Search

The objective of this study was to assess the role of NETs in BPD of hyperoxia-induced rat model and the effect of heparin on alveolarization and vascular development in BPD. The neonatal rats exposed to 90% oxygen continuously for 7 days to mimic BPD, meanwhile, the rats were injected by different doses of histones to evaluate the impact on lung injury. The newborn rats exposed to hyperoxia were injected by different doses of heparin (250 U/kg, 500 U/kg) or anti-H4 antibody to evaluate the effect of heparin. Histones and hyperoxia impaired alveolarization with the increase of mean linear intercept (MLI) and the decrease of radial alveolar count (RAC), decreased lung angiogenesis with the decrease expression of VEGF, and increased the expression of NETs, histones and pro-inflammatory factor. However, low dose heparin (250U/kg) administration enhanced survival, improved alveolarization and vascular development in hyperoxia-induced BPD, as well as reduced expression of NETs, histones and pro-inflammatory factor. We concluded that heparin improves alveolarization and vascularization in BPD by inhibiting NETs.

The centrosome is a unique organelle: the semi-conservative nature of its duplication generates an inherent asymmetry between ‘mother’ and ‘daughter’ centrosomes, which differ in their age. This asymmetry has captivated many cell biologists, but its meaning has remained enigmatic. In the last two decades, many stem cell types have been shown to display stereotypical inheritance of either the mother or daughter centrosome. These observations have led to speculation that the mother and daughter centrosomes bear distinct information, contributing to differential cell fates during asymmetric cell divisions. This review summarizes recent progress and discusses how centrosome asymmetry may promote asymmetric fates during stem cell divisions.

The piRNA pathway protects germline genomes from selfish genetic elements (e.g. transposons) through their transcript cleavage in the cytoplasm and/or their transcriptional silencing in the nucleus. Here, we describe a mechanism by which the nuclear and cytoplasmic arms of the piRNA pathway are linked. We find that during mitosis of Drosophila spermatogonia, nuclear Piwi interacts with nuage, the compartment that mediates the cytoplasmic arm of the piRNA pathway. At the end of mitosis, Piwi leaves nuage to return to the nucleus. Dissociation of Piwi from nuage occurs at the depolymerizing microtubules of the central spindle, mediated by a microtubule-depolymerizing kinesin, Klp10A. Depletion of klp10A delays the return of Piwi to the nucleus and affects piRNA production, suggesting the role of nuclear-cytoplasmic communication in piRNA biogenesis. We propose that cell cycle-dependent communication between the nuclear and cytoplasmic arms of the piRNA pathway may play a previously unappreciated role in piRNA regulation., Author summary The piRNA pathway that defends germline from selfish elements operates in two subpathways, one mediated by Piwi in Drosophila to silence transcription of targets in the nucleus and the other mediated by Aub and Ago3 to cleave transcripts of targets in the cytoplasm. How these two subpathways might coordinate with each other, particularly at the cell biological level, remains elusive. This study shows that Piwi interacts with Aub/Ago3 specifically in mitosis in nuage, the organelle that serves as the platform for piRNA cytoplasmic subpathway. Piwi returns to the nucleus at the end of mitosis, and our study suggests that dissociation of Piwi from nuage is facilitated by microtubule depolymerization by a kinesin Klp10A at the central spindle. We propose that cell-cycle-dependent interaction of two piRNA subpathways may play an important role in piRNA production.

Asymmetrically dividing stem cells often show asymmetric behavior of the mother versus daughter centrosomes, whereby the self-renewing stem cell selectively inherits the mother or daughter centrosome. Although the asymmetric centrosome behavior is widely conserved, its biological significance remains largely unclear. Here, we show that Alms1a, aDrosophilahomolog of the human ciliopathy gene Alstrom syndrome, is enriched on the mother centrosome inDrosophilamale germline stem cells (GSCs). Depletion ofalms1ain GSCs, but not in differentiating germ cells, results in rapid loss of centrosomes due to a failure in daughter centriole duplication, suggesting that Alms1a has a stem-cell-specific function in centrosome duplication. Alms1a interacts with Sak/Plk4, a critical regulator of centriole duplication, more strongly at the GSC mother centrosome, further supporting Alms1a’s unique role in GSCs. Our results begin to reveal the unique regulation of stem cell centrosomes that may contribute to asymmetric stem cell divisions.

Purpose We aimed to explore the value of Routine blood parameters, such as the lymphocyte (LYM) count, platelet (PLT) count, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), LYM*PLT and mean platelet volume-to-platelet ratio (MPV/PLT), are widely used to predict the prognosis of infectious diseases, for predicting influenza virus infection in children. Methods We conducted a single-center, retrospective, observational study on fever with influenza-like symptom in pediatric outpatients in different age groups and evaluated the predictive value of various routine blood parameters within 48 hours of the onset of fever after influenza virus infection. Results The LYM count, PLT count, LMR and LYM*PLT were lower, and the NLR and MPV/PLT were higher in the infected children. The LYM count, LMR and LYM*PLT in the infected group were lower in the 1- to 6-year-old group, and the LMR and LYM*PLT in the infected group were lower in the > 6-year-old group. In the 1- to 6-year-old group, the cutoff value of the LMR for predicting influenza A virus infection was 3.75, the sensitivity was 81.87%, the specificity was 84.31%, and the AUC was 0.886; the cutoff value of the LMR for predicting influenza B virus infection was 3.71, the sensitivity was 73.58%, the specificity was 84.31%, and the AUC was 0.843. In the > 6-year-old group, the cutoff value of the LMR for predicting influenza A virus infection was 3.05, the sensitivity was 89.27%, the specificity was 89.61%, and the AUC was 0.949; the cutoff value of the LMR for predicting influenza B virus infection was 2.88, the sensitivity was 83.19%, the specificity was 92.21%, and the AUC was 0.924. Conclusions Routine blood tests are simple, inexpensive and easy to perform, and they are useful for predicting influenza virus infection in children. The LMR had the strongest predictive value for influenza virus infection in children older than 1 year, especially influenza A virus infection.

To detect pathogenic variant in a neonate suspected for Cornelia de Lange syndrome (CdLS).Potential mutations of CdLS-related genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8) were detected by high-throughput target region capture and next-generation sequencing. Suspected variants was verified by Sanger sequencing.The child was found to harbor a heterozygous splice site variant, c.6109-1GA, of the NIPBL gene. Sanger sequencing suggested that neither parent has carried the same variant, suggesting that it was de novo. The variant was unreported by HGMD and ExAC database, and was predicted to alter an acceptor splicing site. No pathogenic variants of SMC1A, SMC3, RAD21 and HDAC8 genes were detected.The heterozygous c.6109-1GA splicing variant of the NIPBL gene may underlie the disease in this child. Above finding has expanded the variant spectrum of the NIPBL gene.

Background and Objective: Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants; predicting the degree of BPD at an early life stage is difficult. Inflammation is a crucial risk factor for BPD pathogenesis, and the neutrophil-to-lymphocyte ratio (NLR) is a potential systemic inflammatory biomarker. We aimed to assess the predictive value of the NLR for BPD. Methods: We carried out a retrospective, single-center, observational study of neonates with gestational ages (GAs)

BACKGROUND Bronchopulmonary dysplasia (BPD) is a major complication of extreme prematurity, characterized by alveolar simplification and pulmonary malfunction. Hyperoxia-induced lung injury in neonatal rats has been used as a model of BPD, as indicated by lung architectural change and alveolar simplification that resembles clinical feature of BPD. s-defensin-2 (BD2) plays an important role in lung diseases by inhibiting inflammation response. However, little is known about its role in BPD. The aim of this study was to determine the effect of human BD2 (hBD2) gene on hyperoxia-induced animal model of BPD. MATERIAL AND METHODS The neonatal rats were exposed to 90% oxygen (O₂) continuously for 14 days to mimic the BPD-like lung injury. These rats were then randomly assigned to the following four groups: in room air (air), in 90% O₂, in 90% O₂ with null adenovirus vector infection (O₂+Ad), and in 90% O₂ with gene therapy through adenovirus transfected hBD2 (O₂+Ad-hBD2). Morphology of lungs, pulmonary function and expression of inflammatory cytokines on P7, P10, P14, and P21 were documented and compared across the 4 groups. RESULTS The overexpression of hBD2 mediated by the adenovirus vector was successfully constructed. hBD2 gene therapy increased hBD2 mRNA expression, increased radial alveolar count (RAC), lung volume and compliance, decreased mean linear intercept (MLI), tissue damping, and elastance. Furthermore, pro-inflammatory cytokines IL-1s, IL-6, and TNF-alpha were inhibited and anti-inflammatory cytokines IL-10 was increased in the lungs of rats in O₂+Ad-hBD2 group. CONCLUSIONS In hyperoxia-induced rat models of BPD, hBD2 promotes alveolarization and improves pulmonary function. The mechanism may contribute in alleviating inflammation response and inhibiting pro-inflammatory factors including IL-1s, IL-6, and TNF-alpha.

Preterm ovarian hyperstimulation syndrome (POHS) is a rare condition with only a few reported cases. The objective of this study is to investigate the clinical characteristics of 21 POHS cases (seven from China and 14 from the literature). Suspected patients (

In many species, germline stem cells (GSCs) function to sustain gametogenesis throughout the life of organismal life span. As the source of gametes, the only cell type that can pass the genetic information to the next generation, GSCs play a fundamental role in maximizing the quantity of gametes that animals produce, while ensuring their highest quality. GSCs are maintained by the signals from their niches, and germ cells that exited the niche undergo differentiation to generate functional gametes. GSC population is sustained by a multitude of mechanisms such as asymmetric stem cell divisions and dedifferentiation of partially differentiated germ cells. In this review, we summarize the mechanisms that maintain GSC homeostasis to ensure life-long production of functional gametes.

Asymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome’s role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.

The midbody ring (MR) is asymmetrically segregated during asymmetric divisions of germline stem cells (GSCs) in Drosophila. Male GSCs, which inherit the mother centrosome, exclude the MR, whereas female GSCs, which inherit the daughter centrosome, inherit the MR. Moreover, stem cell identity correlates with the mode of MR inheritance., Many stem cells, including Drosophila germline stem cells (GSCs), divide asymmetrically, producing one stem cell and one differentiating daughter. Cytokinesis is often asymmetric, in that only one daughter cell inherits the midbody ring (MR) upon completion of abscission even in apparently symmetrically dividing cells. However, whether the asymmetry in cytokinesis correlates with cell fate or has functional relevance has been poorly explored. Here we show that the MR is asymmetrically segregated during GSC divisions in a centrosome age–dependent manner: male GSCs, which inherit the mother centrosome, exclude the MR, whereas female GSCs, which we here show inherit the daughter centrosome, inherit the MR. We further show that stem cell identity correlates with the mode of MR inheritance. Together our data suggest that the MR does not inherently dictate stem cell identity, although its stereotypical inheritance is under the control of stemness and potentially provides a platform for asymmetric segregation of certain factors.

Asymmetric stem cell division is often accompanied by stereotypical inheritance of the mother and daughter centrosomes. However, it remains unknown whether and how stem cell centrosomes are uniquely regulated and how this regulation may contribute to stem cell fate. Here we identify Klp10A, a microtubule-depolymerizing kinesin of the kinesin-13 family, as the first protein enriched in the stem cell centrosome in Drosophila male germline stem cells (GSCs). Depletion of klp10A results in abnormal elongation of the mother centrosomes in GSCs, suggesting the existence of a stem cell-specific centrosome regulation program. Concomitant with mother centrosome elongation, GSCs form asymmetric spindle, wherein the elongated mother centrosome organizes considerably larger half spindle than the other. This leads to asymmetric cell size, yielding a smaller differentiating daughter cell. We propose that klp10A functions to counteract undesirable asymmetries that may result as a by-product of achieving asymmetries essential for successful stem cell divisions. DOI: http://dx.doi.org/10.7554/eLife.20977.001

A novel light-operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer-incorporated G-quadruplex DNA-capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug-carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell-specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery.

Many adult stem cells divide asymmetrically, generating one stem cell (self-renewal) and one differentiating cell. Balancing self-renewal and differentiation is critical for sustaining tissue homeostasis throughout the life of an organism. Failure to execute asymmetric stem cell division can have profound impacts on tissue homeostasis, resulting in tissue degeneration or hyperplasia/tumorigenic overgrowth. Recent studies have expanded our understanding of both the extracellular and intracellular mechanisms that regulate, reinforce and ensure an asymmetric outcome following stem cell division. In this review, we discuss newly discovered aspects of asymmetric stem cell division that, in concert with well-established mechanisms, contribute to balancing self-renewal and differentiation.

A novel proton-fueled molecular gate-like delivery system has been constructed for controlled cargo release using i-motif quadruplex DNA as caps onto pore outlets of mesoporous silica nanoparticles. Start from simple conformation changes, the i-motif DNA cap can open and close the pore system in smart response to pH stimulus. Importantly, the opening/closing and delivery protocol is highly reversible and a partial cargo delivery can be easily controlled at will. A pH-switchable nanoreactor has also been developed to validate the potential of our system for on-demand molecular transport. This proof of concept might open the door to a new generation of carrier materials and could also provide a general route to use other functional nucleic acids/peptide nucleic acids as capping agents in the fields of versatile controlled delivery nanodevices.

A novel multi-functional, proton-fueled DNA tweezers has been constructed. Starting from simple conformation change of i-motif DNA, the nanodevice can accomplish movements such as repeatedly capture or release target DNA and protein. The DNA tweezers, driven by the solution pH without the need of injecting external energy, are robust and highly reversible with the responses of 1–2 orders of magnitude faster than the DNA-fueled machine, and does not accumulate duplex waste products to poison the system. Our work has demonstrated the successful combination of the operating principles of DNA-based nanomechanical device with the unique molecular recognition properties of DNA, which we believed could open an exciting avenue in the design and construction of easy-to-handle, cost-efficient, reliable and high efficient functional nanostructure.

Enzymatic manipulation of DNA on well-dispersed gold nanoparticles (AuNPs) offers an ideal system for high-throughput screening of G-quadruplex ligands and evaluation of their selectivity with respect to duplex and quadruplex DNA (see figure). This work has implications for the future use of nanoparticle-based technologies in the discovery of potential cancer therapeutic agents.

An enzyme responsive nanoparticle system that uses a DNA-gold nanoparticle (AuNP) assembly as the substrate has been developed for the simple, sensitive, and universal monitoring of restriction endonucleases in real time. This new assay takes advantage of the palindromic recognition sequence of the restriction nucleases and the unique optical properties of AuNPs and is simpler than the procedure previously described by by Xu et al. (Angew. Chem. Int. Ed. Engl. 2007, 46, 3468-3470). Because it involves only one type of ssDNA modified AuNPs, this assay can be directed toward most of the endonucleases by simply changing the recognition sequence found within the linker DNA. In addition, the endonuclease activity could be quantitatively analyzed by the value of the reciprocal of hydrolysis half time (t(1/2)(-1)). Furthermore, our new design could also be applied to the assay of methyltransferase activity since the methylation of DNA inhibits its cleavage by the corresponding restriction endonuclease, and thus, this new methodology can be easily adapted to high-throughput screening of methyltransferase inhibitors.

By using AuNP-modified homo-adenine DNA conjugate as a model system, simple colorimetric and resonance Rayleigh scattering assays have been developed for screening small molecules that trigger the formation of the non-Watson-Crick homo-adenine duplexes. The assay presented here is more simplified in format as it involves only one type of ssDNA modified Au-NP, and can be easily adapted to high-throughput screening.

To evaluate the prognostic value of the absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) at diagnosis in diffuse large B-cell lymphoma (DLBCL), we performed a meta-analysis of published studies that provided survival information with reference to the ALC/AMC ratio at diagnosis. Nine studies covering a total of 4198 subjects were included in this analysis. The summary hazard ratios of low ALC/AMC ratio for overall survival were 2.00 (p = 0.000) in the population that received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 1.12 (p = 0.479) in the population that received CHOP. The corresponding ratios for event-free survival and progression-free survival were 1.93 (p = 0.000) and 2.31 (p = 0.000) in the population that received R-CHOP. These results may justify risk-adapted therapeutic strategies for patients with DLBCL treated with R-CHOP to account for the ALC/AMC ratio at diagnosis.

Nano-Al2O3 is dispersed onto the surface of the glassy carbon electrode (GCE). This nanostructured film modified GCE exhibits a great enhancement to the oxidation of estradiol (E2), especially when adequate concentration of cationic surfactant such as cetyltrimethylammonium bromide (CTAB) is added into the sample solution. Due to the nanoparticle's unique properties and its inclination to selectively combine with some groups of bimolecules, as well as synergistic adsorption of E2 and CTAB on the electrode surface, E2 gives a more sensitive voltammetric response compared with bare GCE performed in the absence of CTAB. The lowest detectable concentration (3σ) of E2 is estimated to be 8×10−8 mol l−1 (accumulation for 2 min). The linear relationship between peak current and concentration of E2 holds in the range 4×10−7–4×10−5 mol l−1 (R=0.9932). The electrochemical properties of E2 on this modified electrode are investigated by linear scan voltammetry and cyclic voltammetry. Scanning electron microscope (SEM) and BET are employed to characterize the surface of the electrode modified with nano-Al2O3 film.

We have designed and synthesized an intelligent mesoporous silica nanoparticle–DNA hydrogel bioreactor system that can be controlled by external stimuli. The system allowed the simultaneous incorporation of multiple components, and the separation between the components can be destroyed by a structural change of the DNA to initiate a reaction.

Metal ions play important roles in amyloid aggregation and neurotoxicity. Metal-ion chelation therapy has been used in clinical trials for Alzheimer's disease (AD) treatment. However, clinical trial studies have shown that long-term use of metal chelator can cause adverse side effect, subacute myelo-optic neuropathy. Nanoparticle engineering processes have become promising approaches for efficiently drugs delivery. A series of modified mesoporous silica nanoparticles (MSNs) using redox, pH, competitive binding, light, and enzyme as actuators have been demonstrated. Recently, significant advances in sensing oxidative stress have been made by taking advantage of specific chemistry between cellular oxidants such as H(2) O(2) . Here we report a biocompatible delivery platform by using H(2) O(2) responsive controlled-release system to realize target delivery of AD therapeutic metal chelator. The advantage of this novel strategy is that metal chelator can only be released by the increased levels of H(2) O(2) , thus, it would not interfere with the healthy metal homeostasis and can overcome strong side effect of metal chelator after long-term use. By taking advantage of the good biocompatibility, cellular uptake properties, and efficient intracellular release of metal chelators, the delivery system is promising for future in vivo controlled-release biomedical applications.

Dopamine exhibits intriguing reactivity with silver nanoparticles through Ag-catechol interaction, which results in non-crosslinking AgNP aggregation, thus providing a novel approach for colorimetric detection of dopamine with high sensitivity and selectivity.

A label-free colorimetric assay, using non-crosslinking AuNP aggregation, has been developed for the screening of specific triplex DNA binders. The relative binding affinities can be simultaneously determined. Our novel assay is simple in design and fast in operation, avoiding either AuNPs modification or oligonucleotide labeling, and easy to implement for visual detection. This strategy may offer a new approach for developing low cost, sensitive and high-throughput screening platform that is likely to be highly useful in a wide range of applications.

Based on selective pore-opening in the presence of protease, we have developed a novel signal amplification assay for multiple proteases detection and their inhibition using protein-capped mesoporous scaffolding as the substrate.