Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus.

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus

Emergence and fate of stem cell-like Tcf7⁺ CD8⁺ T cells during a primary immune response to viral infection.

In response to infection, naïve CD8 <sup>+</sup> T (T <sub>N</sub> ) cells yield a large pool of short-lived terminal effector (T <sub>TE</sub> ) cells that eliminate infected host cells. In parallel, a minor population of stem cell-like central memory (T <sub>CM</sub> ) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like T <sub>CM</sub> cells arise by dedifferentiation from a subset of cytolytic T <sub>TE</sub> cells or whether priming generates stem-like cells capable of seeding the T <sub>CM</sub> compartment and, if so, when cytolytic T <sub>TE</sub> cells branch off. Here, we show that CD8 <sup>+</sup> T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs T <sub>N</sub> cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1 <sup>+</sup> cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1 <sup>+</sup> T <sub>CM</sub> cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1 <sup>+</sup> cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a T <sub>TE</sub> state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1 <sup>+</sup> relative to TCF1 <sup>-</sup> cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default

Engineering Robust Metallic Zero-Mode States in Olympicene Graphene Nanoribbons

Metallic graphene nanoribbons (GNRs) represent a critical component in the toolbox of low-dimensional functional materials technolo-gy serving as 1D interconnects capable of both electronic and quantum information transport. The structural constraints imposed by on-surface bottom-up GNR synthesis protocols along with the limited control over orientation and sequence of asymmetric monomer building blocks during the radical step-growth polymerization has plagued the design and assembly of metallic GNRs. Here we report the regioregular synthesis of GNRs hosting robust metallic states by embedding a symmetric zero-mode superlattice along the backbone of a GNR. Tight-binding electronic structure models predict a strong nearest-neighbor electron hopping interaction between adjacent zero-mode states resulting in a dispersive metallic band. First principles DFT-LDA calculations confirm this prediction and the robust, metallic zero-mode band of olympicene GNRs (oGNRs) is experimentally corroborated by scanning tunneling spectroscopy.Comment: 8 pages, 4 figure

Enhancing reductive cleavage of aromatic carboxamides

[GRAPHICS] A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)amine in most cases in nearly quantitative yields, Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH4 are given

Precis of epistemic angst:Book Symposium: Duncan Pritchard, Epistemic Angst (Princeton University Press, 2015, xiii + 236 pages)

ABSTRACT This book symposium features three critical pieces dealing with Duncan Pritchard's book, 'Epistemic Angst'; the symposium also contains Pritchard's replies to his critics

Inferring the role of transcription factors in regulatory networks

<p>Abstract</p> <p>Background</p> <p>Expression profiles obtained from multiple perturbation experiments are increasingly used to reconstruct transcriptional regulatory networks, from well studied, simple organisms up to higher eukaryotes. Admittedly, a key ingredient in developing a reconstruction method is its ability to integrate heterogeneous sources of information, as well as to comply with practical observability issues: measurements can be scarce or noisy. In this work, we show how to combine a network of genetic regulations with a set of expression profiles, in order to infer the functional effect of the regulations, as inducer or repressor. Our approach is based on a consistency rule between a network and the signs of variation given by expression arrays.</p> <p>Results</p> <p>We evaluate our approach in several settings of increasing complexity. First, we generate artificial expression data on a transcriptional network of <it>E. coli </it>extracted from the literature (1529 nodes and 3802 edges), and we estimate that 30% of the regulations can be annotated with about 30 profiles. We additionally prove that at most 40.8% of the network can be inferred using our approach. Second, we use this network in order to validate the predictions obtained with a compendium of real expression profiles. We describe a filtering algorithm that generates particularly reliable predictions. Finally, we apply our inference approach to <it>S. cerevisiae </it>transcriptional network (2419 nodes and 4344 interactions), by combining ChIP-chip data and 15 expression profiles. We are able to detect and isolate inconsistencies between the expression profiles and a significant portion of the model (15% of all the interactions). In addition, we report predictions for 14.5% of all interactions.</p> <p>Conclusion</p> <p>Our approach does not require accurate expression levels nor times series. Nevertheless, we show on both data, real and artificial, that a relatively small number of perturbation experiments are enough to determine a significant portion of regulatory effects. This is a key practical asset compared to statistical methods for network reconstruction. We demonstrate that our approach is able to provide accurate predictions, even when the network is incomplete and the data is noisy.</p

Physiochemical property space distribution among human metabolites, drugs and toxins

<p>Abstract</p> <p>Background</p> <p>The current approach to screen for drug-like molecules is to sieve for molecules with biochemical properties suitable for desirable pharmacokinetics and reduced toxicity, using predominantly biophysical properties of chemical compounds, based on empirical rules such as Lipinski's "rule of five" (Ro5). For over a decade, Ro5 has been applied to combinatorial compounds, drugs and ligands, in the search for suitable lead compounds. Unfortunately, till date, a clear distinction between drugs and non-drugs has not been achieved. The current trend is to seek out drugs which show metabolite-likeness. In identifying similar physicochemical characteristics, compounds have usually been clustered based on some characteristic, to reduce the search space presented by large molecular datasets. This paper examines the similarity of current drug molecules with human metabolites and toxins, using a range of computed molecular descriptors as well as the effect of comparison to clustered data compared to searches against complete datasets.</p> <p>Results</p> <p>We have carried out statistical and substructure functional group analyses of three datasets, namely human metabolites, drugs and toxin molecules. The distributions of various molecular descriptors were investigated. Our analyses show that, although the three groups are distinct, present-day drugs are closer to toxin molecules than to metabolites. Furthermore, these distributions are quite similar for both clustered data as well as complete or unclustered datasets.</p> <p>Conclusion</p> <p>The property space occupied by metabolites is dissimilar to that of drugs or toxin molecules, with current drugs showing greater similarity to toxins than to metabolites. Additionally, empirical rules like Ro5 can be refined to identify drugs or drug-like molecules that are clearly distinct from toxic compounds and more metabolite-like. The inclusion of human metabolites in this study provides a deeper insight into metabolite/drug/toxin-like properties and will also prove to be valuable in the prediction or optimization of small molecules as ligands for therapeutic applications.</p

Alpha thalassaemia-mental retardation, X linked

X-linked alpha thalassaemia mental retardation (ATR-X) syndrome in males is associated with profound developmental delay, facial dysmorphism, genital abnormalities and alpha thalassaemia. Female carriers are usually physically and intellectually normal. So far, 168 patients have been reported. Language is usually very limited. Seizures occur in about one third of the cases. While many patients are affectionate with their caregivers, some exhibit autistic-like behaviour. Patients present with facial hypotonia and a characteristic mouth. Genital abnormalities are observed in 80% of children and range from undescended testes to ambiguous genitalia. Alpha-thalassaemia is not always present. This syndrome is X-linked recessive and results from mutations in the ATRX gene. This gene encodes the widely expressed ATRX protein. ATRX mutations cause diverse changes in the pattern of DNA methylation at heterochromatic loci but it is not yet known whether this is responsible for the clinical phenotype. The diagnosis can be established by detection of alpha thalassaemia, identification of ATRX gene mutations, ATRX protein studies and X-inactivation studies. Genetic counselling can be offered to families. Management is multidisciplinary: young children must be carefully monitored for gastro-oesophageal reflux as it may cause death. A number of individuals with ATR-X are fit and well in their 30s and 40s