predictive accuracies (correct classification rates of 0.688-0.764 on test sets). To address the complex mechanisms of human skin sensitization, the Dempster-Shafer theory was applied to merge multiple QSAR models, resulting in an evidence-based integrated decision model. Various evidence combinations and combination rules were explored, with the self-defined Q3 rule showing superior balance. The combination of evidence such as GPMT and KeratinoSens and h-CLAT achieved a correct classification rate (CCR) of 0.880 and coverage of 0.893 while maintaining the competitiveness of other combinations. Additionally, the Shapley additive explanations (SHAP) method was used to interpret important features and substructures related to skin sensitization. A comparative analysis of an external human test set demonstrated the superior performance of the proposed method. Finally, to enhance accessibility, the workflow was implemented into a user-friendly software named HSkinSensDS.

Exploring the impact of hydrogen sulfide on hematologic malignancies: A review.

Hydrogen sulfide (H2S) is one of the three most crucial gaseous messengers in the body. The discovery of H2S donors, coupled with its endogenous synthesis capability, has sparked hope for the treatment of hematologic malignancies. In the last decade, the investigation into the impact of H2S has expanded, particularly within the fields of cardiovascular function, inflammation, infection, and neuromodulation. Hematologic malignancies refer to a diverse group of cancers originating from abnormal proliferation and differentiation of blood-forming cells, including leukemia, lymphoma, and myeloma. In this review, we delve deeply into the complex interrelation between H2S and hematologic malignancies. In addition, we comprehensively elucidate the intricate molecular mechanisms by which both H2S and its donors intricately modulate the progression of tumor growth. Furthermore, we systematically examine their impact on pivotal aspects, encompassing the proliferation, invasion, and migration capacities of hematologic malignancies. Therefore, this review may contribute novel insights to our understanding of the prospective therapeutic significance of H2S and its donors within the realm of hematologic malignancies.

In Silico Prediction of Chemical Acute Dermal Toxicity Using Explainable Machine Learning Methods.

The research on acute dermal toxicity has consistently been a crucial component in assessing the potential risks of human exposure to active ingredients in pesticides and related plant protection products. However, it is difficult to directly identify the acute dermal toxicity of potential compounds through animal experiments alone. In our study, we separately integrated 1735 experimental data based on rabbits and 1679 experimental data based on rats to construct acute dermal toxicity prediction models using machine learning and deep learning algorithms. The best models for the two animal species achieved AUC values of 78.0 and 82.0%, respectively, on 10-fold cross-validation. Additionally, we employed SARpy to extract structural alerts, and in conjunction with Shapley additive explanation and attentive FP heatmap, we identified important features and structural fragments associated with acute dermal toxicity. This approach offers valuable insights for the detection of positive compounds. Moreover, a standalone software tool was developed to make acute dermal toxicity prediction easier. In summary, our research would provide an effective tool for acute dermal toxicity evaluation of pesticides, cosmetics, and drug safety assessment.

AttentiveSkin: To Predict Skin Corrosion/Irritation Potentials of Chemicals via Explainable Machine Learning Methods.

Skin Corrosion/Irritation (Corr./Irrit.) has long been a health hazard in the Globally Harmonized System (GHS). Several in silico models have been built to predict Skin Corr./Irrit. as an alternative to the increasingly restricted animal testing. However, current studies are limited by data amount/quality and model availability. To address these issues, we compiled a traceable consensus GHS data set comprising 731 Corr., 1283 Irrit., and 1205 negative (Neg.) samples from 6 governmental databases and 2 external data sets. Then, a series of binary classifiers were developed with five machine learning (ML) algorithms and six molecular representations. For 10-fold cross-validation, the best Corr. vs Neg. classifier achieved an Area Under the Receiver Operating Characteristic Curve (AUC) of 97.1%, while the best Irrit. vs Neg. classifier achieved an AUC of 84.7%. Compared with existing in silico tools on external validation, our Attentive FP classifiers showed the highest metrics on Corr. vs Neg. and the second highest accuracy on Irrit. vs Neg. The SHapley Additive exPlanation approach was further applied to figure out important molecular features, and the attention weights were visualized to perform interpretable prediction. Structural alerts associated with Skin Corr./Irrit. were also identified. The interpretable Attentive FP classifiers were integrated into the software AttentiveSkin at https://github.com/BeeBeeWong/AttentiveSkin. The conventional ML classifiers are also provided on our platform admetSAR at http://lmmd.ecust.edu.cn/admetsar2/. Considering the data deficiency and the limited model availability of Skin Corr./Irrit., we believe that our data set and models could facilitate chemical safety assessment and relevant studies.

The associations of obesity phenotypes with the risk of hypertension and its transitions among middle-aged and older Chinese adults.

OBJECTIVES: This study aimed to investigate the associations of obesity phenotypes with hypertension stages, phenotypes, and transitions among middle-aged and older Chinese. METHODS: Using the 2011-2015 waves of the China Health and Retirement Longitudinal Study, we conducted a cross-sectional analysis included 9,015 subjects and a longitudinal analysis included 4,961 subjects, with 4,872 having full data on the hypertension stage and 4,784 having full data on the hypertension phenotype. Based on body mass index and waist circumstance, subjects were categorized into 4 mutually exclusive obesity phenotypes: normal weight with no central obesity (NWNCO), abnormal weight with no central obesity (AWNCO), normal weight with central obesity (NWCO), and abnormal weight with central obesity (AWCO). Hypertension stages were classified into normotension, pre-hypertension, stage 1 hypertension, and stage 2 hypertension. Hypertension phenotypes were categorized as normotension, pre-hypertension, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH). The association between obesity phenotypes and hypertension was estimated by logistic regression. A comparison between different sexes was conducted by testing the interaction effect of sex. RESULTS: NWCO was associated with normal→stage 2 (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.11 to 3.42), maintained stage 1 (OR, 1.62; 95% CI, 1.14 to 2.29), and normal→ISH (OR, 1.39; 95% CI, 1.05 to 1.85). AWCO was associated with normal→stage 1 (OR, 1.75; 95% CI, 1.40 to 2.19), maintained stage 1 (OR, 2.77; 95% CI, 2.06 to 3.72), maintained stage 2 (OR, 2.80; 95% CI, 1.50 to 5.25), normal→ISH (OR, 1.56; 95% CI, 1.20 to 2.02), and normal→SDH (OR, 2.54; 95% CI, 1.72 to 3.75). An interaction effect of sex existed in the association between obesity phenotypes and hypertension stages. CONCLUSIONS: This study highlights the importance of various obesity phenotypes and sex differences in hypertension progression. Tailored interventions for different obesity phenotypes may be warranted in hypertension management, taking into account sex-specific differences to improve outcomes.

High myopia and macular vascular density: an optical coherence tomography angiography study.

OBJECTIVE: To investigate whether there are differences inmacular vascular density (VD) between patients with high-myopia (HM) and those with non-high myopia (NHM) using Optical Coherence Tomography Angiography (OCTA). METHOD: OCTA was performed on 35 eyes with HM with spherical equivalence (SE) > - 6.00D and 35 eyes with NHM with SE ≤ -6.00D. Vascular densities of the macula (overall macula, fovea, parafovea, superior hemi and inferior hemi) were measured in each of the superficial, deep and choriocapillaris layers of the retina. RESULTS: In the superficial retinal layer, overall macular VFD was significantly higher in the NHM compared to the HM group (51.27 ± 3.74 vs. 48.07 ± 5.69, p < 0.05). There were significant differences between the NHM and HM in parafovea (52.58 ± 5.78 vs. 49.4 ± 6.43, p < 0.05), superior-hemi (53.38 ± 4.03 vs 49.78 ± 6.84, p < 0.05) and inferior-hemi regions (53.49 ± 4.61 vs 49.05 ± 6.41, p < 0.05), but not in the fovea region. Similarly, in the deep retinal layer, overall macular VFD was significantly higher in the NHM group compared to the HM group (58.69 ± 2.46 vs. 56.90 ± 4.08, p < 0.05). There was significant differences between the HM and NHM in superior-hemi region (61.97 ± 2.68 vs. 60.08 ± 3.98, p < 0.05), but not in the fovea, parafovea, and inferior-hemi region. In the choriocapillaris, there was no difference in the overall macular VFD, nor any of the individual sectors between the HM and the NHM groups. CONCLUSION: VFD in the superficial and deep retinal layers of the macula are significantly increased in the NHM compared to HM eyes. This is not the case in the choroidal capillary layers of the retina.

Integrated Tear Proteome and Metabolome Reveal Panels of Inflammatory-Related Molecules via Key Regulatory Pathways in Dry Eye Syndrome.

Dry eye syndrome (DES) is a growing public health concern with a high global prevalence; however, the fundamental processes involved in its pathogenic mechanisms remain poorly understood. In the present study, we applied nanoscale liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (nanoLC/Q-TOF-MS/MS) and ultraperformance LC/Q-TOF-MS/MS technologies on tear samples obtained from 18 dry eye patients and 19 healthy controls for integrated proteomic and metabolomic analyses. Overall, 1031 tear proteins were detected, while 190 proteins were determined to be significantly expressed in dry eye patients. Further functional analysis suggested that various biological processes were highly expressed and involved in the pathogenesis of DES, especially immune and inflammatory processes. In total, 156 named metabolites were identified, among which 34 were found to be significantly changed in dry eye patients. The results highlighted the key elements, especially inflammatory-related proteins and metabolites that played important roles in the development of DES. Further, the regulatory roles of primary pathways, including complement and coagulation cascades, glycolysis/gluconeogenesis, and amino acid metabolism, were also identified as processes involved in DES. Collectively, our work not only provided insight into the potential biomarkers of DES for diagnostic and prognostic purposes but extended our knowledge of the physiopathology of this syndrome.

Metabolic characterization of human aqueous humor in relation to high myopia.

High myopia is the common eye disorder worldwide, which may contribute to increase the risk of serious disorders including glaucoma and cataract. Although various studies including genomics, transcriptomics, and proteomics have been implicated to identify potential biomarkers (genes or proteins) for predicting high myopia and to reveal the underlying mechanism, the comprehensive metabolomics in relation to high myopia is very limited. In this study, we identified 242 metabolites in aqueous humor (AH) from a set of 40 cataract patients (including 20 with high myopia and 20 for controls), using a non-targeted metabolomic technology, gas chromatography coupled to time-of-flight mass spectrometer (GC/TOF MS). Further statistical analysis showed that 29 metabolites were significantly changed (Variable important for the projection, VIP ≥ 1 and p ≤ 0.05), between those two groups, while only 2 decreased metabolites were included. Moreover, for the first time, metabolite-metabolite correlations for AH were analyzed, which may dissect key regulatory elements or pathways involved in metabolism of amino acids, carbohydrates, and lipids. Accordingly, metabolic network was constructed based on those 29 changed metabolites in patients with high myopia. More than half of the changed metabolites were highly and positively associated, suggesting important roles of pathways involved in the metabolism of these metabolites in relation to high myopia. Altogether, this work not only provided potential biomarkers for the diagnosis and monitoring of high myopia formation, but also provided new insights into the underlying mechanisms.

Large Brains, Small Guts: The Expensive Tissue Hypothesis Supported within Anurans.

Brain size differs substantially among species, and several hypotheses have been proposed to explain the evolution of brain size. Because the brain is among the most energetically expensive organs in the vertebrate body, trade-offs have been hypothesized to exert constraints on brain size evolution. Prominently, the expensive tissue hypothesis (ETH) proposes that reducing the size of another expensive organ, such as the gut, should compensate for the cost of a large brain. But energetic constraints may also drive covariation between the brain and other costly traits-such as body maintenance, locomotion, or reproduction-as formulated in the energy trade-off hypothesis. To date, these hypotheses have mainly been tested in homeothermic animals and within the ectothermic animals, primarily in fishes. Here, we undertake a comparative test of the interplay between energetic limitations and brain size evolution within amphibians. After controlling for phylogenetic relationships and body size, we find a negative correlation between brain mass and the length of the digestive tract within 30 species of anurans. We further find that the evolution of large brain size is accompanied by an increase in female reproductive investment into egg size. Our results suggest that the evolution of brain size follows general patterns across vertebrate clades.

Geographic variation in life-history traits: growth season affects age structure, egg size and clutch size in Andrew's toad (Bufo andrewsi).

BACKGROUND: Environmental variation associated with season length is likely to promote differentiation in life-history traits, but has been little studied in natural populations of ectotherms. We investigated patterns of variation in egg size, clutch size, age at sexual maturity, maximum age, mean age, growth rate and adult body size in relation to growth season length among 17 populations of Andrew's toad (Bufo andrewsi) at different latitudes and altitudes in the Hengduan Mountains, western China. RESULTS: We found that egg size, age at sexual maturity, and mean age increased with decreasing length of the growth season, whereas clutch size showed a converse cline. Body size did not increase with decreasing length of the growth season, but was tightly linked to lifetime activity (i.e. the estimated number of active days during lifetime). Males and females differed in their patterns of geographic variation in growth rates, which may be the result of forces shaping the trade-off between growth and reproduction in different environments. CONCLUSIONS: Our findings suggest that growth season plays an important role in shaping variation in life-history traits in B. andrewsi across geographical gradients.

Sexual selection impacts brain anatomy in frogs and toads.

Natural selection is a major force in the evolution of vertebrate brain size, but the role of sexual selection in brain size evolution remains enigmatic. At least two opposing schools of thought predict a relationship between sexual selection and brain size. Sexual selection should facilitate the evolution of larger brains because better cognitive abilities may aid the competition for mates. However, it may also restrict brain size evolution due to energetic trade-offs between brain tissue and sexually selected traits. Here, we examined the patterns of selection on brain size and brain anatomy in male anurans (frogs and toads), a group where the strength of sexual selection differs markedly among species, using a phylogenetically controlled generalized least-squared (PGLS) regression analyses. The analysis revealed that in 43 Chinese anuran species, neither mating system, nor type of courtship, or testes mass was significantly associated with relative brain size. While none of those factors related to the relative size of olfactory nerves, optic tecta, telencephalon, and cerebellum, the olfactory bulbs were relatively larger in monogamous species and those using calls during courtship. Our findings support the mosaic model of brain evolution and suggest that while the investigated aspects of sexual selection do not seem to play a prominent role in the evolution of brain size of anurans, they do impact their brain anatomy.

Evolution of sperm morphology in anurans: insights into the roles of mating system and spawning location.

BACKGROUND: The degree of postcopulatory sexual selection, comprising variable degrees of sperm competition and cryptic female choice, is an important evolutionary force to influence sperm form and function. Here we investigated the effects of mating system and spawning location on the evolution of sperm morphology in 67 species of Chinese anurans. We also examined how relative testes size as an indicator of the level of sperm competition affected variation in sperm morphology across a subset of 29 species. RESULTS: We found a significant association of mating system and spawning location with sperm morphology. However, when removing the effects of body mass or absolute testes mass for species for which such data were available, this effect became non-significant. Consistent with predictions from sperm competition theory, we found a positive correlation between sperm morphology and relative testes size after taking phylogeny into account. CONCLUSIONS: Our findings suggest that sexual selection in Chinese anurans favors longer sperm when the level of sperm competition is high. Pre-copulatory male-male competition and spawning location, on the other hand, do not affect the evolution of sperm morphology after taking body mass and absolute testes mass into account.

Altitudinal variation in age and body size in Yunnan pond frog (Pelophylax pleuraden).

Large-scale systematic patterns of body size are a basic concern of evolutionary biology. Identifying body size variation along altitudinal gradients may help us to understand the evolution of life history of animals. In this study, we investigated altitudinal variation in body size, age and growth rate in Chinese endemic frog, Pelophylax pleuraden. Data sampled from five populations covering an altitudinal span of 1413 to 1935 m in Sichuan province revealed that body size from five populations did not co-vary with altitudes, not following Bergmann's rule. Average adult SVL differed significantly among populations in males, but not in females. For both sexes, average adult age differed significantly among populations. Post-metamorphic growth rate did not co-vary with altitude, and females grew faster than males in all populations. When controlling the effect of age, body size did not differ among populations in both sexes, suggesting that age did not affect variation in body size among populations. For females, there may be other factors, such as the allocation of energy between growth and reproduction, that eliminated the effect of age on body size. To our minds, the major reason of body size variation among populations in male frogs may be related to individual longevity. Our findings also suggest that factors other than age and growth rate may contribute to size differences among populations.

Testis asymmetry and sperm length in Rhacophorus omeimontis.

Theory predicts that the degree of testes asymmetry should be positively correlated with male body condition in species with directional testis asymmetry. We tested this prediction in Rhacophorus omeimontis, a species in which females mate with more than one male. Our results showed that the treefrogs did not exhibit the absence of directional asymmetry in testis size, but rather the occurrence of fluctuating asymmetry. Moreover, we also tested differences in body size, body mass, testis mass, testis asymmetry, and sperm size among initially paired, jointly paired, and unpaired males. We found that body size and mass, testis mass, testis asymmetry and sperm length did not differ among the three male types. Testis mass showed a positive relationship with soma mass, but the correlations between the extent of fluctuating testis asymmetry and sperm length, and between testis mass and sperm length were not significant. Our data suggest that testes size and sperm length do not play an important role in determining male mating success in the presence of sperm competition.