Hemoglobinopathies are the most common inherited diseases in southern China. However, there have been only a few epidemiological studies of hemoglobinopathies in Guangdong province.
Materials and Methods
Peripheral blood samples were collected from 15299 “healthy” unrelated subjects of dominantly ethnic Hakka in the Meizhou region, on which hemoglobin electrophoresis and routine blood tests were performed. Suspected cases with hemoglobin variants and hereditary persistence of fetal hemoglobin (HPFH) were further characterized by PCR, DNA sequencing, reverse dot blot (RDB) or multiplex ligation-dependent probe amplification (MLPA). In addition, 1743 samples were randomly selected from the 15299 subjects for thalassemia screening, and suspected thalassemia carriers were identified by PCR and RDB.
The gene frequency of hemoglobin variants was 0.477% (73/15299). The five main subgroups of the ten hemoglobin variants were Hb E, Hb G-Chinese, Hb Q-Tahiland, Hb New York and Hb J-Bangkok. 277 cases (15.89%, 277/1743) of suspected thalassemia carriers with microcytosis (MCV<82 fl) were found by thalassemia screening, and were tested by a RDB gene chip to reveal a total of 196 mutant chromosomes: including 124 α-thalassemia mutant chromosomes and 72 β-thalassemia mutant chromosomes. These results give a heterozygote frequency of 11.24% for common α and β thalassemia in the Hakka population in the Meizhou region. 3 cases of HPFH/δβ-thalassemia were found, including 2 cases of Vietnamese HPFH (FPFH-7) and a rare Belgian Gγ(Aγδβ)0–thalassemia identified in Chinese.
Our results provide a detailed prevalence and molecular characterization of hemoglobinopathies in Hakka people of the Meizhou region. The estimated numbers of pregnancies each year in the Meizhou region, in which the fetus would be at risk for β thalassemia major or intermedia, Bart’s hydrops fetalis, and Hb H disease, are 25 (95% CI, 15 to 38), 40 (95% CI, 26 to 57), and 15 (95% CI, 8 to 23), respectively.
The DNase domain-containing protein TATDN1 is a conserved nuclease in both prokaryotes and eukaryotes. It was previously implicated to play a role in apoptotic DNA fragmentation in yeast and C. elegans. However, its biological function in higher organisms, such as vertebrates, is unknown. Here, we report that zebrafish TATDN1 (zTATDN1) possesses a novel endonuclease activity, which first makes a nick at the DNA duplex and subsequently converts the nick into a DNA double-strand break in vitro. This biochemical property allows zTATDN1 to catalyze decatenation of catenated kinetoplast DNA to produce separated linear DNA in vitro. We further determine that zTATDN1 is predominantly expressed in eye cells during embryonic development. Knockdown of TATDN1 in zebrafish embryos results in an abnormal cell cycle progression, formation of polyploidy and aberrant chromatin structures. Consequently, the TATDN1-deficient morphants have disordered eye cell layers and significantly smaller eyes compared with the WT control. Altogether, our current studies suggest that zTATDN1 plays an important role in chromosome segregation and eye development in zebrafish.
TATDN1; nuclease; decatenation; cell cycle; zebrafish; eye
JUNB inactivation in transgenic mice results in a myeloproliferative disorder that closely resembles human chronic myelogenous leukemia (CML). It has been reported that downregulation of JUNB expression is a universal phenomenon in patients with CML due aberrant DNA methylation of its promoter. Based on this, we studied methylation and gene expression levels of JUNB in CML. We analyzed the methylation status of the JUNB gene in 6 cell lines and in 102 patients with CML using several bisulfite PCR assays. JUNB expression was analyzed using real-time PCR and gene expression profiling. JUNB methylation was not observed in any of the cell lines studied, and only in 3% of patients with CML. Despite the lack of JUNB methylation, JUNB was expressed at low levels both in CML cell lines (median dCT −6.86; range −5.87 to −9.61), and in patients with CML in blastic phase (BP) (median dCT −3.95; range −1.48 to −6.29) (p=0.002). Finally, we evaluated JUNB expression in 82 additional patients with CML by gene expression arrays. We found that JUNB was significantly downregulated in advanced phase CML in contrast to chronic phase CML (median log ratio difference in expression = 0.53). Overall, our results indicate that JUNB expression is downregulated in advanced phase CML through a mechanism independent from DNA methylation.
JUNB; DNA methylation; chronic myelogenous leukemia
The term epigenetics refers to the study of a number of biochemical modifications of chromatin that have an impact on gene expression regulation. Aberrant epigenetic lesions, in particular DNA methylation of promoter associated CpG islands, are common in acute lymphocytic leukemia (ALL). Recent data from multiple laboratories indicates that several hundred genes, involving dozens of critical molecular pathways, are epigenetically suppressed in ALL. Because these lesions are potentially reversible, the reactivation of these pathways using, for instance, hypomethylating agents may have therapeutic potential in this disease. Furthermore, the analysis of epigenetic alterations in ALL may allow: 1) the identification of subsets of patients with poor prognosis when treated with conventional therapy; 2) development of new techniques to evaluate minimal residual disease; 3) better understanding of the differences between pediatric and adult ALL; and 4) new therapeutic interventions by incorporating agents with hypomethylating activity to conventional chemotherapeutic programs. In this review, we desribe the role of epigenetic alterations in ALL from a translational perspective.
Acute lymphocytic leukemia; DNA methylation; epigenetics
Radiotherapy is one of the major therapeutic strategies in cancer treatment. The telomere-binding protein TPP1 is an important component of the shelterin complex at mammalian telomeres. Our previous reports showed that TPP1 expression was elevated in radioresistant cells, but the exact effects and mechanisms of TPP1 on radiosensitivity is unclear.
In this study, we found that elevated TPP1 expression significantly correlated with radioresistance and longer telomere length in human colorectal cancer cell lines. Moreover, TPP1 overexpression showed lengthened telomere length and a significant decrease of radiosensitivity to X-rays. TPP1 mediated radioresistance was correlated with a decreased apoptosis rate after IR exposure. Furthermore, TPP1 overexpression showed prolonged G2/M arrest mediated by ATM/ATR-Chk1 signal pathway after IR exposure. Moreover, TPP1 overexpression accelerated the repair kinetics of total DNA damage and telomere dysfunction induced by ionizing radiation.
We demonstrated that elevated expressions of TPP1 in human colorectal cancer cells could protect telomere from DNA damage and confer radioresistance. These results suggested that TPP1 may be a potential target in the radiotherapy of colorectal cancer.
Scatter hoarders are not able to defend their caches. A longer hoarding distance combined with lower cache density can reduce cache losses but increase the costs of hoarding and retrieving. Scatter hoarders arrange their cache density to achieve an optimal balance between hoarding costs and main cache losses. We conducted systematic cache sampling investigations to estimate the effects of food availability on cache patterns of Eurasian red squirrels (Sciurus vulgaris). This study was conducted over a five-year period at two sample plots in a Korean pine (Pinus koraiensis)-dominated forest with contrasting seed production patterns. During these investigations, the locations of nest trees were treated as indicators of squirrel space use to explore how space use affected cache pattern. The squirrels selectively hoarded heavier pine seeds farther away from seed-bearing trees. The heaviest seeds were placed in caches around nest trees regardless of the nest tree location, and this placement was not in response to decreased food availability. The cache density declined with the hoarding distance. Cache density was lower at sites with lower seed production and during poor seed years. During seed mast years, the cache density around nest trees was higher and invariant. The pine seeds were dispersed over a larger distance when seed availability was lower. Our results suggest that 1) animal space use is an important factor that affects food hoarding distance and associated cache densities, 2) animals employ different hoarding strategies based on food availability, and 3) seed dispersal outside the original stand is stimulated in poor seed years.
Ultrasound elastography could be used as a new noninvasive technique for detecting early osteoarthritis. As the first critical step, this study theoretically predicted the excitation power and the measurement errors in detecting cartilage detect. A finite element model was used to simulate wave propagation of elastography in the cartilage. The wave was produced by a force F, and the wave speed C was calculated. The normal cartilage model was used to define the relationship between the wave speed and elastic modulus. Various stiffness values were simulated. F = 10 N with a duration of 0.5 ms was required for having measurable deformation (10 μm) at the distal site. The deformation had a significant rise when the wave crossed the defect. The relationship between the wave speed and elastic parameters was found as C = 1.57 × (E)/(2 × ρ(1+μ)))1/2, where E was the elastic modulus, μ was Poisson's ratio, and ρ was the density. For the simulated defect with an elastic modulus of 7 MPa which was slightly stiffer than the normal cartilage, the measurement error was 0.1 MPa. The results suggested that, given the simulated conditions, this new technique could be used to detect the defect in early osteoarthritis.
Scrub typhus is endemic to a 13,000,000-km2 area of the Asia-Pacific region, and causes an annual incidence of 1 million people. The mortality rate of scrub typhus ranges from 6.1% to 25% in Southeast Asia. Natural infection of Orientia tsutsugamushi has been identified in domestic rodents in Shandong Province. However, infestation of chiggers and ticks on the domestic rodents and prevalence and genotypes of O. tsutsugamushi in these Acarina remain unclear.
During September 2010 to March 2012, 3134 chiggers and 89 ticks were collected from domestic rodents captured in three counties of Shandong Province. We amplified and sequenced the 56-kDa type-specific antigen gene of O. tsutsugamushi from DNA samples of these Acarina and designated to genotype according to sequence analysis.
Overall, the infestation rate of chiggers on domestic rodents was 17.0%, and the chigger index was 5.38. The infestation rate of ticks on rodents was 3.1%. Natural infection of O. tsutsugamushi was found in Leptotrombidium taishanicum, L. linhuaikongense, L. intermedium, L. scutellare, L. palpale, and Ixodes spp., the minimum positive rates of which were 5.9%, 3.2%, 1.2%, 0.8%, 0.8%, and 2.2%, respectively. Kawasaki-like genotypes were predominant in chiggers and ticks on domestic rodents, which were detected from L. taishanicum, L. intermedium, L. scutellare, L. palpale, and Ixodes spp. Shimokoshi-like genotype was detected from L. palpale.
In the present study we investigated the infestation of chiggers and ticks on domestic rodents in Shandong Province, and identified the prevalence and genotypes of O. tsutsugamushi in the Acarina. Infestation of vector chiggers in domestic rodents, prevalence of O. tsutsugamushi in infested chiggers, and high nucleotide homologies among the O. tsutsugamushi sequences from the Acarina, their animal hosts and scrub typhus patients, implied that domestic rodents may play an important role in the transmission of scrub typhus in Shandong, China. Further studies are needed to verify the vector significance of chiggers and ticks that tested positive for O. tsutsugamushi, and to assess the risk of human exposure to chiggers and ticks on domestic rodents.
Scrub typhus; Orientia tsutsugamushi; Chigger; Tick; Rodents
Advances in technology have led to the generation of massive amounts of complex and multifarious biological data in areas ranging from genomics to structural biology. The volume and complexity of such data leads to significant challenges in terms of its analysis, especially when one seeks to generate hypotheses or explore the underlying biological processes. At the state-of-the-art, the application of automated algorithms followed by perusal and analysis of the results by an expert continues to be the predominant paradigm for analyzing biological data. This paradigm works well in many problem domains. However, it also is limiting, since domain experts are forced to apply their instincts and expertise such as contextual reasoning, hypothesis formulation, and exploratory analysis after the algorithm has produced its results. In many areas where the organization and interaction of the biological processes is poorly understood and exploratory analysis is crucial, what is needed is to integrate domain expertise during the data analysis process and use it to drive the analysis itself.
In context of the aforementioned background, the results presented in this paper describe advancements along two methodological directions. First, given the context of biological data, we utilize and extend a design approach called experiential computing from multimedia information system design. This paradigm combines information visualization and human-computer interaction with algorithms for exploratory analysis of large-scale and complex data. In the proposed approach, emphasis is laid on: (1) allowing users to directly visualize, interact, experience, and explore the data through interoperable visualization-based and algorithmic components, (2) supporting unified query and presentation spaces to facilitate experimentation and exploration, (3) providing external contextual information by assimilating relevant supplementary data, and (4) encouraging user-directed information visualization, data exploration, and hypotheses formulation. Second, to illustrate the proposed design paradigm and measure its efficacy, we describe two prototype web applications. The first, called XMAS (Experiential Microarray Analysis System) is designed for analysis of time-series transcriptional data. The second system, called PSPACE (Protein Space Explorer) is designed for holistic analysis of structural and structure-function relationships using interactive low-dimensional maps of the protein structure space. Both these systems promote and facilitate human-computer synergy, where cognitive elements such as domain knowledge, contextual reasoning, and purpose-driven exploration, are integrated with a host of powerful algorithmic operations that support large-scale data analysis, multifaceted data visualization, and multi-source information integration.
The proposed design philosophy, combines visualization, algorithmic components and cognitive expertise into a seamless processing-analysis-exploration framework that facilitates sense-making, exploration, and discovery. Using XMAS, we present case studies that analyze transcriptional data from two highly complex domains: gene expression in the placenta during human pregnancy and reaction of marine organisms to heat stress. With PSPACE, we demonstrate how complex structure-function relationships can be explored. These results demonstrate the novelty, advantages, and distinctions of the proposed paradigm. Furthermore, the results also highlight how domain insights can be combined with algorithms to discover meaningful knowledge and formulate evidence-based hypotheses during the data analysis process. Finally, user studies against comparable systems indicate that both XMAS and PSPACE deliver results with better interpretability while placing lower cognitive loads on the users. XMAS is available at: http://tintin.sfsu.edu:8080/xmas. PSPACE is available at: http://pspace.info/.
Our previous studies have demonstrated that the urotensin (UII) and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM), but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK) mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.
Technologies allowing for specific regulation of endogenous genes are valuable for the study of gene functions and have great potential in therapeutics. We created the CRISPR-on system, a two-component transcriptional activator consisting of a nuclease-dead Cas9 (dCas9) protein fused with a transcriptional activation domain and single guide RNAs (sgRNAs) with complementary sequence to gene promoters. We demonstrate that CRISPR-on can efficiently activate exogenous reporter genes in both human and mouse cells in a tunable manner. In addition, we show that robust reporter gene activation in vivo can be achieved by injecting the system components into mouse zygotes. Furthermore, we show that CRISPR-on can activate the endogenous IL1RN, SOX2, and OCT4 genes. The most efficient gene activation was achieved by clusters of 3-4 sgRNAs binding to the proximal promoters, suggesting their synergistic action in gene induction. Significantly, when sgRNAs targeting multiple genes were simultaneously introduced into cells, robust multiplexed endogenous gene activation was achieved. Genome-wide expression profiling demonstrated high specificity of the system.
CRISPR; transcription factor; synthetic biology; gene expression; artificial transcription factor
Recent success in the derivation of haploid embryonic stem cells (haESCs) from mouse via parthenogenesis and androgenesis has enabled genetic screening in mammalian cells and generation of gene-modified animals. However, whether haESCs can be derived from primates remains unknown. Here, we report the derivation of haESCs from parthenogenetic blastocysts of Macaca fascicularis monkeys. These cells, termed as PG-haESCs, are pluripotent and can differentiate to cells of three embryonic germ layers in vitro or in vivo. Interestingly, the haploidy of one monkey PG-haESC line (MPH1) is more stable compared with that of the other one (MPH2), as shown by the existence of haploid cells for more than 140 days without fluorescence-activated cell sorting (FACS) enrichment of haploid cells. Importantly, transgenic monkey PG-haESC lines can be generated by lentivirus- and piggyBac transposon-mediated gene transfer. Moreover, genetic screening is feasible in monkey PG-haESCs. Our results demonstrate that PG-haESCs can be generated from monkeys, providing an ideal tool for genetic analyses in primates.
embryonic stem cell; haploid cells; monkey
Wilson’s disease (WD) is a genetic disorder which can be controlled fairly well with decupuration therapy. However, symptoms, on rare occasions, can worsen even when WD is being treated. Herein, we report a case involving unusual neurological deterioration during decupuration therapy for WD.
A 28-year-old man was diagnosed with WD 13 years prior to his clinical visit; however, his drug compliance has been poor over the years. He was treated with trientine because tremors and dysarthria have presented in recent years. However, dysarthria and dystonia developed in his limbs, which were worse on the right side and had been aggravated for several weeks despite good drug compliance. His symptoms were fluctuating. It was initially misdiagnosed as dystonia; although, it turned out to be a seizure due to cortical degeneration. These symptoms were completely resolved with antiepileptic drugs. Moreover, the cortical enhancement of bifrontal degeneration has disappeared on the MRI.
This case showed unusual epileptic neurologic deterioration due to cortical degeneration during decupuration therapy. Seizures in WD can easily be mistaken as part of dystonia. However, the fluctuating symptoms suggest a seizure.
Wilson’s disease; Seizure; Dystonia; Cortical lesion: MRI
Benzodiazepines are excluded from prescription drug coverage under Medicare Part D. The objectives of this study were twofold: to provide national estimates of benzodiazepine utilization and expenditure patterns and to examine the impact of drug coverage and other factors associated with utilization of benzodiazepines and potential benzodiazepine substitute classes.
The 2002 Medicare Current Beneficiary Survey provided national estimates of benzodiazepine use and expenditures among Medicare beneficiaries. Multivariate logistic regression was conducted to assess the relationships between independent variables and use of benzodiazepines and potential substitute classes. The independent variable of interest was drug coverage, assessed by payer source. Other covariates included in the models were chronic conditions associated with benzodiazepine use, age, sex, race, and income.
In 2002, 13.7% of Medicare beneficiaries received at least one benzodiazepine fill, with an average of 5.8 benzodiazepine prescriptions filled at an annual cost of $190. Specific sources of prescription drug coverage were not significantly associated with benzodiazepine use. Female gender, chronic mental illness, age under 65, and lower income were significantly positively associated with benzodiazepine use in the Medicare population, whereas black and other races were significantly negatively associated with benzodiazepine use in this population. Compared with Medicare beneficiaries without supplemental drug coverage, beneficiaries with supplemental drug coverage were more likely to use potential benzodiazepine substitute classes than benzodiazepines.
Benzodiazepines were widely used by Medicare beneficiaries. Drug coverage influences access to benzodiazepines and potential substitute classes. These findings have important implications for identifying beneficiaries potentially affected by the exclusion of benzodiazepine coverage under Medicare Part D.
Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1–induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand–induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases.
adhesion; Eph; EphB2; ephrin-B1; invasion; medulloblastoma
Detection of chromosomal structural abnormalities using conventional cytogenetic methods poses a challenge for prenatal genetic counseling due to unpredictable clinical outcomes and risk of recurrence. Of the 1,726 prenatal cases in a 3-year period, we performed oligonucleotide array comparative genomic hybridization (aCGH) analysis on 11 cases detected with various structural chromosomal abnormalities. In nine cases, genomic aberrations and gene contents involving a 3p distal deletion, a marker chromosome from chromosome 4, a derivative chromosome 5 from a 5p/7q translocation, a de novo distal 6q deletion, a recombinant chromosome 8 comprised of an 8p duplication and an 8q deletion, an extra derivative chromosome 9 from an 8p/9q translocation, mosaicism for chromosome 12q with added material of initially unknown origin, an unbalanced 13q/15q rearrangement, and a distal 18q duplication and deletion were delineated. An absence of pathogenic copy number changes was noted in one case with a de novo 11q/14q translocation and in another with a familial insertion of 21q into a 19q. Genomic characterization of the structural abnormalities aided in the prediction of clinical outcomes. These results demonstrated the value of aCGH analysis in prenatal cases with subtle or complex chromosomal rearrangements. Furthermore, a retrospective analysis of clinical indications of our prenatal cases showed that approximately 20% of them had abnormal ultrasound findings and should be considered as high risk pregnancies for a combined chromosome and aCGH analysis.
prenatal diagnosis; chromosomal structural abnormalities; genomic imbalances; array comparative genomic hybridization (aCGH)
MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N = 64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in CD34+ cells had a tendency for shorter survival compared to the ones with lower MYD88, which was significant when controlled for IPSS and age. We then evaluated effect of MYD88 blockade in the CD34+ cells of patients with lower-risk MDS. Colony formation assays indicated that MYD88 blockade using a MYD88 inhibitor resulted in increased erythroid colony formation. MYD88 blockade also negatively regulated the secretion of interleukin-8. Treatment of MDS CD34+ cells with an IL-8 antibody also increased formation of erythroid colonies. These results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.
The aim of this study was to investigate the modified Ross criteria score and the diagnostic cut-off level for plasmatic amino-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of pediatric heart failure, by analyzing the receiver operating characteristic (ROC) curve. The plasma NT-proBNP level was measured in 80 children diagnosed with heart failure according to the modified Ross criteria, 80 children with non-cardiogenic dyspnea and 80 healthy children. The NT-proBNP levels were then compared using an F-test. The cut-off score for heart failure in the modified Ross criteria and the diagnostic cut-off level for plasmatic NT-proBNP in pediatric heart failure were determined by ROC curve analysis. The results demonstrated that the NT-proBNP level was markedly increased in 76 of the 80 children with heart failure, and the correlation with the modified Ross criteria was 95%. Based on ROC curve analysis, the diagnosis of pediatric heart failure was most accurate when the modified Ross criteria score was ≥4 and the plasmatic NT-proBNP level was ≥598 ng/l. The NT-proBNP level was normal (0–300 ng/l) in the children with non-cardiogenic dyspnea and the healthy children. Significant differences were observed in the comparison of the three groups (P<0.01). In conclusion, a NT-proBNP level of ≥598 ng/l, combined with a modified Ross criteria score ≥4, is highly diagnostic of heart failure in children.
heart failure; amino-terminal pro-B-type natriuretic peptide; diagnostic criteria; children
Mammalian oocytes undergo a cortical reaction after fertilization, releasing cortical granules and other proteins into the perivitelline space and inhibiting polyspermy. Few studies have evaluated the biological functions and properties of these proteins.
We investigated mouse oocytes in which the zona pellucida (ZP) was present (ZP-intact group) or absent (ZP-free group).
After being activated by Srcl2, secreted proteins are collected from mouse oocytes. Mass spectrometry analysis was performed that identified proteins such as Ldhb, PADi6, Uchl1, Pebp1, Alb, Hsp90aa1, Prss1, trypsinogen 7, trypsin 4, trypsin 10, Sod1, Zp1, Zp2, Zp3, Akap8, Npm2, Pkm2 and Ppia in the ZP-free group. Proteins such as Ldhb, Uchl1, Prss1, trypsin 10, trypsinogen 7, and Ast1 were identified in the ZP-intact groups. The expression of some proteins, including Ldhb, Alb and Sod1, were initially detected following oocyte activation. The finding of four trypsin subtypes, such as Prss1, further support previous observations. Studies investigating the physiological functions and properties of these proteins are ongoing.
Research on these cortical proteins provides a theoretical basis for understanding polyspermy inhibition at the level of ZP and gives technological support for fertilization detection, assessment of oocyte quality and embryonic culture.
Oocyte; Secretome; Activation; Mass spectrometry
Alzheimer’s disease (AD) is one of most prevalent dementias, which is characterized by the deposition of extracellular amyloid-beta protein (Aβ) and the formation of neurofibrillary tangles within neurons. Although stereotaxic transplantation of mesenchymal stem cells (MSCs) into the hippocampus of AD animal model as immunomodulatory cells has been suggested as a potential therapeutic approach to prevent the progress of AD, it is invasive and difficult for clinical perform. Systemic and central nervous system inflammation play an important role in pathogenesis of AD. T regulatory cells (Tregs) play a crucial role in maintaining systemic immune homeostasis, indicating that transplantation of Tregs could prevent the progress of the inflammation. In this study, we aimed to evaluate whether systemic transplantation of purified autologous Tregs from spleens of AβPPswe/PS1dE9 double-transgenic mice after MSCs from human umbilical cords (UC-MSCs) education in vitro for 3 days could improve the neuropathology and cognition deficits in AβPPswe/PS1dE9 double-transgenic mice. We observed that systemic transplantation of autologous Tregs significantly ameliorate the impaired cognition and reduced the Aβ plaque deposition and the levels of soluble Aβ, accompanied with significantly decreased levels of activated microglia and systemic inflammatory factors. In conclusion, systemic transplantation of autologous Tregs may be an effective and safe intervention to prevent the progress of AD.
Two dimension (2D) layered molybdenum disulfide (MoS2) has emerged as a promising candidate for the anode material in lithium ion batteries (LIBs). Herein, 2D MoSx (2 ≤ x ≤ 3) nanosheet-coated 1D multiwall carbon nanotubes (MWNTs) nanocomposites with hierarchical architecture were synthesized via a high-throughput solvent thermal method under low temperature at 200°C. The unique hierarchical nanostructures with MWNTs backbone and nanosheets of MoSx have significantly promoted the electrode performance in LIBs. Every single MoSx nanosheet interconnect to MWNTs centers with maximized exposed electrochemical active sites, which significantly enhance ion diffusion efficiency and accommodate volume expansion during the electrochemical reaction. A remarkably high specific capacity (i.e., > 1000 mAh/g) was achieved at the current density of 50 mA g−1, which is much higher than theoretical numbers for either MWNTs or MoS2 along (~372 and ~670 mAh/g, respectively). We anticipate 2D nanosheets/1D MWNTs nanocomposites will be promising materials in new generation practical LIBs.
Cell therapy is a potential therapeutic approach for neurodegenerative disorders, such as Alzheimer disease (AD). Neuronal differentiation of stem cells before transplantation is a promising procedure for cell therapy. However, the therapeutic impact and mechanisms of action of neuron-like cells differentiated from human umbilical cord mesenchymal stem cells in AD have not been determined.
In this study, we used tricyclodecan-9-yl-xanthogenate (D609) to induce human mesenchymal stem cells isolated from Wharton jelly of the umbilical cord (HUMSCs) to differentiate into neuron-like cells (HUMSC-NCs), and transplanted the HUMSC-NCs into an AβPP/PS1 transgenic AD mouse model. The effects of HUMSC-NC transplantation on the cognitive function, synapsin I level, amyloid β-peptides (Aβ) deposition, and microglial function of the mice were investigated.
We found that transplantation of HUMSC-NCs into AβPP/PS1 mice improved the cognitive function, increased synapsin I level, and significantly reduced Aβ deposition in the mice. The beneficial effects were associated with “alternatively activated” microglia (M2-like microglia). In the mice transplanted with HUMSC-NCs, M2-like microglial activation was significantly increased, and the expression of antiinflammatory cytokine associated with M2-like microglia, interleukin-4 (IL-4), was also increased, whereas the expression of proinflammatory cytokines associated with classic microglia (M1-like microglia), including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), was significantly reduced. Moreover, the expression of Aβ-degrading factors, insulin-degrading enzyme (IDE) and neprilysin (NEP), was increased substantially in the mice treated with HUMSC-NCs.
HUMSC-NC transplantation decreased Aβ deposition and improved memory in AβPP/PS1 mice by a mechanism associated with activating M2-like microglia and modulating neuroinflammation. Transplantation of neuron-like cells differentiated from mesenchymal stem cells might be a promising cell therapy for Alzheimer disease.
Alzheimer disease; AβPP/PS1 mouse; Amyloid-β peptides; Neuronal differentiation; Alternatively activated microglia; Neuroinflammation
We screened Orientia tsutsugamushi from 385 domestic rodents and 19 humans with scrub typhus in rural Tai’an District, Shandong Province, a new scrub typhus epidemic area in northern China. Sequence analysis identified 7 genotypes in the rodents, of which 2 were also identified in the humans.
scrub typhus; Orientia tsutsugamushi; genotype; phylogeny; parasites; China; rodents; humans
Tumor necrosis factor alpha (TNFα) is a classic proinflammatory cytokine implicated in the pathogenesis of several autoimmune and inflammatory diseases including viral encephalitis. Macrophages being major producers of TNFα are thus attractive targets for in vivo RNA interference (RNAi) mediated down regulation of TNFα. The application of RNAi technology to in vivo models however presents obstacles, including rapid degradation of RNA duplexes in plasma, insufficient delivery to the target cell population and toxicity associated with intravenous administration of synthetic RNAs and carrier compounds.
We exploited the phagocytic ability of macrophages for delivery of Dicer-substrate small interfering RNAs (DsiRNAs) targeting TNFα (DsiTNFα) by intraperitoneal administration of lipid-DsiRNA complexes that were efficiently taken up by peritoneal macrophages and other phagocytic cells. We report that DsiTNFα-lipid complexes delivered intraperitoneally altered the disease outcome in an acute sepsis model. Down-regulation of TNFα in peritoneal CD11b+ monocytes reduced liver damage in C57BL/6 mice and significantly delayed acute mortality in mice treated with low dose LPS plus D-galactosamine (D-GalN).