Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Autoimmune diseases: targets, biology, and drug discovery.

Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing ß cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens.

HPV-infection status and urinary incontinence: a population-based analysis of the NHANES 2005-2016.

PURPOSE: Urinary incontinence is a common condition and reduces the quality of life. The purpose of this study was to assess the association between HPV infection and urinary incontinence among adult women in the USA. METHODS: We examined a cross-sectional study using the National Health and Nutrition Examination Survey database. Women who had valid HPV DNA vaginal swab test results and answered the questionnaire about urinary incontinence were selected from six consecutive survey cycles (2005-2006 to 2015-2016). The association between HPV status and urinary incontinence was analyzed using weighted logistic regression. Models adjusted for potential variables were established. RESULTS: In total, 8348 females aged between 20 and 59 years old were enrolled in this study. 47.8% of participants had a history of urinary incontinence and 43.9% of women were HPV DNA positive. After adjusting for all confounders, women with HPV infection were less likely to have urinary incontinence (OR = 0.88, 95%CI 0.78-0.98). Low-risk HPV infection correlated with a lower incidence of incontinence (OR = 0.88, 95%CI 0.77-1.00). For women aged below 40 years, low-risk HPV infection negatively correlated with stress incontinence (20-29ys: OR = 0.67, 95%CI 0.49-0.94; 30-39ys: OR = 0.71, 95%CI 0.54-0.93). However, low-risk HPV infection positively correlated with stress incontinence (OR = 1.40, 95%CI 1.01-1.95) for women 50-59 years old. CONCLUSION: This study revealed a negative association between HPV infection and urinary incontinence in females. Low-risk HPV correlated with stress urinary incontinence, with the reverse trend for participants of different ages.

Comprehensive Profiling of ceRNA (circRNA-miRNA-mRNA) Networks in Hypothalamic-Pituitary-Mammary Gland Axis of Dairy Cows under Heat Stress.

Heat stress (HS) is directly correlated with mammary gland dysfunction and the hypothalamic-pituitary-mammary gland (HPM) axis is involved in regulating stress responses and lactation in dairy cows. Circular RNAs (circRNAs) play major roles in regulating transcription and post-transcription but their expression in the HPM axis of dairy cows under HS is still unclear. In the present study, we performed RNA sequencing to identify diferentially expressed (DE) circRNAs, DE microRNAs(miRNAs) and DEmRNAs, and performed bioinformatics analysis on those in HPM axis-related tissues of heat-stressed and normal cows. A total of 1680, 1112 and 521 DEcircRNAs, 120, 493 and 108 DEmiRNAs, 274, 6475 and 3134 DEmRNAs were identified in the hypothalamic, pituitary, and mammary gland tissues, respectively. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses indicated that the MAPK signaling pathway is potentially a key pathway. Competitive endogenous RNA (ceRNA) networks related to HS response and lactation regulation were established in three tissues. In conclusion, our results indicate that HS induces differential circRNA expression profiles in HPM axis-related tissues, and the predicted ceRNA network provides a molecular basis for regulating the stress response and lactation regulation in heat-stressed dairy cows.

The utilization of microwaves in revitalizing peroxymonosulfate for tetracycline decomposition: optimization via response surface methodology.

Antibiotic contamination in water has received significant attention in recent years for the reason that the residuals of antibiotics can promote the progression of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs). It is difficult to treat antibiotics using conventional biological treatment methods. In order to investigate an efficient new method of treating antibiotics in water, in this study, microwave (MW) was employed in revitalizing peroxymonosulfate (PMS) to treat typical antibiotic tetracycline (TC). The Box-Behnken design (BBD) was applied to organize the experimental schemes. The response surface methodology (RSM) optimization was run to derive the best experimental conditions and validated using actual data. Moreover, the main mechanisms of PMS activation via MW were resolved. The results demonstrated that the relationship between TC removal rate and influencing factors was consistent with a quadratic model, where the P-value was less than 0.05, and the model was considered significant. The optimal condition resulting from the model optimization were power = 800 W, [PMS] = 0.4 mM, and pH = 6.0. Under such conditions, the actual removal of TC was 99.3%, very close to the predicted value of 99%. The quenching experiment confirmed that SO4•- and •OH were jointly responsible for TC removal.

The honey-trap of workplace friendship: Developing and testing a three-way interaction model to understand when and why workplace friendship triggers employee withdrawal behaviour.

Although previous research has found that workplace friendship has beneficial effects on employees' and organisations' consequences, knowledge regarding the complexity and dark sides of workplace friendship is limited. Our purpose is to develop and test a three-way interaction model that explains when and how negative outcomes of workplace friendship are likely to unfold considering both individual personality and contextual conditions. Based on the stressor-emotion model, we argue that workplace friendship may also be a stressor due to its conflicting and contradictory dual roles, which in turn triggers negative employees' emotions, thus, leading to withdrawal behaviour. Furthermore, we propose that emotional reactivity and task interdependence are individual and contextual factors that induce and catalyse the negative effect of workplace friendship. By analysing the data from 429 respondents, the result supported our hypotheses. Overall, our research provides a theoretical and empirical foundation for future research on the dark sides of workplace friendship.

Mechanism underlying liquid-to-solid phase transition in fused in sarcoma liquid droplets.

The RNA-binding protein fused in sarcoma (FUS) forms ribonucleoprotein granules via liquid-liquid phase separation (LLPS) in the cytoplasm. The phase separation of FUS accelerates aberrant liquid-solid phase separation and leads to the onset of familial amyotrophic lateral sclerosis (ALS). We previously found that FUS forms two types of liquid condensates in equilibrium, specifically LP-LLPS (i.e., normal type) and HP-LLPS (i.e., aberrant type), each with different partial molar volumes. However, it is unclear how liquid condensates are converted to the pathogenic solid phase. Here, we report a mechanism underlying the aberrant liquid-to-solid phase transition of FUS liquid condensates and the inhibition of this transition with small molecules. We found that the liquid condensate formed via HP-LLPS had greatly reduced dynamics, which is a common feature of aged wild-type FUS droplets and the droplet-like assembly of the ALS patient-type FUS variant. The longer FUS remained on the HP-LLPS, the harder it was to transform it into a mixed state (i.e., one-phase). These results indicate that liquid-to-solid phase transition, namely the aging of droplets, is accelerated with HP-LLPS. Interestingly, arginine suppressed the aging of droplets and HP-LLPS formation more strongly than LP-LLPS formation. These data indicate that the formation of HP-LLPS via the one-phase state or LP-LLPS is a pathway leading to irreversible solid aggregates. Dopamine and pyrocatechol also suppressed HP-LLPS formation. Our data highlight the potential of HP-LLPS to be used as a therapeutic target and arginine as a plausible drug candidate for ALS-causing FUS.

Nicotinamide mononucleotide alleviates heat stress-induced oxidative stress and apoptosis in BMECs through reducing mitochondrial damage and endoplasmic reticulum stress.

Heat stress is directly correlated to mammary gland dysfunction in dairy cows, especially in summer. Abnormally high environmental temperature induces oxidative stress and apoptosis in bovine mammary epithelial cells (BMECs). Nicotinamide mononucleotide (NMN) has beneficial effects in maintaining the cellular physiological functions. In this study, we evaluate the protective effect of NMN on heat stress-induced apoptosis of BMECs and explore the potential underlying mechanisms. Our results showed that heat stress considerably decreased cell viability in BMECs, whereas pretreatment of BMECs with NMN (150 µM) for 24 h significantly alleviated the negative effects of heat stress on cells. NMN protected BMECs from heat stress-induced oxidative stress by inhibiting the excessive accumulation of reactive oxygen species (ROS) and increasing the activity of antioxidant enzymes. It also inhibited apoptosis by reducing the ratio of Bax/Bcl2 and blocking proteolytic the cleavage of Caspase-3 in heat stressed-BMECs. Importantly, NMN treatment could reduce mitochondrial damage through mediating the expression of mitochondrial fission and fusion-related genes, including Dynamin related protein 1 (Drp1), Mitochondrial fission 1 protein (Fis1), and Mitofusin1, 2 (MFN1, 2); and suppress endoplasmic reticulum stress through unfolded protein response regulator Glucose regulated protein 78 (GRP78), and downstream elements Recombinant activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Above all, our results demonstrate that NMN supplemention attenuates heat stress-induced oxidative stress and apoptosis in BMECs by maintaining mitochondrial fission and fusion, and regulating endoplasmic reticulum stress, which provides the convincing evidence that NMN has valuable potential in alleviating mammary gland injury of dairy cows caused by environmental heat stress.

Upregulation Sestrin2 protects against hydrogen peroxide-induced oxidative damage bovine mammary epithelial cells via a Keap1-Nrf2/ARE pathway.

Sestrin2 (SESN2) is a highly conservative oxidative stress protein that can regulate energy metabolism, cell proliferation, apoptosis, and mitochondria autophagy processes. It plays a role as an antioxidant in various diseases. The aims of the present study were to explore the underlying role of SESN2 after hydrogen peroxide (H2 O2 ) treatment in bovine mammary epithelial cells (MAC-T cells) by the methods of knockout or overexpression of SESN2. The results show that knockout of Sestrin2 exacerbate apoptosis, upregulate the expressions of Bax/Bcl2 in H2 O2 -treated MAC-T cells. Moreover, knockout of SESN2 also promoted reactive oxygen species (ROS) generation and exacerbated oxidative damage in H2 O2 -treated MAC-T cells. On the contrary, overexpression of SESN2 decreased apoptosis by downregulation of Bax/Bcl2 level decreased ROS generation and blocked oxidative damage in H2 O2 -treated MAC-T cells. In addition, results indicate that the Kelch-like ECH-associated protein-1 (Keap1)-nuclear factor (erythroid-derived 2) like2 (Nrf2)/antioxidant response element (ARE) signaling pathway was activated by H2 O2 ; upregulation of SESN2 could relieve oxidative stress by inducing the expression of Keap1, Nrf2, HO-1, and NDPH: quinone oxidoreductase-1 protein. In conclusion, this study demonstrates that expression of SESN2 was significantly increased after H2 O2 treatment and that SESN2 can alleviate oxidative stress and cell apoptosis in H2 O2 -treated MAC-T cells through activation of the Keap1-Nrf2/ARE pathway.

Pressure-Jump Kinetics of Liquid-Liquid Phase Separation: Comparison of Two Different Condensed Phases of the RNA-Binding Protein, Fused in Sarcoma.

The RNA-binding protein fused in sarcoma (FUS) undergoes liquid-liquid phase separation (LLPS) both in vivo and in vitro. Self-assembled liquid droplets of FUS transform into reversible hydrogels and into more irreversible and toxic aggregates. Although LLPS can be a precursor of irreversible aggregates, a generic method to study kinetics of the formation of LLPS has not been developed. Here, we demonstrated the pressure-jump kinetics of phase transition between the 1-phase state and FUS-LLPS states observed at low pressure (<2 kbar, LP-LLPS) and high pressure (>2 kbar, HP-LLPS) using high-pressure UV/vis spectroscopy. Absorbance (turbidity) changes were reproduced repeatedly using pressure cycles. The Johnson-Mehl-Avrami-Kolmogorov theory was used to understand droplet formation occurring via nucleation and growth. The Avrami exponent n, representing the dimensionality of growing droplets, and the reaction rate constant k were calculated. The HP-LLPS formation rate was ∼2-fold slower than that of LP-LLPS. The Avrami exponent obtained for both LLPS states could be explained by diffusion-limited growth. Nucleation and growth rates decreased during LP-LLPS formation (n = 0.51), and the nucleation rate decreased with a constant growth rate in HP-LLPS formation (n = 1.4). The HP-LLPS vanishing rate was ∼20-fold slower than that of LP-LLPS. This difference in vanishing rates indicates a stronger intermolecular interaction in HP-LLPS than in LP-LLPS, which might promote transformation into irreversible aggregates in the droplets. Further, direct transition from HP-LLPS to LP-LLPS was observed. This indicates that interconversion between LP-LLPS and HP-LLPS occurs in equilibrium. Formation of reversible liquid droplets, followed by phase transition into another liquid phase, could thus be part of the physiological maturation process of FUS-LLPS.

Transcriptomic analysis reveals that the small protein MgtS contributes to the virulence of uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) is the most common pathogen causing urinary tract infections (UTIs). The pathogenesis of UPEC relies on the formation of intracellular bacterial communities (IBCs) after invading bladder epithelial cells (BECs). In this study, the gene expression profiles of UPEC after invading BECs were comprehensively analyzed using RNA sequencing to reveal potential virulence-related genes. The small protein MgtS, which is transcriptionally upregulated in BECs, was further investigated. It was found that MgtS contributed positively to UPEC invasion of BECs and colonization in murine bladders. A two-component regulatory system, PhoPQ was confirmed as a direct activator of mgtS expression in BECs, and magnesium limitation is proposed as a host cue for the activation. This study provides the first comprehensive analysis of the transcriptome profile of UPEC during its intra-BECs life, revealing a new virulence-associated gene and its regulatory mechanism.

QTL mapping for foxtail millet plant height in multi-environment using an ultra-high density bin map.

KEY MESSAGE: Using a fixed RIL population derived from a widely used foxtail millet backbone breeding line and an elite cultivar, we constructed a high-density bin map and identified six novel multi-environment effect QTLs and seven candidate genes for dwarf phenotype. Plant height is an important trait that determines tradeoffs between competition and resource allocation, which is crucial for yield potential. To improve the C4 model plant foxtail millet (Setaria italica) productivity, it is necessary to isolate plant height-related genes that contribute to ideal plant architecture in breeding. In the present study, we generated a foxtail millet population of 333 recombinant inbred lines (RILs) derived from a cross between a backbone line Ai 88 and an elite cultivar Liaogu 1. We evaluated plant height in 13 environmental conditions across 4 years, the mean plant height of the RIL population ranged from 89.5 to 149.9 cm. Using deep re-sequencing data, we constructed a high-density bin map with 3744 marker bins. Quantitative trait locus (QTL) mapping identified 26 QTLs significantly associated with plant height. Of these, 13 QTLs were repeatedly detected under multiple environments, including six novel QTLs that have not been reported before. Seita.1G242300, a gene encodes gibberellin 2-oxidase-8, which was detected in nine environments in a 1.54-Mb interval of qPH1.3, was considered as an important candidate gene. Moreover, other six genes involved in GA biosynthesis or signaling pathways, and fifteen genes encode F-box domain proteins which might function as E3 ligases, were also considered as candidate genes in different QTLs. These QTLs and candidate genes identified in this study will help to elucidate the genetic basis of foxtail millet plant height, and the linked markers will be useful for marker-assistant selection of varieties with ideal plant architecture and high yield potential.

Genetic control and phenotypic characterization of panicle architecture and grain yield-related traits in foxtail millet (Setaria italica).

KEY MESSAGE: Multi-environment QTL mapping identified 23 stable loci and 34 co-located QTL clusters for panicle architecture and grain yield-related traits, which provide a genetic basis for foxtail millet yield improvement. Panicle architecture and grain weight, both of which are influenced by genetic and environmental factors, have significant effects on grain yield potential. Here, we used a recombinant inbred line (RIL) population of 333 lines of foxtail millet, which were grown in 13 trials with varying environmental conditions, to identify quantitative trait loci (QTL) controlling nine agronomic traits related to panicle architecture and grain yield. We found that panicle weight, grain weight per panicle, panicle length, panicle diameter, and panicle exsertion length varied across different geographical locations. QTL mapping revealed 159 QTL for nine traits. Of the 159 QTL, 34 were identified in 2 to 12 environments, suggesting that the genetic control of panicle architecture in foxtail millet is sensitive to photoperiod and/or other environmental factors. Eighty-eight QTL controlling different traits formed 34 co-located QTL clusters, including the triple QTL cluster qPD9.2/qPL9.5/qPEL9.3, which was detected 23 times in 13 environments. Several candidate genes, including Seita.2G388700, Seita.3G136000, Seita.4G185300, Seita.5G241500, Seita.5G243100, Seita.9G281300, and Seita.9G342700, were identified in the genomic intervals of multi-environmental QTL or co-located QTL clusters. Using available phenotypic and genotype data, we conducted haplotype analysis for Seita.2G002300 and Seita.9G064000,which showed high correlations with panicle weight and panicle exsertion length, respectively. These results not only provided a basis for further fine mapping, functional studies and marker-assisted selection of traits related to panicle architecture in foxtail millet, but also provide information for comparative genomics analyses of cereal crops.

On the mechanisms of development in monocot and eudicot leaves.

Contents Summary 706 I. Introduction 707 II. Leaf zones in monocot and eudicot leaves 707 III. Monocot and eudicot leaf initiation: differences in degree and timing, but not kind 710 IV. Reticulate and parallel venation: extending the model? 711 V. Flat laminar growth: patterning and coordination of adaxial-abaxial and mediolateral axes 713 VI. Stipules and ligules: ontogeny of primordial elaborations 715 VII. Leaf architecture 716 VIII. Stomatal development: shared and diverged mechanisms for making epidermal pores 717 IX. Conclusion 719 Acknowledgements 720 References 720 SUMMARY: Comparisons of concepts in monocot and eudicot leaf development are presented, with attention to the morphologies and mechanisms separating these angiosperm lineages. Monocot and eudicot leaves are distinguished by the differential elaborations of upper and lower leaf zones, the formation of sheathing/nonsheathing leaf bases and vasculature patterning. We propose that monocot and eudicot leaves undergo expansion of mediolateral domains at different times in ontogeny, directly impacting features such as venation and leaf bases. Furthermore, lineage-specific mechanisms in compound leaf development are discussed. Although models for the homologies of enigmatic tissues, such as ligules and stipules, are proposed, tests of these hypotheses are rare. Likewise, comparisons of stomatal development are limited to Arabidopsis and a few grasses. Future studies may investigate correlations in the ontogenies of parallel venation and linear stomatal files in monocots, and the reticulate patterning of veins and dispersed stoma in eudicots. Although many fundamental mechanisms of leaf development are shared in eudicots and monocots, variations in the timing, degree and duration of these ontogenetic events may contribute to key differences in morphology. We anticipate that the incorporation of an ever-expanding number of sequenced genomes will enrich our understanding of the developmental mechanisms generating eudicot and monocot leaves.

Generation of mode-locked square-shaped and chair-like pulse based on reverse saturable absorption effect of nonlinear multimode interference.

In this paper, the phenomenon of reverse saturable absorption of offset-spliced graded index multimode fibers (OS-GIMF) is revealed. And based on that, the stable square-shaped and chair-like mode-locked pulses are demonstrated with the maximum pulse energy of 0.14 µJ and 23.8 nJ respectively, while the OS-GIMF acts as a saturable absorber (SA) in fiber laser. By adjusting polarization controller (PC) and the pump power, square-shaped and chair-like pulse can be switched to each other. This multimode SA could sever as high power light source owing to its high damage threshold, compact structure and low cost.

Polyoxotungstate Cluster Species Connected by Glutamic Acid and Europium.

An organic-inorganic hybridized polyoxotungstate which contains two kinds of covalently linked tungstate clusters in its polyanion has been obtained. The three clusters are connected by glutamic acid molecules and europium atoms through Eu-O-C bonds. The cluster in the middle position is a tetramer. Two of the same clusters at two sides are dimers that are functionalized by glutamic acid molecules. The solid-state luminescence of this compound exhibited the characteristic emission of Eu3+ centers with a lifetime of 232 µs.

Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects.

Phosphodiesterase type 4 (PDE4) inhibitors can prevent the breakdown of the second messenger cyclic adenosine monophosphate (cAMP) and improve cognitive performances in several animal models of cognition. However, the clinical development of PDE4 inhibitors has been seriously hampered by severe side effects, such as vomiting and nausea. In this study, we investigated the effect and mechanism of roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), on learning and memory abilities in the APP/PS1 mouse model of Alzheimer's disease (AD). APP/PS1 transgenic mice received 3 intragastric doses of roflumilast (0.1, 0.2 and 0.4 mg/kg) daily for 3 weeks followed by behavioral tests. Chronic administration of roflumilast significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the novel object recognition task, Morris water maze, and the step-down passive avoidance task. In addition, roflumilast increased the cAMP, phosphorylated cAMP response-element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels, and reduced the nuclear translocation of nuclear factor-kappa B (NF-κB) p65, and proinflammatory cytokine (IL-6, TNF-a and IL-1ß) levels in the hippocampus of APP/PS1 transgenic mice. In conclusion, these findings suggest that roflumilast can enhance cognitive function in APP/PS1 transgenic mice, which may be related to its stimulation of the cAMP/CREB/BDNF pathway and anti-neuroinflammatory effects.

Schizandrin A Alleviates LPS-Induced Injury in Human Keratinocyte Cell Hacat Through a MicroRNA-127-Dependent Regulation.

BACKGROUND/AIMS: Inflammatory skin diseases are the most common problems in dermatology. Schizandrin A (SchA) has been reported to have anti-inflammatory properties. Herein, we aimed to investigate the protective effects of SchA on lipopolysaccharide (LPS)-induced injury in keratinocyte HaCaT cells. METHODS: Inflammation injury in HaCaT cells was induced by LPS treatment. Cell viability, apoptotic cell rate, and apoptosis-related proteins were analyzed by cell counting kit-8 (CCK-8) assay, Annexin V-(fluorescein isothiocyanate (FITC)/ Propidium Iodide (PI) double staining method, and western blot, respectively. The pro-inflammatory factors were analyzed by western blot and quantified by enzyme linked immunosorbent assay (ELISA). Expression of miR-127 in SchA-treated cells was analyzed by qRT-PCR. The effects of SchA on activations of p38MAPK/ERK and JNK pathways were analyzed by western blot. RESULTS: SchA protected HaCaT cells from LPS-induced inflammation damage via promoting cell viability, suppressing apoptosis. Meanwhile, SchA inhibited IL-1ß, IL-6, and TNF-α expression. miR-127 expression was up-regulated in LPS-treated HaCaT cells but down-regulated after SchA treatment. Overexpression of miR-127 inhibited cell growth and induced expression of IL-1ß, IL-6 and TNF-α. Additionally, miR-127 overexpression impaired the protective effects of SchA, implying miR-127 might be correlated to the anti-inflammation property of SchA and also involved in inactivation of p38MAPK/ERK and JNK pathways by SchA. CONCLUSION: miR-127 is involved in the protective functions of SchA on LPS-induced inflammation injury in human keratinocyte cell HaCaT, which might inactivates of p38MAPK/ERK and JNK signaling pathways in HaCaT cells.

Chirp-adjustable square-wave pulse in a passively mode-locked fiber laser.

A passively mode-locked fiber laser to generate chirp-adjustable square-wave pulses is reported. A simple chirp measurement system is designed to study the output chirp of the fiber laser. The results indicate that the chirp of the square-wave pulses in our fiber laser can be adjusted by the polarization controllers inside the cavity. Three typical chirp states, including random chirp, V-shaped chirp and linear chirp, are achieved. This kind of fiber laser cannot only help to further understand the characteristics of square-wave pulse but also serve as multifunction light source for potential applications.

Directly probing the dissociation effects of graphene oxide nanosheets on hIAPP fibrils.

The aggregation of human islet amyloid polypeptides (hIAPP) to mature fibrils is considered as the main cause of type II diabetes. Therefore destroying the pre-formed hIAPP fibrils is expected to be a promising strategy for therapeutic treatments. In this work, the dissociation effects of graphene oxide (GO) nanosheets on hIAPP mature fibrils are investigated. The results clearly demonstrate that hIAPP fibrils can be quickly adsorbed on the GO surface and efficiently broken into short fragments. Meanwhile, the ß-sheet structures of hIAPP fibrils are greatly destroyed. Particularly, in situ atomic force microscopy was applied to monitor the real-time interaction between hIAPP fibrils and GO nanosheets. It provides distinct evidence that the disruption of hIAPP fibrils by GO nanosheets mainly occurs at the GO edges. Size-dependent experiments further justify the interfere of edge contribution, which suggest small-sized GO nanosheets exhibit better dissociation ability than large-sized ones. Therefore, this study not only provides valuable information that GO nanosheets (especially small-sized ones) can act as efficient nanoblades to break hIAPP fibrils, but also suggests a powerful and widely available methodology for investigating real-time interaction between nanomaterials and biomolecules.