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MicroRNAs (miRNAs) are a group of endogenous noncoding small RNAs frequently 21 nucleotides long. miRNAs act as negative regulators of their target genes through sequence-specific mRNA cleavage, translational repression, or chromatin modifications. Alterations of the expression of a miRNA or its targets often result in a variety of morphological and physiological abnormalities, suggesting the strong impact of miRNAs on plant development. Here, we review the recent advances on the functional studies of plant miRNAs. We will summarize the regulatory networks of miRNAs in a series of developmental processes, including meristem development, establishment of lateral organ polarity and boundaries, vegetative and reproductive organ growth, etc. We will also conclude the conserved and species-specific roles of plant miRNAs in evolution and discuss the strategies for further elucidating the functional mechanisms of miRNAs during plant development.

Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.

The Daxing’anling, situated within the high-latitude transition zone between continuous and sporadic permafrost, mark the southern boundary of the Northern Hemisphere’s permafrost distribution. The thermally sensitive Xing’an Baikal permafrost in this region was investigated through uniaxial compression tests on remolded silty clay under controlled freezing temperatures (− 7.5 to − 0.5 °C). Results revealed a triphasic strength-temperature relationship: strength increased at 79.99 kPa/°C between − 0.5 and − 2.0 °C, surged to 1842.00 kPa/°C from − 2.0 to − 3.0 °C, then declined to 316.20 kPa/°C below − 3.0 °C. A brittle-ductile transition occurred at − 3.0 °C, shifting failure modes from plastic to brittle deformation. Building on Lemaitre’s strain equivalence principle and Weibull statistics, we developed a dual-variable damage model integrating thermal and mechanical damage, enabling quantitative cryogenic damage assessment, coupled damage evolution equations, and full temperature-regime stress–strain predictions. This work advances theoretical tools for engineering stability evaluation in the Xing’an Baikal permafrost environments.

The outbreak of the 2022 Russia-Ukraine conflict exacerbated the natural gas supply shortage in European countries. European countries restarted coal-fired power plants to maintain economic and social operations. The uneven distribution of coal resources in the world makes coal international trade inevitable. The intricate trade relations between trading countries have formed a coal trade network. When a country’s coal exports are limited due to geopolitical factors, it will cause coal supply risks. The risk will spread to more countries along the trade network, eventually leading to the collapse of the trade network. This paper builds a crisis propagation model of the coal supply under the Russia-Ukraine conflict using the cascading failure model. The results showed that the Czech Republic, Ireland, Portugal, and Bulgaria become abnormal as the proportion of coal exports β increases. When the Russian Federation reduced its coal exports by 80% and countries maintained only 10% coal exports against crisis, 23 European countries were the worst. Iceland, Ireland, Turkey and other countries were spread by the indirect risk and became abnormal countries. The Czech Republic and Bulgaria were spread by multiple risk and became abnormal countries.

Objective To explore the mechanism of action of MicroRNAs-34a (miR-34a) and Eurite growth guiding factor 1 (Netrin1) in cisplatin resistance in gastric cancer (GC), providing new clues for overcoming tumor resistance and optimizing anti-tumor therapy for GC. Methods The Cancer Genome Atlas (TCGA), Differentially Expressed MicroRNAs (miRNAs) in human cancers (dbDEMC), and Starbase online databases were used to analyze the correlation between miR-34a and Netrin-1 and prognosis in GC, and to predict and verify the targeted binding of miR-34a to Netrin-1. The experimental methods including Cell transfection, real-time polymerase chain reaction (RT-PCR), Cell-Counting-Kit-8 (CCK8) assay, flow cytometry, wound scratch assay, transwell assay, and western blotting were used to investigate the effects of miR-34a and Netrin1 on chemotherapy resistance and biological characteristics in cisplatin-resistant GC cells (HGC27/DDP), and to analyze the molecular mechanism of cisplatin resistance. Results miR-34a expression was downregulated in gastric cancer clinical samples and cisplatin-resistant cells, while Netrin1 was upregulated, and was related to overall survival (OS). Upregulation of miR-34a can significantly reduce the IC 50 value of cisplatin(0.65 vs 1.6 ng/mL) and Multidrug Resistance 1 (MDR-1) protein level, inhibit the proliferation activity, reduce the expression levels of proliferating cell nuclear antigen (PCNA) and ki-67 protein, and induce the increase of apoptosis rate and the enhancement of cycle arrest. Upregulation of miR-34a can also significantly reduce the expression level of Matrix metalloproteinase 9 (MMP9) protein, promote the expression of E-cadherin protein, reduce the wound healing rate and invasion number to inhibit migration and invasion ability in drug-resistant gastric cancer cells. Moreover, overexpression of Netrin1 on the basis of upregulation of miR-34a can weaken the above changes caused by upregulation of miR-34a. In addition, upregulation of miR-34a can significantly inhibit the Mitogen-activated protein kinase kinase (MEK) / Extracellular regulated protein kinases (ERK) pathway, while overexpression of Netrin1 can activate the MEK/ERK pathway, and inhibition of MEK/ERK pathway can effectively counteract the protein expression of Netrin1, and reverse changes in the expression of cisplatin IC 50 and MDR-1 proteins caused by co-upregulation of miR-34a/Netrin1 in HGC27/DDP, as well as changes in proliferation, apoptosis, migration and invasion. In addition, upregulation of miR-34a can significantly inhibit the MEK/ERK pathway, while overexpression of Netrin1 can activate the MEK/ERK pathway. If the MEK/ERK pathway was inhibited, it can effectively counteract the protein overexpression of Netrin1, and reverse the changes in the expression of cisplatin IC 50 and MDR-1 proteins in HGC27/DDP induced by co-upregulation of miR-34a / Netrin1, as well as changes in proliferation, apoptosis, migration and invasion. Conclusion miR-34a targets and negatively regulates Netrin1 to mediate the proliferation, apoptosis, apoptosis, migration, and invasion of drug-resistant gastric cancer cells via the MEK/ERK pathway, and change the chemosensitivity in GC cells. miR-34a/Netrin1/MEK/ERK axis may serve as a novel therapeutic target for chemoresistance in GC, it is of great significance for overcoming drug resistance and developing new therapeutic strategies for GC.

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H 2 O 2 , an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

Quantitative assessment of donor kidney quality remains challenging in transplantation medicine. This study investigated the correlation between Shore durometer-measured renal hardness and established quality indicators (hypothermic machine perfusion [HMP] parameters and pathological scores) in deceased donor kidneys. We prospectively analyzed 58 kidneys from 29 deceased donors. Renal hardness was measured at 10 standardized locations before and after perfusion using a Shore durometer (Type OOO). HMP parameters (flow rate and resistance index [RI]) were recorded during machine perfusion, and histological assessment was performed using Remuzzi scoring. Pearson correlation analysis examined relationships between hardness parameters (pre-perfusion, post-perfusion, and perfusion-induced difference) and quality indicators. Pre-perfusion hardness correlated significantly with HMP resistance (  = 0.745,  < 0.001) and vascular damage scores (  = 0.299,  = 0.023). The perfusion-induced hardness difference showed strong negative correlations with all pathological scores (Remuzzi: =-0.602; glomerulosclerosis: =-0.517; interstitial fibrosis: =-0.454; tubular atrophy: =-0.403; vascular damage: =-0.385; all  < 0.05). Shore durometer-measured kidney hardness significantly correlates with both HMP parameters and histological scores, with perfusion-induced hardness change emerging as a particularly promising indicator of underlying pathology. These findings support incorporating quantitative hardness assessment into donor kidney evaluation protocols.

Abstract Context Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. Objective To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure. Design/Participants Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. Setting 4 international centers. Interventions/Main Outcome Measures The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. Results There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P < .0001) and nonsuppressible aldosterone production postdexamethasone (r = 0.40, P < .0001). Beyond participants who met the criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of nonsuppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy and the remainder were treated with mineralocorticoid receptor antagonists. Conclusion In the context of a low-renin phenotype, there is a continuum of primary aldosteronism and dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low renin may benefit from aldosterone-directed therapy.

Information regarding relationships between forage yield and soil enzymes of legume–grass mixtures under nitrogen (N) fertilization can guide the decision-making during sustainable forage production. The objective was to evaluate the responses of forage yield, nutritional quality, soil nutrients, and soil enzyme activities of different cropping systems under various N inputs. Alfalfa ( Medicago sativa L.), white clover ( Trifolium repens L.), orchardgrass ( Dactylis glomerata L.), and tall fescue ( Festuca arundinacea Schreb.) were grown in monocultures and mixtures (A1: alfalfa, orchardgrass, and tall fescue; A2: alfalfa, white clover, orchardgrass, and tall fescue) under three N inputs (N1: 150 kg ha −1 ; N2, 300 kg ha −1 ; and N3: 450 kg ha −1 ) in a split plot arrangement. The results highlight that A1 mixture under N2 input had a greater forage yield of 13.88 t ha −1 year −1 than the other N inputs, whereas A2 mixture under N3 input had a greater forage of 14.39 t ha −1 year −1 than N1 input, but it was not substantially greater than N2 input (13.80 t ha −1 year −1 ). The crude protein (CP) content of grass monocultures and mixtures significantly ( P < 0.05) increased with an increase in the rate of N input, and A1 and A2 mixtures under N3 input had a greater CP content of 18.91% and 18.94% dry matter, respectively, than those of grass monocultures under various N inputs. The A1 mixture under N2 and N3 inputs had a substantially greater ( P < 0.05) ammonium N content of 16.01 and 16.75 mg kg −1 , respectively, whereas A2 mixture under N3 had a greater nitrate N content of 4.20 mg kg −1 than the other cropping systems under various N inputs. The A1 and A2 mixtures under N2 input had a substantial higher ( P < 0.05) urease enzyme activity of 0.39 and 0.39 mg g −1 24 h −1 and hydroxylamine oxidoreductase enzyme activity of 0.45 and 0.46 mg g −1 5 h −1 , respectively, than the other cropping systems under various N inputs. Taken together, growing legume–grass mixtures under N2 input is cost-effective, sustainable, and eco-friendly, which provide greater forage yield and improved nutritional quality by the better utilization of resources.

Background Family caregivers of elderly patients with spinal tumours experience considerable pain and burden during the care process. This study aims to investigate the factors associated with caregiver burden in family caregivers of elderly patients with spinal tumours. Methods A total of 220 elderly patients with spinal tumours (age ≥ 65 years) hospitalized at the spine centre of our hospital from January 2015 to December 2017 and their family caregivers were recruited for this cross-sectional study. All participants completed a sociodemographic questionnaire. Caregiver burden, social support and self-efficacy were assessed by the Chinese version of the Zarit Burden Interview (ZBI), the Social Support Rating Scale (SSRS) and the General Self-Efficacy Scale (GSE), respectively. The factors related to caregiver burden were analysed by multivariate analysis. P  < 0.05 was considered statistically significant. Results The 216 elderly patients with spinal tumours were 71.59 ± 8.49 years old, and their caregivers were 70.46 ± 9.13 years old. A total of 170 patients were cared for by their spouses, who accounted for 78.7% of all caregivers. The ZBI score for the family caregivers was 35.5 ± 7.5, and most caregivers (84.5%) reported a moderate or heavy burden. The factors related to caregiver burden included patient paralysis, the primary cancer site, chemotherapy and/or radiation, cognitive dysfunction, functional status, monthly income, pain score, caregivers’ SSRS score, and GSE score. Conclusions Most family caregivers of elderly patients with spinal tumours have a considerable caregiver burden. Interventions based on social support and self-efficacy can help reduce caregiver burden.