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Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/beta-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

A search for a massive resonance decaying into a standard-model-like Higgs boson (H) and a W or Z boson is reported. The analysis is performed on a data sample corresponding to an integrated luminosity of 19.7 fb(-1), collected in proton-proton collisions at a centre-of-mass energy of 8 TeV with the CMS detector at the LHC. Signal events, in which the decay products of Higgs, W, or Z bosons at high Lorentz boost are contained within single reconstructed jets, are identified using jet substructure techniques, including the tagging of b hadrons. This is the first search for heavy resonances decaying into HW or HZ resulting in an all-jet final state, as well as the first application of jet substructure techniques to identify H -> WW* -> 4q decays at high Lorentz boost. No significant signal is observed and limits are set at 95% confidence level on the production cross sections of W' and Z' in a model with mass-degenerate charged and neutral spin-1 resonances. Resonance masses are excluded for W' in the interval [1.0, 1.6] TeV, for Z' in the intervals [1.0, 1.1] and [1.3, 1.5] TeV, and for mass-degenerate W' and Z' in the interval [1.0, 1.7] TeV.

We investigate the motion of a single particle moving on a two-dimensional square lattice whose sites are occupied by right and left rotators. These left and right rotators deterministically rotate the particle's velocity to the right or left, respectively and flip orientation from right to left or from left to right after scattering the particle. We study three types of configurations of left and right rotators, which we think of as types ofmedia, through with the particle moves. These are completely random (CR), random periodic (RP), and completely periodic (CP) configurations. For CR configurations the particle's dynamics depends on the ratio r of right to left scatterers in the following way. For small r similar or equal to 0, when the configuration is nearly homogeneous, the particle subdiffuses with an exponent of 2/3, similar to the diffusion of a macromolecule in a crowded environment. Also, the particle's trajectory has a fractal dimension of d(f) similar or equal to 4/3, comparable to that of a self-avoiding walk. As the ratio increases to r similar or equal to 1, the particle's dynamics transitions from subdiffusion to anomalous diffusion with a fractal dimension of d(f) similar or equal to 7/4, similar to that of a percolating cluster in 2-d. In RP configurations, which are more structured than CR configurations but also randomly generated, we find that the particle has the same statistic as in the CR case. In contrast, CP configurations, which are highly structured, typically will cause the particle to go through a transient stage of subdiffusion, which then abruptly changes to propagation. Interestingly, the subdiffusive stage has an exponent of approximately 2/3 and a fractal dimension of d(f) similar or equal to 4/3, similar to the case of CR and RP configurations for small r.

During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which, in turn, is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is the convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde prodegenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal.

A search for pair production of first and second generation leptoquarks is performed in final states containing either two charged leptons and two jets, or one charged lepton, one neutrino and two jets, using proton-proton collision data at root s = 8 TeV. The data, corresponding to an integrated luminosity of 19.7 fb(-1), were recorded with the CMS detector at the LHC. First-generation scalar leptoquarks with masses less than 1010 (850) GeV are excluded for beta = 1.0 (0.5), where beta is the branching fraction of a leptoquark decaying to a charged lepton and a quark. Similarly, second-generation scalar leptoquarks with masses less than 1080 (760) GeV are excluded for beta = 1.0 (0.5). Mass limits are also set for vector leptoquark production scenarios with anomalous vector couplings, and for R-parity violating supersymmetric scenarios of top squark pair production resulting in similar final-state signatures. These are the most stringent limits placed on the masses of vector leptoquarks and RPV top squarks to date.

Influenza viruses cause mild to moderate respiratory illness in most people, and only rarely devastating or fatal infections. The virulence factors encoded by viral genes can explain seasonal or geographic differences at the population level but are unlikely to account for inter-individual clinical variability. Inherited or acquired immunodeficiencies may thus underlie severe cases of influenza. The crucial role of host genes was first demonstrated by forward genetics in inbred mice, with the identification of interferon (IFN)-alpha/beta-inducible Mx1 as a canonical influenza susceptibility gene. Reverse genetics has subsequently characterized the in vivo role of other mouse genes involved in IFN-alpha/beta and -lambda immunity. A series of in vitro studies with mouse and human cells have also refined the cell-intrinsic mechanisms of protection against influenza viruses. Population-based human genetic studies have not yet uncovered variants with a significant impact. Interestingly, human primary immunodeficiencies affecting T and B cells were also not found to predispose to severe influenza. Recently however, human IRF7 was shown to be essential for IFN-alpha/beta- and IFN-lambda-dependent protective immunity against primary influenza in vivo, as inferred from a patient with life-threatening influenza revealed to be IRF7-deficient by whole exome sequencing. Next generation sequencing of human exomes and genomes will facilitate the analysis of the human genetic determinism of severe influenza.

Background Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility. Methodology An association scan of the LRRK2 locus was performed using 156 single-nucleotide poly-morphisms (SNPs). Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL) analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels. Principal Findings A total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863) that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen. Significance The results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn's disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases.

TGF-beta signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-beta mediator Smad4. We show that TGF-beta induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-beta-sensitive PDA cells, EMT becomes lethal by converting TGF-beta-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-beta. TGF-beta-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-beta tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

The Chlamydomonas genome has been sequenced, assembled, and annotated to produce a rich resource for genetics and molecular biology in this well-studied model organism. The annotated genome is very rich in open reading frames upstream of the annotated coding sequence ('uORFs'): almost three quarters of the assigned transcripts have at least one uORF, and frequently more than one. This is problematic with respect to the standard 'scanning' model for eukaryotic translation initiation. These uORFs can be grouped into three classes: class 1, initiating in-frame with the coding sequence (CDS) (thus providing a potential in-frame N-terminal extension); class 2, initiating in the 59 untranslated sequences (5UT) and terminating out-of-frame in the CDS; and class 3, initiating and terminating within the 5UT. Multiple bioinformatics criteria (including analysis of Kozak consensus sequence agreement and BLASTP comparisons to the closely related Volvox genome, and statistical comparison to cds and to random sequence controls) indicate that of similar to 4000 class 1 uORFs, approximately half are likely in vivo translation initiation sites. The proposed resulting N-terminal extensions in many cases will sharply alter the predicted biochemical properties of the encoded proteins. These results suggest significant modifications in similar to 2000 of the similar to 20,000 transcript models with respect to translation initiation and encoded peptides. In contrast, class 2 uORFs may be subject to purifying selection, and the existent ones (surviving selection) are likely inefficiently translated. Class 3 uORFs are found in more than half of transcripts, frequently multiple times per transcript; however, they are remarkably similar to random sequence expectations with respect to size, number, and composition, and therefore may in most cases be selectively neutral.

While searching for new therapeutics against malaria, Lanzavecchia and colleagues discovered that antibodies can be diversified by DNA sequences encoded outside of antibody genes.