Serum S-adenosylhomocysteine levels are associated with first stroke in Chinese adults with hypertension.

BACKGROUND: The association between S-adenosylhomocysteine (SAH) and stroke has not been confirmed due to the specialized equipment and time requirements necessary for S-adenosylhomocysteine testing. We aimed to explore the association between SAH and stroke. METHODS: A nested, case-control study drawn from the China Stroke Primary Prevention Trial of rural adults with hypertension, including 557 first stroke cases and 557 matched controls was conducted. Serum SAH was measured by stable-isotope dilution liquid chromatography-tandem mass spectrometry using 4500MD. Multiple conditional logistic regression models were used to evaluate the association between SAH and first stroke. RESULTS: In females, SAH levels were significantly higher in the stroke population than in the control group (16.0 ng/mL vs. 14.6 ng/mL). When SAH was assessed as quartiles, the odds of stroke were 1.78 (95 % CI: 1.02-3.09) in Quartile 2, 1.31 (95 % CI: 0.73-2.33) in Quartile 3, and 1.93 (95 % CI: 1.03-3.62) in Quartile 4, compared to Quartile 1. When Quartiles 2-4 were combined, the adjusted odds ratio of first stroke was 1.64 (95 % CI: 1.03-2.62) compared with Quartile 1. In subgroup analysis, a significant SAH-stroke association was observed in the lower vitamin D3 group (OR = 3.35, 95 % CI:1.72-6.53; P interaction, 0.035). In males, higher levels of SAH were associated with an increased risk of stroke in those under age 60. Compared with the reference group, the adjusted odds ratio of total stroke was 2.40 (95 % CI: 1.02-5.91) in the combined group (Quartile 2-4). In contrast, no significant association between SAH and stroke was found in males aged 60 or older. CONCLUSIONS: This study reveals that SAH is associated with a higher risk of stroke independently of homocysteine, especially in females. SAH may be a second predictor of stroke in the metabolic pathway of methionine, after homocysteine.

Impacts of cadmium accumulation on the diversity, assembly processes, and co-occurrence patterns of archaeal communities in marine sediments.

There is limited understanding regarding the changes in the ecological processes and the mechanisms of archaeal community in response to heavy metal contamination in the marine sediments. In this study, sediment samples were collected from 46 locations near harbors, and the concentration of heavy metals and the diversity of archaeal communities were investigated to understand the impact of Cd on archaeal communities. The results demonstrated a significant correlation between the diversity of archaeal community and Cd concentration, particularly showing a linear decrease in the species richness with rising Cd concentration. ANME-1b was identified as a significantly enriched archaeal taxon in the higher Cd environment. Null model and neutral community model indicated that the ecological assembly of archaeal communities in marine sediments was primarily governed by the stochastic processes, with dispersal limitation being the primary factor. The contribution of deterministic process to the assembly of archaeal communities in higher Cd environments increased clearly, accompanied by a notable reduction in species migration rates and widths of ecological niche of archaeal populations. Co-occurrence network analysis revealed an obvious increase in species interactions in higher Cd environments, with an apparent rise in the proportion of competitive relationships and an increase in the number of keystone species. Moreover, archaeal species formed a more complex and stable community to cope with Cd stress. This study provides new insights into the impacts of heavy metals on the ecological processes of marine microorganisms and the underlying mechanisms.

Development of Antibacterial Peptides with Membrane Disruption and Folate Pathway Inhibitory Activities against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial peptides (AMPs) offer an opportunity to overcome multidrug resistance. Here, novel peptides were designed based on AMP fragments derived from sea cucumber hemolytic lectin to enhance anti-methicillin-resistant Staphylococcus aureus (MRSA) activity with less side effects. Two designed peptides, CGS19 (LARVARRVIRFIRRAW-NH2) and CGS20 (RRRLARRLIFFIRRAW-NH2), exhibited strong antibacterial activities against clinically isolated MRSA with MICs of 3-6 µM, but no obvious cytotoxicity was observed. Consistently, CGS19 and CGS20 exerted rapid bactericidal activity and effectively induced 5.9 and 5.8 log reduction of MRSA counts in mouse subeschar, respectively. Further, CGS19 and CGS20 kill bacteria not only through disturbing membrane integrity but also by binding formate-tetrahydrofolate ligase, a key enzyme in the folate metabolism pathway, thereby inhibiting the folate pathway of MRSA. CGS19 and CGS20 are promising lead candidates for drug development against MRSA infection. The dual mechanisms on the identical peptide sequence or scaffold might be an underappreciated manner of treating life-threatening pathogens.

Poor sleep quality association with higher lung cancer risk: a nested case-control study.

Background: Little is known about the relationship between sleep quality and lung cancer incidence. Thus, this study was conducted to investigate the potential connection between sleep quality and lung cancer incidence. Methods: We performed and selected a nested case-control study that included 150 lung cancer cases and 150 matched controls based on the Lianyungang cohort. Univariate and multivariate logistic regression was utilized to investigate the connection between potential risk factors and lung cancer incidence risk. Results: In this study, the average age of participants was 66.5 ± 9.1 years, with 58.7% being male, and 52.7% reportedly experiencing sleep quality problems. The results of multivariate logistic regression showed that poor sleep quality was connected to an increased lung cancer incidence risk (P = 0.033, odds ratio = 1.83, 95% confidence interval = [1.05-3.19]) compared with those with good sleep quality. The stratified analyses showed a significantly positive connection between poor sleep quality (vs. good sleep quality) and cancer risk in smokers (vs. non-smoker, P for interaction = 0.085). The combined effect analysis indicated that smokers with poor sleep quality suffered from a 2.79-fold increase in cancer incidence rates when compared with non-smokers with good sleep quality. Conclusions: Poor sleep quality was positively connected to an increased lung cancer incidence risk. In addition, among those individuals with poor sleep quality, smoking increased the lung cancer incidence risk.

Evaluation of retinal vascularization in retinopathy of prematurity regressed after intravitreal ranibizumab monotherapy or without treatment based on fluorescein angiography.

To investigate the fluorescein angiography (FA) findings and compare the extent of retinal vascularization in retinopathy of prematurity (ROP), recovered after intravitreal ranibizumab (IVR) monotherapy and those regressed spontaneously. Infants with a history of ROP who underwent FA between April 2018 and November 2021 were retrospectively included. The patients were divided into two groups based on whether they had received IVR (IVR group) or had ROP that regressed spontaneously without treatment (untreated group). The differences between the two groups in zone II ROP were also compared, to equalize the subgroups as much as possible in terms of disease severity. FA findings were recorded. The extent of vascularization was measured by the ratio of the distance from the center of the disk to the border of the vascularized zone (DB) and the distance from the center of the disk to the center of the fovea (DF). The width of the persistent avascular retina (PAR) was counted by disc diameters (DD). One hundred and ten eyes of 55 infants were included in the IVR group and 76 eyes of 38 babies in the untreated group. The ratio of abnormal shape of vessels was significantly higher in the IVR group than in the untreated group (50.9% vs. 35.5%; P = 0.038), while the linear choroidal filling pattern, tortuosity of vessels over the posterior pole, dye leakage, anomalous branching of vessels, circumferential vessels, arteriovenous shunt, abnormal capillary bed, and macular abnormalities were similarly. There was a smaller temporal DB/DF ratio (4.48 vs. 4.63; P = 0.003) and greater PAR (2.63 vs. 1.76; P < 0.001) in the IVR group compared to the untreated group. In zone II ROP, the progression of retinal vascularization was significantly larger in the IVR group than that in the untreated group (P = 0.003), while no statistical differences were observed in FA features, the DB/DF ratio, and PAR between the two subgroups. The residual vascular abnormalities and PAR may be common results of ROP regression. The DB/DF ratio of 4.0 temporally and 3.3 nasally could be used as the preliminary indicators for safe retinal vascularization in the completion of ROP regression.

Deubiquitinase OTUD6A Regulates Innate Immune Response via Targeting UBC13.

OTUD6A is a deubiquitinase that plays crucial roles in various human diseases. However, the precise regulatory mechanism of OTUD6A remains unclear. In this study, we found that OTUD6A significantly inhibited the production of type I interferon. Consistently, peritoneal macrophages and bone marrow-derived macrophages from Otud6a-/- mice produced more type I interferon after virus infection compared to cells from WT mice. Otud6a-/-- mice also exhibited increased resistance to lethal HSV-1 and VSV infections, as well as LPS attacks due to decreased inflammatory responses. Mechanistically, mass spectrometry results revealed that UBC13 was an OTUD6A-interacting protein, and the interaction was significantly enhanced after HSV-1 stimulation. Taken together, our findings suggest that OTUD6A plays a crucial role in the innate immune response and may serve as a potential therapeutic target for infectious disease.

Inhibitory effects of Ganoderma lucidum triterpenoid on the growth and metastasis of hepatocellular carcinoma.

OBJECTIVE: To investigate the inhibitory effects and mechanisms of triterpenoids from Ganoderma lucidum (G. lucidum triterpenoids) on the growth and metastasis of hepatocellular carcinoma (HCC) both in vitro and in vivo. METHODS: In in-vitro experiments, the inhibitory effects of G. lucidum triterpenoids on human HCC SMMC-7721 cell lines were investigated by observing the proliferation, apoptosis, migration and invasion phenotypes of the cell line and assessing the cell cycles as well as the cell apoptosis and proliferation. In in-vivo experiments, nude mouse SMMC-7721 tumor models were established and divided into control group, treatment group A (low concentration group) and treatment group B (high concentration group) according to the treatment models received. Magnetic resonance imaging (MRI) was performed 3 times on each mouse model to calculate their tumor volumes. The liver and kidney functions of the models were evaluated. Tissues harvested from their solid organs were subjected to HE staining, and the tumor tissues were subjected to HE staining and immunohistochemical staining (E-cad, Ki-67, and Tunel), respectively. RESULTS: i. In in-vitro experiments, G. lucidum triterpenoids could inhibit the growth of human HCC SMMC-7721 cell lines via regulating their proliferation and apoptosis phenotype. ii. In in-vivo experiments, the comparison of tumor volumes of mouse models obtained from the second and third MIR scanning was found to be statistically significant between the control group and treatment group A (P<0.05); and statistically significant differences were also found in the tumor volumes from the second and third MRI scanning between the control group and treatment group B (P<0.05). iii. No significant acute injuries or adverse effects were observed in the liver or kidney of the nude mice. CONCLUSION: G. lucidum triterpenoids could inhibit the growth of tumor cells via blocking their proliferation, accelerating apoptosis, and inhibiting migration and invasion, without marked toxic effects on normal organs and tissues in the body.

The Particle Breakage Effect on Abrasive Wear Process of Rubber/Steel Seal Pairs under High/Low Pressure.

Pressure has a significant effect on rubber seal performance in the abrasive environments of drilling. The micro-clastic rocks intruding into the seal interface are prone to fracture, which will change the wear process and mechanism, but this process is not yet known at present. To explore this issue, abrasive wear tests were carried out to compare the failure characteristics of the particles and the variation wear process under high/low pressures. The results show that non-round particles are prone to fracture under different pressures, resulting in different damage patterns and wear loss on the rubber surface. A single particle force model was established at the soft rubber-hard metal interface. Three typical breakage types of particles were analyzed, including ground, partially fractured, and crushed. At high load, more particles were crushed, while at low load, shear failure was more likely to occur at the edges of particles. These different particle fracture characteristics not only change the particle size, but also the state of motion and thus the subsequent friction and wear processes. Therefore, the tribological behavior and wear mechanism of abrasive wear are different at high pressure and low pressure. Higher pressure reduces the invasion of the abrasive particles, but also intensifies the tearing and wear of the rubber. However, no significant differences in damage were found for steel counterpart throughout the wear process under high/low load tests. These results are critical to understanding the abrasive wear of rubber seals in drilling engineering.

Dose-Response Associations of Dietary Inflammatory Potential With Health Outcomes: A Prospective Cohort Study of 198,265 UK Biobank Participants.

To investigate the dose-response associations of dietary inflammatory potential with all-cause mortality and incident cardiovascular disease (CVD) and cancer. METHODS: This was a prospective cohort study of 198,265 UK Biobank participants who completed at least 1 dietary assessment. A web based 24 hours recall questionnaire was used to derive the energy-adjusted dietary inflammatory index (E-DII). All-cause mortality and incident CVD and cancer ascertained from linked records. RESULTS: After adjusting for socio-demographic and lifestyle factors, there were J-shaped associations of E-DII with all-cause mortality and CVD, and a relatively linear association with cancer. When E-DII was <0, E-DII was not associated with any of the outcomes. When E-DII was ≥0, the linear associations were strongest in all-cause mortality (HR 1.09, 95% CI, 1.05-1.13), followed by CVD (HR 1.06, 95% CI, 1.03-1.09), and cancer (HR 1.03, 95%,CI, 1.01-1.05). CONCLUSION: Dietary inflammatory potential was associated with mortality and CVD primarily when the diet is proinflammatory.

Hydroxysafflor Yellow A Exerts Neuroprotective Effect by Reducing Aß Toxicity Through Inhibiting Endoplasmic Reticulum Stress in Oxygen-Glucose Deprivation/Reperfusion Cell Model.

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 µM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-ß peptides (Aß) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aß toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.

Inverse Association Between Baseline Plasma Selenium Concentrations and Risks of Renal Function Decline in Hypertensive Adults.

BACKGROUND: The kidney has the highest level of selenium (Se) in the body, but the role of plasma Se in chronic kidney disease is uncertain. OBJECTIVE: We aimed to investigate the longitudinal association between baseline plasma Se and renal function decline in adults with hypertension and to explore possible effect modifiers. METHODS: This was a post hoc analysis of 935 men and women with hypertension aged 40 to 75 years from a folic-acid intervention trial (the China Stroke Primary Prevention Trial) in China. The baseline plasma Se was analyzed both as a continuous variable and as tertiles. The primary outcome was a rapid decline in renal function, defined as a mean decline in the estimated glomerular filtration rate of ≥ 5 mL/(min × 1.73 m2) per year. RESULTS: The median follow-up duration from baseline to outcome was 4.4 years. After multivariate adjustment, there was an inverse association between plasma Se and a rapid decline in renal function (per 10-unit increment; OR: 0.85; 95% CI: 0.73, 0.99). When the baseline plasma Se was assessed as tertiles, compared to the lowest tertile (<74.5 µg/L), a lower trend of the primary outcome was found in the second tertile (74.5 to < 89.4 µg/L; OR: 0.60; 95% CI: 0.34, 1.07) and the highest tertile (89.4 to <150 µg/L; OR: 0.42; 95% CI: 0.22, 0.80; Ptrend = 0.006). Furthermore, the Se-renal association was more pronounced among participants with folic acid treatment or with a higher baseline folate concentration (both Pinteraction values < 0.05). CONCLUSIONS: In this sample of Chinese adults with hypertension, baseline plasma Se concentrations were inversely associated with the risk of renal function decline. The China Stroke Primary Prevention Trial was registered at clinicaltrials.gov as NCT00794885.

Serum total folate, 5-methyltetrahydrofolate and vitamin B12 concentrations on incident risk of lung cancer.

Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.

Impact of partial bile duct ligation with or without repeated magnetic resonance imaging examinations in mice.

Partial bile duct ligation (pBDL) is considered a well-tolerated cholestatic model. Magnetic resonance imaging (MRI) is one of the most widely used tools in noninvasive imaging. However, no systematic studies have reported the possible effects of repeated MRI assessments in the pBDL model. Sixty BALB/C mice were investigated. MRI images of each mouse were recorded once every 2 weeks for 6 weeks after pBDL or sham surgery. The reproducibility of the pBDL model and the reliability of MRI were examined by behavioral, physiological, biochemical, and pathological parameters. The mice showed no alterations on behavioral and physiological tests (P > 0.05) at 2, 4, and 6 weeks after pBDL. Repeated general anesthesia did not result in any impairment after pBDL (P > 0.05). The behavioral and biochemical parameters were not affected by repeated MRIs or repeated contrast-enhanced MRIs (P > 0.05). Pathological staining showed the homogeneous formation of collagenous fiber in the pBDL mice and did not indicate any influence of repeated contrast-enhanced MRI on the number of inflammatory cells or fibrotic formation (P > 0.05). Thus, pBDL is a reproducible model with many advantages for animal welfare and scientific research. Additionally, MRI, as a safe tool for longitudinal evaluation and is well tolerated in mice with cholestasis.

Associations between psycho-behavioral risk factors and diabetic retinopathy: NHANES (2005-2018).

Introduction: Diabetes mellitus (DM) and diabetic retinopathy (DR) increase the global burden. Since their pathogenesis is complex, it is necessary to use the biopsychosocial model to discover the most effective strategies. The study is aimed to investigate the psycho-behavioral factors of DR and confirm the discrepancies from previous studies. Research design and methods: The study comprised seven cycles of cross-sectional data of the National Health and Nutrition Examination Survey (NHANES) from 2005-2006 to 2017-2018. Samples of DM were selected from this complex multi-stage probability sample and divided into the non-DR and DR groups, where 4,426 samples represented 18,990,825 individuals after weighting. This study comprehensively explored the biological, social, and psychological risk factors of DR, among which the biological factors included blood pressure, blood routine, HbA1c%, blood glucose, the duration of DM, family history, comorbidities, and treatment methods. Social aspects include gender, education, income, insurance, smoking, drinking, sleep habits, and recreational activities. The Patient Health Questionnaire-9 (PHQ-9) was used to assess the psychological state. Taylor series regression was used to examine the connection between factors and DR. Results: Men accounted for 55.5% of the DR group (P = 0.0174). Lymphocyte count, insulin treatment, heart failure, stroke, liver condition, and renal failure showed significant differences in DR (P < 0.05). The incidence of depression in DR was 40.5%. Mild to moderate depression [odds ratio was associated with DR [(OR) = 1.37, 95% confidence interval (CI): 1.06-1.79], but there was no statistical difference in severe depression (OR = 1.34, 95% CI: 0.83-2.17). Although ≤ 6 h of sleep was associated with DR (OR = 1.38, 95% CI: 1.01-1.88), we found no statistical differences in alcohol consumption, recreational activities, or sedentary time between the two groups in our current study (P > 0.05). Conclusions: The biological risk factors of DR are significant. It showed that stroke is associated with DR, and retinal exams have the potential value as a screening tool for the brain. Besides, psycho-behavioral risk factors of DR should also be paid attention. Our study highlights that mild and moderate depression and ≤6 h of sleep are distinguishably associated with DM complicated with DR. It indicates that psycho-behavioral risk factors confer a vital influence on diabetic health care and DR.

A sensitive UPLC-MS/MS method for simultaneous quantification of one-carbon metabolites & co-factors in human plasma.

One-carbon metabolism is an important metabolic pathway involved in many diseases, such as congenital malformations, tumours, cardiovascular diseases, anaemia, depression, cognitive diseases and liver disease. However, the current methods have specific defects in detecting and qualifying the related compounds of one-carbon metabolism. In this study, a validated method was established to simultaneously quantify 22 one-carbon metabolites & co-factors in human plasma and applied to the study of correlation between one-carbon metabolism and colorectal cancer in human plasma samples, which were from 44 healthy subjects and 55 colorectal cancer patients. The method used ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-MS/MS), and the analytes included betaine, L-carnitine, L-cystathionine, L-cysteine, dimethylglycine, DL-homocysteic acid, homocysteine, methionine, pyridoxal hydrochloride, pyridoxamine dihydrochloride, pyridoxine dihydrochloride, S-(5'-Adenosyl)-L-homocysteine, serine, choline chloride, folic acid, glycine, pyridoxal phosphate monohydrate, riboflavin, taurine, 5-methyltetrahydrofolate, S-(5'-adenosyl)-L-methionine disulfate salt, trimethylamine oxide. The developed method was successfully applied to the quantification of 22 one-carbon metabolites & co-factors in human plasma from colorectal cancer patients and healthy individuals. The plasma concentrations of dimethylglycine was significantly decreased in the patients compared with the healthy individuals, while L-cystathionine was increased.

Iron-modified biochar-based bilayer permeable reactive barrier for Cr(VI) removal.

Iron (Fe)-modified biochar (FeBC) has been developed to remove hexavalent chromium (Cr(VI)) from groundwater and is suitable for use in permeable reactive barriers (PRBs). However, Cr(VI) removal behavior and chemical processes in FeBC-based PRBs are not fully understood, and the potential for Fe release has not been addressed. In this study, three FeBC-based PRBs were assessed in column experiments for 563 days with respect to their ability to remove Cr(VI). Bilayer column filled with FeBC+limestone and BC+limestone in two separate layers (FeBC_Ca_BC) showed the best performance in terms of Cr(VI) removal with a low treatment cost. The corrosion of FeBC was mainly related to pH and Cr(VI) concentration rather than flow rate. Leached Fe was attenuated by BC and limestone and reutilized in FeBC_Ca_BC. Cr(VI) was reduced to Cr(III) and then adsorbed or precipitated on the biochars. Cr and Fe formed inner-sphere complexes and then transformed from double corner sharing to edge sharing. During the reaction, Cr penetrated from the surface to the interior of the biochars and became a more stable species. This study provides evidence of the effectiveness of a new combination of biochars for Cr(VI) removal and insights into the reaction mechanisms.

The Significance of the Ocular Adverse Effect Induced by Systemic Taxane Application.

In recent years, in-depth research on anti-tumor therapy has brought the emergence of new active chemotherapeutic agents and combination regimens. However, as one of them, taxane drugs are widely used in clinical practice, but it should be noted that many side reactions caused by their application bring some difficulties to routine management. Among the side reactions related to taxane anti-tumor therapy, ocular adverse reactions are occasionally reported and are not life-threatening but may seriously affect patients' life quality. Thus, the continuation, reduction and cessation of taxane chemotherapy still need to be further evaluated by ophthalmologists and oncologists once the side effects show up. To prevent ocular side reactions, close attention should be paid to complications during medication. To facilitate the oncology department and ophthalmologists to comprehensively understand the ophthalmic adverse reactions of taxane drugs and their possible mechanisms and improve drug use efficiency, we collected relevant literature and reviewed and provided some suggestions for the monitoring and managing of ophthalmic toxicity.

The NtNRAMP1 transporter is involved in cadmium and iron transport in tobacco (Nicotiana tabacum).

Plant natural resistance-associated macrophage protein (NRAMP) plays an important role in maintaining intracellular metal homeostasis and coping with environmental heavy metal stress. Until now, studies on NRAMP in tobacco have been limited. In this study, NtNRAMP1 was cloned from tobacco cultivar TN90, and the highest expression level was observed in the roots, which was strongly induced by Fe deficiency. Heterologously expressed NtNRAMP1 significantly increased the Cd sensitivity of the yeast Δycf1 mutant. Three overexpressed NtNRAMP1 lines were generated to reveal the biofunction of NtNRAMP1. In the soil pot experiments under natural conditions, the contents of Fe and total chlorophyll were increased in the leaves of transgenic tobacco compared with the WT. To reveal the characteristics of NtNRAMP1 in metal transport, transgenic plants were cultured in hydroponic solution with 50 µM Cd and 200 µM Fe. Compared with the WT, the Cd concentrations in transgenic plants increased by 1.26-2.02-fold in the roots. Interestingly, the Cd content in the shoots of transgenic plants was slightly reduced compared with that of the WT. Overexpression of NtNRAMP1 did not promote Fe uptake from the external environment into the roots but enhanced the transfer of Fe from the roots to shoots. Additionally, Fe overload in the leaves of transgenic tobacco resulted in increased levels of MDA and H2O2 while Fe toxicity may be relieved by POD. In conclusion, overexpression of NtNRAMP1 in tobacco could promote Cd uptake and Fe transport from the roots to shoots while disturbing Fe homeostasis in the leaves of transgenic tobacco.

Notch-Regulated c-Kit-Positive Liver Sinusoidal Endothelial Cells Contribute to Liver Zonation and Regeneration.

BACKGROUND & AIMS: Liver sinusoidal endothelial cells (SECs) promote the proliferation of hepatocytes during liver regeneration. However, the specific subset of SECs and its mechanisms during the process remain unclear. In this study, we investigated the potential role of c-kit+ SECs, a newly identified subset of SECs in liver regeneration. METHODS: Partial hepatectomy mice models were established to induce liver regeneration. Hepatic c-kit expression was detected by quantitative reverse-transcription polymerase chain reaction, immunofluorescent staining, and fluorescence-activated cell sorting. VE-cadherin-cyclization recombinase-estrogen receptor (Cdh5-Cre-ERT) Notch intracellular domain and Cdh5-Cre recombination signal binding protein Jκfloxp mice were introduced to mutate Notch signaling. c-Kit+ SECs were isolated by magnetic beads. Single-cell RNA sequencing was performed on isolated SECs. Liver injuries were induced by CCl4 or quantitative polymerase chain reaction injection. RESULTS: Hepatic c-kit is expressed predominantly in SECs. Liver resident SECs contribute to the increase of c-kit during partial hepatectomy-induced liver regeneration. Isolated c-kit+ SECs promote hepatocyte proliferation in vivo and in vitro by facilitating angiocrine. The distribution of c-kit shows distinct spatial differences that are highly coincident with the liver zonation marker wingless-type MMTV integration site family, member2 (Wnt2). Notch mutation reshapes the c-kit distribution and liver zonation, resulting in altered hepatocyte proliferation. c-Kit+ SECs were shown to regulate hepatocyte regeneration through angiocrine in a Wnt2-dependent manner. Activation of the Notch signaling pathway weakens liver regeneration by inhibiting positive regulatory effects of c-kit+ SECs on hepatocytes. Furthermore, c-kit+ SEC infusion attenuates toxin-induced liver injuries in mice. CONCLUSIONS: Our results suggest that c-kit+ SECs contributes to liver zonation and regeneration through Wnt2 and is regulated by Notch signaling, providing opportunities for novel therapeutic approaches to liver injury in the future. Transcript profiling: GEO (accession number: GSE134037).

Characterizing Fibrosis and Inflammation in a Partial Bile Duct Ligation Mouse Model by Multiparametric Magnetic Resonance Imaging.

BACKGROUND: Partial bile duct ligation (PBDL) model is a reliable cholestatic fibrosis experimental model that showed complex histopathological changes. Magnetic resonance imaging (MRI) features of PBDL have not been well characterized. PURPOSE: To investigate the potential of MRI parameters in assessing fibrosis in PBDL and explore the relationships between MRI and pathological features. ANIMAL MODEL: Established PBDL models. POPULATION: Fifty-four mice were randomly divided into four timepoints PBDL groups and one sham group. FIELD STRENGTH/SEQUENCE: 3.0 T; MRI sequences included T1-weighted fast spin-echo (FSE), T2-weighted single shot FSE, variable flip angle T1 mapping, multi-echo SE T2 mapping, multi-echo gradient-echo T2* mapping, and multi-b-value diffusion-weighted imaging. ASSESSMENT: MRI examination was performed at the corresponding timepoints after surgery. Native T1, ΔT1 (T1native-T1post), T2, T2*, apparent diffusion coefficient (ADC) values, histogram parameters (skewness and kurtosis), intravoxel incoherent motion parameters (f, D, and D* ) within the entire ligated (PBDL), non-ligated liver (PBDL), and whole liver (sham) were obtained. Fibrosis and inflammation were assessed in Masson and H&E staining slices using the Metavir and activity scoring system. STATISTICAL TESTS: One-way ANOVA, Spearman's rank correlation, and receiver operating characteristic curves were performed. P < 0.05 was considered statistically significant. RESULTS: Fibrosis and inflammation were finally staged as F3 and A3 in ligated livers but were not observed in non-ligated or sham livers. Ligated livers displayed significantly elevated native T1, ΔT1, T2, and reduced ADC and T2* than other livers. Spearman's correlation showed better correlation with inflammation (r = 0.809) than fibrosis (r = 0.635) in T2 and both ΔT1 and ADC showed stronger correlation with fibrosis (r = 0.704 and r = -0.718) than inflammation (r = 0.564 and r = -0.550). Area under the curve (AUC) for ΔT1 performed the highest (0.896). When combined with all relative parameters, AUC increased to 0.956. DATA CONCLUSION: Multiparametric MRI can evaluate and differentiate pathological changes in PBDL. ΔT1 and ADC better correlated with fibrosis while T2 stronger with inflammation. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.