Differential systems associated with tableaux over Lie algebras

We give an account of the construction of exterior differential systems based on the notion of tableaux over Lie algebras as developed in [Comm. Anal. Geom 14 (2006), 475-496; math.DG/0412169]. The definition of a tableau over a Lie algebra is revisited and extended in the light of the formalism of the Spencer cohomology; the question of involutiveness for the associated systems and their prolongations is addressed; examples are discussed.Comment: 16 pages; to appear in: "Symmetries and Overdetermined Systems of Partial Differential Equations" (M. Eastwood and W. Miller, Jr., eds.), IMA Volumes in Mathematics and Its Applications, Springer-Verlag, New Yor

A solution of a problem of Sophus Lie: Normal forms of 2-dim metrics admitting two projective vector fields

We give a complete list of normal forms for the 2-dimensional metrics that admit a transitive Lie pseudogroup of geodesic-preserving transformations and we show that these normal forms are mutually non-isometric. This solves a problem posed by Sophus Lie.Comment: This is an extended version of the paper that will appear in Math. Annalen. Some typos were corrected, references were updated, title was changed (as in the journal version). 31 page

The Complexity of the Empire Colouring Problem

We investigate the computational complexity of the empire colouring problem (as defined by Percy Heawood in 1890) for maps containing empires formed by exactly $r > 1$ countries each. We prove that the problem can be solved in polynomial time using $s$ colours on maps whose underlying adjacency graph has no induced subgraph of average degree larger than $s/r$. However, if $s \geq 3$, the problem is NP-hard even if the graph is a forest of paths of arbitrary lengths (for any $r \geq 2$, provided $s < 2r - \sqrt(2r + 1/4+ 3/2)$. Furthermore we obtain a complete characterization of the problem's complexity for the case when the input graph is a tree, whereas our result for arbitrary planar graphs fall just short of a similar dichotomy. Specifically, we prove that the empire colouring problem is NP-hard for trees, for any $r \geq 2$, if $3 \leq s \leq 2r-1$ (and polynomial time solvable otherwise). For arbitrary planar graphs we prove NP-hardness if $s<7$ for $r=2$, and $s < 6r-3$, for $r \geq 3$. The result for planar graphs also proves the NP-hardness of colouring with less than 7 colours graphs of thickness two and less than $6r-3$ colours graphs of thickness $r \geq 3$.Comment: 23 pages, 12 figure

Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial.

Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity. In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells. The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ. An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab. The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063)

Changes in supramolecular organization of cyanobacterial thylakoid membrane complexes in response to far-red light photoacclimation

Cyanobacteria are ubiquitous in nature and have developed numerous strategies that allow them to live in a diverse range of environments. Certain cyanobacteria synthesize chlorophylls d and f to acclimate to niches enriched in far-red light (FRL) and incorporate paralogous photosynthetic proteins into their photosynthetic apparatus in a process called FRL-induced photoacclimation (FaRLiP). We characterized the macromolecular changes involved in FRL-driven photosynthesis and used atomic force microscopy to examine the supramolecular organization of photosystem I associated with FaRLiP in three cyanobacterial species. Mass spectrometry showed the changes in the proteome of Chroococcidiopsis thermalis PCC 7203 that accompany FaRLiP. Fluorescence lifetime imaging microscopy and electron microscopy reveal an altered cellular distribution of photosystem complexes and illustrate the cell-to-cell variability of the FaRLiP response

Identifying challenges and opportunities for improved nutrient management through U.S.D.A's Dairy Agroecosystem Working Group

Nutrient management is a priority of U.S. dairy farms, although specific concerns vary across regions and management systems. To elucidate challenges and opportunities to improving nutrient use efficiencies, the USDA’s Dairy Agroecosystems Working Group investigated 10 case studies of confinement (including open lots and free stall housing) and grazing operations in the seven major U.S. dairy producing states. Simulation modeling was carried out using the Integrated Farm Systems Model over 25 years of historic weather data. Dairies with a preference for importing feed and exporting manure, common for simulated dry lot dairies of the arid west, had lower nutrient use efficiencies at the farm gate than freestall and tie-stall dairies in humid climates. Phosphorus (P) use efficiencies ranged from 33 to 82% of imported P, while N use efficiencies were 25 to 50% of imported N. When viewed from a P budgeting perspective, environmental losses of P were generally negligible, especially from dry lot dairies. Opportunities for greater P use efficiency reside primarily in increasing on-farm feed production and reducing excess P in diets. In contrast with P, environmental losses of nitrogen (N) were 50 to 75% of annual farm N inputs. For dry lot dairies, the greatest potential for N conservation is associated with ammonia (NH3) control from housing, whereas for freestall and tie-stall operations, N conservation opportunities vary with soil and manure management system. Given that fertilizer expenses are equivalent to 2 to 6% of annual farm profits, cost incentives do exist to improve nutrient use efficiencies. However, augmenting on-farm feed production represents an even greater opportunity, especially on large operations with high animal unit densities

The delivery of personalised, precision medicines via synthetic proteins

Introduction: The design of advanced drug delivery systems based on synthetic and su-pramolecular chemistry has been very successful. Liposomal doxorubicin (Caelyx®), and liposomal daunorubicin (DaunoXome®), estradiol topical emulsion (EstrasorbTM) as well as soluble or erodible polymer systems such as pegaspargase (Oncaspar®) or goserelin acetate (Zoladex®) represent considerable achievements. The Problem: As deliverables have evolved from low molecular weight drugs to biologics (currently representing approximately 30% of the market), so too have the demands made of advanced drug delivery technology. In parallel, the field of membrane trafficking (and endocytosis) has also matured. The trafficking of specific receptors i.e. material to be recycled or destroyed, as well as the trafficking of protein toxins has been well characterized. This, in conjunction with an ability to engineer synthetic, recombinant proteins provides several possibilities. The Solution: The first is using recombinant proteins as drugs i.e. denileukin diftitox (Ontak®) or agalsidase beta (Fabrazyme®). The second is the opportunity to use protein toxin architecture to reach targets that are not normally accessible. This may be achieved by grafting regulatory domains from multiple species to form synthetic proteins, engineered to do multiple jobs. Examples include access to the nucleocytosolic compartment. Herein the use of synthetic proteins for drug delivery has been reviewed

Proof of projective Lichnerowicz conjecture for pseudo-Riemannian metrics with degree of mobility greater than two

We prove an important partial case of the pseudo-Riemannian version of the projective Lichnerowicz conjecture stating that a complete manifold admitting an essential group of projective transformations is the round sphere (up to a finite cover).Comment: 32 pages, one .eps figure. The version v1 has a misprint in Theorem 1: I forgot to write the assumption that the degree of mobility is greater than two. The versions v3, v4 have only cosmetic changes wrt v

Genetic plasticity of the Shigella virulence plasmid is mediated by intra- and inter-molecular events between insertion sequences

Acquisition of a single copy, large virulence plasmid, pINV, led to the emergence of Shigella spp. from Escherichia coli. The plasmid encodes a Type III secretion system (T3SS) on a 30kb pathogenicity island (PAI), and is maintained in a bacterial population through a series of toxin:antitoxin (TA) systems which mediate post-segrega tional killing (PSK). The T3SS imposes a significant cost on the bacterium, and strains which have lost the plasmid and/or genes encoding the T3SS grow faster than wild-type strains in the laboratory, and fail to bind the indicator dye Congo Red (CR). Our aim was to define the molecular events in Shigella flexneri that cause loss of Type III secretion (T3S), and to examine whether TA systems exert positional effects on pINV. During growth at 37°C, we found that deletions of regions of the plasmid including the PAI lead to the emergence of CR-negative colonies; deletions occur through intra-molecula r recombination events between insertion sequences (ISs) flanking the PAI. Furthermore, by repositioning MvpAT (which belongs to the VapBC family of TA systems) near the PAI, we demonstrate that the location of this TA system alters the rearrangements that lead to loss of T3S, indicating that MvpAT acts both globally (by reducing loss of pINV through PSK) as well as locally (by preventing loss of adjacent sequences). During growth at environmental temperatures, we show for the first time that pINV spontaneously integrates into different sites in the chromosome, and this is mediated by inter-molecular events involving IS 1294. Integration leads to reduced PAI gene expression and impaired secretion through the T3SS, while excision of pINV from the chromosome restores T3SS function. Therefore, pINV integration provides a reversible mechanism for Shigella to circumvent the metabolic burden imposed by pINV. Intra- and inter-molecular events between ISs, which are abundant in Shigella spp., mediate plasticity of S. flexneri pINV

Search for Bs0B^{0}_{s} oscillations using inclusive lepton events

A search for Bs oscillations is performed using a sample of semileptonic b-hadron decays collected by the ALEPH experiment during 1991-1995. Compared to previous inclusive lepton analyses, the prop er time resolution and b-flavour mistag rate are significantly improved. Additional sensitivity to Bs mixing is obtained by identifying subsamples of events having a Bs purity which is higher than the average for the whole data sample. Unbinned maximum likelihood amplitude fits are performed to derive a lower limit of Dms>9.5 ps-1 at 95% CL. Combining with the ALEPH Ds based analyses yields Dms>9.6 ps-1 at 95% CL.A search for B0s oscillations is performed using a sample of semileptonic b-hadron decays collected by the ALEPH experiment during 1991-1995. Compared to previous inclusive lepton analyses, the proper time resolution and b-flavour mistag rate are significantly improved. Additional sensitivity to B0s mixing is obtained by identifying subsamples of events having a B0s purity which is higher than the average for the whole data sample. Unbinned maximum likelihood amplitude fits are performed to derive a lower limit of Deltam_s>9.5ps^-1 at 95% CL. Combining with the ALEPH D-s based analyses yields Deltam_s>9.6ps^-1 at 95% CL