Diving technique of cochlear implant electrode insertion for hearing preservation: how I do it.

BACKGROUND: Preservation of intracochlear structures and residual hearing has become a major concern in modern cochlear implant. Consequently, many efforts have been made to minimize intraoperative trauma, especially while cochlear fenestration and electrode insertion. METHODS: Building on the core concept of "soft surgery", a modified approach, described as diving technique for cochlear implant electrode array insertion is proposed. Steps and technical points are presented with figures, video and review of relevant anatomy. CONCLUSIONS: This novel diving technique is operationally feasible and safe, promising to minimize intraoperative invasion and thus preserve residual hearing in cochlear implant.

Structural basis of tethered agonism and G protein coupling of protease-activated receptors.

Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the Gq and Gi heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming ß-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the Gα subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1's versatility in G protein coupling.

A rhinopithecus swarm optimization algorithm for complex optimization problem.

This paper introduces a novel meta-heuristic algorithm named Rhinopithecus Swarm Optimization (RSO) to address optimization problems, particularly those involving high dimensions. The proposed algorithm is inspired by the social behaviors of different groups within the rhinopithecus swarm. RSO categorizes the swarm into mature, adolescent, and infancy individuals. Due to this division of labor, each category of individuals employs unique search methods, including vertical migration, concerted search, and mimicry. To evaluate the effectiveness of RSO, we conducted experiments using the CEC2017 test set and three constrained engineering problems. Each function in the test set was independently executed 36 times. Additionally, we used the Wilcoxon signed-rank test and the Friedman test to analyze the performance of RSO compared to eight well-known optimization algorithms: Dung Beetle Optimizer (DBO), Beluga Whale Optimization (BWO), Salp Swarm Algorithm (SSA), African Vultures Optimization Algorithm (AVOA), Whale Optimization Algorithm (WOA), Atomic Retrospective Learning Bare Bone Particle Swarm Optimization (ARBBPSO), Artificial Gorilla Troops Optimizer (GTO), and Harris Hawks Optimization (HHO). The results indicate that RSO exhibited outstanding performance on the CEC2017 test set for both 30 and 100 dimension. Moreover, RSO ranked first in both dimensions, surpassing the mean rank of the second-ranked algorithms by 7.69% and 42.85%, respectively. Across the three classical engineering design problems, RSO consistently achieves the best results. Overall, it can be concluded that RSO is particularly effective for solving high-dimensional optimization problems.

Suppression of viral rebound by a Rev-dependent lentiviral particle in SIV-infected rhesus macaques.

Persistence of human immunodeficiency virus (HIV) reservoirs prevents viral eradication, and consequently HIV-infected patients require lifetime treatment with antiretroviral therapy (ART) [1-5]. Currently, there are no effective therapeutics to prevent HIV rebound upon ART cessation. Here we describe an HIV/SIV Rev-dependent lentiviral particle that can be administered to inhibit viral rebound [6-9]. Using simian immunodeficiency virus (SIV)-infected rhesus macaques as a model, we demonstrate that the administration of pre-assembled SIV Rev-dependent lentiviral particles into SIVmac239-infected Indian rhesus macaques can lead to reduction of viral rebound upon ART termination. One of the injected animals, KC50, controlled plasma and CNS viremia to an undetectable level most of the time for over two years after ART termination. Surprisingly, detailed molecular and immunological characterization revealed that viremia control was concomitant with the induction of neutralizing antibodies (nAbs) following the administration of the Rev-dependent vectors. This study emphasizes the importance of neutralizing antibodies (nAbs) for viremia control [10-15], and also provides proof of concept that the Rev-dependent vector can be used to target viral reservoirs, including the CNS reservoirs, in vivo. However, future large-scale in vivo studies are needed to understand the potential mechanisms of viremia control induced by the Rev-dependent vector.

Chromone-deferiprone hybrids as novel MAO-B inhibitors and iron chelators for the treatment of Alzheimer's disease.

A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.

Pulse-doubling perovskite nanowire lasers enabled by phonon-assisted multistep energy funneling.

Laser pulse multiplication from an optical gain medium has shown great potential in miniaturizing integrated optoelectronic devices. Perovskite multiple quantum wells (MQWs) structures have recently been recognized as an effective gain media capable of doubling laser pulses that do not rely on external optical equipment. Although the light amplifications enabled with pulse doubling are reported based on the perovskite MQWs thin films, the micro-nanolasers possessed a specific cavity for laser pulse multiplication and their corresponding intrinsic laser dynamics are still inadequate. Herein, a single-mode double-pulsed nanolaser from self-assembled perovskite MQWs nanowires is realized, exhibiting a pulse duration of 28 ps and pulse interval of 22 ps based on single femtosecond laser pulse excitation. It is established that the continuous energy building up within a certain timescale is essential for the multiple population inversion in the gain medium, which arises from the slowing carrier localization process owning to the stronger exciton-phonon coupling in the smaller-n QWs. Therefore, the double-pulsed lasing is achieved from one fast energy funnel process from the adjacent small-n QWs to gain active region and another slow process from the spatially separated ones. This report may shed new light on the intrinsic energy relaxation mechanism and boost the further development of perovskite multiple-pulse lasers.

Association between heatwaves and risk and economic burden of injury related hospitalizations in China.

BACKGROUND: Public health is greatly affected by heatwaves, especially as a result of climate change. It is unclear whether heatwaves affect injury hospitalization, especially as developing countries facing the impact of climate change. OBJECTIVES: To assess the impact of heatwaves on injury-related hospitalization and the economic burden. METHODS: The daily hospitalizations and meteorological data from 2014 to 2019 were collected from 23 study sites in 11 meteorological geographic zones in China. We conducted a two-stage time series analysis based on a time-stratified case-crossover design, combined with DLNM to assess the association between heatwaves and daily injury hospitalization, and to further assess the regional and national economic losses resulting from hospitalization by calculating excess hospitalization costs (direct economic losses) and labor losses (indirect economic losses). To determine the vulnerable groups and areas, we also carried out stratified analyses by age, sex, and region. RESULTS: We found that 6.542% (95%CI: 3.939%, 9.008 %) of injury hospitalization were attributable to heatwaves during warm season (May to September) from 2014 to 2019. Approximately 361,447 injury hospitalizations were attributed to heatwaves each year in China, leading to an excess economic loss of 5.173 (95%CI: 3.104, 7.196) billion CNY, of which 3.114 (95%CI: 1.454, 4.720) billion CNY for males and 4.785 (95%CI: 3.203, 6.321) billion CNY for people aged 15-64 years. The attributable fraction (AF) of injury hospitalizations due to heatwaves was the highest in the plateau mountain climate zone, followed by the subtropical monsoon climate zone and the temperate monsoon climate zone. CONCLUSIONS: Heatwaves significantly increase the disease and economic burden of injury hospitalizations, and vary across populations and regions. Our findings implicate the necessity for targeted measures, including raising public awareness, improving healthcare infrastructure, and developing climate resilience policies, to reduce the threat of heatwaves to vulnerable populations and the associated disease and economic burden.

Can Electrochemical Impedance Spectroscopy be Replaced by Direct Current Techniques in Battery Diagnosis?

Electrochemical impedance spectroscopy (EIS), a conventional and alternating-current-(AC)-based technique for impedance measurement, is commonly used in battery diagnosis. However, it requires expensive equipment and demanding operating conditions and is complex and model-dependent in data analysis. Recently, novel direct current (DC) analytics have emerged as an alternative to EIS. They are simple yet powerful, being capable of revealing impedance information that traditionally could only be obtained through EIS and determining Li-ion diffusion coefficient. Besides, a complete EIS spectrum can be predicted based on constant current charging curves in the support of machine learning methods. This work highlights the similarities and discrepancies between DC techniques and EIS in the electrochemical analysis of Liion batteries. Looking ahead, DC techniques may be a promising substitute for EIS in future battery diagnosis, requiring simplified equipment while offering a deep understanding of battery impedance and its underlying electrochemical processes.

Composition Distribution of the Thermal Soluble Organics from Naomaohu Lignite and Structural Characteristics of the Corresponding Insoluble Portions.

With cyclohexane (CH), benzene (BE), and ethyl acetate (EA) as solvents, Naomaohu lignite (NL, a typical oil-rich, low-rank coal) from Hami, Xinjiang, was thermally dissolved (TD) to obtain three types of soluble organics (NLCH, NLBE, and NLEA) and the corresponding insoluble portions (NLCH-R, NLBE-R, and NLEA-R). Ultimate analysis, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TG-DTG), and gas chromatography-mass spectrometry (GC/MS) were used to characterize NL and its soluble and insoluble portions. Results showed that, compared with NL, the C element in NLCH-R, NLBE-R, and NLEA-R increased, while the O element decreased significantly, indicating that thermal dissolution is a carbon enrichment process and an effective deoxidation method. The GC/MS results showed that oxygen-containing organic compounds (OCOCs) are dominant in NLCH, NLBE, and NLEA. NLCH is mainly composed of ketones (11.90%) and esters (19.04%), while NLBE and NLEA are composed of alcohols (12.18% and 2.42%, respectively) and esters (66.09% and 84.08%, respectively), with alkyl and aromatic acid esters as the main components. Among them, EA exhibits significant selective destruction for oxygen-containing functional groups in NL. XPS, FTIR, and TG-DTG results showed that thermal dissolution can not only affect the macromolecular network structure of NL, but also improve its pyrolysis reactivity. In short, thermal dissolution can effectively obtain oxygen-containing organic compounds from NL.

Toward Enhancing Low Temperature Performances of Lithium-Ion Transport for Metal-Organic Framework-Based Solid-State Electrolyte: Nanostructure Engineering or Crystal Morphology Controlling.

Metal-organic frameworks (MOFs) have emerged as attractive candidates for Li+ conducting electrolytes due to their regular channels and controllable morphology, making their presence prominent in the field of solid-state lithium batteries. However, most MOF-based electrolytes are researched at or near room temperature, which poses a challenge to their practical applications at low temperatures. Herein, a thin layer flower-shaped 2D Cu-MOF (CuBDC-10)-based solid-state electrolytes (SSEs) for lithium-ion batteries (LIBs) are developed for facilitating Li+ transport at lower temperatures, which achieve an ion conductivity of 10-4 S cm-1 at -30 °C. The CuBDC-10-based SSE exhibits outstanding ionic conductivity over a wide temperature range of -40 to 100 °C (0.073-3.68 × 10-3 S cm-1). This work provides strategies for exploring MOF-based SSEs with high ionic transport performances at low temperatures.

Automatic detection of pulmonary embolism on computed tomography pulmonary angiogram scan using a three-dimensional convolutional neural network.

OBJECTIVE: To propose a convolutional neural network (EmbNet) for automatic pulmonary embolism detection on computed tomography pulmonary angiogram (CTPA) scans and to assess its diagnostic performance. METHODS: 305 consecutive CTPA scans between January 2019 and December 2021 were enrolled in this study (142 for training, 163 for internal validation), and 250 CTPA scans from a public dataset were used for external validation. The framework comprised a preprocessing step to segment the pulmonary vessels and the EmbNet to detect emboli. Emboli were divided into three location-based subgroups for detailed evaluation: central arteries, lobar branches, and peripheral regions. Ground truth was established by three radiologists. RESULTS: The EmbNet's per-scan level sensitivity, specificity, positive predictive value (PPV), and negative predictive value were 90.9%, 75.4%, 48.4%, and 97.0% (internal validation) and 88.0%, 70.5%, 42.7%, and 95.9% (external validation). At the per-embolus level, the overall sensitivity and PPV of the EmbNet were 86.0% and 61.3% (internal validation), and 83.5% and 57.5% (external validation). The sensitivity and PPV of central emboli were 89.7% and 52.0% (internal validation), and 94.4% and 43.0% (external validation); of lobar emboli were 95.2% and 76.9% (internal validation), and 93.5% and 72.5% (external validation); and of peripheral emboli were 82.6% and 61.7% (internal validation), and 80.2% and 59.4% (external validation). The average false positive rate was 0.45 false emboli per scan (internal validation) and 0.69 false emboli per scan (external validation). CONCLUSION: The EmbNet provides high sensitivity across embolus locations, suggesting its potential utility for initial screening in clinical practice.

Identification of a Novel Aflatoxin B1-Degrading Strain, Bacillus halotolerans DDC-4, and Its Response Mechanisms to Aflatoxin B1.

Aflatoxin B1 (AFB1) contamination is a food safety issue threatening human health globally. Biodegradation is an effective method for overcoming this problem, and many microorganisms have been identified as AFB1-degrading strains. However, the response mechanisms of these microbes to AFB1 remain unclear. More degrading enzymes, especially of new types, need to be discovered. In this study, a novel AFB1-degrading strain, DDC-4, was isolated using coumarin as the sole carbon source. This strain was identified as Bacillus halotolerans through physiological, biochemical, and molecular methods. The strain's degradation activity was predominantly attributable to thermostable extracellular proteins (degradation rate remained approximately 80% at 90 °C) and was augmented by Cu2+ (95.45% AFB1 was degraded at 48 h). Alpha/beta hydrolase (arylesterase) was selected as candidate AFB1-degrading enzymes for the first time as a gene encoding this enzyme was highly expressed in the presence of AFB1. Moreover, AFB1 inhibited many genes involved in the nucleotide synthesis of strain DDC-4, which is possibly the partial molecular mechanism of AFB1's toxicity to microorganisms. To survive under this stress, sporulation-related genes were induced in the strain. Altogether, our study identified a novel AFB1-degrading strain and explained its response mechanisms to AFB1, thereby providing new insights for AFB1 biodegradation.

Analysis of tumor microenvironment alterations in partially responsive rectal cancer patients treated with neoadjuvant chemoradiotherapy.

PURPOSE: Achieving a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) remains a challenge for most patients with rectal cancer. Exploring the potential of combining NCRT with immunotherapy or targeted therapy for those achieving a partial response (PR) offers a promising avenue to enhance treatment efficacy. This study investigated the impact of NCRT on the tumor microenvironment in locally advanced rectal cancer (LARC) patients who exhibited a PR. METHODS: This was a retrospective, observational study. Five patients demonstrating a PR after neoadjuvant treatment for LARC were enrolled in the study. Biopsy samples before treatment and resected specimens after treatment were stained with a panel of 26 antibodies targeting various immune and tumor-related markers, each labeled with distinct metal tags. The labeled samples were then analyzed using the Hyperion imaging system. RESULTS: Heterogeneity within the tumor microenvironment was observed both before and after NCRT. Notably, tumor-associated macrophages, CD4 + T cells, CD8 + T cells, CD56 + natural killer cells, tumor-associated neutrophils, cytokeratin, and E-cadherin exhibited slight increase in abundance within the tumor microenvironment following treatment (change ratios = 0.78, 0.2, 0.27, 0.32, 0.17, 0.46, 0.32, respectively). Conversely, the number of CD14 + monocytes, CD19 + B cells, CD45 + CD4 + T cells, collagen I, α-smooth muscle actin, vimentin, and ß-catenin proteins displayed significant decreases post-treatment (change ratios = 1.73, 1.92, 1.52, 1.25, 1.52, 1.12, 2.66, respectively). Meanwhile, Foxp3 + regulatory cells demonstrated no significant change (change ratio = 0.001). CONCLUSIONS: NCRT has diverse effects on various components of the tumor microenvironment in LARC patients who achieve a PR after treatment. Leveraging combination therapies may optimize treatment outcomes in this patient population.

Enhanced brain-targeting and efficacy of cannabidiol via RVG-Exo/CBD nanodelivery system.

This study introduces an innovative brain-targeted drug delivery system, RVG-Exo/CBD, utilizing rabies virus glycoprotein (RVG)-engineered exosomes for encapsulating cannabidiol (CBD). The novel delivery system was meticulously characterized, confirming the maintenance of exosomal integrity, size, and successful drug encapsulation with a high drug loading rate of 83.0 %. Evaluation of the RVG-Exo/CBD's brain-targeting capability demonstrated superior distribution and retention in brain tissue compared to unmodified exosomes, primarily validated through in vivo fluorescence imaging. The efficacy of this delivery system was assessed using a behavioral sensitization model in mice, where RVG-Exo/CBD notably suppressed methamphetamine-induced hyperactivity more effectively than CBD alone, indicating a reduction in effective dose and enhanced bioavailability. Overall, the RVG-Exo/CBD system emerges as a promising strategy for enhancing the therapeutic efficacy and safety of CBD, particularly for neurological applications, highlighting its potential for addressing the limitations associated with traditional CBD administration in clinical settings.

[Effect of CD8+ CD28- T Cells on Acute Graft-Versus-Host Disease after Haploidentical Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To investigate the effect of CD8+ CD28- T cells on acute graft-versus-host disease(aGVHD) after haploidentical hematopoietic stem cell transplantation(haplo-HSCT). METHODS: The relationship between absolute count of CD8+ CD28- T cells and aGVHD in 60 patients with malignant hematological diseases was retrospectively analyzed after haplo-HSCT, and the differences in the incidence rate of chronic graft-versus host disease(cGVHD), infection and prognosis between different CD8+ CD28- T absolute cells count groups were compared. RESULTS: aGVHD occurred in 40 of 60 patients after haplo-HSCT, with an incidence rate of 66.67%. The median occurrence time of aGVHD was 32.5(20-100) days. At 30 days after the transplantation, the absolute count of CD8+ CD28- T cells of aGVHD group was significantly lower than that of non-aGVHD group (P =0.03). Thus the absolute count of CD8+ CD28- T cells at 30 days after transplantation can be used to predict the occurrence of aGVHD to some extent. At 30 days after transplantation, the incidence rate of aGVHD in the low cell count group (CD8+ CD28- T cells absolute count < 0.06/µl) was significantly higher than that in the high cell count group (CD8+ CD28- T cells absolute count ≥0.06/µl,P =0.011). Multivariate Cox regression analysis further confirmed that the absolute count of CD8+ CD28-T cells at 30 days after transplantation was an independent risk factor for aGVHD, and the risk of aGVHD in the low cell count group was 2.222 times higher than that in the high cell count group (P =0.015). The incidence of cGVHD, fungal infection, EBV infection and CMV infection were not significantly different between the two groups with different CD8+ CD28- T cells absolute count. The overall survival, non-recurrent mortality and relapse rates were not significantly different between different CD8+ CD28- T cells absolute count groups. CONCLUSION: Patients with delayed CD8+ CD28- T cells reconstitution after haplo-HSCT are more likely to develop aGVHD, and the absolute count of CD8+ CD28- T cells can be used to predict the incidence of aGVHD to some extent. The absolute count of CD8+ CD28- T cells after haplo-HSCT was not associated with cGVHD, fungal infection, EBV infection, and CMV infection, and was also not significantly associated with the prognosis after transplantation.

Gasdermin D Inhibitor Necrosulfonamide Alleviates Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4+ T cells, CD8+ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1ß and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1ß and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.

Genome-wide association studies dissect low-phosphorus stress response genes underling field and seedling traits in maize.

Phosphorus (P) is an essential element for plant growth, and its deficiency can cause decreased crop yield. This study systematically evaluated the low-phosphate (Pi) response traits in a large population at maturity and seedling stages, and explored candidate genes and their interrelationships with specific traits. The results revealed a greater sensitivity of seedling maize to low-Pi stress compared to that at maturity stage. The phenotypic response patterns to low-Pi stress at different stages were independent. Chlorophyll content was found to be a potential indicator for screening low-Pi-tolerant materials in the field. A total of 2900 and 1446 significantly associated genes at the maturity and seedling stages were identified, respectively. Among these genes, 972 were uniquely associated with maturity traits, while 330 were specifically detected at the seedling stage under low-Pi stress. Moreover, 768 and 733 genes were specifically associated with index values (low-Pi trait/normal-Pi trait) at maturity and seedling stage, respectively. Genetic network diagrams showed that the low-Pi response gene Zm00001d022226 was specifically associated with multiple primary P-related traits under low-Pi conditions. A total of 963 out of 2966 genes specifically associated with traits under low-Pi conditions or index values were found to be induced by low-Pi stress. Notably, ZmSPX4.1 and ZmSPX2 were sharply up-regulated in response to low-Pi stress across different lines or tissues. These findings advance our understanding of maize's response to low-Pi stress at different developmental stages, shedding light on the genes and pathways implicated in this response.

Podophyllotoxin via SIRT1/PPAR /NF-κB axis induced cardiac injury in rats based on the toxicological evidence chain (TEC) concept.

BACKGROUND: The study of cardiotoxicity of drugs has become an important part of clinical safety evaluation of drugs. It is commonly known that podophyllotoxin (PPT) and its many derivatives and congeners are broad-spectrum pharmacologically active substances. Clinical cardiotoxicity of PPT and its derivatives has been raised, basic research on the mechanism of cardiotoxicity remains insufficient. PURPOSE: In present study, our group's innovative concept of toxicological evidence chain (TEC) was applied to reveal the cardiac toxicity mechanism of PPT by targeted metabolomics, TMT-based quantitative proteomics and western blot. METHODS: The injury phenotype evidence (IPE) acquired from the toxicity manifestations, such as weight and behavior observation of Sprague-Dawley rat. The damage to rat hearts were assessed through histopathological examination and myocardial enzymes levels, which were defined as Adverse Outcomes Evidence (AOE). The damage to rat hearts was assessed through histopathological examination and myocardial enzyme levels, which were defined as evidence of adverse outcomes.Overall measurements of targeted metabolomics based on energy metabolism and TMT-based quantitative proteomics were obtained after exposure to PPT to acquire the Toxic Event Evidence (TEE). The mechanism of cardiac toxicity was speculated based on the integrated analysis of targeted metabolomics and TMT-based quantitative proteomics, which was verified by western blot. RESULTS: The results indicated that exposure to PPT could result in significant elevation of myocardial enzymes and pathological alterations in rat hearts. In addition, we found that PPT caused disorders in cardiac energy metabolism, characterized by a decrease in energy metabolism fuels. TMT-based quantitative proteomics revealed that the PPAR (Peroxisome proliferators-activated receptor) signaling pathway needs further study. It is worth noting that PPT may suppress the expression of SIRT1, subsequently inhibiting AMPK, decreasing the expression of PGC-1α, PPARα and PPARγ. This results in disorders of glucose oxidation, glycolysis and ketone body metabolism. Additionally, the increase in the expression of p-IKK and p-IκBα, leads to the nuclear translocation of NF-κB p65 from the cytosol, thus triggering inflammation. CONCLUSION: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of cardiotoxicity,suggesting that PPT induced disorders of energy metabolism and inflammation via SIRT1/PPAR/NF-κB axis, potentially contributing to cardiac injury.

Exploring the phosphorus-starch content balance mechanisms in maize grains using GWAS population and transcriptome data.

Examining the connection between P and starch-related signals can help elucidate the balance between nutrients and yield. This study utilized 307 diverse maize inbred lines to conduct multi-year and multi-plot trials, aiming to explore the relationship among P content, starch content, and 100-kernel weight (HKW) of mature grains. A significant negative correlation was found between P content and both starch content and HKW, while starch content showed a positive correlation with HKW. The starch granules in grains with high-P and low-starch content (HPLS) were significantly smaller compared to grains with low-P high-starch content (LPHS). Additionally, mian04185-4 (HPLS) exhibited irregular and loosely packed starch granules. A significant decrease in ZmPHOs genes expression was detected in the HPLS line ZNC442 as compared to the LPHS line SCML0849, while no expression difference was observed in AGPase encoding genes between these two lines. The down-regulated genes in ZNC442 grains were enriched in nucleotide sugar and fatty acid anabolic pathways, while up-regulated genes were enriched in the ABC transporters pathway. An accelerated breakdown of fat as the P content increased was also observed. This implied that HPLS was resulted from elevated lipid decomposition and inadequate carbon sources. The GWAS analysis identified 514 significantly associated genes, out of which 248 were differentially expressed. Zm00001d052392 was found to be significantly associated with P content/HKW, exhibiting high expression in SCML0849 but almost no expression in ZNC442. Overall, these findings suggested new approaches for achieving a P-yield balance through the manipulation of lipid metabolic pathways in grains.