ABSCISIC ACID-INSENSITIVE 5-KIP-RELATED PROTEIN 1-SHOOT MERISTEMLESS modulates reproductive development of Arabidopsis.

Soil (or plant) water deficit accelerates plant reproduction. However, the underpinning molecular mechanisms remain unknown. By modulating cell division/number, ABSCISIC ACID-INSENSITIVE 5 (ABI5), a key bZIP (basic (region) leucine zippers) transcription factor, regulates both seed development and abiotic stress responses. The KIP-RELATED PROTEIN (KRP) cyclin-dependent kinases (CDKs) play an essential role in controlling cell division, and SHOOT MERISTEMLESS (STM) plays a key role in the specification of flower meristem identity. Here, our findings show that abscisic acid (ABA) signaling and/or metabolism in adjust reproductive outputs (such as rosette leaf number and open flower number) under water-deficient conditions in Arabidopsis (Arabidopsis thaliana) plants. Reproductive outputs increased under water-sufficient conditions but decreased under water-deficient conditions in the ABA signaling/metabolism mutants abscisic acid2-1 (aba2-1), aba2-11, abscisic acid insensitive3-1 (abi3-1), abi4-1, abi5-7, and abi5-8. Further, under water-deficient conditions, ABA induced-ABI5 directly bound to the promoter of KRP1, which encodes a CDK that plays an essential role in controlling cell division, and this binding subsequently activated KRP1 expression. In turn, KRP1 physically interacted with STM, which functions in the specification of flower meristem identity, promoting STM degradation. We further demonstrate that reproductive outputs are adjusted by the ABI5-KRP1-STM molecular module under water-deficient conditions. Together, our findings reveal the molecular mechanism by which ABA signaling and/or metabolism regulate reproductive development under water-deficient conditions. These findings provide insights that may help guide crop yield improvement under water deficiency.

Multimodal neuroimaging network associated with executive function in adolescent major depressive disorder patients via cognition-guided magnetic resonance imaging fusion.

Adolescents are high-risk population for major depressive disorder. Executive dysfunction emerges as a common feature of depression and exerts a significant influence on the social functionality of adolescents. This study aimed to identify the multimodal co-varying brain network related to executive function in adolescent with major depressive disorder. A total of 24 adolescent major depressive disorder patients and 43 healthy controls were included and completed the Intra-Extra Dimensional Set Shift Task. Multimodal neuroimaging data, including the amplitude of low-frequency fluctuations from resting-state functional magnetic resonance imaging and gray matter volume from structural magnetic resonance imaging, were combined with executive function using a supervised fusion method named multimodal canonical correlation analysis with reference plus joint independent component analysis. The major depressive disorder showed more total errors than the healthy controls in the Intra-Extra Dimensional Set Shift task. Their performance on the Intra-Extra Dimensional Set Shift Task was negatively related to the 14-item Hamilton Rating Scale for Anxiety score. We discovered an executive function-related multimodal fronto-occipito-temporal network with lower amplitude of low-frequency fluctuation and gray matter volume loadings in major depressive disorder. The gray matter component of the identified network was negatively related to errors made in Intra-Extra Dimensional Set Shift while positively related to stages completed. These findings may help to deepen our understanding of the pathophysiological mechanisms of cognitive dysfunction in adolescent depression.

Robust and Multifunctional Ti3 C2 Tx /Modified Sawdust Composite Paper for Electromagnetic Interference Shielding and Wearable Thermal Management.

Robust, ultrathin, and environmental-friendliness papers that synergize high-efficiency electromagnetic interference (EMI) shielding, personal thermal management, and wearable heaters are essential for next-generation smart wearable devices. Herein, MXene nanocomposite paper with a nacre-like structure for EMI shielding and electrothermal/photothermal conversion is fabricated by vacuum filtration of Ti3 C2 Tx MXene and modified sawdust. The hydrogen bonding and highly oriented structure enhance the mechanical properties of the modified sawdust/MXene composite paper (SM paper). The SM paper with 50 wt% MXene content shows a strength of 23 MPa and a toughness of 13 MJ·M-3 . The conductivity of the SM paper is 10 195 S·m-1 , resulting in an EMI shielding effectiveness (SE) of 67.9 dB and a specific SE value (SSE/t) of 8486 dB·cm2 ·g-1 . In addition, the SM paper exhibits excellent thermal management performance including high light/electro-to-thermal conversion, rapid Joule heating and photothermal response, and sufficient heating stability. Notably, the SM paper exhibits low infrared emissivity and distinguished infrared stealth performance, camouflaging a high-temperature heater surface of 147-81 °C. The SM-based e-skin achieves visualization of Joule heating and realizes human motions monitoring. This work presents a new strategy for designing MXene-based wearable devices with great EMI shielding, artificial intelligence, and thermal management applications.

CcNFYB3-CcMATE35 and LncRNA CcLTCS-CcCS modules jointly regulate the efflux and synthesis of citrate to enhance aluminium tolerance in pigeon pea.

Aluminium (Al) toxicity decreases crop production in acid soils in general, but many crops have evolved complex mechanisms to resist it. However, our current understanding of how plants cope with Al stress and perform Al resistance is still at the initial stage. In this study, the citrate transporter CcMATE35 was identified to be involved in Al stress response. The release of citrate was increased substantially in CcMATE35 over-expression (OE) lines under Al stress, indicating enhanced Al resistance. It was demonstrated that transcription factor CcNFYB3 regulated the expression of CcMATE35, promoting the release of citrate from roots to increase Al resistance in pigeon pea. We also found that a Long noncoding RNA Targeting Citrate Synthase (CcLTCS) is involved in Al resistance in pigeon pea. Compared with controls, overexpression of CcLTCS elevated the expression level of the Citrate Synthase gene (CcCS), leading to increases in root citrate level and citrate release, which forms another module to regulate Al resistance in pigeon pea. Simultaneous overexpression of CcNFYB3 and CcLTCS further increased Al resistance. Taken together, these findings suggest that the two modules, CcNFYB3-CcMATE35 and CcLTCS-CcCS, jointly regulate the efflux and synthesis of citrate and may play an important role in enhancing the resistance of pigeon pea under Al stress.

Glucose status within dark-grown etiolated cotyledons determines seedling de-etiolation upon light irradiation.

Exposure of dark-grown etiolated seedlings to light triggers the transition from skotomorphogenesis/etiolation to photomorphogenesis/de-etiolation. In the life cycle of plants, de-etiolation is essential for seedling development and plant survival. The mobilization of soluble sugars (glucose [Glc], sucrose, and fructose) derived from stored carbohydrates and lipids to target organs, including cotyledons, hypocotyls, and radicles, underpins de-etiolation. Therefore, dynamic carbohydrate biochemistry is a key feature of this phase transition. However, the molecular mechanisms coordinating carbohydrate status with the cellular machinery orchestrating de-etiolation remain largely opaque. Here, we show that the Glc sensor HEXOKINASE 1 (HXK1) interacts with GROWTH REGULATOR FACTOR5 (GRF5), a transcriptional activator and key plant growth regulator, in Arabidopsis (Arabidopsis thaliana). Subsequently, GRF5 directly binds to the promoter of phytochrome A (phyA), encoding a far-red light (FR) sensor/cotyledon greening inhibitor. We demonstrate that the status of Glc within dark-grown etiolated cotyledons determines the de-etiolation of seedlings when exposed to light irradiation by the HXK1-GRF5-phyA molecular module. Thus, following seed germination, accumulating Glc within dark-grown etiolated cotyledons stimulates a HXK1-dependent increase of GRF5 and an associated decrease of phyA, triggering the perception, amplification, and relay of HXK1-dependent Glc signaling, thereby facilitating the de-etiolation of seedlings following light irradiation. Our findings, therefore, establish how cotyledon carbohydrate signaling under subterranean darkness is sensed, amplified, and relayed, determining the phase transition from skotomorphogenesis to photomorphogenesis on exposure to light irradiation.

MRI-based radiomics nomogram for distinguishing solitary fibrous tumor from schwannoma in the orbit: a two-center study.

OBJECTIVES: To investigate the value of magnetic resonance imaging (MRI) radiomics for distinguishing solitary fibrous tumor (SFT) from schwannoma in the orbit. MATERIALS AND METHODS: A total of 140 patients from two institutions were retrospectively included. All patients from institution 1 were randomized into a training cohort (n = 69) and a validation cohort (n = 35), and patients from institution 2 were used as an external testing cohort (n = 36). One hundred and six features were extracted from T2-weighted imaging (T2WI) and contrast-enhanced T1-weighted imaging (CET1WI). A radiomics model was built for each sequence using least absolute shrinkage and selection operator logistic regression, and radiomics scores were calculated. A combined model was constructed and displayed as a radiomics nomogram. Two radiologists jointly assessed tumor category based on MRI findings. The performances of the radiomics models and visual assessment were compared via area under the curve (AUC). RESULTS: The performances of the radiomics nomogram combining T2WI and CET1WI radiomics scores were superior to those of the pooled readers in the training (AUC 0.986 vs. 0.807, p < 0.001), validation (AUC 0.989 vs. 0.788, p = 0.009), and the testing (AUC 0.903 vs. 0.792, p = 0.093), although significant difference was not found in the testing cohort. Decision curve analysis demonstrated that the radiomics nomogram had better clinical utility than visual assessment. CONCLUSION: MRI radiomics nomogram can be used for distinguishing between orbital SFT and schwannoma, which may help tumor management by clinicians. CLINICAL RELEVANCE STATEMENT: It is of great importance and challenging for distinguishing solitary fibrous tumor from schwannoma in the orbit. In the present study, an MRI-based radiomics nomogram were developed and independently validated, which could help the discrimination of the two entities. KEY POINTS: • It is challenging to differentiate solitary fibrous tumor from schwannoma in the orbit due to similar clinical and image features. • A radiomics nomogram based on T2-weighted imaging and contrast-enhanced T1-weighted imaging has advantages over radiologists. • Radiomics can provide a non-invasive diagnostic tool for differentiating between the two entities.

Molecular characterization of Blastocystis spp. in Hotan Black chickens in southern Xinjiang.

To determine the infection status and assess the zoonotic potential of Blastocystis spp. in Hotan Black chickens in southern Xinjiang, China, fecal samples were collected from 617 chickens on 18 large-scale farms. The presence of Blastocystis spp. was determined using polymerase chain reaction based on the small subunit rRNA (SSU rRNA) locus. The results revealed an overall infection rate of 26.3% (162/617). Samples from Farm 1 in Luopu County showed the highest infection rate (76.3%, 29/38). The highest and lowest infection rates were detected in the <30-day (34.4%, 43/125) and > 90-day age groups (12.4%, 11/89), respectively. The infection rate decreased with increasing age. Statistical analysis showed significant differences in the infection rates of Blastocystis spp. among the different sampling sites (p < 0.05) and age groups (p < 0.05). Four Blastocystis spp. subtypes (ST6, ST7, ST10, and ST23) were identified. The infection rates of the zoonotic subtypes, ST6 and ST7, were 3.2% (20/617) and 22.2% (137/617), respectively. The presence of Blastocystis spp. and zoonotic subtypes provided evidence for the potential transmission of this pathogen between Hotan Black chickens and humans, especially in animal handlers in this area.

Analysis of the initial orbital MRI in aquaporin-4 antibody-positive optic neuritis (AQP4-ON): lesion location and lesion length can be predictive of visual prognosis.

PURPOSE: Despite mounting evidence indicating that aquaporin-4 antibody-positive optic neuritis (AQP4-ON) presents a less favorable prognosis than other types of optic neuritis, there exists substantial heterogeneity in the prognostic outcomes within the AQP4-ON cohort. Considering the persistent debate over the role of MRI in assessing the prognosis of optic neuritis, we aim to investigate the correlation between the MRI appearance and long-term visual prognosis in AQP4-ON patients. METHODS: We retrospectively reviewed the ophthalmological and imaging data of AQP4-ON patients admitted to our Neuro-ophthalmology Department from January 2015 to March 2018, with consecutive follow-up visits for a minimum of 3 years. RESULTS: A total of 51 AQP4-ON patients (59 eyes) meeting the criteria were enrolled in this research. After assessing the initial orbital MR images of each patient at the first onset, we observed the involvement of the canalicular segment (p < 0.001), intracranial segment (p = 0.004), optic chiasm (p = 0.009), and the presence of LEON (p = 0.002) were significantly different between recovery group and impairment group. For quantitative measurement, the length of the lesions is significantly higher in the impairment group (20.1 ± 9.3 mm) than in the recovery group (12.5 ± 5.3 mm) (p = 0.001). CONCLUSION: AQP4-ON patients with involvement of canalicular, intracranial segment and optic chiasm of the optic nerve, and the longer range of lesions threaten worse vision prognoses. Timely MR examination during the initial acute phase can not only exclude the intracranial or orbital mass lesions but also indicate visual prognosis in the long term.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Molecular detection and genetic characteristics of Giardia duodenalis in dairy cattle from large-scale breeding farms in Xinjiang, China.

Giardia duodenalis is an intestinal protozoan that can infect both humans and animals, leading to public health issues and economic losses in the livestock industry. G. duodenalis has been reported to infect dairy cattle, but there is limited information available on large-scale dairy farms in Xinjiang, China. The study collected 749 fresh faecal samples from five large-scale cattle farms in Xinjiang, China. The study used a nested PCR assay of the small subunit ribosomal RNA (SSU rRNA*) gene to determine the presence of G. duodenalis. The results showed that 24.0% (180/749) of dairy cattle were positive for G. duodenalis, with the highest infection rate observed in pre-weaned calves (45.1%, 69/153). Among the 180 G. duodenalis positive samples, three assemblages were identified: assemblage E (n = 176), assemblage A (n = 3) and assemblage B (n = 1). Sixty-nine, 67 and 49 sequences were obtained for the beta-giardin (bg*) gene, the glutamate dehydrogenase (gdh*) gene and the triose phosphate isomerase (tpi*) gene, respectively. Thirteen novel sequences of assemblage E were identified, including five sequences from the bg* gene, four sequences from the gdh* gene and four sequences from the tpi* gene. This study found that 32 G. duodenalis assemblage E isolates formed 26 MLGs, indicating genetic variation and geographic isolation-based differentiation in bovine-derived G. duodenalis assemblage E. These findings provide fundamental insights into the genetic diversity of G. duodenalis in dairy cattle and can aid in the prevention and control of its occurrence in large-scale dairy cattle farms.

Molecular detection of Cryptosporidium in Alpine musk deer (Moschus chrysogaster) in Gansu Province, Northwest China.

Cryptosporidium spp. are protozoa commonly found in domestic and wild animals. Limited information is available on Cryptosporidium in deer worldwide. In this study, 201 fecal samples were collected from Alpine musk deer on three farms in Gansu Province, China. Detection and subtyping of Cryptosporidium were performed by PCR and sequence analysis of the SSU rRNA and gp60 genes. The prevalence of Cryptosporidium infection in Alpine musk deer was 3.9% (8/201), with infection rates of 1.0% (1/100), 2.8% (1/36), and 9.2% (6/65) in three different farms. All positive samples for Cryptosporidium were from adult deer. Two Cryptosporidium species were identified, including C. parvum (n = 2) and C. xiaoi (n = 6). The C. parvum isolates were subtyped as IIdA15G1, while the C. xiaoi isolates were subtyped as XXIIIa (n = 2) and XXIIIg (n = 4). The IIdA15G1 subtype of C. parvum was found for the first time in deer. These results provide important insights into the identity and human infectious potential of Cryptosporidium in farmed Alpine musk deer.

How does diagnosis-related group payment impact the health care received by rural residents? Lessons learned from China.

OBJECTIVES: There is growing evidence that differences exist between rural and urban residents in terms of health, access to care and the quality of health care received, especially in low- and middle-income countries (LMICs). To improve health equity and the performance of health systems, a diagnosis-related group (DRG) payment system has been introduced in many LMICs to reduce financial risk and improve the quality of health care. The aim of this study was to examine the impact of DRG payments on the health care received by rural residents in China, and to help policymakers identify and design implementation strategies for DRG payment systems for rural residents in LMICs. STUDY DESIGN: Health impact assessment. METHODS: This study compared the impact of DRG payments on the healthcare received by rural residents in China between the pre- and post-reform periods by applying a difference-in-difference (DID) methodology. The study population included individuals with three common conditions; namely, cerebral infarction, transient ischaemic attack (TIA), and vertebrobasilar insufficiency (VBI). Data on patient medical insurance type were assessed, and those who did not have rural insurance were excluded. RESULTS: This study included 13,088 patients. In total, 33.63% were from Guangdong (n = 4401), 38.21% were from Shandong (n = 5002), and 28.16% were from Guangxi (n = 3685). The DID results showed that the implementation of DRGs was positively associated with hospitalization expense (ß4 = 0.265, P = 0.000), treatment expense (ß4 = 0.343, P = 0.002), drug expense (ß4 = 0.607, P = 0.000), the spending of medical insurance funds (ß4 = 0.711, P = 0.000) and out-of-pocket costs (ß4 = 0.164, P = 0.000). CONCLUSIONS: The findings of this study suggest that the implementation of DRG payments increases health care costs and the financial burden on health systems and rural patients in LMICs. This is contrary to the original intention of implementing the DRG payment system.

Probing the Atomistic Reaction Pathways in CuO/C Catalysts.

CuOx/C catalysts have been used in the selective catalytic reduction of NOx because of the exceptional low-temperature denitration (de-NOx) activity. A fundamental understanding of the reaction between CuO and C is critical for controlling the component of CuOx/C and thus optimizing the catalytic performance. In this study, a transmission electron microscope equipped with an in situ heating device was utilized to investigate the atomic-scale reaction between CuO and C. We report two reaction mechanisms relying on the volume ratio between C and CuO: (1) The reduction from CuO to Cu2O (when the ratio is < ∼31%); (2) the reduction of CuO into polycrystalline Cu (when the ratio is > ∼34%). The atomistic reduction pathway can be well interpreted by considering the diffusion of O vacancy through the first-principle calculations. The atomic-scale exploration of CuO/C offers ample prospects for the design of industrial de-NOx catalysts in the future.

Analysis of morphology, histology characteristics, and circadian clock gene expression of Onychostoma macrolepis at the overwintering period and the breeding period.

Fish typically adapt to their environment through evolutionary traits, and this adaptive strategy plays a critical role in promoting species diversity. Onychostoma macrolepis is a rare and endangered wild species that exhibits a life history of overwintering in caves and breeding in mountain streams. We analyzed the morphological characteristics, histological structure, and expression of circadian clock genes in O. macrolepis to elucidate its adaptive strategies to environmental changes in this study. The results showed that the relative values of O. macrolepis eye diameter, body height, and caudal peduncle height enlarged significantly during the breeding period. The outer layer of the heart was dense; the ventricular myocardial wall was thickened; the fat was accumulated in the liver cells; the red and white pulp structures of the spleen, renal tubules, and glomeruli were increased; and the goblet cells of the intestine were decreased in the breeding period. In addition, the spermatogenic cyst contained mature sperm, and the ovaries were filled with eggs at various stages of development. Throughout the overwintering period, the melano-macrophage center is located between the spleen and kidney, and the melano-macrophage center in the cytoplasm has the ability to synthesize melanin, and is arranged in clusters to form cell clusters or white pulp scattered in it. Circadian clock genes were identified in all organs, exhibiting significant differences between the before/after overwintering period and the breeding period. These findings indicate that the environment plays an important role in shaping the behavior of O. macrolepis, helping the animals to build self-defense mechanisms during cyclical habitat changes. Studying the morphological, histological structure and circadian clock gene expression of O. macrolepis during the overwintering and breeding periods is beneficial for understanding its unique hibernation behavior in caves. Additionally, it provides an excellent biological sample for investigating the environmental adaptability of atypical cavefish species.

Synergistic Effect of Fe Single-Atom Catalyst for Highly Efficient Microwave-Stimulated Remediation of Chloramphenicol-Contaminated Soil.

Chloramphenicol (CAP) has long been used extensively in agriculture and is severely toxic to the biological environment. Microwave catalysis appears a promising method for soil remediation due to its fast and effective heat transfer, but it is challenging to prepare catalysts with good electromagnetic wave absorption and robust catalytic activity. In this study, atomically dispersed Fe on three-dimensional N-doped carbon supports (3D Fe-NC) is firstly used for microwave remediation of soil. Thanks to the synergistic effect of microwave "hot spots" and reactive oxygen species (•OH, •O2 - ), 3D Fe-NC can completely remove 99.9% of CAP in 5 min. The removal rate constant is nearly twice that of commercial activated carbon. Significantly, the germination rate of lettuce seeds in microwave-repaired soil contaminated by CAP reaches 70%. This work demonstrates the application of Fe single-atom catalyst in microwave remediation of contaminated soil, providing a novel insight for agricultural soil remediation.

Integrated transcriptome and physiological analysis revealed core transcription factors that promote flavonoid biosynthesis in apricot in response to pathogenic fungal infection.

MAIN CONCLUSION: Integrated transcriptome and physiological analysis of apricot leaves after Fusarium solani treatment. In addition, we identified core transcription factors and flavonoid-related synthase genes which may function in apricot disease resistance. Apricot (Prunus armeniaca) is an important economic fruit species, whose yield and quality of fruit are limited owing to its susceptibility to diseases. However, the molecular mechanisms underlying the response of P. armeniaca to diseases is still unknown. In this study, we used physiology and transcriptome analysis to characterize responses of P. armeniaca subjected to Fusarium solani. The results showed increasing malondialdehyde (MDA) content, enhanced peroxidase (POD) and catalase (CAT) activity during F. solani infestation. A large number of differentially expressed genes (DEGs), which included 4281 upregulated DEGs and 3305 downregulated DEGs, were detected in P. armeniaca leaves exposed to F. solani infestation. Changes in expression of transcription factors (TFs), including bHLH, AP2/ERF, and WRKY indicated their role in triggering pathogen-responsive genes in P. armeniaca. During the P. armeniaca response to F. solani infestation, the content of total flavonoid was changed, and we identified enzyme genes associated with flavonoid biosynthesis. Ectopic overexpression of PabHLH15 and PabHLH102 in Nicotiana benthamiana conferred elevated resistance to Fspa_1. Moreover, PabHLH15 and PabHLH102 positively interact with the promoter of flavonoid biosynthesis-related genes. A regulatory network of TFs regulating enzyme genes related to flavonoid synthesis affecting apricot disease resistance was constructed. These results reveal the potential underlying mechanisms of the F. solani response of P. armeniaca, which would help improve the disease resistance of P. armeniaca and may cultivate high-quality disease-resistant varieties in the future.

SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy.

OBJECTIVES: The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. METHODS: We applied empagliflozin treatment to lupus-prone MRL/lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. RESULTS: In MRL/lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. CONCLUSION: This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.

Glyphosate induces autophagy in hepatic L8824 cell line through NO-mediated activation of RAS/RAF/MEK/ERK signaling pathway and energy metabolism disorders.

Glyphosate is an herbicide commonly used worldwide, and its substantial use causes widespread pollution with runoff. However, research on glyphosate toxicity has mostly remained at the embryonic level and existing studies are limited. In the present study, we investigated whether glyphosate can induce autophagy in hepatic L8824 cells by regulating energy metabolism and rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular regulated protein kinases (ERK) signaling by activating nitric oxide (NO). First, we selected 0, 50, 200, and 500 µg/mL as the challenge doses, according to the inhibitory concentration of 50% (IC50) of glyphosate. The results showed that glyphosate exposure increased the enzyme activity of inducible nitric oxide synthase (iNOS), which in turn increased the NO content. The activity and expression of enzymes related to energy metabolism, such as hexokinase (HK)1, HK2, phosphofructokinase (PFK), phosphokinase (PK), succinate dehydrogenase (SDH), and nicotinamide adenine dinucleotide with hydrogen (NADH), were inhibited, and the RAS/RAF/MEK/ERK signaling pathway was activated. This led to the negative expression of mammalian target of rapamycin (mTOR) and P62 in hepatic L8824 cells and the activation of the autophagy marker genes microtubule-associated proteins light chain 3 (LC3) and Beclin1 to induce autophagy. The above results were dependent on glyphosate concentration. To verify whether autophagy can be excited by the RAS/RAF/MEK/ERK signaling pathway, we treated L8824 cells with the ERK inhibitor U0126 and found that the autophagy gene LC3 was reduced due to the inhibition of ERK, thus demonstrating the reliability of the results. In conclusion, our results demonstrate that glyphosate can induce autophagy in hepatic L8824 cells by activating NO, thus regulating energy metabolism and the RAS/RAF/MEK/ERK signaling pathway.

Lake Sediment Archive Reveals a Distinct Response to Anthropogenic Pb and Zn Deposition with Historical Periods: Pb-Zn Isotope Evidence.

Anthropogenic activities release large quantities of heavy metals into the atmosphere. In China, the input of these heavy metals through local and trans-boundary atmospheric deposition is poorly understood. To assess this issue, herein, we use Pb and Zn isotopes to constrain the sources of Pb and Zn in a 210Pb-dated sediment core collected from the enclosed lake in South China. We observed a progressive shift toward higher 208Pb/206Pb and Pb fluxes (0.79-4.02 µg·cm-2·a-1) from 1850 to 1950 and a consistent decrease in δ66ZnIRMM (as low as -0.097 ± 0.030‰) coupled with an increase in Pb (1.74-3.36 µg·cm-2·a-1) and Zn (8.07-10.44 µg·cm-2·a-1) fluxes after 1980. These distinguished isotopic signals and flux variations reveal the presence of trans-boundary Pb since 1900, with the addition of local industrial Pb and Zn pollution after 1980. Up to 72.3% of Pb deposited at our site can be attributed to long-distance transportation from previously industrialized countries, resulting in a noteworthy legacy of Pb in China since 1900. Despite the phasing out of leaded gasoline, Chinese gasoline still contributes an average of 20.9%. The contribution of China's mining and smelting activities to Pb has increased steadily since 1980 and remained stable at an average of 25.1% since 2000.

ß-arrestin2 deficiency ameliorates S-100-induced autoimmune hepatitis in mice by inhibiting infiltration of monocyte-derived macrophage and attenuating hepatocyte apoptosis.

Autoimmune hepatitis (AIH) is a progressive hepatitis syndrome characterized by high transaminase levels, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies. Misdiagnosis or delayed treatment of AIH can lead to cirrhosis or liver failure, which poses a major risk to human health. ß-Arrestin2, a key scaffold protein for intracellular signaling pathways, has been found to be involved in many autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. However, whether ß-arrestin2 plays a role in AIH remains unknown. In the present study, S-100-induced AIH was established in both wild-type mice and ß-arrestin2 knockout (Arrb2 KO) mice, and the experiments identified that liver ß-arrestin2 expression was gradually increased, and positively correlated to serum ANA, ALT and AST levels during AIH progression. Furthermore, ß-arrestin2 deficiency ameliorated hepatic pathological damage, decreased serum autoantibody and inflammatory cytokine levels. ß-arrestin2 deficiency also inhibited hepatocyte apoptosis and prevented the infiltration of monocyte-derived macrophages into the damaged liver. In vitro experiments revealed that ß-arrestin2 knockdown suppressed the migration and differentiation of THP-1 cells, whereas ß-arrestin2 overexpression promoted the migration of THP-1 cells, which was regulated by the activation of the ERK and p38 MAPK pathways. In addition, ß-arrestin2 deficiency attenuated TNF-α-induced primary hepatocyte apoptosis by activating the Akt/GSK-3ß pathway. These results suggest that ß-arrestin2 deficiency ameliorates AIH by inhibiting the migration and differentiation of monocytes, decreasing the infiltration of monocyte-derived macrophages into the liver, thereby reducing inflammatory cytokines-induced hepatocytes apoptosis. Therefore, ß-arrestin2 may act as an effective therapeutic target for AIH.