Modeling the functional genomics of autism using human neurons.

Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD

Pillared Vanadium Molybdenum Disulfide Nanosheets: Toward High-Performance Cathodes for Magnesium-Ion Batteries.

If magnesium-ion batteries (MIBs) are to be seriously considered for next-generation energy storage, then a number of major obstacles need to be overcome. The lack of reversible cathode materials with sufficient capacity and cycle life is one of these challenges. Here, we report a new MIB cathode constructed of vertically stacked vanadium molybdenum sulfide (VMS) nanosheets toward addressing this challenge. The integration of vanadium within molybdenum sulfide nanostructures acts so as to improve the total conductivity, enhancing charge transfer, and to produce abundant lattice defects, improving both the accommodation and transport of Mg2+. Additionally, electrolyte additive-induced interlayer expansion provides a means to admit Mg2+ cations into the electrode structure and thus enhance their diffusion. The VMS nanosheets are capable of exhibiting capacities of 211.3 and 128.2 mA h g-1 at current densities of 100 and 1000 mA g-1, respectively. The VMS nanosheets also demonstrate long-term cycling stability, retaining 82.7% of the maximum capacity after 500 cycles at a current density of 1000 mA h g-1. These results suggest that VMS nanosheets could be promising candidates for high-performance cathodes in MIBs

Improved prediction of RNA secondary structure by integrating the free energy model with restraints derived from experimental probing data.

PublishedEvaluation StudiesJournal ArticleResearch Support, Non-U.S. Gov'tRecently, several experimental techniques have emerged for probing RNA structures based on high-throughput sequencing. However, most secondary structure prediction tools that incorporate probing data are designed and optimized for particular types of experiments. For example, RNAstructure-Fold is optimized for SHAPE data, while SeqFold is optimized for PARS data. Here, we report a new RNA secondary structure prediction method, restrained MaxExpect (RME), which can incorporate multiple types of experimental probing data and is based on a free energy model and an MEA (maximizing expected accuracy) algorithm. We first demonstrated that RME substantially improved secondary structure prediction with perfect restraints (base pair information of known structures). Next, we collected structure-probing data from diverse experiments (e.g. SHAPE, PARS and DMS-seq) and transformed them into a unified set of pairing probabilities with a posterior probabilistic model. By using the probability scores as restraints in RME, we compared its secondary structure prediction performance with two other well-known tools, RNAstructure-Fold (based on a free energy minimization algorithm) and SeqFold (based on a sampling algorithm). For SHAPE data, RME and RNAstructure-Fold performed better than SeqFold, because they markedly altered the energy model with the experimental restraints. For high-throughput data (e.g. PARS and DMS-seq) with lower probing efficiency, the secondary structure prediction performances of the tested tools were comparable, with performance improvements for only a portion of the tested RNAs. However, when the effects of tertiary structure and protein interactions were removed, RME showed the highest prediction accuracy in the DMS-accessible regions by incorporating in vivo DMS-seq data.National Key Basic Research Program of China [2012CB316503]; National High-Tech Research and Development Program of China [2014AA021103]; National Natural Science Foundation of China [31271402]; Tsinghua University Initiative Scientific Research Program [2014z21045]; Hong Kong Research Grants Council Early Career Scheme [419612 to K.Y.]; National Science Foundation [1339282 to D.H.M.]; Computing Platform of the National Protein Facilities (Tsinghua University). Funding for open access charge: National Natural Science Foundation of China [31271402]

Genetic diversity among Toxoplasma gondii isolates from different hosts and geographical locations revealed by analysis of ROP13 gene sequences

Toxoplasma gondii can infect almost all the warm-blooded animals and human beings, causing serious public health problems and economic losses worldwide. Rhoptry protein 13 (ROP13) plays some roles in the invasion process of T. gondii. In this study, sequence variation in ROP13 gene among 14 T. gondii isolates from different geographical locations and hosts was examined. The ROP13 gene was amplified from individual isolates and sequenced. Results show that the length of the ROP13 sequences was 1203 bp. In total, there were 44 variable nucleotide positions in the ROP13 sequences, and sequence variations were 0.1 to 2.0% among the 14 examined T. gondii isolates, representing higher rate in transversion than in transition. Intra-specific nucleotide variations were mainly at the second codon positions. Phylogenetic analysis of the 14 examined T. gondii isolates indicate that the ROP13 sequence was not a suitable genetic marker to differentiate T. gondii isolates of different genotypes from different hosts and geographical regions. Low variation in ROP13 gene sequence may suggest that ROP13 gene could represent a good vaccine candidate against toxoplasmosis.Key words: Toxoplasma gondii, toxoplasmosis, rhpotry protein 13 (ROP13), sequence variation, phylogenetic analysis

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Sequence variation in TgROP7 gene among Toxoplasma gondii isolates from different hosts and geographical regions

Toxoplasma gondii can infect a wide range of hosts including mammals and birds, causing toxoplasmosis which is one of the most common parasitic zoonoses worldwide. The present study examined sequence variation in rhoptry 7 (ROP7) gene among different T. gondii isolates from different hosts and geographical localities. Phylogenetic analysis of the examined T. gondii isolates was conducted using the maximum likelihood (ML) method. Sequence analysis revealed that 60 nucleotide positions were variable in the ROP7 gene sequences among the 19 examined T. gondii isolates, corresponding to sequence variations of 0 to 1.7%, which occurred at the first, second and third codons. Phylogenetic analysis indicated that sequence variation in ROP7 gene was low among the examined T. gondii isolates from different hosts and geographical localities, and that the ROP7 sequence was not suitable as genetic marker for the differentiation of T. gondii isolates. The results of the present study suggest that ROP7 gene may be a suitable vaccine candidate.Key words: Sequence variation, rhoptry 7 (ROP7) gene, Toxoplasma gondii, toxoplasmosis, phylogenetic analysis

RNAstructure: software for RNA secondary structure prediction and analysis

<p>Abstract</p> <p>Background</p> <p>To understand an RNA sequence's mechanism of action, the structure must be known. Furthermore, target RNA structure is an important consideration in the design of small interfering RNAs and antisense DNA oligonucleotides. RNA secondary structure prediction, using thermodynamics, can be used to develop hypotheses about the structure of an RNA sequence.</p> <p>Results</p> <p>RNAstructure is a software package for RNA secondary structure prediction and analysis. It uses thermodynamics and utilizes the most recent set of nearest neighbor parameters from the Turner group. It includes methods for secondary structure prediction (using several algorithms), prediction of base pair probabilities, bimolecular structure prediction, and prediction of a structure common to two sequences. This contribution describes new extensions to the package, including a library of C++ classes for incorporation into other programs, a user-friendly graphical user interface written in JAVA, and new Unix-style text interfaces. The original graphical user interface for Microsoft Windows is still maintained.</p> <p>Conclusion</p> <p>The extensions to RNAstructure serve to make RNA secondary structure prediction user-friendly. The package is available for download from the Mathews lab homepage at <url>http://rna.urmc.rochester.edu/RNAstructure.html</url>.</p

Controlling passively-quenched single photon detectors by bright light

Single photon detectors based on passively-quenched avalanche photodiodes can be temporarily blinded by relatively bright light, of intensity less than a nanowatt. I describe a bright-light regime suitable for attacking a quantum key distribution system containing such detectors. In this regime, all single photon detectors in the receiver Bob are uniformly blinded by continuous illumination coming from the eavesdropper Eve. When Eve needs a certain detector in Bob to produce a click, she modifies polarization (or other parameter used to encode quantum states) of the light she sends to Bob such that the target detector stops receiving light while the other detector(s) continue to be illuminated. The target detector regains single photon sensitivity and, when Eve modifies the polarization again, produces a single click. Thus, Eve has full control of Bob and can do a successful intercept-resend attack. To check the feasibility of the attack, 3 different models of passively-quenched detectors have been tested. In the experiment, I have simulated the intensity diagrams the detectors would receive in a real quantum key distribution system under attack. Control parameters and side effects are considered. It appears that the attack could be practically possible.Comment: Experimental results from a third detector model added. Minor corrections and edits made. 11 pages, 10 figure