Synthesis, physicochemical characterization, and investigation of anti-inflammatory activity of water-soluble PEGylated 1,2,4-Triazoles.

A series of water-soluble PEGylated 1,2,4-triazoles 5-8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1. All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and 1H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates. For SAR study, all PEGylated 1,2,4-triazoles 5-8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC50 = 3.42-7.81 µM). Moreover, the western blot result showed PEGylated 1,2,4-triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX-2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a-d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d. Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4-triazole 7d more effectively decreased the inflammatory response in edema and COX-2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.

SDACS: Blockchain-Based Secure and Dynamic Access Control Scheme for Internet of Things.

With the rapid growth of the Internet of Things (IoT), massive terminal devices are connected to the network, generating a large amount of IoT data. The reliable sharing of IoT data is crucial for fields such as smart home and healthcare, as it promotes the intelligence of the IoT and provides faster problem solutions. Traditional data sharing schemes usually rely on a trusted centralized server to achieve each attempted access from users to data, which faces serious challenges of a single point of failure, low reliability, and an opaque access process in current IoT environments. To address these disadvantages, we propose a secure and dynamic access control scheme for the IoT, named SDACS, which enables data owners to achieve decentralized and fine-grained access control in an auditable and reliable way. For access control, attribute-based control (ABAC), Hyperledger Fabric, and interplanetary file system (IPFS) were used, with four kinds of access control contracts deployed on blockchain to coordinate and implement access policies. Additionally, a lightweight, certificateless authentication protocol was proposed to minimize the disclosure of identity information and ensure the double-layer protection of data through secure off-chain identity authentication and message transmission. The experimental and theoretical analysis demonstrated that our scheme can maintain high throughput while achieving high security and stability in IoT data security sharing scenarios.

Influence of Proteins and Building Direction on the Corrosion and Tribocorrosion of CoCrMo Fabricated by Laser Powder Bed Fusion.

Cobalt-chromium-molybdenum (CoCrMo) alloys are common wear-exposed biomedical alloys and are manufactured in multiple ways, increasingly using additive manufacturing processes such as laser powder bed fusion (LPBF). Here, we investigate the effect of proteins and the manufacturing process (wrought vs LPBF) and building orientation (LPBF-XY and XZ) on the corrosion, metal release, tribocorrosion, and surface oxide composition by means of electrochemical, mechanical, microscopic, diffractive, and spectroscopic methods. The study was conducted at pH 7.3 in 5 g/L NaCl and 5 mM 2-(N-morpholino) ethanesulfonic acid (MES) buffer, which was found to be necessary to avoid metal phosphate and metal-protein aggregate precipitation. The effect of 10 g/L bovine serum albumin (BSA) and 2.5 g/L fibrinogen (Fbn) was studied. BSA and Fbn strongly enhanced the release of Co, Cr, and Mo and slightly enhanced the corrosion (still in the passive domain) for all CoCrMo alloys and most for LPBF-XZ, followed by LPBF-XY and the wrought CoCrMo. BSA and Fbn, most pronounced when combined, significantly decreased the coefficient of friction due to lubrication, the wear track width and severity of the wear mechanism, and the tribocorrosion for all alloys, with no clear effect of the manufacturing type. The wear track area was significantly more oxidized than the area outside of the wear track. In the reference solution without proteins, a strong Mo oxidation in the wear track surface oxide was indicative of a pH decrease and cell separation of the anodic and cathodic areas. This effect was absent in the presence of the proteins.

Combining data augmentation and deep learning for improved epilepsy detection.

Introduction: In recent years, the use of EEG signals for seizure detection has gained widespread academic attention. Aiming at the problem of overfitting deep learning models due to the small number of EEG signal data during epilepsy detection, this paper proposes an epilepsy detection method that combines data augmentation and deep learning. Methods: First, the Adversarial and Mixup Data Augmentation (AMDA) method is used to realize the data augmentation, which effectively enriches the number of training samples. To further improve the classification accuracy and robustness of epilepsy detection, this paper proposes a one-dimensional convolutional neural network and gated recurrent unit (AM-1D CNN-GRU) network model based on attention mechanism for epilepsy detection. Results and discussion: The experimental results show that the performance of epilepsy detection achieved by using augmented data is significantly improved, and the accuracy, sensitivity, and area under the subject's working characteristic curve are up to 96.06, 95.48%, and 0.9637, respectively. Compared with the non-augmented data, all indicators are increased by more than 6.2%. Meanwhile, the detection performance was significantly improved compared with other epilepsy detection methods. The results of this research can provide a reference for the clinical application of epilepsy detection.

Customized Enhancement of Thermal Sensitivity of Tumors at Different Subcutaneous Depths by Multichannel Lanthanide Nanocomposites.

The photothermal therapeutic effect on tumors located at different subcutaneous depths varies due to the attenuation of light by tissue. Here, based on the wavelength-dependent optical attenuation properties of tissues, the tumor depth is assessed using a multichannel lanthanide nanocomposite. A zeolitic imidazolate framework (ZIF-8)-coated nanocomposite is able to deliver high amounts of the hydrophilic heat shock protein 90 inhibitor epigallocatechin gallate through a hydrogen-bonding network formed by the encapsulated highly polarized polyoxometalate guest. It is superior to both bare and PEGylated ZIF-8 for drug delivery. With the assessment of tumor depth and accumulated amount of nanocomposite by fluorescence, an irradiation prescription can be customized to release sufficient HSP90 inhibitor and generate heat for sensitized photothermal treatment of tumors, which not only ensured therapeutic efficacy but also minimized damage to the surrounding tissues.

GPro: generative AI-empowered toolkit for promoter design.

MOTIVATION: Promoters with desirable properties are crucial in biotechnological applications. Generative AI (GenAI) has demonstrated potential in creating novel synthetic promoters with significantly enhanced functionality. However, these methods' reliance on various programming frameworks and specific task-oriented contexts limits their flexibilities. Overcoming these limitations is essential for researchers to fully leverage the power of GenAI to design promoters for their tasks. RESULTS: Here, we introduce GPro (Generative AI-empowered toolkit for promoter design), a user-friendly toolkit that integrates a collection of cutting-edge GenAI-empowered approaches for promoter design. This toolkit provides a standardized pipeline covering essential promoter design processes, including training, optimization, and evaluation. Several detailed demos are provided to reproduce state-of-the-art promoter design pipelines. GPro's user-friendly interface makes it accessible to a wide range of users including non-AI experts. It also offers a variety of optional algorithms for each design process, and gives users the flexibility to compare methods and create customized pipelines. AVAILABILITY AND IMPLEMENTATION: GPro is released as an open-source software under the MIT license. The source code for GPro is available on GitHub for Linux, macOS, and Windows: https://github.com/WangLabTHU/GPro, and is available for download via Zenodo repository at https://zenodo.org/doi/10.5281/zenodo.10681733.

A New Advanced Approach: Design and Screening of Affinity Peptide Ligands Using Computer Simulation Techniques.

Peptides acquire target affinity based on the combination of residues in their sequences and the conformation formed by their flexible folding, an ability that makes them very attractive biomaterials in therapeutic, diagnostic, and assay fields. With the development of computer technology, computer-aided design and screening of affinity peptides has become a more efficient and faster method. This review summarizes successful cases of computer-aided design and screening of affinity peptide ligands in recent years and lists the computer programs and online servers used in the process. In particular, the characteristics of different design and screening methods are summarized and categorized to help researchers choose between different methods. In addition, experimentally validated sequences are listed, and their applications are described, providing directions for the future development and application of computational peptide screening and design.

Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats.

BACKGROUND: Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder that significantly diminishes the quality of life for affected individuals. The pathophysiology of IBS remains poorly understood, and available therapeutic options for IBS are limited. The crucial roles of brain-gut interaction, which is mediated by the Hypothalamic-Pituitary-Adrenocortical (HPA) axis and the autonomic nervous system in IBS, have attracted increasing attention. OBJECTIVE: The objective of this study was to examine the impact of paeoniflorin (PF) on anxiety and visceral hypersensitivity in maternal separation-induced IBS-like rats. METHODS: The IBS-like rat model was established through the implementation of Maternal Separation (MS) and subsequently subjected to various doses of PF administered via oral gavage for 14 days. Anxiety-like behavior was evaluated using the Open Field Test (OFT) and Elevated Plus Maze (EPM) test. The assessment of visceral sensitivity involved the utilization of the Abdominal Withdrawal Reflex (AWR) score and electromyographic (EMG) responses of the external oblique muscle in response to colorectal distention. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotrophin-releasing hormone (CRH) were examined by ELISA. Quantitative real-time PCR (qRT-PCR) and immunofluorescence were employed to detect the expressions of CRH receptors 1 (CRHR1) and 2 (CRHR2). Glucocorticoid receptors (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and phospholipase C γ1 (PLCγ1) were examined by Western blot. RESULTS AND DISCUSSION: The results showed that MS induced anxiety-like behavior and visceral hypersensitivity, while PF treatment attenuated these changes. Furthermore, the HPA axis hyperactivity in MS rats was attenuated by PF treatment, indicated by reduced serum ACTH, CORT, and CRH levels and recovered hippocampal CRHR1 and GR expressions. In addition, PF inhibited BDNF/TrkB signaling by downregulating the protein levels of BDNF, TrkB, and phospho-PLCγ1 in the colon. CONCLUSION: These findings suggest that PF alleviated anxiety and visceral hypersensitivity in MS-induced IBS-like rats, which may be the modulation of HPA axis activity and BDNF/TrkB/PLCγ1 signaling pathway.

Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer.

Mounting evidence has highlighted the multifunctional characteristics of glutamine metabolism (GM) in cancer initiation, progression and therapeutic regimens. However, the overall role of GM in the tumour microenvironment (TME), clinical stratification and therapeutic efficacy in patients with ovarian cancer (OC) has not been fully elucidated. Here, three distinct GM clusters were identified and exhibited different prognostic values, biological functions and immune infiltration in TME. Subsequently, glutamine metabolism prognostic index (GMPI) was constructed as a new scoring model to quantify the GM subtypes and was verified as an independent predictor of OC. Patients with low-GMPI exhibited favourable survival outcomes, lower enrichment of several oncogenic pathways, less immunosuppressive cell infiltration and better immunotherapy responses. Single-cell sequencing analysis revealed a unique evolutionary trajectory of OC cells from high-GMPI to low-GMPI, and OC cells with different GMPI might communicate with distinct cell populations through ligand-receptor interactions. Critically, the therapeutic efficacy of several drug candidates was validated based on patient-derived organoids (PDOs). The proposed GMPI could serve as a reliable signature for predicting patient prognosis and contribute to optimising therapeutic strategies for OC.

Bending a Cumulene with Electrons: Stepwise Chemical Reduction and Structural Study of a Tetraaryl[4]Cumulene.

Chemical reduction of a [4]cumulene with cesium metal was explored, and the structural changes stemming from electron acquisition are detailed using X-ray crystallography. It is found that the [4]cumulene undergoes dramatic geometric changes upon stepwise reduction, including bending of the cumulenic core and twisting of the endgroups from orthogonal to planar. The structural deformation is consistent with early theoretical reports that suggest that the twisting should occur upon reduction of both even and odd [n]cumulenes. The current results, on the other hand, are inconsistent with a previous experimental study of a [3]cumulene in which the predicted twisting is not observed upon reduction. DFT calculations reveal that the barrier to deformation is an order of magnitude lower in a [3]cumulene than a [4]cumulene, allowing the barrier to be overcome in the solid-state.

The anti-aromatic dianion and aromatic tetraanion of [18]annulene.

π-Conjugated macrocycles behave differently from analogous linear chains because their electronic wavefunctions resemble a quantum particle on a ring, leading to aromaticity or anti-aromaticity. [18]Annulene, (CH)18, is the archetypal non-benzenoid aromatic hydrocarbon. Molecules with circuits of 4n + 2 π electrons, such as [18]annulene (n = 4), are aromatic, with enhanced stability and diatropic ring currents (magnetic shielding inside the ring), whereas those with 4n π electrons, such as the dianion of [18]annulene, are expected to be anti-aromatic and exhibit the opposite behaviour. Here we use 1H NMR spectroscopy to re-evaluate the structure of the [18]annulene dianion. We also show that it can be reduced further to an aromatic tetraanion, which has the same shape as the dianion. The crystal structure of the tetraanion lithium salt confirms its geometry and reveals a metallocene-like sandwich, with five Li+ cations intercalated between two [18]annulene tetraanions. We also report a heteroleptic sandwich, with [18]annulene and corannulene tetraanion decks.

Discovery of metabolite biomarkers for odontogenic keratocysts.

INTRODUCTION: Odontogenic keratocysts (OKCs) are locally aggressive and have a high rate of recurrence, but the pathogenesis of OKCs is not fully understood. We aimed to investigate the serum metabolomic profile of OKCs and discover potential biomarkers. METHODS: Metabolomic analysis was performed on 42 serum samples from 22 OKC patients and 20 healthy controls (HCs) using gas chromatography‒mass spectrometry to identify dysregulated metabolites in the OKC samples. LASSO regression and receiver operating characteristic (ROC) curve analyses were used to select and validate metabolic biomarkers and develop diagnostic models. RESULTS: A total of 73 metabolites were identified in the serum samples, and 24 metabolites were dysregulated in the OKC samples, of which 4 were upregulated. Finally, a diagnostic panel of 10 metabolites was constructed that accurately diagnosed OKCs (sensitivity of 100%, specificity of 100%, area under the curve of 1.00). CONCLUSION: This study is the first to investigate the metabolic characteristics and potential metabolic biomarkers in the serum of OKC patients using GC‒MS. Our study provides further evidence to explore the pathogenesis of OKC.

Increased resected lymph node stations improved survival of esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery have been recommended as the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC). In addition, nodal metastases decreased in frequency and changed in distribution after neoadjuvant therapy. This study aimed to examine the optimal strategy for lymph node dissection (LND) in patients with ESCC who underwent nCRT. METHODS: The hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were calculated using the Cox proportional hazard model. To determine the minimal number of LNDs (n-LNS) or least station of LNDs (e-LNS), the Chow test was used. RESULTS: In total, 333 patients were included. The estimated cut-off values for e-LNS and n-LNS were 9 and 15, respectively. A higher number of e-LNS was significantly associated with improved OS (HR: 0.90; 95% CI 0.84-0.97, P = 0.0075) and DFS (HR: 0.012; 95% CI: 0.84-0.98, P = 0.0074). The e-LNS was a significant prognostic factor in multivariate analyses. The local recurrence rate of 23.1% in high e-LNS is much lower than the results of low e-LNS (13.3%). Comparable morbidity was found in both the e-LNS and n-LND subgroups. CONCLUSION: This cohort study revealed an association between the extent of LND and overall survival, suggesting the therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, more lymph node stations being sampled leads to higher survival rates among patients who receive nCRT, and standard lymphadenectomy of at least 9 stations is strongly recommended.

Bifico Ameliorates Neurological Deficits After Ischemic Stroke in Mice: Transcriptome Profiling.

BACKGROUND/AIM: Evidence suggests that gut microbiota can affect various neurological diseases, including stroke. Stroke patients have an increase in harmful gut bacteria and a decrease in beneficial bacteria. This increases intestinal permeability, increases the risk of infection, and even affects many inflammatory factors. While probiotics may affect stroke prognosis by improving the gut environment. This study aimed to investigate the effect of probiotic Bifico on the neural function in mice after focal cerebral ischemia and explore its mechanisms of action. MATERIALS AND METHODS: A focal cerebral ischemia model was established in mice. Four weeks before modeling, animals were divided into three groups: Stroke plus Vehicle group, Stroke plus Pre-Bifico group and Bifico group. The infarct volume and neurobehaviors were evaluated. Whole-gene expression profiling was performed at different days after treatment (D1, D7, D14, D28) by RNA-seq. Differentially expressed genes (DEGs) were the processed for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG). Some inflammation and immune related genes were screened and their expression was analyzed. RESULTS: Compared to the Stroke plus Vehicle group and Bifico group, the infarct volume and neurological score were significantly reduced in the Pre-Bifico group. There were 2 DEGs at D1, 193 DEGs at D7, 70 DEGs at D28 between Stroke plus Pre-Bifico group and Stroke plus Vehicle group. For GO analysis, there were 139 significant terms at D7 and 195 at D28. For KEGG, there were 2 significant pathways at D7 and 9 at D28. Among 87 genes related to inflammation and immunity, 6 DEGs were identified. The expression of CCL9 was significantly elevated at most time points after stroke compared to the Stroke plus Vehicle group, while that of CCL6, CXCL10, CD48, CD72 and CLEC7A was highly expressed only in the recovery stage of stroke. CONCLUSION: Oral pre-treatment with Bifico for 28 days can reduce cerebral infarction and promote recovery of neurological function in stroke mice, which may be ascribed to the regulation of immunity and inflammation in the brain.

Homoleptic Rare-Earth-Metal Sandwiches with Dibenzo[a,e]cyclooctatetraene Dianions.

A family of rare-earth complexes [RE(III) = Y, La, Gd, Tb, Dy, and Er] with doubly reduced dibenzo[a,e]cyclooctatetraene (DBCOT) has been synthesized and structurally characterized. X-ray diffraction analysis confirms that all products of the [RE(DBCOT)(THF)4][RE(DBCOT)2] composition consist of the anionic sandwich [RE(DBCOT)2]- and the cationic counterpart [RE(DBCOT)(THF)4]+. Within the sandwich, two elongated π decks are slightly bent toward the metal center (avg. 7.3°) with a rotation angle of 35.9-37.6°. The RE(III) ion is entrapped between the central eight-membered rings of DBCOT2- in a η8 fashion. The trends in the RE-COT bond lengths are consistent with the variations of the ionic radii of RE(III) centers. The 1H NMR spectra of the diamagnetic Y(III) and La(III) analogues illustrate the distinct solution behavior for the cationic and anionic parts in this series. Magnetic measurements for the Dy analogue reveal single-molecule magnetism, which was rationalized by considering the effect of crystal-field splitting for both building units analyzed by electronic structure calculations.

Daturataturin A Ameliorates Psoriasis by Regulating PPAR Pathway.

Psoriasis is a kind of severe immune-mediated systemic skin disorder, becoming a worldwide public health concern. Daturataturin A (DTA), a withanolide compound, exerts excellent anti-inflammatory and anti-proliferative properties. The objective of this study is to elucidate the effect of DTA on psoriasis and its potential mechanism. We established psoriasis-like keratinocytes model by stimulating HaCaT cells with M5 cocktail cytokines including Interleukin (IL)-17A, IL-22, oncostatin M, IL-1α, and tumor necrosis factor-α (TNF-α), followed by intervention with DTA. The potential effects and mechanisms of DTA on psoriasis were evaluated in vitro. DTA was found to be able to inhibit hyperproliferation, promote apoptosis, decrease the release of pro-inflammatory cytokines, downregulate keratin expression, and improve lipid metabolism via regulating the peroxisome proliferator-activated receptor (PPAR) signaling pathway by M5 cocktail cytokines stimulation in HaCaT cells. DTA ameliorated lipid metabolism of psoriasis and exerted the potential anti-psoriasis effects by regulating PPAR pathway in vitro, suggesting that DTA may act as a new therapeutic agent for psoriasis.

An AuNPs-based electrochemical aptasensor for the detection of 25-hydroxy vitamin D3.

Vitamin D3 (VD3) is the main form of vitamin D and an essential nutrient for maintaining human life. Currently, traditional methods for detecting 25-hydroxyvitamin D3(25(OH)D3) are complex and expensive. In this study, we constructed an accurate, sensitive, simple, and cost-effective label-free biosensor based on an aptamer for the detection of 25(OH)D3. The aptamer-modified sulfhydryl adopted self-assembly as a way to stably immobilize at the glassy carbon electrode (GCE) surface modified by gold nanoparticles (AuNPs). Upon 25(OH)D3 binding to the aptamer, the complexes inhibit electron transfer at the electrode surface, leading to reduced [Fe(CN)6]3-/4- redox peak current. Consequently, the quantity of 25(OH)D3 that interacts with the electrode-bound aptamer correlates with the observed electric current response values. The Aptamer/AuNPs/GCE aptasensor achieved direct and highly sensitive detection of 25(OH)D3 over a wide concentration range (1.0-1000 nM), with a limit of detection of 1.0 nM. At the same time, other molecules with a similar structure, such as 25(OH)D2, Vitamin D3, and Vitamin D2, had lower response interference than 25(OH)D3. Therefore, this biosensor has great potential to become a portable diagnostic device for 25(OH)D3.

Predicting new-baseline glomerular filtration rate (NBGFR) after donor nephrectomy: validation of a split renal function (SRF)-based formula.

BACKGROUND: Accurate prediction of post-donor nephrectomy (DN) glomerular filtration rate is potentially useful for evaluating and counselling living kidney donors. Currently, there are limited tools to evaluate post-operative new-baseline glomerular filtration rate (NBGFR) in kidney donors. We aim to validate a conceptually simple formula based on split renal function (SRF) previously developed for radical nephrectomy patients. METHODS: Eighty-three consecutive patients who underwent DN from 2010 to 2016 were included. Pre-operative CT imaging and functional data including pre-DN baseline Global GFR (108.2 ± 13.2 mL/min/1.73m2) were included. Observed NBGFR was defined as the latest eGFR 3-12 months post-DN. SRF, defined as volume of the contralateral non-resected kidney normalised by total volume of kidneys, was determined from pre-operative cross-sectional imaging (49.2 ± 2.36%). The equation derived from Rathi et al. is as detailed: Predicted NBGFR = 1.24 × (Global GFR Pre-DN) x (SRF). RESULTS: The relationship between predicted NBGFR (66.0 ± 8.29 mL/min/1.73m2) and observed NBGFR (74.9 ± 16.4 mL/min/1.73m2) was assessed by evaluating correlation coefficients, bias, precision, accuracy, and concordance. The new SRF-based formula for NBGFR prediction correlated strongly with observed post-operative NBGFR (Pearson's r = 0.729) demonstrating minimal bias (median difference = 7.190 mL/min/1.73m2) with good accuracy (96.4% within ± 30%, 62.7% within ± 15%) and precision (IQR of bias = - 0.094 to 16.227). CONCLUSION: The SRF-based formula was also able to accurately discriminate all but one patient to an NBGFR of > 45 mL/min/1.73m2. We utilised the newly developed SRF-based formula for predicting NBGFR in a living kidney donor population. Counselling of donor post-operative renal outcomes may then be optimised pre-operatively.

Heterogeneity analysis of main driving factors affecting potential evapotranspiration changes across different climate regions.

Exploring the influencing factors of potential evapotranspiration (PET) is of great significance for further understanding the causes of climate change and improving agricultural irrigation efficiency. In this study, modified Mann-Kendall analysis was used to elucidate the temporal variation characteristics of meteorological factors and PET based on a dataset from 710 meteorological stations in China. Furthermore, we revealed the main factors that influence the temporal and climate heterogeneity of PET by combining sensitivity analysis with the contribution analysis method. The results showed that 1) climate factors and PET exhibited trend changes on a yearly scale, with slope variation ranges of temperature (T), relative humidity (RH), net radiation (RN), wind speed (U) and PET of 0.03-0.04 °C/a, 0.03-0.08 %/a, 0.001-0.007[MJ/(m2/day)]/a, -0.005 to -0.012(m/s)/a and -0.30-0.38 mm/a, respectively. 2) The sensitivity coefficient fluctuated greatly inter-annually, but the trend was more pronounced inter-annually. Most sensitive factor for PET was RN in hyperarid (HAR), arid (AR) and semiarid regions (SAR), while it changed to RH in semihumid (SHR) and humid regions (HR). PET was more sensitive to RN in dry and relatively wet hot seasons, while it changed to RH during wet and relatively dry cold seasons. 3) PET changes were determined by the relative changes and the sensitivity coefficient, and significant temporal heterogeneity was observed. In HAR, AR, SAR and SHR, the relative changes in T and U result in higher contributions. In HR, PET changes were primarily caused by its higher sensitivity to RH and RN. 4) In dry region and humid-cold seasons, the bigger relative changes of climate factors were the main drivers affecting PET changes, but in humid region and arid-hot seasons, the they were determined by the strong nonlinear relationship between PET and factors. This finding holds great significance for the scientific understanding of the evolution mechanism of PET under changing environments.