The rockefeller university

Perceptual learning is associated with changes in the functional properties of neurons even in primary sensory areas. In macaque monkeys trained to perform a contour detection task, we have observed changes in contour-related facilitation of neuronal responses in primary visual cortex that track their improvement in performance on a contour detection task. We have previously explored the anatomical substrate of experience-dependent changes in the visual cortex based on a retinal lesion model, where we find sprouting and pruning of the axon collaterals in the cortical lesion projection zone. Here, we attempted to determine whether similar changes occur under normal visual experience, such as that associated with perceptual learning. We labeled the long-range horizontal connections in visual cortex by virally mediated transfer of genes expressing fluorescent probes, which enabled us to do longitudinal two-photon imaging of axonal arbors over the period during which animals improve in contour detection performance. We found that there are substantial changes in the axonal arbors of neurons in cortical regions representing the trained part of the visual field, with sprouting of new axon collaterals and pruning of preexisting axon collaterals. Our findings indicate that changes in the structure of axonal arbors are part of the circuit-level mechanism of perceptual learning, and further support the idea that the learned information is encoded at least in part in primary visual cortex.

Red blood cells suspended in quiescent plasma tend to aggregate into multicellular assemblages, including linearly stacked columnar rouleaux, which can reversibly form more complex clusters or branching networks. While these aggregates play an essential role in establishing hemorheological and pathological properties, the biophysics behind their self-assembly into dynamic mesoscopic structures remains under-explored. We employ coarse-grained molecular simulations to model low-hematocrit erythrocytes subject to short-range implicit depletion forces, and demonstrate not only that depletion interactions are sufficient to account for a sudden dispersion-aggregate transition, but also that the volume fraction of depletant macromolecules controls small aggregate morphology. We observe a sudden transition from a dispersion to a linear column rouleau, followed by a slow emergence of disorderly amorphous clusters of many short rouleaux at larger volume fractions. This work demonstrates how discocyte topology and short-range, non-specific, physical interactions are sufficient to self-assemble erythrocytes into various aggregate structures, with markedly different morphologies and biomedical consequences.

The polymerase-associated factor 1 (Paf1) complex is a general transcription elongation factor of RNA polymerase II, which is composed of five core subunits, Paf1, Ctr9, Cdc73, Leo1, and Rtf1, and functions as a diverse platform that broadly affects gene expression genome-wide. In this study, we solved the 2.9-A crystal structure of the core region composed of the Ctr9-Paf1-Cdc73 ternary complex from a thermophilic fungi, which provides a structural perspective of the molecular details of the organization and interactions involving the Paf1 subunits in the core complex. We find that Ctr9 is composed of 21 tetratricopeptide repeat (TPR) motifs that wrap three circular turns in a right-handed superhelical manner around the N-terminal region of an elongated singlepolypeptide-chain scaffold of Paf1. The Cdc73 fragment is positioned within the surface groove of Ctr9, where it contacts mainly with Ctr9 and minimally with Paf1. We also identified that the Paf1 complex preferentially binds single-strand-containing DNAs. Our work provides structural insights into the overall architecture of the Paf1 complex and paves the road forward for understanding the molecular mechanisms of the Paf1 complex in transcriptional regulation.

Vegetable oil is an important renewable resource for dietary consumption for human and livestock, and more recently for biodiesel production. Lipid traits in crops are controlled by multiple quantitative trait loci (QTLs) and each of them has a small effect on lipid traits. So far, there is limited success to increase lipid yield and improve lipid quality in plants. Here, we reported the identification of a homolog of APETALA2 (AP2) transcription factor WRINKLED1 (JcWRI1) from an oleaginous plant Jatropha curcas and characterized its function in Jatropha and Arabidopsis thaliana. Using physical mapping data, we located JcWRI1 in a QTL region specifying high oleate and lipid content in Jatropha. Overexpression of JcWRI1 in Jatropha elevated seed lipid content and increased seed mass. Lipid profile in seeds of over-expression plants showed higher oleate content which will be beneficial to improve biodiesel quality. Overexpression of JcWRI1 activated lipid-related gene expression and JcWRI1 was shown to directly bind to the AW-box of promoters of some of these genes. In conclusion, we were able to increase seed lipid content and improve seed lipid quality in Jatropha by manipulating one key transcription factor JcWRI1.

Mdn1 is an essential AAA (ATPase associated with various activities) protein that removes assembly factors from distinct precursors of the ribosomal 60S subunit. However, Mdn1's large size (similar to 5,000 amino acid [aa]) and its limited homology to other well-studied proteins have restricted our understanding of its remodeling function. Here, we present structures for S. pombe Mdn1 in the presence of AMPPNP at up to similar to 4 angstrom or ATP plus Rbin-1, a chemical inhibitor, at similar to 8 angstrom resolution. These data reveal that Mdn1's MIDAS domain is tethered to its ring-shaped AAA domain through an similar to 20 nm long structured linker and a flexible similar to 500 aa Asp/Glu-rich motif. We find that the MIDAS domain, which also binds other ribosome-assembly factors, docks onto the AAA ring in a nucleotide state-specific manner. Together, our findings reveal how conformational changes in the AAA ring can be directly transmitted to the MIDAS domain and thereby drive the targeted release of assembly factors from ribosomal 60S-subunit precursors.

We read with interest the findings by Cynthia Farquhar and colleagues (Feb 3, p 441),1 and the accompanying Comment,2 relating to the use of intrauterine inseminations (IUIs) in the treatment of so-called unexplained infertility. Although we applaud the basic hypothesis behind the study, we object to the design and, in particular, the interpretation of the study. We also decry the uncritical acceptance of the reported findings and interpretation in the accompanying editorial.

MicroRNA-206 (miR-206) has demonstrated tumor suppressive effects in a variety of cancers. Numerous studies have identified aberrantly expressed targets of miR-206 that contribute to tumor progression and metastasis, however, the broader gene-networks and pathways regulated by miR-206 remain poorly defined. Here, we have ectopically expressed miR-206 in lung adenocarcinoma cell lines and tumors to identify differentially expressed genes, and study the effects on tumor growth and metastasis. In H1299 tumor xenograft assays, stable expression of miR-206 suppressed both tumor growth and metastasis in mice. Profiling of xenograft tumors using small RNA sequencing and a targeted panel of tumor progression and metastasis-related genes revealed a network of genes involved in TGF-beta signalling that were regulated by miR-206. Among these were the TGFB1 ligand, as well as direct transcriptional targets of Smad3. Other differentially expressed genes included components of the extracellular matrix involved in TGF-beta activation and signalling, including Thrombospondin-1, which is responsible for the activation of latent TGF-beta in the stroma. In cultured lung adenocarcinoma cells treated with recombinant TGF-beta, ectopic expression of miR-206 impaired canonical signalling, and expression of TGF-beta target genes linked to epithelial-mesenchymal transition. This was due at least in part to the suppression of Smad3 protein levels in lung adenocarcinoma cells with ectopic miR-206 expression. Together, these findings indicate that miR-206 can suppress tumor progression and metastasis by limiting autocrine production of TGF-beta, and highlight the potential utility of TGF-beta inhibitors for the treatment of lung adenocarcinomas.

Measurements of azimuthal angle and transverse momentum (p(T)) correlations of isolated photons and associated jets are reported for pp and PbPb collisions at root s(NN) = 5.02 TeV. The data were recorded with the CMS detector at the CERN LHC. For events containing a leading isolated photon with p(T)(gamma) > 40 GeV/c and an associated jet with p(T)(jet) > 30 GeV/c, the photon+jet azimuthal correlation and p(T) imbalance in PbPb collisions are studied as functions of collision centrality and p(T)(gamma). The results are compared to pp reference data collected at the same collision energy and to predictions from several theoretical models for parton energy loss. No evidence of broadening of the photon+jet azimuthal correlations is observed, while the ratio p(T)(jet)/p(T)(gamma) decreases significantly for PbPb data relative to the pp reference. All models considered agree within uncertainties with the data. The number of associated jets per photon with p(T)(gamma) > 80GeV/c is observed to be shifted towards lower p(T)(jet) in central PbPb collisions compared to pp collisions. (C) 2018 The Author. Published by Elsevier B.V.

Two of the most predominant features of the Alzheimer's disease (AD) brain are deposition of beta-amyloid (A beta) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate the deposition of A beta. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through alpha-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain's immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development.