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Abstract Objective Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. Method Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. Result Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. Conclusion The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a leading public health problem worldwide. Approximately one fourth of patients with nonalcoholic fatty liver (NAFL) progress to nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD. Hence, there is an urgent need to make a better understanding of NAFLD heterogeneity and facilitate personalized management of high-risk NAFLD patients who may benefit from more intensive surveillance and preventive intervene. Methods In this study, a series of bioinformatic methods were performed to identify NAFLD progression-specific pathways and genes, and three machine learning approaches were combined to construct a risk-stratification gene signature to quantify risk assessment. In addition, bulk RNA-seq, single-cell RNA-seq (scRNA-seq) transcriptome profiling data and whole-exome sequencing (WES) data were comprehensively analyzed to reveal the genomic alterations and altered pathways between distinct molecular subtypes. Results Two distinct subtypes of NAFL were identified with the NAFLD progression-specific genes, and one subtype has a high similarity of the inflammatory pattern and fibrotic potential with NASH. The established risk-stratification gene signature could discriminate advanced samples from overall NAFLD. COL1A2, one key gene closely related to NAFLD progression, is specifically expressed in fibroblasts involved in hepatocellular carcinoma (HCC), and significantly correlated with EMT and angiogenesis in pan-cancer. Moreover, the β-catenin/COL1A2 axis might play a critical role in fibrosis severity and inflammatory response during NAFLD-HCC progression. Conclusion In summary, our study provided evidence for the necessity of molecular classification and established a risk-stratification gene signature to quantify risk assessment of NAFLD, aiming to identify different risk subsets and to guide personalized treatment.

Abstract Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens of chronic liver disease worldwide. Currently, the research mechanism is not clear, and there is no specific targeted drug for direct treatment. Phosphorylation is widely regarded as the most common type of protein modification, closely linked to steatotic liver disease in previous studies. However, there is no systematic review to clarify the relationship and investigate from the perspective of phosphorylation. Phosphorylation has been found to mainly regulate molecule stability, affect localization, transform molecular function, and cooperate with other protein modifications. Among them, adenosine 5’-monophosphate-activated protein kinase (AMPK), serine/threonine kinase (AKT), and nuclear factor kappa-B (NF-kB) are considered the core mechanisms in steatotic liver disease. As to treatment, lifestyle changes, prescription drugs, and herbal ingredients can alleviate symptoms by influencing phosphorylation. It demonstrates the significant role of phosphorylation as a mechanism occurrence and a therapeutic target in steatotic liver disease, which could be a new star for future exploration.

Abstract Background and aims Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2−/− mice) and elucidate the underlying mechanisms. Methods Mdr2−/−mice (12–14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC–MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing. Results BBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota. Conclusion BBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.

Background: Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes, with the incidence rate increasing yearly, which is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease. Abelmoschus Manihot capsule, as a proprietary Chinese patent medicine, is widely used for treating CKD in China. Currently, the combination of Abelmoschus Manihot (AM) capsule and renin-angiotensin-aldosterone system inhibitor (RASI) has gained popularity as a treatment option for DKD, with more and more randomized control trials (RCTs) in progress. However, the high-quality clinical evidence supporting its application in DKD is still insufficient.Aim of the study: To comprehensively and systematically evaluate the efficacy and safety of AM capsule combined with RASI in the treatment of DKD.Materials and methods: English and Chinese databases such as Pubmed, Cochrane Library, Embase, CNKI, SinoMed, WF, and VIP were searched to collect the RCTs of AM capsule in treatment of DKD. Then Two investigators independently reviewed and extracted data from the RCTs which met the inclusion criteria. The quality of the data was assessed using the Cochrane risk of bias assessment tool, and meta-analysis was performed using RevMan 5.4 software.Results: 32 RCTs with a total of 2,881 DKD patients (1,442 in the treatment group and 1,439 in the control group) were included. The study results showed that AM capsule combined with RASI could be more effective in decreasing 24h-UTP [MD = −442.05, 95% CI (−609.72, −274.38), p < 0.00001], UAER [MD = −30.53, 95% CI (−39.10, −21.96), p < 0.00001], UACR [MD = −157.93, 95% CI (−288.60, −27.25), p < 0.00001], Scr [MD = −6.80, 95% CI (−9.85, −3.74), p < 0.0001], and BUN [MD = −0.59, 95% CI (−1.07, −0.12), p = 0.01], compared to using RASI alone. According to the subgroup analyses, the combination of AM and ARB seems to be more effective in reducing UAER than the combination of ACEI, and the addition of AM may achieve a more significant clinical effect on decreasing Scr for DKD patients with 24h-UTP>2 g or Scr>110–133 μmol/L and >133 μmol/L. Furthermore, no additional adverse reactions were observed in the combination group [OR = 1.06; 95%CI: (0.66, 1.69), p = 0.82].Conclusion: Combining AM with RASI may be a superior strategy for DKD treatment compared to RASI monotherapy. However, due to significant heterogeneity, the results should be interpreted with great caution, and more high-quality RCTs with multi-centers, different stages of DKD, large sample sizes, and long follow-up periods are still needed to improve the evidence quality of AM for DKD in the future.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/#recordDetails; Identifier CRD42022351422

ObjectiveWe aimed to explore the value of Huobahuagen tablet (HBT) in improving decreased renal function for patients with diabetic kidney disease (DKD) over time.MethodsThis was a single-center, retrospective, real-world study on eligible 122 DKD patients who continued to use HBT + Huangkui capsule (HKC) therapy or HKC therapy without interruption or alteration in Jiangsu Province Hospital of Chinese Medicine from July 2016 to March 2022. The primary observation outcomes included estimated glomerular filtration rate (eGFR) at baseline and 1-, 3-, 6-, 9-, and 12-month follow-up visits and changes in eGFR from baseline (ΔeGFR). Propensity score (PS) and inverse probability treatment weighting (IPTW) were used to control for confounders.ResultseGFR was significantly higher in the HBT + HKC group than in the HKC alone group at the 6-, 9-, and 12-month follow-up visits (p = 0.0448, 0.0002, and 0.0037, respectively), indicating the superiority of HBT + HKC over HBT alone. Furthermore, the ΔeGFR of the HBT + HKC group was significantly higher than that of the HKC alone group at the 6- and 12-month follow-up visits (p = 0.0369 and 0.0267, respectively). In the DKD G4 patients, eGFR was higher in the HBT + HKC group at the 1-, 3-, 6-, 9-, and 12-month follow-up visits compared with baseline, with statistically significant differences at the 1-, 3-, and 6- month follow-up visits (p = 0.0256, 0.0069, and 0.0252, respectively). The fluctuations in ΔeGFR ranged from 2.54 ± 4.34 to 5.01 ± 5.55 ml/min/1.73 m2. Change in the urinary albumin/creatinine ratio from baseline did not exhibit a significant difference between the two groups at any of the follow-up visits (p > 0.05 for all). Adverse event incidence was low in both groups.ConclusionThe findings of this study based on real-world clinical practice indicate that HBT + HKC therapy exhibited better efficacy in improving and protecting renal function with a favorable safety profile than HKC therapy alone. However, further large-scale prospective randomized controlled trials are warranted to confirm these results.

[Objectives] To evaluate the clinical efficacy and safety of Kunkui Kidney Preserving Paste in the treatment of diabetic kidney disease (DKD) patients with damp-heat stasis syndrome in the clinical proteinuria stage. [Methods] Retrospective analysis was made on 30 patients with DKD who were diagnosed with damp-heat stasis syndrome in the clinical proteinuria stage from March 2021 to March 2023 in Jiangsu Province Hospital of Chinese Medicine, and who took Kunkui Kidney Preserving Paste continuously for six months. The urinary albumin/creatinine ratio (UACR), urinary complement C3, and urea nitrogen (BUN) of DKD patients before and after treatment were compared, and estimated glomerular filtration rate (eGFR), blood creatinine (Scr), and cystatin C (CysC) were estimated, and the therapeutic effects on renal function and urinary protein were evaluated. [Results] After treatment, UACR significantly decreased (P<0.01), and urinary complement C3 and Scr decreased (P<0.05), while other indicators showed no significant statistical difference (P>0.05). In terms of evaluating the efficacy of urinary protein therapy, 8 cases showed recent relief; 8 cases showed significant effect; 9 cases were effective, and 5 cases were invalid after treatment, with a total effective rate of 83.33%. In terms of renal function efficacy evaluation, 8 cases showed significant effect; 4 cases were effective; 11 cases were stable, and 7 cases were invalid, with a total effective rate of 76.67%. In the safety evaluation, there were no obvious adverse reactions. [Conclusions] The Kunkui Kidney Preserving Past has significant clinical efficacy and safety in treating DKD patients with damp-heat stasis syndrome in the clinical proteinuria period. It has significant advantages in reducing urinary protein and protecting renal function, which is worthy of clinical promotion. [ABSTRACT FROM AUTHOR]

To explore the effect of temperature on the phase transformation of HCP→FCC during compression, the uniaxial compression process of AZ31 magnesium alloy was simulated by the molecular dynamics method, and the changes of crystal structure and dislocation evolution were observed. The effects of temperature on mechanical properties, crystal structure, and dislocation evolution of magnesium alloy during compression were analyzed. It is concluded that some of the Shockley partial dislocation is related to FCC stacking faults. With the help of TEM characterization, the correctness of the correlation between some of the dislocations and FCC stacking faults is verified. Through the combination of simulation and experiment, this paper provides an idea for the in-depth study of the solid-phase transformation of magnesium alloys and provides reference and guidance for the design of magnesium alloys with good plasticity and formability at room temperature.

Detecting and attributing vegetation variations in the Yellow River Basin (YRB) is vital for adjusting ecological restoration strategies to address the possible threats posed by changing environments. On the basis of the kernel normalized difference vegetation index (kNDVI) and key climate drivers (precipitation (PRE), temperature (TEM), solar radiation (SR), and potential evapotranspiration (PET)) in the basin during the period from 1982 to 2022, we utilized the multivariate statistical approach to analyze the spatiotemporal patterns of vegetation dynamics, identified the key climate variables, and discerned the respective impacts of climate change (CC) and human activities (HA) on these variations. Our analysis revealed a widespread greening trend across 93.1% of the YRB, with 83.2% exhibiting significant increases in kNDVI (p < 0.05). Conversely, 6.9% of vegetated areas displayed a browning trend, particularly concentrated in the alpine and urban areas. With the Hurst index of kNDVI exceeding 0.5 in 97.5% of vegetated areas, the YRB tends to be extensively greened in the future. Climate variability emerges as a pivotal determinant shaping diverse spatial and temporal vegetation patterns, with PRE exerting dominance in 41.9% of vegetated areas, followed by TEM (35.4%), SR (13%), and PET (9.7%). Spatially, increased PRE significantly enhanced vegetation growth in arid zones, while TEM and SR controlled vegetation variations in alpine areas and non-water-limited areas such as irrigation zones. Vegetation dynamics in the YRB were driven by a combination of CC and HA, with relative contributions of 55.8% and 44.2%, respectively, suggesting that long-term CC is the dominant force. Specifically, climate change contributed to the vegetation greening seen in the alpine region and southeastern part of the basin, and human-induced factors benefited vegetation growth on the Loess Plateau (LP) while inhibiting growth in urban and alpine pastoral areas. These findings provide critical insights that inform the formulation and adaptation of ecological conservation strategies in the basin, thereby enhancing resilience to changing environmental conditions.

The Loess Plateau (LP) is a typical climate-sensitive and ecologically delicate area in China. Clarifying the vegetation–climate interaction in the LP over 40+ years, particularly pre- and post-Grain to Green Program (GTGP) implementation, is crucial for addressing potential climate threats and achieving regional ecological sustainability. Utilizing the kernel Normalized Difference Vegetation Index (kNDVI) and key climatic variables (precipitation (PRE), air temperature (TEM), and solar radiation (SR)) between 1982 and 2022, we performed an extensive examination of vegetation patterns and their reaction to changes in climate using various statistical methods. Our findings highlight a considerable and widespread greening on the LP from 1982 to 2022, evidenced by a kNDVI slope of 0.0020 yr−1 (p < 0.001) and a 90.9% significantly increased greened area. The GTGP expedited this greening process, with the kNDVI slope increasing from 0.0009 yr−1 to 0.0036 yr−1 and the significantly greened area expanding from 39.1% to 84.0%. Over the past 40 years, the LP experienced significant warming (p < 0.001), slight humidification, and a marginal decrease in SR. Post-GTGP implementation, the warming rate decelerated, while PRE and SR growth rates slightly accelerated. Since the hurst index exceeded 0.5, most of the vegetated area of the LP is expected to be greening, warming, and humidification in the future. In the long term, 75% of the LP vegetated area significantly benefited from the increase in PRE, especially in relatively dry environments. In the LP, 61% of vegetated areas showed a positive correlation between kNDVI and TEM, while 4.9% exhibited a significant negative correlation, mainly in arid zones. SR promoted vegetation growth in 23% of the vegetated area, mostly in the eastern LP. The GTGP enhanced the sensitivity of vegetation to PRE, increasing the area corresponding to a significant positive correlation from 15.3% to 59.9%. Overall, PRE has emerged as the dominant climate driver for the vegetation dynamics of the LP, followed by TEM and SR. These insights contribute to a comprehensive understanding of the climate-impact-related vegetation response mechanisms, providing guidance for efforts toward regional sustainable ecological development amid the changing climate.

Heterosis has been widely used in rice breeding, especially in improving rice yield. But it has rarely been studied in rice abiotic stress, including the drought tolerance, which is becoming one of the most important threaten in decreasing rice yield. Therefore, it is essential to studying the mechanism underlying heterosis in improving drought tolerance of rice breeding. In this study, Dexiang074B (074B) and Dexiang074A (074A) served as maintainer lines and sterile lines. Mianhui146 (R146), Chenghui727 (R727), LuhuiH103 (RH103), Dehui8258 (R8258), Huazhen (HZ), Dehui938 (R938), Dehui4923 (R4923), and R1391 served as restorer lines. The progeny were Dexiangyou (D146), Deyou4727 (D4727), Dexiang 4103 (D4103), Deyou8258 (D8258), Deyou Huazhen (DH), Deyou 4938 (D4938), Deyou 4923 (D4923), and Deyou 1391 (D1391). The restorer line and hybrid offspring were subjected to drought stress at the flowering stage. The results showed that Fv/Fm values were abnormal and oxidoreductase activity and MDA content were increased. However, the performance of hybrid progeny was significantly better than their respective restorer lines. Although the yield of hybrid progeny and restorer lines decreased simultaneously, the yield in hybrid offspring is significantly lower than the respective restorer line. Total soluble sugar content was consistent with the yield result, so we found that 074A can enhance drought tolerance in hybrid rice.

Abstract To develop and design mg-based nanoalloys with excellent properties, it is necessary to explore the forming process. In this paper, to explore the effect of different loading directions on the phase transformation of magnesium alloy, the model of AZ31 magnesium alloy was established, the process of Uniaxial Compression (UC) of magnesium alloy in different directions was simulated, the changes of atomic position and phase structure were observed, and the phase transformation mechanism of AZ31 magnesium alloy under uniaxial compression under different loading directions was summarized. The conclusions are as follows: the stress and strain, potential energy and volume change, void evolution, phase structure change and dislocation evolution of magnesium alloy are consistent, and there is no significant difference. In the process of uniaxial compression, the phase transformation of hexagonal closely packed (HCP) → face-centered cubic (FCC) is the main, and its structure evolves into HCP → Other → FCC. Shockley partial dislocations always precede FCC stacking faults by about 4.5%, and Shockley partial dislocations surround FCC stacking faults. In this paper, the phase transformation mechanism of AZ31 magnesium alloy under uniaxial compression under different loading directions is summarized, which provides a theoretical basis for the processing and development of magnesium-based nanoalloys.

Abstract The objective of the study was to understand the genetic basis of eight traits conferring grain appearance and yield in a recombinant inbred line (RIL8) derived from a cross between cultivated Indica rice varieties Dexiang074B and Pujiang6. We conducted whole genome re‐sequencing for the two parental lines and genotyping by sequencing (GBS) for the RIL8 population. Next, we aligned the clean reads to the rice genome Nipponbare IRGSP 1.0, constructed the genetic linkage map (GLM), and performed the quantitative trait loci (QTL) analysis. In total, 2631 high‐quality markers were generated for 315 RIL8 samples. We identified a rice GLM containing 12 linkage groups (total map distance: 1946.71 cM; average map distance: 0.74 cM) and 98 QTLs related to the rice yield, including 31 high credible QTLs. In addition, 39 QTLs were identified to be associated with the G*E interaction. While most of the QTLs were co‐localized with previously reported rice QTLs, some novel QTLs were identified for the first time in this study. These findings provide a genetic basis for developing cultivated rice with good economic characteristics based on molecular breeding technologies.

Samples were cut from an extruded AZ31 magnesium alloy bar for uniaxial tensile and EBSD characterization tests. The long axis and bar extrusion directions were 0° (T0 sample), 45° (T45 sample), and 90° (T90 sample). The effects of loading direction on the tensile behavior, microstructure, and texture evolution of the magnesium alloy were studied. Results show that the obvious mechanical anisotropy of tensile behavior is affected by the loading direction, and the T0 sample with a grain c-axis perpendicular to the extrusion direction has a strong basal texture and high flow stress and yield strength. The loading direction has a significant influence on the microstructure characteristics of different samples, especially the number of {10–12} tensile twins and {10–11} compression twins. Texture evolution results show that the loading direction and the effect of deformation mode on the deformation mechanism lead to variations in texture evolution: the basal slip and prismatic slip during the plastic deformation of the T0 specimen, the compression twin of the T45 specimen, and the tensile twin of the T90 specimen.

Based on the stress characteristics of the instantaneous cross-section deformation of the wall reducing section during the cold rolling of two-roll Pilger pipes, the rectangular samples with 0° and 90° to the extrusion direction (ED) were cut from the extruded AZ31 magnesium alloy bar for 3% pre-deformation test to simulate its stress state equivalently. The sample was then cut from the pre-deformed sample by wire cutting for secondary compression, and the sample that is not pre-deformed is selected. The mechanical behavior and texture evolution of AZ31 magnesium alloy under different loading conditions were respectively studied by EBSD experiment and VPSC simulation. Results show that the true stress–strain curve and texture evolution characteristics of AZ31 magnesium alloy during the secondary compression process are in good agreement with the prediction of the VPSC model. The secondary compression behavior can be effectively explained by the relative activity of the deformation modes. The pre-deformation in the ∥ED (⊥ED) direction is conducive to the shift of the pole density of the {0001} basal surface texture to the positive and negative directions of the ED (TD). The pre-deformed sample exhibits a higher yield strength than the non-pre-deformed sample in the same loading direction. The high ductility of magnesium alloys can be achieved by activating pyramidal 〈c + a〉 slippage.