Robust inference for causal mediation analysis of recurrent event data.

Recurrent events, including cardiovascular events, are commonly observed in biomedical studies. Understanding the effects of various treatments on recurrent events and investigating the underlying mediation mechanisms by which treatments may reduce the frequency of recurrent events are crucial tasks for researchers. Although causal inference methods for recurrent event data have been proposed, they cannot be used to assess mediation. This study proposed a novel methodology of causal mediation analysis that accommodates recurrent outcomes of interest in a given individual. A formal definition of causal estimands (direct and indirect effects) within a counterfactual framework is given, and empirical expressions for these effects are identified. To estimate these effects, a semiparametric estimator with triple robustness against model misspecification was developed. The proposed methodology was demonstrated in a real-world application. The method was applied to measure the effects of two diabetes drugs on the recurrence of cardiovascular disease and to examine the mediating role of kidney function in this process.

An efficient approach for identifying important biomarkers for biomedical diagnosis.

In this paper, we explore the challenges associated with biomarker identification for diagnosis purpose in biomedical experiments, and propose a novel approach to handle the above challenging scenario via the generalization of the Dantzig selector. To improve the efficiency of the regularization method, we introduce a transformation from an inherent nonlinear programming due to its nonlinear link function into a linear programming framework under a reasonable assumption on the logistic probability range. We illustrate the use of our method on an experiment with binary response, showing superior performance on biomarker identification studies when compared to their conventional analysis. Our proposed method does not merely serve as a variable/biomarker selection tool, its ranking of variable importance provides valuable reference information for practitioners to reach informed decisions regarding the prioritization of factors for further investigations.

Role of microglial metabolic reprogramming in Parkinson's disease.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by damage to nigrostriatal dopaminergic neurons. Key pathogenic mechanisms underlying PD include alpha-synuclein misfolding and aggregation, impaired protein clearance, mitochondrial dysfunction, oxidative stress, and neuroinflammation. However, to date, no study has confirmed the specific pathogenesis of PD. Similarly, current PD treatment methods still have shortcomings. Although some emerging therapies have proved effective for PD, the specific mechanism still needs further clarification. Metabolic reprogramming, a term first proposed by Warburg, is applied to the metabolic energy characteristics of tumor cells. Microglia have similar metabolic characteristics. Pro-inflammatory M1 type and anti-inflammatory M2 type are the two types of activated microglia, which exhibit different metabolic patterns in glucose, lipid, amino acid, and iron metabolism. Additionally, mitochondrial dysfunction may be involved in microglial metabolic reprogramming by activating various signaling mechanisms. Functional changes in microglia resulting from metabolic reprogramming can cause changes in the brain microenvironment, thus playing an important role in neuroinflammation or tissue repair. The involvement of microglial metabolic reprogramming in PD pathogenesis has been confirmed. Neuroinflammation and dopaminergic neuronal death can effectively be reduced by inhibiting certain metabolic pathways in M1 microglia or reverting M1 cells to the M2 phenotype. This review summarizes the relationship between microglial metabolic reprogramming and PD and provides strategies for PD treatment.

Modulating tumour vascular normalisation using triptolide-loaded NGR-functionalized liposomes for enhanced cancer radiotherapy.

Radiotherapy is an effective therapy in tumour treatment. However, the characteristics of the tumour microenvironment, including hypoxia, low pH, and interstitial fluid pressure bring about radioresistance. To improve the anti-tumour effect of radiotherapy, it has been demonstrated that antiangiogenic therapy can be employed to repair the structural and functional defects of tumour angiogenic vessels, thereby preventing radioresistance or poor therapeutic drug delivery. In this study, we prepared triptolide (TP)-loaded Asn-Gly-Arg (NGR) peptide conjugated mPEG2000-DSPE-targeted liposomes (NGR-PEG-TP-LPs) to induce tumour blood vessel normalisation, to the end of increasing the sensitivity of tumour cells to radiotherapy. Further, to quantify the tumour vessel normalisation window, the structure and functionality of tumour blood vessels post NGR-PEG-TP-LPs treatment were evaluated. Thereafter, the anti-tumour effect of radiotherapy following these treatments was evaluated using HCT116 xenograft-bearing mouse models based on the tumour vessel normalisation period window. The results obtained showed that NGR-PEG-TP-LPs could modulate tumour vascular normalisation to increase the oxygen content of the tumour microenvironment and enhance the efficacy of radiotherapy. Further, liver and kidney toxicity tests indicated that NGR-PEG-TP-LPs are safe for application in cancer treatment.

Recent research progress on metabolic syndrome and risk of Parkinson's disease.

Parkinson's disease (PD) is one of the most widespread neurodegenerative diseases. PD is associated with progressive loss of substantia nigra dopaminergic neurons, including various motor symptoms (e.g., bradykinesia, rigidity, and resting tremor), as well as non-motor symptoms (e.g., cognitive impairment, constipation, fatigue, sleep disturbance, and depression). PD involves multiple biological processes, including mitochondrial or lysosomal dysfunction, oxidative stress, insulin resistance, and neuroinflammation. Metabolic syndrome (MetS), a collection of numerous connected cerebral cardiovascular conditions, is a common and growing public health problem associated with many chronic diseases worldwide. MetS components include central/abdominal obesity, systemic hypertension, diabetes, and atherogenic dyslipidemia. MetS and PD share multiple pathophysiological processes, including insulin resistance, oxidative stress, and chronic inflammation. In recent years, MetS has been linked to an increased risk of PD, according to studies; however, the specific mechanism remains unclear. Researchers also found that some related metabolic therapies are potential therapeutic strategies to prevent and improve PD. This article reviews the epidemiological relationship between components of MetS and the risk of PD and discusses the potentially relevant mechanisms and recent progress of MetS as a risk factor for PD. Furthermore, we conclude that MetS-related therapies are beneficial for the prevention and treatment of PD.

Experimental observation of the electron beam focusing effect induced by plasma currents with opposite directions.

We report on the experimental observation of the focusing effect of a 50MeV accelerator electron beam in a gas-discharge plasma target. The plasma is generated by igniting an electric discharge in two collinear quartz tubes, with the currents up to 1.5kA flowing in opposite directions in either of the two tubes. In such plasma current configuration, the electron beam is defocused in the first discharge tube and focused with a stronger force in the second one. With symmetric plasma currents, asymmetric effects are, however, induced on the beam transport process and the beam radius is reduced by a factor of 2.6 compared to the case of plasma discharge off. Experimental results are supported by two-dimensional particle-in-cell simulations.

Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

Evaluation of plasma LC3B+extracellular vesicles as a potential novel diagnostic marker for hepatocellular carcinoma.

BACKGROUND: Circulating extracellular vesicles (EVs) are recognized as a promising source of cancer biomarkers. We previously reported that tumor cell-released autophagosomes, a new subgroup of EVs expressing the mature autophagosome-specific marker LC3B (LC3B+ EVs), are critical modulators of host anti-tumor immunity. This study aimed to assess the level of plasma LC3B+ EVs and the correlation with clinical outcomes in liver cancer patients. METHODS: The plasma and ascites samples were obtained from patients with liver cancer, non-malignant liver disease, and healthy controls. EVs were isolated by differential centrifugation and characterized using flow cytometry, nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of plasma LC3B+ EVs or HSP90α+LC3B+ EVs from liver cancer patients. The relationship between the expression levels of HSP90AA1 or MAP1LC3B and survival were analyzed using patient data from the TCGA database. The correlation between HSP90α in LC3B+ EVs and PD-1highCD8+ exhausted T cells from the ascites and peripheral blood of liver cancer patients was also evaluated. RESULTS: The EVs preparation from liver cancer patients contained LC3B+ EVs expressing epithelial tumor cell adhesion molecules (EpCAM), indicating that these LC3B+ EVs originated from epithelial tumor cells. The levels of plasma LC3B+ EVs and HSP90α+LC3B+ EVs in liver cancer patients were significantly higher than in non-malignant liver disease patients and healthy controls. The expression of HSP90α in plasma LC3B+ EVs (AUC 0.9595, sensitivity 86.00%, specificity 96.67%) accurately differentiated liver cancer patients from non-liver cancer controls. Additionally, a significant decrease in the levels of plasma LC3B+ EVs and HSP90α+LC3B+ EVs was found post-surgery in each patient, and high expression of HSP90AA1 or MAP1LC3B in the tumor tissue correlated with significantly worse survival compared to those with low expression. We also observed that the level of LC3B+ EVs and HSP90α+LC3B+ EVs positively correlated with the PD-1highCD8+ exhausted T cells in liver cancer patients. Human CD8+ T cells treated with purified LC3B+ EVs in vitro exhibited a dose-dependent increase in the percentage of PD-1+CD8+ T cells, whereas the production of IFN-γ was decreased. CONCLUSIONS: We demonstrated that isolation and detection of plasma LC3B+ EVs carrying bioactive molecules is an effective diagnostic marker of liver cancer, and may also be used as a potential marker for immune monitoring and predicting prognosis clinically.

Severe COVID-19-associated sepsis is different from classical sepsis induced by pulmonary infection with carbapenem-resistant klebsiella pneumonia (CrKP).

PURPOSE: COVID-19 is also referred to as a typical viral septic pulmonary infection by 2019-nCoV. However, little is known regarding its characteristics in terms of systemic inflammation and organ injury, especially compared with classical bacterial sepsis. This article aims to investigate the clinical characteristics and prognosis between COVID-19-associated sepsis and classic bacterial-induced sepsis. METHODS: In this retrospective cohort study, septic patients with COVID-19 in the intensive care unit (ICU) of a government-designed therapy center in Shenzhen, China between January 14, 2020 and March 10, 2020, and septic patients induced by carbapenem-resistant klebsiella pneumonia (CrKP) admitted to the ICU of the Second People's Hospital of Shenzhen, China between January 1, 2014 and October 30, 2019 were enrolled. Demographic and clinical parameters including comorbidities, critical illness scores, treatment, and laboratory data, as well as prognosis were compared between the two groups. Risk factors for mortality and survival rate were analyzed using multivariable logistic regression and survival curve, respectively. RESULTS: A total of 107 patients with COVID-19 and 63 patients with CrKP were enrolled. A direct comparison between the two groups demonstrated more serious degrees of primary lung injury following 2019-nCoV infection (indicated by lower PaO2/FiO2), but milder systemic inflammatory response, lower sequential organ failure assessment score and better functions of the organs like heart, liver, kidney, coagulation, and circulation. However, the acquired immunosuppression presented in COVID-19 patients was more severe, which presented as lower lymphocyte counts (0.8×109/L vs. 0.9×109/L). Moreover, the proportion of COVID-19 patients treated with corticosteroid therapy and extracorporeal membrane oxygenation was larger compared with CrKP patients (78.5% vs. 38.1% and 6.5% vs. 0, respectively) who required less invasive mechanical ventilation (31.6% vs. 54.0%). The incidence of hospitalized mortality and length of ICU stay and total hospital stay were also lower or shorter in viral sepsis (12.1% vs. 39.7%, 6.5 days vs. 23.0 days and 21.0 days vs. 33.0 days, respectively) (all p < 0.001). Similar results were obtained after being adjusted by age, gender, comorbidity and PaO2/FiO2. Lymphocytopenia and high acute physiology and chronic health evaluation II scores were common risk factors for in-hospital death. While the death cases of COVID-19 sepsis mostly occurred at the later stages of patients' hospital stay. CONCLUSION: Critical COVID-19 shares clinical characteristics with classical bacterial sepsis, but the degree of systemic inflammatory response, secondary organ damage and mortality rate are less severe. However, following 2019-nCoV infection, the level of immunosuppression may be increased and thus induce in more death at the later stage of patients' hospitalstay.

Network Pharmacology-Based Analysis on the Curative Effect of Kunxian Capsules against Rheumatoid Arthritis.

Kunxian capsules (KCs), a Chinese patent medicine, have been clinically proven to be effective in the treatment of rheumatoid arthritis (RA). However, the chemical profile of KC remains to be characterized, and the mechanism underlying the protective effect against RA is yet to be elucidated. Here, a network pharmacology-based approach was adopted, integrated with the chemical profiling of KC by UHPLC-Q-TOF/MS. As a result, a total of 67 compounds have been identified from KC extract, among which 43 were authenticated by comparison to the mass spectrum of standard chemicals. ADME behaviors of the chemical constituents of KC were predicted, resulting in 35 putative active ingredients. Through target prediction of both active ingredients of KC and RA and PPI analysis, core targets were screened out, followed by biological process and related pathway enrichment. Then, a TCM-herb-ingredient-target-pathway network was constructed and a multicomponent, multitarget, and multipathway synergistic mechanism was proposed, providing an information basis for further investigation. The active pharmaceutical ingredients included mainly terpenoids (such as triptolide and celastrol), sesquiterpene pyridines (such as wilforgine and wilforine), and flavonoids (such as icariin, epimedin A, B, and C, and 2″-O-rhamnosylicariside II).

Evaluation of the etiology and risk factors for maternal sepsis: A single center study in Guangzhou, China.

BACKGROUND: Maternal sepsis is a major cause of gestational morbidity and neonatal mortality worldwide and particularly in China. AIM: To evaluate the etiology of maternal sepsis and further identify its risk factors. METHODS: In this retrospective study, we evaluated 70698 obstetric patients who were admitted to the Third Affiliated Hospital of Guangzhou Medical University between January 1, 2009 and June 30, 2018. Subjects were divided into sepsis group and non-sepsis group based on the incidence of sepsis. Data about medical history (surgical and obstetric history) and demographic information were collected. The Mann-Whitney U test was used to compare patient age, gestational age and duration of hospitalization between the two groups. Univariate and multivariate logistic regression models were used to analyze the etiology and the risk factors for maternal sepsis. Unadjusted and adjusted odds ratios (OR) are reported. RESULTS: A total of 561 of 70698 obstetric patients were diagnosed with infection; of the infected patients, 492 had non-sepsis associated infection (87.7%), while 69 had sepsis (12.3%). The morbidity rate of maternal sepsis was 9.76/10000; the fatality rate in the sepsis group was 11.6% (8/69). Emergency admission (OR = 2.183) or transfer (OR = 2.870), irregular prenatal care (OR = 2.953), labor induction (OR = 4.665), cervical cerclage (OR = 14.214), first trimester (OR = 6.806) and second trimester (OR = 2.09) were significant risk factors for maternal sepsis. CONCLUSION: Mode of admission, poor prenatal care, labor induction, cervical cerclage, first trimester and second trimester pregnancy were risk factors for maternal sepsis. Escherichia coli was the most common causative organism for maternal sepsis, and the uterus was the most common site of infection.

Standardized Ultrasound Diagnosis of Nuchal Cord.

OBJECTIVE: This study aims to investigate the formation factors that affect the angle of nuchal cord and explore the types of nuchal cord that exist and the process of standardized ultrasound diagnosis of nuchal cord. METHODS: Ultrasonography was performed on 707 fetuses with nuchal cord, to observe the direction of the coil, determine the type of coil, and analyze the correlation between the fetal position, placental location, and the direction of the coil with the angle of the umbilical cord. RESULTS: Among the 707 fetuses, those with 1 loop accounted for 89.67%, fetuses with 2 loops accounted for 6.08%, fetuses with 3 loops accounted for 0.28%, and fetuses with partial draping of the umbilical cord accounted for 3.96%. Nuchal cord mostly occurred in fetuses where the placenta was attached to the anterior wall of the uterus, and the α-shaped and C-shaped types were in the majority. The C-shaped type accounted for 43.14%, the α-shaped type for 40.88%, the O-shaped type for 12.02%, and the L-shaped type for 3.96%. CONCLUSION: The direction of the coil of the umbilical cord can be determined by blood flow vector observation. The fetal position, placental location, and the direction of the coil are the three factors affecting the coiling angle of the umbilical cord. Ultrasonic classification of nuchal cord can provide detailed information, which can be used by physicians when performing surgery on the fetus. The advances in the diagnosis procedure allow the diagnosis of nuchal cord to be carried out in an orderly manner, making it more accurate and standardized.

Collective energy-spectrum broadening of a proton beam in a gas-discharge plasma.

An accurate understanding of ion-beam transport in plasmas is crucial for applications in inertial fusion energy and high-energy-density physics. We present an experimental measurement on the energy spectrum of a proton beam at 270 keV propagating through a gas-discharge hydrogen plasma. We observe the energies of the beam protons changing as a function of the plasma density and spectrum broadening due to a collective beam-plasma interaction. Supported by linear theory and three-dimensional particle-in-cell simulations, we attribute this energy modulation to a two-stream instability excitation and further saturation by beam ion trapping in the wave. The widths of the energy spectrum from both experiment and simulation agree with the theory.

Association between Procalcitonin and Acute Kidney Injury in Patients with Bacterial Septic Shock.

OBJECTIVE: The objective of this study was to assess the relationship between serum procalcitonin (PCT) and acute kidney injury (AKI) induced by bacterial septic shock. METHODS: A retrospective study was designed which included patients who were admitted to the ICU from January 2015 to October 2018. Multiple logistic regression and receiver operating characteristic (ROC) as well as smooth curve fitting analysis were used to assess the relationship between the PCT level and AKI. RESULTS: Of the 1,631 patients screened, 157 patients were included in the primary analysis in which 84 (53.5%) patients were with AKI. Multiple logistic regression results showed that PCT (odds ratio [OR] = 1.017, 95% confidence interval [CI] 1.009-1.025, p < 0.001) was associated with AKI induced by septic shock. The ROC analysis showed that the cutoff point for PCT to predict AKI development was 14 ng/mL, with a sensitivity of 63% and specificity 67%. Specifically, in multivariate piecewise linear regression, the occurrence of AKI decreased with the elevation of PCT when PCT was between 25 ng/mL and 120 ng/mL (OR 0.963, 95% CI 0.929-0.999; p = 0.042). The AKI increased with the elevation of PCT when PCT was either <25 ng/mL (OR 1.077, 95% CI 1.022-1.136; p = 0.006) or >120 ng/mL (OR 1.042, 95% CI 1.009-1.076; p = 0.013). Moreover, the PCT level was significantly higher in the AKI group only in female patients aged ≤75 years (p = 0.001). CONCLUSIONS: Our data revealed a nonlinear relationship between PCT and AKI in septic shock patients, and PCT could be used as a potential biomarker of AKI in female patients younger than 75 years with bacterial septic shock.

Clinical Characteristics and Risk Factors for Critically Ill Patients with Carbapenem-Resistant Klebsiella pneumonia e (CrKP): A Cohort Study from Developing Country.

BACKGROUND: Increasing evidence indicates carbapenem-resistant Klebsiella pneumoniae (CrKP) is increasingly prevalent in intensive care unit (ICU), but its clinical characteristics and risk factors remain unknown. AIM: The aim of the present study was to evaluate clinical characteristics, risk factors in critically ill patients with CrKP infection. METHODS: A retrospective study was included in patients from January 2013 to October 2019. Clinical data were collected from CrKP patients on the day of specimen collection admitted to ICU. Multivariable logistic regression was used for risk factors. Receiver operating curve (ROC) and the area under the curve (AUC) with DeLong method of MedCalc software were used. Two-way repeated-measures ANOVA analysis was used to analyze the characteristics of independent risk factors over time. FINDINGS: A total of 147 adult patients with CrKP were screened, among them, 89 (median age 64.0 years, 66 (74.15%) males) patients with CrKP were finally included, of which 38 patients (42.7%) were non-survival group. Multivariate logistic regression analysis indicated that lactic acid (OR3.04 95% CI 1.38-6.68, P = 0.006), APACHE II score (OR 1.20, 95% CI 1.09-1.33, P < 0.001), tigecycline combined with fosfomycin treatment (OR0.15, 95% CI 0.04-0.65, P = 0.011) are independent risk factors for 28-day mortality in patients with CRKP infection (P<0.05). Combined lactic acid with APACHE II score could predict 28-day mortality, of which AUC value was 0.916 (95% CI, 0.847-0.985), with sensitivity 0.76 and specificity 0.98. ANOVA analysis showed that APACHE II score and lactic acid between the two groups at three-time points were statistically significant, which interactive with time and showed an upward and downward trend with time (P < 0.05). CONCLUSION: Therapeutic strategy based on improving lactic acid and APACHE II would contribute to the outcome in patients with CrKP infection. Tigecycline combined with fosfomycin could reduce the 28-day mortality in patients with CrKP infection in developing country.

Subclinical subretinal fluid detectable only by optical coherence tomography in choroidal naevi-the SON study.

BACKGROUND: Subretinal fluid is a risk factor for growth and malignant transformation of choroidal naevi, however it is unclear if this applies to subclinical fluid that is only detectable by optical coherence tomography (OCT). The objective of this study was to determine the prevalence and associations of subclinical but OCT-detectable subretinal fluid over choroidal naevi. METHODS: Cross-sectional study of 309 consecutive cases of choroidal naevi imaged by OCT between July 2017 to January 2019. Multicentre international study involving ten retinal specialist centres. All patients presenting to retinal specialists had routine clinical examination and OCT imaging. The prevalence of subclinical OCT-detectable subretinal fluid over choroidal naevi and its associations with other features known to predict growth and malignant transformation were noted and analysed. RESULTS: Of 309 identified consecutive cases, the mean patient age was 65 years, 89.3% of patients were Caucasian and 3.9% were Asian. The prevalence of subclinical but OCT-detectable subretinal fluid associated with choroidal naevi was 11.7% (36/309). Naevi with fluid were associated with larger basal diameters, greater thickness, presence of a halo, orange pigmentation, hyperautofluorescence, and hypodensity on B-scan ultrasonography. CONCLUSION AND RELEVANCE: Of choroidal naevi where subretinal fluid is not visible on clinical examination, 11.7% demonstrate subretinal fluid on OCT scans. These naevi more commonly exhibit features known to be associated with growth and transformation to melanoma. The presence of subclinical OCT-detectable fluid over choroidal naevi may assist in their risk stratification.

Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors.

In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC50 = 5.9 nM, ß/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.

Electronic structures of WS2 armchair nanoribbons doped with transition metals.

Armchair WS2 nanoribbons are semiconductors with band gaps close to 0.5 eV. If some of the W atoms in the ribbon are replaced by transition metals, the impurity states can tremendously affect the overall electronic structure of the doped ribbon. By using first-principles calculations based on density functional theory, we investigated substitutional doping of Ti, V, Cr, Mn, Fe, and Co at various positions on WS2 ribbons of different widths. We found that Fe-doped ribbons can have two-channel conduction in the middle segment of the ribbon and at the edges, carrying opposite spins separately. Many Co-doped ribbons are transformed into spin filters that exhibit 100% spin-polarized conduction. These results will be useful for spintronics and nanoelectronic circuit design.

Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice.

Lactoferrin (Lf), an iron-binding glycoprotein, has been shown to possess antioxidant and anti-inflammatory properties and exert modulatory effects on lipid homeostasis and non-alcoholic fatty liver disease (NAFLD), but our understanding of its regulatory mechanisms is limited and inconsistent. We used leptin-deficient (ob/ob) mice as the rodent model of NAFLD, and administered recombinant human Lf (4 mg per kg body weight) or control vehicle by intraperitoneal injection to evaluate the hepatoprotective effects of Lf. After 40 days of treatment with Lf, insulin sensitivity and hepatic steatosis in ob/ob mice were significantly improved with the down-regulation of sterol regulatory element binding protein-2 (SREBP2), indicating an improvement in hepatic lipid metabolism and function. We further explored the mechanism, and found that Lf may increase the hepatocellular iron output by targeting the hepcidin-ferroportin (FPn) axis, and then maintains the liver oxidative balance through a nonenzymatic antioxidant system, ultimately suppressing the death of hepatocytes. In addition, the cytoprotective role of Lf may be associated with the inhibition of endoplasmic reticulum (ER) stress and inflammation, promotion of autophagy of damaged hepatocytes and induction of up-regulation of hypoxia inducible factor-1α/vascular endothelial growth factor (HIF-lα/VEGF) to facilitate liver function recovery. These findings suggest that recombinant human Lf might be a potential therapeutic agent for mitigating or delaying the pathological process of NAFLD.