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Succinic acid is a valuable bulk chemical, which has been extensively applied in food, medicine, surfactants and biodegradable plastics industries. As a substitute for chemical raw material, bio-based succinic acid production has received increasing attention due to the depletion of fossil fuels and environmental issues. Meanwhile, the effective bioconversion of lignocellulosic biomass has always been a hot spot of interest owning to the advantages of low expense, abundance and renewability. Consolidated bioprocessing (CBP) is considered to be an alternative approach with outstanding potential, as CBP can not only improve the product yield and productivity, but also reduce the equipment and operating costs. In addition, the current emerging microbial co-cultivation systems provide strong competitiveness for lignocellulose utilization through CBP. This article comprehensively discusses different strategies for the bioconversion of lignocellulose to succinic acid. Based on the principles and technical concepts of CBP, this review focuses on the progress of succinic acid production under different CBP strategies (metabolic engineering based and microbial co-cultivation based). Moreover, the main challenges faced by CBP-based succinic acid fermentation are analyzed, and the future direction of CBP production is prospected.

Cerebrospinal fluid (CSF) is a vital liquid, providing nutrients, signalling molecules, and clearing out toxic byproducts from the brain. The CSF is produced by the choroid plexus (ChP), a protective epithelial barrier that also prevents free entry from the blood. Here, we establish human ChP organoids with a selective barrier and CSF-like fluid secretion in self-contained compartments. We show that this in vitro barrier exhibits the same selectivity to small molecules as in vivo, and that ChP-CSF organoids can predict CNS permeability of novel compounds. The transcriptomic and proteomic signature of ChP-CSF organoids reveal a high degree of similarity to in vivo. Finally, the intersection of single cell transcriptomics and proteomic analysis uncovers key human CSF components produced by previously unidentified specialized epithelial subtypes.

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation is deleterious for perinatal neurodevelopment, but how CSF leaves the brain during this critical period is unknown. We found in mice a postnatal neurodevelopmental transition phase featuring precipitous CSF K+ clearance, accompanied by water, through the choroid plexus (ChP). The period corresponds to a human fetal stage when canonical CSF clearance pathways have yet to form and congenital hydrocephalus begins to manifest. Unbiased ChP metabolic and ribosomal profiling highlighted this transition phase with increased ATP yield and activated energy-dependent K+ transporters, in particular the Na+-K+-Cl− and water cotransporter NKCC1. ChP-targeted NKCC1 overexpression enhanced K+-driven CSF clearance and enabled more permissive cerebral hydrodynamics. Moreover, ventriculomegaly in an obstructive hydrocephalus model was improved by ChP-targeted NKCC1 overexpression. Collectively, we identified K+-driven CSF clearance through ChP during a transient but critical neurodevelopmental phase, with translational value for pathologic conditions.

Air purification techniques have been advancing forward rapidly due to the fast development of related technologies and materials. Various nanomaterials have been successfully developed for the separation and purification of gases over the past few decades. This chapter introduces the basic knowledge on air purification with artificial nanostructured materials and some practical instances. To begin with some general principles of air pollutants removal, especially those utilizing nanomaterials are presented. Then typical reactive nanomaterials with well-defined physical and chemical structures are introduced. Common air pollutants and challenges in air purification are briefly reviewed. A description on eliminating various air pollutants through adsorption, separation, and catalytic processes is included to present the advantages of nanomaterials for practical applications. A perspective on air pollutants controlling with nanomaterials is presented at the end.

Additional file 1. SOAPTyping Supplement materials. Table S1. HLA molecules and the respective exon regions that can be analyzed by SOAPTyping. Table S2. Icons involved in the pane of Sample List. Table S3. Colors and their meanings in the pane of Base Navigator. Table S4. Detailed columns showed in the pane of Allele Match List. Table S5. Descriptions of each row in the pane of Sequence Display. Table S6. Descriptions of icons in the pane of Toolbar. Table S7. alleleTable. Table S8. gsspTable. Table S9. geneTable. Table S10. fileTable. Table S11. gsspFileTable. Table S12. sampleTable. Figure S1. The main window of SOAPTyping Figure S2. Best practices and proposed workflow for SOAPTyping Figure S3. Loading input file. Figure S4. An example exported report. Figure S5. Files required for database updates. Figure S6. The GSSP information window. Figure S7. Files required for GSSP database update. Figure S8. Allele alignment tool. Table S8. SOAPTyping results of 36 samples from UCLA International DNA Exchange. Table S9. The HLA typing results of 100 clinical samples. Table S10. The running time of 100 clinical samples.

The choroid plexus (ChP) epithelium is a source of secreted signaling factors in cerebrospinal fluid (CSF) and a key barrier between blood and brain. Here, we develop imaging tools to interrogate these functions in adult lateral ventricle ChP in wholemount explants and in awake mice. By imaging epithelial cells in intact ChP explants, we observed calcium activity and secretory events that increased in frequency following delivery of serotonergic agonists. Using chronic two-photon imaging in awake mice, we observed spontaneous subcellular calcium events as well as strong agonist-evoked calcium activation and cytoplasmic secretion into CSF. Three-dimensional imaging of motility and mobility of multiple types of ChP immune cells at baseline and following immune challenge or focal injury revealed a range of surveillance and defensive behaviors. Together, these tools should help illuminate the diverse functions of this understudied body-brain interface.

This paper adopts a combination of MobileNet and SSD method to recognize facial expressions, and then apply it to Nao robots. MobileNet is a lightweight deep network model for mobile devices. The standard convolution is decomposed by depthwise separable convolution to decompose the calculation and reduce the amount of computation. The SSD model evolves from the VGG16 model and maintains excellent object detection performance despite a sharp decrease in the number of parameters. This paper combines MobileNet V2 with SSD for expression recognition, which not only meets the real-time requirements, but also keeps high recognition accuracy. Since the robot's processor performance is limited, while the deep neural network can automatically extract the image feature for accurate classification, it is of great significance to use lightweight deep neural network to apply the real-time detection and recognition of the Nao robot.

BACKGROUND Amniocentesis is a common procedure, the primary purpose of which is to collect cells from the fetus to allow testing for abnormal chromosomes, altered chromosomal copy number, or a small number of genes that have small single- to multibase defects. Here we demonstrate the feasibility of generating an accurate whole-genome sequence of a fetus from either the cellular or cell-free DNA (cfDNA) of an amniotic sample. METHODS cfDNA and DNA isolated from the cell pellet of 31 amniocenteses were sequenced to approximately 50× genome coverage by use of the Complete Genomics nanoarray platform. In a subset of the samples, long fragment read libraries were generated from DNA isolated from cells and sequenced to approximately 100× genome coverage. RESULTS Concordance of variant calls between the 2 DNA sources and with parental libraries was >96%. Two fetal genomes were found to harbor potentially detrimental variants in chromodomain helicase DNA binding protein 8 (CHD8) and LDL receptor-related protein 1 (LRP1), variations of which have been associated with autism spectrum disorder and keratosis pilaris atrophicans, respectively. We also discovered drug sensitivities and carrier information of fetuses for a variety of diseases. CONCLUSIONS We were able to elucidate the complete genome sequence of 31 fetuses from amniotic fluid and demonstrate that the cfDNA or DNA from the cell pellet can be analyzed with little difference in quality. We believe that current technologies could analyze this material in a highly accurate and complete manner and that analyses like these should be considered for addition to current amniocentesis procedures.

The pear quantity is not consistent with the quality of pear paste products due to different proportions of edible cane sugar (sucrose) added during food processing. To determine sucrose addition rate in pear paste, a mathematical model was established to quantify soluble solid concentration, sucrose-adding ratio and d -allose concentration. Gas chromatography-mass spectrometer (GC-MS) results showed that 18 compounds were detected in pear paste. When the total soluble solids (TSS) concentration of pear paste was constant, there was a negative linear relationship between d -allose content and the Ratio of Sucrose Added (RSA) (0.97 ≤R2 ≤ 0.99)., Accordingly, the mathematical model of TSS-RSA-Allose concentration was fitted. It was found that the theoretical values of the pear paste at varied RSAs were comparable with the actual values under different conditions: 85% of the verified values differed by ≤ 10%. This study provides some reference for product testing departments to analyze products and establish the evaluation standard of sucrose ratioin pear paste.

Seizures are due to excessive, synchronous neuronal firing in the brain and are characteristic of epilepsy, the fourth most prevalent neurological disease. We report handling-induced and spontaneous seizures in mice deficient for CD39, a cell-surface ATPase highly expressed on microglial cells. CD39-/- mice with handling-induced seizures had normal input-output curves and paired-pulse ratio measured from hippocampal slices and lacked microgliosis, astrogliosis or overt cell loss in the hippocampus and cortex. As expected, however, the cerebrospinal fluid of CD39-/- mice contained increased levels of ATP and decreased levels of adenosine. To determine if immune activation was involved in seizure progression, we challenged mice with lipopolysaccharide (LPS) and measured the effect on microglia activation and seizure severity. Systemic LPS challenge resulted in increased cortical staining of Iba1/CD68 and gene array data from purified microglia predicted increased expression of interleukin-8, triggering receptor expressed on myeloid cells 1, p38, pattern recognition receptors, death receptor, nuclear factor-κB , complement, acute phase, and interleukin-6 signalling pathways in CD39-/- versus CD39+/+ mice. However, LPS treatment did not affect handling-induced seizures. In addition, microglia-specific CD39 deletion in adult mice was not sufficient to cause seizures, suggesting instead that altered expression of CD39 during development or on non-microglial cells such as vascular endothelial cells may promote the seizure phenotype. In summary, we show a correlation between altered extracellular ATP/adenosine ratio and a previously unreported seizure phenotype in CD39-/- mice. This work provides groundwork for further elucidation of the underlying mechanisms of epilepsy.

Background and aims Peroxisome proliferator-activated receptor-α (PPAR-α) activation has been reported to reduce myocardial ischemia-reperfusion (I/R) injury by inhibiting cell apoptosis. However, the antiapoptotic mechanism of PPAR-α is still unknown. Fenofibrate is a PPAR-α agonist In the present study, we investigate the effects and relevant mechanism of fenofibrate on experimental myocardial ischemia-reperfusion (I/R) injury in rats. Methods Adult male Wistar rats were pretreated with fenofibrate (80 mg/kg) daily for a period of 7 days. After the treatment period, myocardial I/R injury model was made by left anterior descending coronary artery ligation for 45 min and reperfusion for 120 min. Myocardial infarct size, malondialdehyde (MDA) cleaved-caspase-9 protein expression, PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue were detected Cell apoptosis was detected by Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Serum lactate dehydrogenase and creatine kinase activities were measured in rats pretreated with fenofibrate The ultrastructure of myocardial tissues was observed. Results Significant increases in myocardial cell apoptosis, malondialdehyde (MDA) level and cleaved-caspase-9 protein expression level in myocardial tissue were observed, along with reductions of PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue of the experimental myocardial ischemia-reperfusion (I/R) injury in rats. Impaired mitochondria were also observed under electron microscopic. However, pretreatment of ischemia/reperfusion rats with fenofibrate brought the biochemical parameters and related genes expression levels to near normalcy, indicating the protective effect of fenofibrate against myocardial ischemia/reperfusion injury in rats. Conclusions The PPAR-α activator fenofibrate conferred cytoprotective effect against myocardial ischemia-reperfusion (I/R) injury in rats. Associated mechanisms involved decreased cleaved-caspase-9 expression and decreased cell apoptosis.

5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5HHMF) and 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone (5HPMF) are the predominant polymethoxyflavones in orange peel. Here, we showed how 5HHMF or 5HPMF modulated the amount of pre-existing and newly synthesized glycosaminoglycans (GAG) in lung and colon cancer cells. 5HPMF treatment disrupted the formation of FGF/FGFR1c/GAG ternary signaling complex in cell surface. Moreover, 5HHMF remarkably decreased the content of nonsulfated and 3- or 6-sulfated disaccharides of heparan sulfate while no significant changes occurred in that of chondroitin sulfate detected by 1-phenyl-3-methyl-5-pyrazolone (PMP) isotope labeling plus LC/MS analysis. Furthermore, quantification of metabolic incorporating 34S isotope-labeled sulfate into GAG of cultured cells indicated that 5HHMF decreased the sulfated disaccharides of the newly synthesized GAGs by 54%. Overall, the results indicated that 5HHMF and 5HPMF were potential inhibitors of GAG biosynthesis. Our results indicated that GAGs might be the long sought signaling molecules affected by 5HHMF and 5HPMF that lead to lung and colon cancer cell death.

Soluble oligomers of amyloid β-protein (oAβ) isolated from the brains of Alzheimer's disease (AD) patients have been shown experimentally (in the absence of amyloid plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, and impair memory in normal adult rodents. Nevertheless, there has been controversy about what types of oligomers actually confer these AD-like phenotypes. Here, we show that the vast majority of soluble Aβ species obtained from brains of humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography. These species have little or no cytotoxic activity in several bioassays. However, incubation of HMW oAβ in mildly alkaline buffer led to their quantitative dissociation into low molecular weight oligomers (∼8–70 kDa), and these were now far more bioactive: they impaired hippocampal LTP, decreased neuronal levels of β2-adrenergic receptors, and activated microglia in wt micein vivo. Thus, most soluble Aβ assemblies in AD cortex are large and inactive but under certain circumstances can dissociate into smaller, highly bioactive species. Insoluble amyloid plaques likely sequester soluble HMW oligomers, limiting their potential to dissociate. We conclude that conditions that destabilize HMW oligomers or retard the sequestration of their smaller, more bioactive components are important drivers of Aβ toxicity. Selectively targeting these small, cytotoxic forms should be therapeutically beneficial.SIGNIFICANCE STATEMENTOligomers of amyloid β-protein (oAβ) are tought to play an important role in Alzheimer's disease (AD), but there is confusion and controversy about what types and sizes of oligomers have disease-relevant activity. Using size-exclusion chromatography and three distinct measures of bioactivity, we show that the predominant forms of Aβ in aqueous extracts of AD brain are high molecular weight (HMW) and relatively inactive. Importantly, under certain conditions, the abundant HMW oAβ can dissociate into low molecular weight species, and these low molecular weight oligomers are significantly more bioactive on synapses and microglia than the HMW species from which they are derived. We conclude that conditions that destabilize HMW oAβ or retard the sequestration of smaller, more bioactive components are important drivers of Aβ toxicity.

SummaryThe human leukocyte antigen (HLA) gene family plays a key role in the immune response and thus is crucial in many biomedical and clinical settings. Utilizing Sanger sequencing - the gold standard technology for HLA typing – enables accurate identification of HLA alleles with high-resolution. However, there exists a current hurdle that only commercial software such as UType, SBT-Assign and SBTEngine, instead of any open source tools could be applied to perform HLA typing based on Sanger sequencing. To fill the gap, we developed a stand-alone, open-source and cross-platform software, known as SOAPTyping, for Sanger-based typing in HLA class I and II alleles.Availability and implementationSOAPTyping is implemented in C++ language and Qt framework, which is supported on Windows, Mac and Linux. Source code and detailed documentation are accessible via the project GitHub page: https://github.com/BGI-flexlab/SOAPTyping.Contactfangl@genomics.cnSupplementary informationSupplementary data are available at Bioinformatics online.

Melanoma is one of the most malignant and aggressive types of cancer worldwide. Fibroblast growth factor 2 (FGF2) is one of the critical regulators of melanoma angiogenesis and metastasis, thus, it might be an effective anti-cancer strategy to explore FGF2-targeting drug candidates from existing drugs. In this study, we evaluate the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) on FGF2-mediated angiogenesis and invasion. The data shows that FGF2 selectively bound to PSS with high affinity. PSS inhibited FGF2-mediated angiogenesis in a rat aortic ring model and suppressed FGF2-mediated invasion, but not the migration of murine melanoma B16-F10 cells. The further mechanism study indicates that PSS decreased the expression of activated matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and also suppressed their activity. In addition, PSS was found to decrease the level of Vimentin in B16-F10 cells, which is known to participate in the epithelial&ndash, mesenchymal transition. Notably, PSS did not elicit any changes in cancer cell viability. Based on the results above, we conclude that PSS might be a potential drug to regulate the tumor microenvironment in order to facilitate the recovery of melanoma patients.

The choroid plexus (ChP) epithelium is a source of secreted signaling factors in cerebrospinal fluid (CSF) and a key barrier between blood and brain. Here, we develop imaging tools to interrogate these functions in adult lateral ventricle ChP in whole-mount explants and in awake mice. By imaging epithelial cells in intact ChP explants, we observed calcium activity and secretory events that increased in frequency following delivery of serotonergic agonists. Using chronic two-photon imaging in awake mice, we observed spontaneous subcellular calcium events as well as strong agonist-evoked calcium activation and cytoplasmic secretion into CSF. Three-dimensional imaging of motility and mobility of multiple types of ChP immune cells at baseline and following immune challenge or focal injury revealed a range of surveillance and defensive behaviors. Together, these tools should help illuminate the diverse functions of this understudied body-brain interface.

Epileptic activity may be more prevalent in early stage Alzheimer’s disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials in stratum radiatum and population spikes in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording population spikes (PS) revealed that oAβ increased PS frequency and reduced LTP, and the latter effect was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.

The application of high-throughput microarray has led to massive gene expression data, urging effective methodology for analysis. Biclustering comes out and serves as a useful tool, performing simultaneous clustering on rows and columns to find subsets of coherently expressed genes and conditions. Specially, in analysis of time–series gene expression data, it is meaningful to restrict biclusters to contiguous time points concerning coherent evolutions. In this paper, BCCC-Bicluster is proposed as an extension of CCC-Bicluster. An exact algorithm based on frequent sequential mining is proposed to find all maximal BCCC-Biclusters. The newly defined Frequent-Infrequent Tree-Array (FITA) is constructed to speed up the traversal process, with useful strategies originating from Apriori property to avoid redundant work. To make it more efficient, the bitwise operation XOR is applied to capture identical or opposite contiguous patterns between two rows. The algorithm is tested in simulated data, yeast microarray data and human microarray data. The experimental results show the proposed algorithm had better performance on the ability to recover the planted biclusters in the synthetic data than CCC-Biclusters and outperformed the one without FITA in speed and scalability. In the enrichment analysis, BCCC-Biclusters are proven to find more significant GO terms involved in biological processes than other three kinds of up-to-date biclusters.

Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE9s anti‐inflammatory protection of brain microglia against soluble oligomers of human amyloid β‐protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β‐adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β‐adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ‐induced inflammation as did mice in EE. Conversely, mice in EE fed the β‐adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2‐adrenergic receptors showed no protection of microglia by EE. In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial‐specific analysis of β2‐adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE. Thus, enhanced β‐adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers in vivo .

Cell-free DNA (cfDNA) testing for common fetal trisomies (T21, T18, T13) is highly effective. However, the usefulness of cfDNA testing in detecting other chromosomal abnormalities is unclear. We evaluated the performance of cfDNA testing for genome-wide abnormalities, and analyzed the incremental yield by reporting extra abnormalities. We performed genome-wide cfDNA testing in 15,626 consecutive pregnancies prospectively enrolled in this study. cfDNA testing results were reported and counseling was given depending on the presence of extra chromosomal abnormalities. cfDNA testing identified 190 cases (1.2%) of chromosomal abnormalities including 100 common trisomies and 90 additional abnormalities. By expanding the cfDNA reporting range to genome-wide abnormalities, the false positive rate increased to 0.39% (P

The genetic variation in Northern Asian populations is currently undersampled. To address this, we generated a new genetic variation reference panel by whole-genome sequencing of 175 ethnic Mongolians, representing six tribes. The cataloged variation in the panel shows strong population stratification among these tribes, which correlates with the diverse demographic histories in the region. Incorporating our results with the 1000 Genomes Project panel identifies derived alleles shared between Finns and Mongolians/Siberians, suggesting that substantial gene flow between northern Eurasian populations has occurred in the past. Furthermore, we highlight that North, East, and Southeast Asian populations are more aligned with each other than these groups are with South Asian and Oceanian populations.

Amniocentesis is typically performed to identify large chromosomal abnormalities within the fetus. Here we demonstrate that it is feasible to generate an accurate whole genome sequence (WGS) of a fetus from an amniotic sample. DNA from cells and the amniotic fluid were isolated and sequenced from 31 amniocenteses. Concordance of variant calls between the two DNA sources and with parental libraries was high. Two fetal genomes were found to harbor potentially detrimental variants inCHD8andLRP1, variations in these genes have been associated with Autism Spectrum Disorder (ASD) and Keratosis pilaris atrophicans, respectively. We also discovered drug sensitivities and carrier information of fetuses for a variety of diseases. In this study, we demonstrate for the first time the sequencing of the whole genome of fetuses from amniotic fluid and show that much more information than large chromosomal abnormalities can be gained from an amniocentesis.

Seizures are due to excessive, synchronous neuronal firing in the brain and are characteristic of epilepsy, the fourth most prevalent neurological disease. We report handling‐induced and spontaneous seizures in mice deficient for CD39, a cell‐surface ATPase highly expressed on microglial cells. CD39−/− mice with handling‐induced seizures had normal input–output curves and paired‐pulse ratio measured from hippocampal slices and lacked microgliosis, astrogliosis or overt cell loss in the hippocampus and cortex. As expected, however, the cerebrospinal fluid of CD39−/− mice contained increased levels of ATP and decreased levels of adenosine. To determine if immune activation was involved in seizure progression, we challenged mice with lipopolysaccharide (LPS) and measured the effect on microglia activation and seizure severity. Systemic LPS challenge resulted in increased cortical staining of Iba1/CD68 and gene array data from purified microglia predicted increased expression of interleukin‐8, triggering receptor expressed on myeloid cells 1, p38, pattern recognition receptors, death receptor, nuclear factor‐κB , complement, acute phase, and interleukin‐6 signalling pathways in CD39−/− versus CD39+/+ mice. However, LPS treatment did not affect handling‐induced seizures. In addition, microglia‐specific CD39 deletion in adult mice was not sufficient to cause seizures, suggesting instead that altered expression of CD39 during development or on non‐microglial cells such as vascular endothelial cells may promote the seizure phenotype. In summary, we show a correlation between altered extracellular ATP/adenosine ratio and a previously unreported seizure phenotype in CD39−/− mice. This work provides groundwork for further elucidation of the underlying mechanisms of epilepsy.

Background Norcantharidin (NCTD) is a Chinese FDA approved, chemically synthesized drug for cancer treatment. The effect of NCTD on signaling proteins of EGFR and c-Met was systematically elucidated in current study. Methods Two human colon cancer cell lines, HCT116 and HT29, were used as model systems to investigate the anti-cancer molecular mechanism of NCTD. Cell cycle arrest and early/late apoptosis were analyzed by flow cytometry. The levels of EGFR, phospho-EGFR, c-Met, phospho-c-Met and other related proteins were quantified by western blot analysis. Results NCTD induced cell cycle arrest at G2/M phase in both cell lines. The early and late apoptosis was also observed. Further investigation indicated that NCTD suppressed not only the expression of the total EGFR and the phosphorylated EGFR but also the expression of the total c-Met and the phosphorylated c-Met in colon cancer cells. Moreover, EGFR expression could be mostly restored by co-treatment with MG132, a proteasome inhibitor. In addition, NCTD-induced cell death was comparable to that of the anti-cancer drug gefitinib, a tyrosine kinase inhibitor for EGFR, based on the immunoblot analysis of the expressed proteins after the drug treatment. Conclusions NCTD might be a useful and inexpensive drug candidate to substitute for gefitinib to serve the treatment needs of cancer patients.

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.

Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer9s disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain9s innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble Aβ oligomers (oAβ) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oAβ-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNFα) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oAβ extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oAβ, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain9s innate immune system. SIGNIFICANCE STATEMENT Environmental enrichment (EE) is a potential therapy to delay Alzheimer9s disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human Aβ oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.

APOBEC3A belongs to a family of single-stranded DNA (ssDNA) DNA cytosine deaminases that are known for restriction of HIV through deamination-induced mutational inactivation, e.g. APOBEC3G, or initiation of somatic hypermutation and class switch recombination (activation-induced cytidine deaminase). APOBEC3A, which is localized to both the cytoplasm and nucleus, not only restricts HIV but can also initiate catabolism of cellular DNA. Despite being ascribed these roles, there is a paucity of data available on the biochemical mechanism by which APOBEC3A deaminates ssDNA. Here we assessed APOBEC3A deamination activity on ssDNA and in dynamic systems modeling HIV replication (cytoplasmic event) and DNA transcription (nuclear event). We find that APOBEC3A, unlike the highly processive APOBEC3G, exhibits low or no processivity when deaminating synthetic ssDNA substrates with two cytosines located 5-63 nucleotides apart, likely because of an apparent K(d) in the micromolar range (9.1 μm). APOBEC3A was able to deaminate nascently synthesized (-)DNA in an in vitro model HIV replication assay but induced fewer mutations overall in comparison to APOBEC3G. However, the data indicate that the target deamination motif (5'-TC for APOBEC3A and 5'-CC for APOBEC3G) and not the number of mutations best predicted the ability to mutationally inactivate HIV. We further assessed APOBEC3A for the ability to deaminate dsDNA undergoing transcription, which could allow for collateral deaminations to occur in genomic DNA similar to the action of activation-induced cytidine deaminase. That APOBEC3A was able to deaminate dsDNA undergoing transcription suggests a genomic cost of a deamination-based retroviral restriction system.

The biclustering is a useful tool in analysis of massive gene expression data, which performs simultaneous clustering on rows and columns of the data matrix to find subsets of coherently expressed genes and conditions. Especially, in analysis of time-series gene expression data, it is meaningful to restrict biclusters to contiguous time points concerning coherent evolutions. In this paper, the BCCC-Bicluster is proposed as an extension of the CCC-Bicluster. An algorithm based on the frequent sequential mining is proposed to find all maximal BCCC-Biclusters. The newly defined Frequent-Infrequent Tree-Array (FITA) is constructed to speed up the traversal process, with useful strategies originating from Apriori Property to avoid redundant search. To make it more efficient, the bitwise operation XOR is applied to capture identical or opposite contiguous patterns between two rows. The algorithm is tested on the yeast microarray data. Experimental results show that the proposed algorithm is able to find all embedded BCCC-Biclusters, which are proven to reveal significant GO terms involved in biological processes.

Background With the speedy development of sequencing technologies, noninvasive prenatal testing (NIPT) has been widely applied in clinical practice for testing for fetal aneuploidy. The cell-free fetal DNA (cffDNA) concentration in maternal plasma is the most critical parameter for this technology because it affects the accuracy of NIPT-based sequencing for fetal trisomies 21, 18 and 13. Several approaches have been developed to calculate the cffDNA fraction of the total cell-free DNA in the maternal plasma. However, most approaches depend on specific single nucleotide polymorphism (SNP) allele information or are restricted to male fetuses. Methods In this study, we present an innovative method to accurately deduce the concentration of the cffDNA fraction using only maternal plasma DNA. SNPs were classified into four maternal-fetal genotype combinations and three boundaries were added to capture effective SNP loci in which the mother was homozygous and the fetus was heterozygous. The median value of the concentration of the fetal DNA fraction was estimated using the effective SNPs. A depth-bias correction was performed using simulated data and corresponding regression equations for adjustments when the depth of the sequencing data was below 100-fold or the cffDNA fraction is less than 10%. Results Using our approach, the median of the relative bias was 0.4% in 18 maternal plasma samples with a median sequencing depth of 125-fold. There was a significant association (r = 0.935) between our estimations and the estimations inferred from the Y chromosome. Furthermore, this approach could precisely estimate a cffDNA fraction as low as 3%, using only maternal plasma DNA at the targeted region with a sequencing depth of 65-fold. We also used PCR instead of parallel sequencing to calculate the cffDNA fraction. There was a significant association (r = 98.2%) between our estimations and those inferred from the Y chromosome.