Retinal microcirculation changes in prediabetic patients with short-term increased blood glucose using optical coherence tomography angiography.

BACKGROUND: Retinal microcirculation alterations are early indicators of diabetic microvascular complications. Optical coherence tomography angiography (OCTA) is a noninvasive method to assess these changes. This study analyzes changes in retinal microcirculation in prediabetic patients during short-term increases in blood glucose using OCTA. AIM: To investigate the changes in retinal microcirculation in prediabetic patients experiencing short-term increases in blood glucose levels using OCTA. METHODS: Fifty volunteers were divided into three groups: Group 1 [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)], Group 2 (both IFG and IGT), and a control group. Retinal microcirculation parameters, including vessel density (VD), perfusion density (PD), and foveal avascular zone (FAZ) metrics, were measured using OCTA. Correlations between these parameters and blood glucose levels were analyzed in both the fasting and postprandial states. RESULTS: One hour after glucose intake, the central VD (P = 0.023), central PD (P = 0.026), and parafoveal PD (P < 0.001) were significantly greater in the control group than in the fasting group. In Group 1, parafoveal PD (P < 0.001) and FAZ circularity (P = 0.023) also increased one hour after glucose intake. However, no significant changes were observed in the retinal microcirculation parameters of Group 2 before or after glucose intake (P > 0.05). Compared with the control group, Group 1 had a larger FAZ area (P = 0.032) and perimeter (P = 0.018), whereas Group 2 had no significant differences in retinal microcirculation parameters compared with the control group (P > 0.05). Compared with Group 1, Group 2 had greater central VD (P = 0.013) and PD (P = 0.008) and a smaller FAZ area (P = 0.012) and perimeter (P = 0.010). One hour after glucose intake, Group 1 had a larger FAZ area (P = 0.044) and perimeter (P = 0.038) than did the control group, whereas Group 2 showed no significant differences in retinal microcirculation parameters compared with the control group (P > 0.05). Group 2 had greater central VD (P = 0.042) and PD (P = 0.022) and a smaller FAZ area (P = 0.015) and perimeter (P = 0.016) than Group 1. At fasting, central PD was significantly positively correlated with blood glucose levels (P = 0.044), whereas no significant correlations were found between blood glucose levels and OCTA parameters one hour after glucose intake. CONCLUSION: A short-term increase in blood glucose has a more pronounced effect on retinal microcirculation in prediabetic patients with either IFG or IGT.

Longitudinal Patterns of Ankle-Brachial Index and Their Association With Progression of CKD in Patients With Type 2 Diabetes and Elevated Body Mass Index.

RATIONALE & OBJECTIVE: Ankle-brachial index (ABI) is used to screen for vascular complications in the setting of diabetes. This study sought to examine the relationship of longitudinal ABI data and chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D) and elevated body mass index (BMI). STUDY DESIGN: A post-hoc analysis of the Look AHEAD trial. SETTING & PARTICIPANTS: This study included 3,631 participants in the Look AHEAD trial with a baseline glomerular filtration rate (eGFR) >60 ml/min/1.73 m2. EXPOSURES: Average ABI and average annual change in ABI were calculated based on annual ABI measurements during the first 4 years of the study. OUTCOME: CKD progression, defined as kidney failure requiring maintenance dialysis or the occurrence of eGFR<60 ml/min/1.73 m2 with a drop of ≥30% at a follow-up visit relative to the first eGFR measurement. ANALYTICAL APPROACH: Restricted cubic spline and Cox proportional hazards models were fit to estimate associations and to explore non-linearity. RESULTS: Over a median follow-up of 10.1 years, 1,051 participants developed CKD progression. There was a reversed J-shaped relationship of CKD progression with average ABI (when ABI <1.17: HR (per SD decrement), 1.23; 95%CI, 1.06-1.42; when ABI ≥ 1.17: HR (per SD increment), 1.10; 95%CI, 1.00-1.22) and average annual change in ABI (when change in ABI <-0.007: HR (per SD decrement), 1.37; 95%CI, 1.12-1.66; when change in ABI ≥-0.007: HR (per SD increment), 1.13; 95%CI, 1.03-1.24). LIMITATIONS: Observational study, potential unmeasured confounding. CONCLUSIONS: Low and high average ABI, even at clinically normal values, as well as decreasing and increasing average annual ABI, were associated a higher risk of CKD progression in patients with T2D and elevated BMI. Monitoring ABI and its changes over time may facilitate CKD risk stratification in patients with T2D.

Urinary Cytokeratin 20 as a Biomarker for AKI-CKD Transition among Patients with Acute Decompensated Heart Failure and AKI.

BACKGROUND: Predicting the risk of AKI-CKD transition remains a major challenge in management of acute decompensated heart failure and AKI. This study investigated the clinical utility of urinary cytokeratin 20 (CK20), a novel biomarker reflecting severity of histological acute tubular injury, for identifying patients at risk of AKI-CKD progression. METHODS: This prospective cohort study included a Test set comprising 279 consecutive hospitalized patients with acute decompensated heart failure and AKI in 5 centers and a Validation set enrolling 206 similar patients at an external center. Urinary CK20 and seven reported renal tubular injury biomarkers at the time of AKI diagnosis were measured. The primary outcome was a composite of AKI-CKD transition 90 days after AKI or all-cause death within 90 days. The secondary outcome was AKI-CKD progression 90 days after AKI. RESULTS: In the Test set, 115 (41%) patients reached the primary endpoint. Concentrations of urinary CK20 peaked on the day of AKI diagnosis and remained elevated 14 days after AKI. After multivariable adjustment, the highest tertile of urinary CK20 was associated with 21-fold higher risk of the primary outcome and 29-fold higher risk of the secondary outcome. For predicting the primary and the secondary outcomes, urinary CK20 at the time of AKI diagnosis had area under the receiver-operating characteristic curves (AUC) of 0.82 (95% confidence interval [CI], 0.77-0.87) and 0.81 (95% CI, 0.75-0.87), and outperformed other reported biomarkers reflecting acute tubular injury and the risk of CKD. Adding urinary CK20 to the clinical variables improved the ability for predicting the primary outcome with an AUC of 0.90 (95% CI, 0.85-0.94), and largely improved the risk reclassification. The ability of urinary CK20 in predicting AKI-CKD transition was further confirmed in the Validation set. CONCLUSIONS: Urinary CK20 improved prediction of the risk for transition from AKI to CKD in patients with acute decompensated heart failure and AKI.

Development and validation of a multimodal deep learning framework for vascular cognitive impairment diagnosis.

Cerebrovascular disease (CVD) is the second leading cause of dementia worldwide. The accurate detection of vascular cognitive impairment (VCI) in CVD patients remains an unresolved challenge. We collected the clinical non-imaging data and neuroimaging data from 307 subjects with CVD. Using these data, we developed a multimodal deep learning framework that combined the vision transformer and extreme gradient boosting algorithms. The final hybrid model within the framework included only two neuroimaging features and six clinical features, demonstrating robust performance across both internal and external datasets. Furthermore, the diagnostic performance of our model on a specific dataset was demonstrated to be comparable to that of expert clinicians. Notably, our model can identify the brain regions and clinical features that significantly contribute to the VCI diagnosis, thereby enhancing transparency and interpretability. We developed an accurate and explainable clinical decision support tool to identify the presence of VCI in patients with CVD.

ß-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis.

Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that ß-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by ß-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored ß-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of ß-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.

Bifocal lenses with adjustable intensities enabled by bilayer liquid crystal structures.

In this paper, we propose bifocal lenses based on bilayer structures composed of a liquid crystal (LC) cell and LC polymer, and the relative intensity of two foci can be adjusted arbitrarily through applying an external voltage. Two LC layers have different light modulation functions: when circularly polarized light passes through the first layer, part of the outgoing light is converted with PB phase modulation and another part is not converted; followed by the second layer, PB modulation of these two parts would be simultaneously realized but with opposite signs; thus the transmitted left- and right-handed circularly polarized (LCP and RCP) light can be independently controlled. As proof-of-concept examples, longitudinal and transverse bifocal lenses are designed to split an incident LCP light into two convergent beams with orthogonal helicity, and the position of the two foci can be flexibly arranged. Benefitting from the electrically controlled polarization conversion efficiency (PCE) of the LC cell, the relative intensity of the two foci can be adjusted arbitrarily. Experimental results agree well with theoretical calculations. Besides, a broadband polarization and an edge imaging system based on the proposed bifocal LC lenses have also been demonstrated. This paper presents a simple method to design a functional multilayer LC device and the proposed bifocal lenses may have potentials in the optical interconnection, biological imaging, and optical computing.

Potential protective role of chlorogenic acid against cyclophosphamide-induced reproductive damage in male mice.

Background: Cyclophosphamide (CP) is an anticancer drug; however, clinical utilization of CP is limited, resulting from its considerable toxicities. This research was performed to explore the protective effects of Chlorogenic acid (CGA) on reproductive damage induced by CP in mice. Methods: Blood samples were collected for analysis of hormone content subsequently; semen samples were evaluated for quality, and testis samples were used for histopathological evaluation and analysis of oxidative stress biomarkers, protein and gene expression levels of steroid regulatory factors, and steroid synthase. Results: The results noted that CGA increased serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) activity; increased SOD, GPx, and GSH oxidative stress levels in testis tissue; and decreased MDA content in testis tissue. Testicular cells in the CGA treatment group gradually returned to normal morphology, and CYP11A1 and CYP17A1 levels increased after CGA treatment. The mRNA levels of CYP11A1, CYP17A1, StAR, 3ß-HSD, and 17ß-HSD were significantly raised in the CGA dose group. In the test dose range, CGA can improve sperm quality, quantitative abnormality, and serum T synthesis disorder caused by CP. This mechanism may be correlated with the inhibition of oxidative stress and antioxidation levels. Conclusions: Therefore, CGA has a protective impact on testicular injuries arising from CP in mice.

LTBR acts as a novel immune checkpoint of tumor-associated macrophages for cancer immunotherapy.

Tumor-associated macrophages (TAMs) greatly contribute to immune checkpoint inhibitor (ICI) resistance of cancer. However, its underlying mechanisms and whether TAMs can be promising targets to overcome ICI resistance remain to be unveiled. Through integrative analysis of immune multiomics data and single-cell RNA-seq data (iMOS) in lung adenocarcinoma (LUAD), lymphotoxin ß receptor (LTBR) is identified as a potential immune checkpoint of TAMs, whose high expression, duplication, and low methylation are correlated with unfavorable prognosis. Immunofluorescence staining shows that the infiltration of LTBR+ TAMs is associated with LUAD stages, immunotherapy failure, and poor prognosis. Mechanistically, LTΒR maintains immunosuppressive activity and M2 phenotype of TAMs by noncanonical nuclear factor kappa B and Wnt/ß-catenin signaling pathways. Macrophage-specific knockout of LTBR hinders tumor growth and prolongs survival time via blocking TAM immunosuppressive activity and M2 phenotype. Moreover, TAM-targeted delivery of LTΒR small interfering RNA improves the therapeutic effect of ICI via reversing TAM-mediated immunosuppression, such as boosting cytotoxic CD8+ T cells and inhibiting granulocytic myeloid-derived suppressor cells infiltration. Taken together, we bring forth an immune checkpoint discovery pipeline iMOS, identify LTBR as a novel immune checkpoint of TAMs, and propose a new immunotherapy strategy by targeting LTBR+ TAMs.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Kidney function-specific cut-off values of high-sensitivity cardiac troponin T for the diagnosis of acute myocardial infarction.

Background: The diagnosis of acute myocardial infarction (AMI) using high-sensitivity cardiac troponin T (hs-cTnT) remains challenging in patients with kidney dysfunction. Methods: In this large, multicenter cohort study, a total of 20 912 adults who underwent coronary angiography were included. Kidney function-specific cut-off values of hs-cTnT were determined to improve the specificity without sacrificing sensitivity, as compared with that using traditional cut-off value (14 ng/L) in the normal kidney function group. The diagnostic accuracy of the novel cut-off values was validated in an independent validation cohort. Results: In the derivation cohort (n = 12 900), 3247 patients had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Even in the absence of AMI, 50.2% of participants with eGFR <60 mL/min/1.73 m2 had a hs-cTnT concentration ≥14 ng/L. Using 14 ng/L as the threshold of hs-cTnT for diagnosing AMI led to a significantly reduced specificity and positive predictive value in patients with kidney dysfunction, as compared with that in patients with normal kidney function. The kidney function-specific cut-off values were determined as 14, 18 and 48 ng/L for patients with eGFR >60, 60-30 and <30 mL/min/1.73 m2, respectively. Using the novel cut-off values, the specificities for diagnosing AMI in participants with different levels of kidney dysfunction were remarkably improved (from 9.1%-52.7% to 52.8-63.0%), without compromising sensitivity (96.6%-97.9%). Similar improvement of diagnostic accuracy was observed in the validation cohort (n = 8012). Conclusions: The kidney function-specific cut-off values of hs-cTnT may help clinicians to accurately diagnose AMI in patients with kidney dysfunction and avoid the potential overtreatment in practice.

Investigation of TMEM41A's function in breast cancer prognosis and its connection to immune cell infiltration.

BACKGROUND: Globally, breast cancer is the most common type of malignant tumor. It has been demonstrated that TMEM41A is abnormally expressed in a number of cancers and is linked to a dismal prognosis. TMEM41A's involvement in breast cancer remains unknown, though. METHODS: Data from databases such as TCGA were used in this study. Expression differences were compared using non-parametric tests. Cox regression analysis was employed, and analyses such as Nomogram were used to assess the significance of TMEM41A in predicting the prognosis of breast cancer. Lastly, it was looked into how immune cell infiltration in breast cancer is related to TMEM41A expression levels. RESULTS: The results suggest that TMEM41A is overexpressed in breast cancer and correlates with poor prognosis (P = 0.01), particularly in early-stage and ductal A breast cancer (P < 0.01). Breast cancer patients' expression of TMEM41A was found to be an independent risk factor (HR = 1.132, 95% CI 1.036-1.237) by multifactorial Cox regression analysis. The Nomogram prediction model's c-index was 0.736 (95% CI 0.684-0.787). The results of GSEA biofunctional enrichment analysis included the B cell receptor signaling pathway (P < 0.05). Ultimately, there was a significant correlation (P < 0.05) between TMEM41A expression in breast cancer and an infiltration of twenty immune cells. CONCLUSIONS: Breast cancer tissues overexpress TMEM41A, which is linked to immune cell infiltration and prognosis (particularly in early stage and luminal A breast cancer). Overexpression of TMEM41A is anticipated to serve as a novel prognostic indicator and therapeutic target for breast cancer.

PSD-ELGAN: A pseudo self-distillation based CycleGAN with enhanced local adversarial interaction for single image dehazing.

Compared to pixel-level content loss, domain-level style loss in CycleGAN-based dehazing algorithms just imposes relatively soft constraints on the intermediate translated images, resulting in struggling to accurately model haze-free features from real hazy scenes. Furthermore, globally perceptual discriminator may misclassify real hazy images with significant scene depth variations as clean style, thereby resulting in severe haze residue. To address these issues, we propose a pseudo self-distillation based CycleGAN with enhanced local adversarial interaction for image dehazing, termed as PSD-ELGAN. On the one hand, we leverage the characteristic of CycleGAN to generate pseudo image pairs during training. Knowledge distillation is employed in this unsupervised framework to transfer the informative high-quality features from the self-reconstruction network of real clean images to the dehazing generator of paired pseudo hazy images, which effectively improves its haze-free feature representation ability without increasing network parameters. On the other hand, in the output of dehazing generator, four non-uniform image patches severely affected by residual haze are adaptively selected as input samples. The local discriminator could easily distinguish their hazy style, thereby further compelling the dehazing generator to suppress haze residues in such regions, thus enhancing its dehazing performance. Extensive experiments show that our PSD-ELGAN can achieve promising results and better generality across various datasets.

Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS -mutated colorectal cancer.

Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS -mutated mCRC. Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS -mutated mCRC. Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro , and we validated the efficacy of the drugs in vivo . Methods: HTS was performed using 3-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with 2 clinically ready libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the effects of the drugs on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts. Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS -mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell cycle progression and increases in microtubule stability that resulted in significantly higher defects in the mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS -mutant patient-derived xenograft mouse models. Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS -mutated, metastatic CRC.

Clinical sequencing reveals diagnostic, therapeutic, and prognostic biomarkers for adult-type diffuse gliomas.

Diffuse gliomas in adults are highly infiltrative and largely incurable. Whole exome sequencing (WES) has been demonstrated very useful in genetic analysis. Here WES was performed to characterize genomic landscape of adult-type diffuse gliomas to discover the diagnostic, therapeutic and prognostic biomarkers. Somatic and germline variants of 66 patients with adult-type diffuse gliomas were detected by WES based on the next-generation sequencing. TCGA and CGGA datasets were included to analyze the integrated diagnosis and prognosis. Among 66 patients, the diagnosis of 9 cases was changed, in which 8 cases of astrocytoma were corrected into IDH-wildtype glioblastoma (GBM), and 1 oligodendroglioma without 1p/19q co-deletion into astrocytoma. The distribution of mutations including ATRX/TP53 differed in three cohorts. The genetic mutations in GBM mainly concentrated on the cell cycle, PI3K and RTK pathways. The mutational landscape of astrocytoma was more similar to that of GBM, with the highest frequency in germline variants. Patients with IDH-mutant astrocytoma harboring SNVs of PIK3CA and PIK3R1 showed a significantly worse overall survival (OS) than wild-type patients. AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

Motion Artifact Correction for OCT Microvascular Images Based on Image Feature Matching.

Optical coherence tomography angiography (OCTA), a functional extension of optical coherence tomography (OCT), is widely employed for high-resolution imaging of microvascular networks. However, due to the relatively low scan rate of OCT, the artifacts caused by the involuntary bulk motion of tissues severely impact the visualization of microvascular networks. This study proposes a fast motion correction method based on image feature matching for OCT microvascular images. First, the rigid motion-related mismatch between B-scans is compensated through the image feature matching based on the improved oriented FAST and rotated BRIEF algorithm. Then, the axial motion within A-scan lines in each B-scan image is corrected according to the displacement deviation between the detected boundaries achieved by the Scharr operator in a non-rigid transformation manner. Finally, an optimized intensity-based Doppler variance algorithm is developed to enhance the robustness of the OCTA imaging. The experimental results demonstrate the effectiveness of the method.

Transplantation of miR-145a-5p modified M2 type microglia promotes the tissue repair of spinal cord injury in mice.

BACKGROUND: The traumatic spinal cord injury (SCI) can cause immediate multi-faceted function loss or paralysis. Microglia, as one of tissue resident macrophages, has been reported to play a critical role in regulating inflammation response during SCI processes. And transplantation with M2 microglia into SCI mice promotes recovery of motor function. However, the M2 microglia can be easily re-educated and changed their phenotype due to the stimuli of tissue microenvironment. This study aimed to find a way to maintain the function of M2 microglia, which could exert an anti-inflammatory and pro-repair role, and further promote the repair of spinal cord injury. METHODS: To establish a standard murine spinal cord clip compression model using Dumont tying forceps. Using FACS, to sort microglia from C57BL/6 mice or CX3CR1GFP mice, and further culture them in vitro with different macrophage polarized medium. Also, to isolate primary microglia using density gradient centrifugation with the neonatal mice. To transfect miR-145a-5p into M2 microglia by Lipofectamine2000, and inject miR-145a-5p modified M2 microglia into the lesion sites of spinal cord for cell transplanted therapy. To evaluate the recovery of motor function in SCI mice through behavior analysis, immunofluorescence or histochemistry staining, Western blot and qRT-PCR detection. Application of reporter assay and molecular biology experiments to reveal the mechanism of miR-145a-5p modified M2 microglia therapy on SCI mice. RESULTS: With in vitro experiments, we found that miR-145a-5p was highly expressed in M2 microglia, and miR-145a-5p overexpression could suppress M1 while promote M2 microglia polarization. And then delivery of miR-145a-5p overexpressed M2 microglia into the injured spinal cord area significantly accelerated locomotive recovery as well as prevented glia scar formation and neuron damage in mice, which was even better than M2 microglia transplantation. Further mechanisms showed that overexpressed miR-145a-5p in microglia inhibited the inflammatory response and maintained M2 macrophage phenotype by targeting TLR4/NF-κB signaling. CONCLUSIONS: These findings indicate that transplantation of miR-145a-5p modified M2 microglia has more therapeutic potential for SCI than M2 microglia transplantation from epigenetic perspective.

Association of accelerometer-derived "weekend warrior" moderate to vigorous physical activity, chronic kidney disease and acute kidney injury.

OBJECTIVE: To examine the relationship between an accelerometer-derived "weekend warrior" pattern, characterized by achieving the most moderate to vigorous physical activity (MVPA) over 1-2 days, as opposed to more evenly distributed patterns, with risk of chronic kidney disease (CKD) and acute kidney injury (AKI). METHODS: 77,977 participants without prior kidney diseases and with usable accelerometer data (collected between 2013 and 2015) were included from the UK Biobank. Three physical activity patterns were compared: active weekend warrior pattern (achieving ≥150 min MVPA per week and accumulating ≥50 % of total MVPA in 1-2 days), active regular pattern (achieving ≥150 min MVPA but not meeting active weekend warrior criteria per week), and inactive pattern (<150 min MVPA per week). The study outcomes included incident CKD and AKI, ascertained through self-report data and data linkage with primary care, hospital admissions, and death registry records. RESULTS: During a median follow-up of 6.8 years, 1324 participants developed CKD and 1515 developed AKI. In multivariable-adjusted models, when compared with inactive participants, individuals with active weekend warrior pattern (CKD: hazard ratio [HR], 0.79, 95 % confidence interval [CI], 0.69-0.89; AKI: HR, 0.70, 95 %CI, 0.62-0.79) and those with active regular pattern (CKD: HR, 0.81, 95 %CI, 0.69-0.95; AKI: HR, 0.79, 95 %CI, 0.68-0.91) exhibited a similar and significantly lower risk of incident CKD and AKI. Similar findings were observed at the median threshold of ≥230.4 min of MVPA per week. CONCLUSION: Concentrated MVPA within 1 to 2 days is as effective as distributed ones in decreasing the risk of renal outcomes.

Phosphorus fertilization enhanced overwintering, root system and forage yield of late-seeded alfalfa in sodic soils.

Sowing date and soil fertility are very important factors in the overwintering and production performance of alfalfa (Medicago sativa L.), yet there's a knowledge gap in knowledge on how late-seeded alfalfa responds to phosphorus (P) fertilization. A field study was conducted in Inner Mongolia from 2020 to 2022 using a split-plot design. The main plots consisted of five sowing dates (31 July, 8, 16, and 24 August, and 1 September), while the subplots involved five P application rates (0, 40, 70, 100, and 130 kg P2O5 ha-1). Throughout the growing seasons, the overwintering rate, root traits, forage yield, and yield components were measured. The results revealed a consistent decrease in overwintering ability and productivity with the delayed sowing. This reduction in overwintering rate was mainly due to diminished root traits, while the decrease in forage yield was largely associated with a reduction in plants per square meter. However, P fertilizer application to late-seeded alfalfa demonstrated potential in enhancing the diameter of both the crown and taproot, thus strengthening the root system and improving the overwintering rate, the rate of increase ranges from 11.6 to 49%. This adjustment could also improve the shoots per square meter and mass per shoot, increasing by 9.4-31.3% and 15.0-27.1% respectively in 2 years, which can offset the decline in forage yield caused by late sowing and might even increase the forage yield. Regression and path analysis indicated that alfalfa forage yield is primarily affected by mass per shoot rather than shoots per square meter. This study recommended that the sowing of alfalfa in similar regions of Inner Mongolia should not be later than mid-August. Moreover, applying P fertilizer (P2O5) at 70.6-85.9 kg ha-1 can enhance the forage yield and persistence of late-seeded alfalfa. Therefore, appropriate late sowing combined with the application of P fertilizer can be used as an efficient cultivation strategy for alfalfa cultivation after a short-season crop harvest in arid and cold regions.

A new isoprenyl-phenol-type meroterpenoid from mangrove endophytic fungus Aspergillus sp. GXNU-Y65.

Asperphenol A (1), a new isoprenyl-phenol-type meroterpenoid, was isolated from the mangrove endophytic fungus Aspergillus sp. GXNU-Y65 together with five known compounds (2-6). All structures were assigned using extensive NMR spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1-6 were evaluated for their cytotoxic activity against A549 and T24 human cancer cell lines. Among them, compounds 1 and 5 exhibited moderate inhibitory activities against T24 cancer cell lines with the IC50 values of 26.71 and 43.50 µM, respectively.