Organ Systems Research Articles

Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment

The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1–3 month) and long-term (6-month) animal studies. Our goal was to determine if there were differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 out of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.

Determining the Feasibility of a Cadmium Exposure Model to Activate the Inflammatory Arm of PANoptosis in Murine Monocytes.

A prevalence of cigarette smoking can cause the accumulation of cadmium (Cd2+) in the lungs, kidneys, and blood. The effects of exposure can cause multiple chronic disease types to emerge in the affected organ systems. The only moderately effective therapeutic option is chelation therapy; the health risks associated with this therapy have caused much criticism. The disease types associated with Cd2+ toxicity have inflammatory components and greatly impact innate immunity. These factors are affected at the cellular level and cause pathways like apoptosis, pyroptosis, and necroptosis. A development in understanding these pathways stipulates that these three pathways act as one complex of pathways, known together as PANoptosis. The inflammatory mechanisms of PANoptosis are particularly interesting in Cd2+ toxicity due to its inflammatory effects. Proteins in the gasdermin family act to release inflammatory cytokines, like interleukin-1β, into the extracellular environment. Cytokines cause inflammatory disease pathologies like fibrosis and cancer. RAW 264.7 monocytes are key in the murine immune system and provide an excellent model to investigate Cd2+ toxicity. Exposure of 0-15 µM CdCl2 was sufficient to increase expression of cleaved gasdermin D (GSDMD) and gasdermin E (GSDME) in this cell type. Cd2+ also exhibits a dose-dependent cytotoxicity in this cell type.

Oligometastatic non-small cell lung cancer: Impact of local and contemporary systemic treatment approaches on clinical outcome.

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.

Analysis of the morpho-genetic features of the phylogenesis of the сlass Reptilia

Aim. The aim of the study was to establish the species composition of the extinct herpetofauna of reptiles in the European continent, identify plesiomorphic, apomorphic characteristics, autapomorphies, and idioadaptations, as well as to analyze the patterns of morphogenesis of the class Reptilia. Methods. Used methods of literature analysis, mapping of places of discovery of dinosaurian paleontological remains in Europe, comparative, mathematical-statistical, and correlation analysis methods of metric measurements of the detected species. Results. It was established that in the extinct fauna of the class Reptilia of the European continent, with taxonomic richness (equal to 27); the species composition consisted of seven species. A correlation dependence between ontogenetic growth parameters of animals was revealed. In particular, in the pair of absolute (length - mass) and relative (growth per year) growth parameters, a strong functional relationship is traced, while the correlation between growth (L) and age parameters is medium, and between body mass (M) and animal age is weak. Conclusions. According to the hypothesis of additive typogenesis, it has been confirmed that new morphological structures (apomorphies) do not arise as a result of simultaneous changes in all organ systems but are the result of individual gradual mutations that arise within narrow limits, possibly in separate populations of reptiles.

Extragustatory bitter taste receptors in head and neck health and disease.

Taste receptors, first described for their gustatory functions within the oral cavity and oropharynx, are now known to be expressed in many organ systems. Even intraoral taste receptors regulate non-sensory pathways, and recent literature has connected bitter taste receptors to various states of health and disease. These extragustatory pathways involve previously unexplored, clinically relevant roles for taste signaling in areas including susceptibility to infection, antibiotic efficacy, and cancer outcomes. Among other physicians, otolaryngologists who manage head and neck diseases should be aware of this growing body of evidence and its relevance to their fields. In this review, we describe the role of extragustatory taste receptors in head and neck health and disease, highlighting recent advances, clinical implications, and directions for future investigation. Additionally, this review will discuss known TAS2R polymorphisms and the associated implications for clinical prognosis.

The impact of multimorbidity on QoL in inflammatory myopathies: COVAD cluster analysis.

The presence of comorbidities can substantially affect patients' quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs), and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined Basic Multimorbidity (BM) as the presence of ≥ 2 non-rheumatic chronic conditions and Complex Multimorbidity (CM) as the presence of ≥ 3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical Clustering on Principal Components was performed for grouping. Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs, and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (OR: 1.62 vs oAIRDs and 2.95 vs HCs, p< 0.01), BM (OR 1.66 vs oAIRDs and 3.52 vs HCs, p< 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, p< 0.01), and mental health disorders (MHDs) (OR 1.33 vs oAIRDs and 2.63 vs HCs, p< 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all p< 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM, and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

Factors Controlling Differences in Morphology and Fractal Characteristics of Organic Pores of Longmaxi Shale in Southern Sichuan Basin, China

Shale gas is a prospective cleaner energy resource and the exploration and development of shale gas has made breakthroughs in many countries. Structure deformation is one of the main controlling factors of shale gas accumulation and enrichment in complex tectonic areas in southern China. In order to estimate the shale gas capacity of structurally deformed shale reservoirs, it is necessary to understand the systematic evolution of organic pores in the process of structural deformation. In particular, as the main storage space of high-over-mature marine shale reservoirs, the organic matter pore system directly affects the occurrence and migration of shale gas; however, there is a lack of systematic research on the fractal characteristics and deformation mechanism of organic pores under the background of different tectonic stresses. Therefore, to clarify the above issues, modular automated processing system (MAPS) scanning, low-pressure gas adsorption, quantitative evaluation of minerals by scanning (QEMSCAN), and focused ion beam scanning electron microscopy (FIB-SEM) were performed and interpreted with fractal and morphology analyses to investigate the deformation mechanisms and structure of organic pores from different tectonic units in Silurian Longmaxi shale. Results showed that in stress concentration areas such as around veins or high-angle fractures, the organic pore length-width ratio and the fractal dimension are higher, indicating that the pore is more obviously modified by stress. Under different tectonic backgrounds, the shale reservoir in Weiyuan suffered severe denudation and stronger tectonic compression during burial, which means that the organic pores are dominated by long strip pores and slit-shaped pores with high fractal dimension, while the pressure coefficient in Luzhou is high and the structural compression is weak, resulting in suborbicular pores and ink bottle pores with low fractal dimension. The porosity and permeability of different forms of organic pores are also obviously different; the connectivity of honeycomb pores with the smallest fractal dimension is the worst, that of suborbicular organic pores is medium, and that of long strip organic pores with the highest fractal dimension is the best. This study provides more mechanism discussion and case analysis for the microscopic heterogeneity of organic pores in shale reservoirs and also provides a new analysis perspective for the mechanism of shale gas productivity differences in different stress–strain environments.

Integrated Management of Sclerotinia Stem Rot of Soybean Including Organically-Allowed Fungicides in the Midwest United States

Sclerotinia stem rot (SSR) is an economically important disease of soybean, especially in the Great Lakes region of the United States. Few studies on SSR have considered organic management practices and how integrated management techniques best apply in these systems. Trials in Wisconsin and Indiana aimed to evaluate management techniques available to organic farmers for their efficacy in SSR control while preserving yield. The practices evaluated included genetically resistant cultivars, tillage techniques, and the application of Organic Materials Review Institute (OMRI) listed foliar fungicides. The resistant cultivar had significantly lower SSR than the susceptible cultivar in three site-years (P &lt; 0.01). The resistant cultivar also had significantly greater yield than the susceptible cultivar in two site-years (P &lt; 0.05). Using a roller-crimped rye cover crop resulted in mixed results on SSR and yield. No effect on SSR or yield by OMRI listed foliar fungicides was observed (P &gt; 0.05). Overall, the results emphasize the importance of planting a resistant soybean cultivar to manage SSR in organic farming systems in the Midwestern United States.

Responses of Soil Macro-Porosity, Nutrient Concentrations and Stoichiometry Following Conversion of Rice–Wheat Rotation to Organic Greenhouse Vegetable System

Responses of Soil Macro-Porosity, Nutrient Concentrations and Stoichiometry Following Conversion of Rice–Wheat Rotation to Organic Greenhouse Vegetable System

Nine Neuroimaging-AI Endophenotypes Unravel Disease Heterogeneity and Partial Overlap across Four Brain Disorders: A Dimensional Neuroanatomical Representation.

Disease heterogeneity poses a significant challenge for precision diagnostics. Recent work leveraging artificial intelligence has offered promise to dissect this heterogeneity by identifying complex intermediate brain phenotypes, herein called dimensional neuroimaging endophenotypes (DNEs). We advance the argument that these DNEs capture the degree of expression of respective neuroanatomical patterns measured, offering a dimensional neuroanatomical representation for studying disease heterogeneity and similarities of neurologic and neuropsychiatric diseases. We investigate the presence of nine such DNEs derived from independent yet harmonized studies on Alzheimer's disease (AD1-2)1, autism spectrum disorder (ASD1-3)2, late-life depression (LLD1-2)3, and schizophrenia (SCZ1-2)4, in the general population of 39,178 participants in the UK Biobank study. Phenome-wide associations revealed prominent associations between the nine DNEs and phenotypes related to the brain and other human organ systems. This phenotypic landscape aligns with the SNP-phenotype genome-wide associations, revealing 31 genomic loci associated with the nine DNEs (Bonferroni corrected P-value < 5×10-8/9). The DNEs exhibited significant genetic correlations, colocalization, and causal relationships with multiple human organ systems and chronic diseases. A causal effect (odds ratio=1.25 [1.11, 1.40], P-value=8.72×10-4) was established from AD2, characterized by focal medial temporal lobe atrophy, to AD. The nine DNEs, along with their polygenic risk scores, significantly enhanced the predictive accuracy for 14 systemic disease categories, particularly for conditions related to mental health and the central nervous system, as well as mortality outcomes. These findings underscore the potential of the nine DNEs to capture the expression of disease-related brain phenotypes in individuals of the general population and to relate such measures with genetics, lifestyle factors, and chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine/.

Post-marketing safety profile of solriamfetol: A real-world disproportionality analysis using FDA adverse event reporting system (FAERS) database

Solriamfetol is a selective dopamine and noradrenalin reuptake inhibitor applied in adult patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). However, the post-marketing safety profile of solriamfetol in large number of people was unrevealed. The purpose of our study is to unravel solriamfetol's adverse events (AEs) in real-world to refine medication safety using Food and Drug Administration Adverse Event Reporting System (FAERS) database. We derived the data associated with solriamfetol from FAERS between 2019 and 2023, and removed the duplicated entries. We evaluated the disproportionality of solriamfetol's AEs by reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS). Among 8,846,085 AE reports, 1659 recorded solriamfetol as the ‘primary suspected (PS)’. 74 significant disproportionality preferred terms (PTs) were retained across 27 organ systems. Moreover, 16 unexpected AEs not mentioned in the FDA label of solriamfetol were identified. Our findings provided the post-marketing safety profile of solriamfetol, highlighting potential solriamfetol's AEs. Further researches are significant to define the causality between solriamfetol and newly identified AEs.

Modeling Hemodynamics in Three-Dimensional, Biomimetic, Branched, Microfluidic, Vascular Networks.

Neovascularization has been extensively studied because of its significant role in both physiological processes and diseases. The significance of vascular microfluidic platforms lies in its essential role in recreating an in vitro environment capable of supporting cellular and tissue systems through the process of neovascularization. Biomechanical properties in a tissue engineered system use fluid flow and transport properties to recapitulate physiological systems. This enables mimicry of organ systems which can further personalized and regenerative medicine. Thus, fluid hemodynamics can be used to study these flow patterns and create a system that mimics real physiological pathways and processes. The establishment of stable flow pathways encourages endothelial cells (ECs) ECs to undergo neovascularization. Specifically, the shear stress applied in capillary beds generates the increased proliferation and differentiation of ECs to build larger microcirculatory beds. Here, we describe a mathematical model that uses branching patterns and vessel morphology to predict hemodynamic parameters in capillary beds. A retinal capillary bed is used as one-use case of our model to show how the mathematical framework can be used to determine hemodynamic parameters for any microfluidic system. In doing so, this tool can be altered to be used to supplement emerging research areas in neovascularization.

Drug Delivery System That Self-Emulsify: Transportation of Drug From Gut to Target Organs

Microemulsions are highly popular for their specific uses, including vivid applications and this is due to their special properties, which include very high interfacial interactions with demonstrated stability from a thermodynamics point of view, and on the other hand, also very low interfacial tension, which is required to solubilize highly immiscible dispersions. This review’s goal is to briefly outline potential uses of micro-emulsion systems, their uses, limitations and possible in-vitro and in-vivo techniques. To characterise such dispersion systems, it is commonly known that adding the right surfactant or surfactant mixture can combine large amounts of two non-dissolving-target liquids, such as water and oil, into a single phase that is macroscopically homogeneous but microscopically heterogeneous. Owing to the advantages of lymph drug delivery, the drug-lipid conjugates, when they enter the lymph route, become an ideal approach for enhancing the absorption of such drugs to combat metastatic cancers of the lymph nodes and their drainage to specific organ systems where the cancer is already spread. As the route of lymph delivery is important where a tumor has already been cancerous, this formulation approach has distinct opportunities to transport needy molecules to cancerous sites in various organs, which also includes the lymph nodes. This review, particularly, lays more stress on an overview of microemulsions in general, the in-vivo and in-vitro characterization methods and potential applications related to target drug delivery via the lymphatic circulatory system.

Assessing disease activity in scleroderma-related interstitial lung disease: a review and practical guide to management.

Systemic sclerosis (SSc) is a heterogeneous disease with a propensity to involve multiple organ systems. There is a significant proportion of these patients with interstitial lung disease (ILD) who are at risk of mortality and morbidity. There are limited available tools to assess the severity of parenchymal lung involvement and are subject to confounding factors, including the presence of pulmonary hypertension and concomitant smoking history. The diagnostic tools include careful clinical history, examination, thoracic imaging, and pulmonary function tests. One of the limitations of assessing disease severity in SSc-ILD is the lack of standardized definitions for disease activity and serum biomarkers to predict future progression. Although there has been significant progress in managing SSc-related ILD over the last couple of decades with a few randomized double-blind clinical trials assessing the role of immunosuppression (mainly Cyclophosphamide and Mycophenolate Mofetil), the efficacy of these therapies is at best modest and is associated with significant toxicities. Furthermore, Nintedanib has shown promise in reducing forced vital capacity decline in SSc-ILD and in progressive fibrotic-ILD of a range of etiologies. Data are emerging for therapies like Rituximab and Tocilizumab, and we are likely to see further evidence of similar drugs being efficacious in this disease cohort. A relatively simplified algorithm is proposed in this review to guide clinicians dealing with ILD and SSc. It is imperative that clinicians take a multi-disciplinary approach to managing this complex disease in a changing therapeutic landscape.

Comparative Effect of Oyster and Button Mushroom Loaded Phytosomes with Glibenclamide on Renal Function in STZ Induced Diabetic Rats.

Diabetes is a chronic, life-threatening condition that can affect a vast variety of organ systems, including the kidney. The present study is based on the effect of phytosome-based mushroom extract of oyster and button mushroom on renal functioning factors such urea, uric acid, and creatine as well as the glucose level in streptozocin (STZ) -induced rats with diabetes. The results indicated the blood sugar level was found to decrease significantly in the groups treated with a combination of lactobacillus with phytosomes of oyster mushroom and button mushroom in contrast to a control group of diabetics (p

Health Hazards Associated with Dietary Exposure of Female Rat to Cadmium-Contaminated Cooked Rice: Biochemical, Hormonal, and Histopathological Analysis.

The actual exposure, bioavailability, and body burden of dietary cadmium (Cd) vary with the food matrix. Here, we evaluated the health hazards of 45-day long-term exposure of growing Sprague-Dawley (SD) female rats to a natural and endogenous Cd-contaminated brown and white cooked rice dietary model. Cd was found mainly in the duodenum, kidney, and liver; the cecum and colon also contained substantial amounts of Cd in rats fed Cd-contaminated cooked white rice (cWR-test) but not Cd-contaminated cooked brown rice (cBR-test). Damage due to Cd exposure was reflected in liver dysfunction, altered estradiol levels, and distinctive pathologies in organ systems, although urinary Cd (U-Cd) excretion and blood Cd (B-Cd) were not detectable, suggesting that these are not the most accurate or appropriate biomarkers for evaluating dietary Cd exposure. Brown rice, despite being higher in Cd, can reduce Cd absorption and distribution in organs and increase the volume of Cd-containing feces, even achieving slightly higher excretion and lower apparent absorption rates of Cd than white rice, thereby reducing Cd damage to the body. The beneficial components of brown rice such as more dietary fiber, rice bran oil and polyphenol were speculated therefore to confer a degree of protection or repair. Nevertheless, the high apparent absorption levels observed here (> 5%) and signs of significant physical damage indicate that more stringent Cd intake guidelines and measures are needed to minimize Cd levels in rice.

Thermodynamic analysis of a cascade organic Rankine cycle power generation system driven by hybrid geothermal energy and liquefied natural gas

The combination of renewable energy and liquefied natural gas (LNG) cold energy can effectively improve energy utilization efficiency and achieve the goal of energy conservation and emission reduction, which is one of the important directions of future development. This work proposed a cascade organic Rankine cycle (ORC) driven by a geothermal heat source and an LNG heat sink. Seven organic fluids are chosen as candidates to form different working fluid pairs. The effects of the main design parameters on system performance are carried out through the thermodynamic analysis. Then, the optimal design conditions and fluid selection schemes are searched based on the single-objective optimization results. Finally, the exergy destruction study is conducted under the optimal design conditions and working fluid pair. Results showed that the cascade ORC system using the working fluid pair of R601/R290 had the highest exergy efficiency, which could reach 20.02%. At the same time, under the optimal design conditions, the secondary cycle condenser and LNG direct expansion brought high exergy destruction, which was respectively 29.3% and 25.8%, and followed by the two turbines in the cascade ORC system, which were 16.1%, 11.2% and 7.7%.

Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects

Chronic alcohol (ethanol) use is increasing in the United States and has been linked to numerous health issues in multiple organ systems including neurological dysfunction and diseases. Ethanol toxicity is mainly driven by the metabolite acetaldehyde, which is generated through three pathways: alcohol dehydrogenase (ADH2), catalase (CAT), and cytochrome P450 2E1 (CYP2E1). ADH2, while the main ethanol clearance pathway in the liver, is not expressed in the mammalian brain, resulting in CAT and CYP2E1 driving local metabolism of ethanol in the central nervous system. CYP2E1 is known to generate reactive metabolites and reactive oxygen species and localizes to the mitochondria (mtCYP2E1) and endoplasmic reticulum (erCYP2E1). We sought to understand the consequences of mtCYP2E1 and erCYP2E1 in the nervous system during acute ethanol exposure. To answer this question, we generated transgenic Caenorhabditis elegans roundworms expressing human CYP2E1 in the mitochondria, endoplasmic reticulum, or both and exposed them to ethanol. We found that at lower concentrations, wild-type and mtCYP2E1-expressing worms had a small but significant inhibition of locomotion, whereas the erCYP2E1-expressing worms showed protection from this inhibition. At higher doses, all strains had reduced locomotion, but the erCYP2E1-expressing worms recovered faster than wild-type controls. CYP2E1 expression, regardless of organellar targeting, reduced mitochondrial respiration in response to ethanol. Similarly, transgenic expression of CYP2E1 in either organelle in PC-12 rat neuronal cell lines sensitized them to ethanol-induced cell death. Together, these findings suggest that subcellular localization of CYP2E1 impacts behavioral effects of ethanol and should be further studied in the mammalian central nervous system.

The Clinical Spectrum of Mosaic Genetic Disease.

Genetic mosaicism is defined as the presence of two or more cell lineages with different genotypes arising from a single zygote. Mosaicism has been implicated in hundreds of genetic diseases with diverse genetic etiologies affecting every organ system. Mosaic genetic disease (MDG) is a spectrum that, on the extreme ends, enables survival from genetic severe disorders that would be lethal in a non-mosaic form. On the milder end of the spectrum, mosaicism can result in little if any phenotypic effects but increases the risk of transmitting a pathogenic genotype. In the middle of the spectrum, mosaicism has been implicated in reducing the phenotypic severity of genetic disease. In this review will describe the spectrum of mosaic genetic disease whilst discussing the status of the detection and prevalence of mosaic genetic disease.

Thermal stability of MDM and oxidative decomposition mechanism under the condition of air infiltration: A combined experimental, ReaxFF-MD and DFT study

When siloxanes are used as the working fluids of organic Rankine cycle systems, there is a possibility of air infiltration due to the large vacuum present in the condenser. To address this issue, experimental and simulation studies were conducted on the thermal stability and pyrolysis product characteristics of octamethyltrisiloxane (MDM) in the presence of air. The results indicated that air significantly promotes the decomposition of MDM at the temperatures above 250 °C. Air was helpful in increasing the formation of CH2O, CO, and CO2, and also enhanced polymerization of decomposition product of siloxane, leading to higher yields of MD2M, MD3M, MD4M, D3, D4, and D5. By combining reactive force field molecular dynamics (ReaxFF-MD) simulations with density functional theory (DFT) calculations, the microscopic mechanisms of MDM's oxidative decomposition by O2 in air and H2O under humid conditions were elucidated. O2 can easily combine with unsaturated Si atoms to form Si-O bonds, combine with CH3 radicals to form C-O bonds, and undergoes hydrogen extraction reactions to initiate decomposition. H2O mainly undergoes initial decomposition through CH3 radical hydrogenation and binding with unsaturated Si atoms. The generated O2H, O, and OH radicals tend to bind with Si atoms in molecules and radicals, facilitating polymerization reactions.