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When deciding where to place access points in a wireless network, it is useful to model the signal propagation loss between a proposed antenna location and the areas it may cover. The indoor dominant path (IDP) model, introduced by W\"{o}lfle et al., is shown in the literature to have good validation and generalization error, is faster to compute than competing methods, and is used in commercial software such as WinProp, iBwave Design, and CellTrace. Previously, the algorithms known for computing it involved a worst-case exponential-time tree search, with pruning heuristics to speed it up. We prove that the IDP model can be reduced to a parametric shortest path computation on a graph derived from the walls in the floorplan. It therefore admits a quasipolynomial-time (i.e., $n^{O(\log n)}$) algorithm. We also give a practical approximation algorithm based on running a small constant number of shortest path computations. Its provable worst-case additive error (in dB) can be made arbitrarily small via appropriate choices of parameters, and is well below 1dB for reasonable choices. We evaluate our approximation algorithm empirically against the exact IDP model, and show that it consistently beats its theoretical worst-case bounds, solving the model exactly (i.e., no error) in the vast majority of cases., Comment: 12 pages, 8 figures, accepted to MobiHoc 2018

Earthwork remains of a small rectangular, stone-built structure were identified by field walking in Upper Pasture to the west of the hamlet of Selside in Horton in Ribblesdale civil parish. Most archaeological sites in Upper Ribblesdale have hitherto been identified as most probably of Romano-British date but none had been conclusively dated. Excavation of this structure was conceived to test the hypothesis that it was an early medieval shieling associated with transhumant stock rearing rather than a Romano-British building.Remarkably, significant quantities of Early Neolithic chert, some of it worked, were recovered from within the structure but radiocarbon dating of two charcoal samples impressed into the floor within the building produced identical radiocarbon dates of cal ad 660–780, thereby confirming an early medieval provenance for it. No early medieval metal objects or bone were recovered, and the site was aceramic.

In this paper, we consider two special cases of the “cover-by-pairs” optimization problem that arises when we need to place facilities so that each customer is served by two facilities that reach it by disjoint shortest paths. These problems arise in a network traffic-monitoring scheme proposed by Breslau et al. and have potential applications to content distribution. The “set-disjoint” variant applies to networks that use the open shortest path first routing protocol, and the “path-disjoint” variant applies when multiprotocol label switching routing is enabled, making better solutions possible at the cost of greater operational expense. Although we can prove that no polynomial-time algorithm can guarantee good solutions for either version, we are able to provide heuristics that do very well in practice on instances with real-world network structure. Fast implementations of the heuristics, made possible by exploiting mathematical observations about the relationship between the network instances and the corresponding instances of the cover-by-pairs problem, allow us to perform an extensive experimental evaluation of the heuristics and what the solutions they produce tell us about the effectiveness of the proposed monitoring scheme. For the set-disjoint variant, we validate our claim of near-optimality via a new lower-bounding integer programming formulation. Although computing this lower bound requires solving the NP-hard hitting set problem and can underestimate the optimal value by a linear factor in the worst case, it can be computed quickly by CPLEX, and it equals the optimal solution value for all the instances in our extensive test bed.

A series of small-scale controlled inoculation experiments has been conducted during 2005–2009 to determine whether temperature and controlled atmosphere (CA) storage conditions affect significantly the incidence of Botrytis cinerea and Neonectria galligena rots of apples and to assess whether CA regimes can be ‘fine-tuned’ to suppress fungal rotting. The incidence of B. cinerea and N. galligena rots on apple was reduced consistently by storage in lower temperatures (1.5–2°C). In no case was the disease incidence significantly higher than that under air storage conditions. However, the effect of CA conditions on rot development varied greatly from year to year so that overall there were no significant effects of CA conditions on the incidence of rot during storage till the following April. Thus, we can neither fine-tune CA conditions to reduce rot development nor exploit the advantages of lower storage temperatures for Cox and Bramley for this purpose due to inevitable development of low temperature breakdown. Further research is needed to study the effects of ethylene control technologies and modulated storage temperatures on rot development.

As Berlin developed into a modern metropolis in the nineteenth century, writers took note of the connections between the city's expanding geography and its burgeoning leisure and consumer culture. Varying accounts in novels, feuilleton essays, and city guides documented the incessant changes to the city's leisure landscapes and helped residents and tourists alike discover all the various outlets for amusement, diversion, and refuge.1 One such writer, the novelist and journalist Julius Rodenberg, connected the growing popular enthusiasm for leisure to the geographical expanse of the city. In 1 882, he asked: "Wohin nun, mein Freund? Ganz Berlin gehort dir; entscheide, triff deine Wahl" (50-51). While Rodenberg celebrated the empowering potential of Berlin's seemingly limitless options for amusements, others identified particular areas of the city as centers of leisure. Berlin W, for instance, became the moniker not only for the affluent residential areas west of the Tiergarten, but also a synonym for an urban space of consumption and entertainment. In the area of central Berlin known as Berlin C, Leipzigerstrase, Unter den Linden, and FriedrichstrafSe became alternatively known as "Kaufstrase," "Laufstrase," and "Saufstrase."2 Such labels not only underscored the variety of amusements and diversions available, but also their increasing accessibility. Indeed, the city's demographic and geographic growth, coupled with its improvements in transportation infrastructure and an emerging leisure industry, helped foster a so-called democratization of leisure.3 Whereas leisure had once been the domain of the aristocracy, all Berliners, regardless of class, could now find an array of locations for recreation, relaxation, and refuge. Theodor Fontane's Berlin novels, in particular L'Adultera (1880), Irrungen, Wirrungen (1887), Frau Jenny Treibel (1892), and Die Poggenpuhls (1896), provide ambivalent explorations of the varied manifestations and ramifications of this democratization of leisure. In each of these texts, particular sites for leisure, from well-known locations such as the Tiergarten, Stralau, and Treptow to new attractions such as Hankels Ablage and Halensee, become contested terrains in this process. As such, the geographic concepts of place and space help to elucidate the courses and outcomes of these contestations. As Yi-Fu Tuan notes, space is abstract and undifferentiated; it only becomes place when we get to know it better and endow it with value (6) . In terms of Berlin' s leisure sites, writers like Rodenberg, with their celebratory profiles of the city, sought to create defined, knowable, and masterable places of leisure that were comfortably set apart from the city's chaotic spaces of masses, traffic, and other urban ills. Fontane's Berlin novels, in contrast, demonstrate how the distinction between place and space is blurry and subject to the vagaries of modern urban life.4 In so doing, these texts perform, to use the words of Michel de Certeau, "a labor that constantly transforms places into spaces and spaces into places" (118). The leisure sites in Fontane's works are sometimes idyllic places of comfort, but also spatial manifestations of the worst of urban life: crowds, noise, chaos, and even existential danger. Moreover, the commercialization of such sites sometimes becomes so apparent that leisure emerges much more as a marketing concept than an actual experience. Yet, the new opportunities available at these leisure sites also sometimes challenge the idea that urban space is inherently bad and place intrinsically good. While the comforts of place can be illusory, the chaotic dimensions of urban leisure spaces can break down stifling traditional social structures, open up new opportunities for those less privileged, and constitute new sources of amusement and pleasure. These varied and inconsistent outcomes underscore how Fontane's novels do not provide harmonious narratives of life in the modern metropolis, but instead reveal the vicissitudes and paradoxes of this experience. …

Indices for site prioritization are widely used to address the question: which sites are most important for conservation of biodiversity? We investigate the theoretical underpinnings of target-based prioritization, which measures sites’ contribution to achieving predetermined conservation targets. We show a strong connection between site prioritization and the mathematical theory of voting power. Current site prioritization indices are afflicted by well-known paradoxes of voting power: a site can have zero priority despite having non-zero habitat (the paradox of dummies) and discovery of habitat in a new site can raise the priority of existing sites (the paradox of new members). These paradoxes arise because of the razor’s edge nature of voting, and therefore we seek a new index that is not strictly based on voting. By negating such paradoxes, we develop a set of intuitive axioms that an index should obey. We introduce a simple new index, “fraction-of-spare,” that satisfies all the axioms. For single-species site prioritization, the fraction-of-spare(s) of a site s equals zero if s has no habitat for the species and one if s is essential for meeting the target area for the species. In-between those limits it is linearly interpolated, and equals area(s)/(total area – target). In an evaluation involving multi-year scheduling of site acquisitions for conservation of forest types in New South Wales under specified clearing rates, fraction-of-spare outperforms 58 existing prioritization indices. We also compute the optimal schedule of acquisitions for each of three evaluation measures (under the assumed clearing rates) using integer programming, which indicates that there is still potential for improvement in site prioritization for conservation scheduling.

Monoclonal antibodies (mAbs) have proven to be extremely effective immuno-oncology therapeutics that lead to previously unseen durable responses in melanoma, bladder cancer, RCC, lung cancer, and other malignancies. Most mAb therapeutics, including current anti-PD-1 drugs, were discovered by mouse immunization followed by hybridoma isolation. Unfortunately, mouse hybridomas are highly inefficient, capturing only about 0.1% of the total B-cell diversity in immunized mice. As a result, discovery programs that use mouse hybridomas often struggle to find high-affinity, developable antibodies against certain challenging targets, even when using humanized mice. We have developed a novel method for mouse mAb discovery that leverages microfluidics, multiplex PCR, yeast single chain variable fragment (scFv) display, and fluorescence-activated cell sorting (FACS). Our technology is significantly faster and more comprehensive than conventional hybridoma screening. We recently embarked on a discovery campaign for 17 immuno-oncology targets, including PD-1, CTLA-4, GITR, and OX40. We injected chimeric humanized mice (Trianni) with antigen twice weekly for three weeks. Lymph nodes, splenocytes, and bone marrow were removed from the mice and made into single-cell suspensions. We then isolated B cells using negative selection magnetic beads, and used microfluidics to process >4 million cells per mouse, generating DNA libraries that keep single cell heavy and light chain immunoglobulin (Ig) pairing intact. We built yeast scFv libraries for each of the 17 antigen-specific B cell repertoires with a C-terminal c-myc tag. To select scFv-expressing cells that bind to antigen, biotinylated antigen was added to the yeast cells at 7-250nM and then stained with fluorescent streptavidin. We then flow sorted for the top double-positive cells (c-myc+/antigen+). Finally, we deep sequenced the libraries of enriched high-affinity scFvs, which yielded the sequences for >2,000 candidate scFv binders. Hundreds of these candidate scFvs were engineered into full-length mAb constructs and expressed transiently in Chinese hamster ovary (CHO) cells. To develop candidates for clinical use, we performed assays for binding kinetics, cell surface antigen binding, in vitro T-cell activation, and epitope binning. Candidates that are high affinity, bind cell surface antigen, and induce immune cell activation are now being tested in combinations for in vitro and in vivo efficacy. Combinations that have significantly better in vitro and in vivo efficacy than benchmark checkpoint inhibitors currently on the market will be moved forward into clinical studies. Citation Format: David S. Johnson, Adam S. Adler, Rena Mizrahi, Carter Keller. Discovery of therapeutic human monoclonal antibody combinations using microfluidics and molecular genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5764.

Promoters are important regulatory elements that contain the necessary sequence features for cells to initiate transcription. To functionally characterize a large set of human promoters, we measured the transcriptional activities of 4575 putative promoters across eight cell lines using transient transfection reporter assays. In parallel, we measured gene expression in the same cell lines and observed a significant correlation between promoter activity and endogenous gene expression (r = 0.43). As transient transfection assays directly measure the promoting effect of a defined fragment of DNA sequence, decoupled from epigenetic, chromatin, or long-range regulatory effects, we sought to predict whether a promoter was active using sequence features alone. CG dinucleotide content was highly predictive of ubiquitous promoter activity, necessitating the separation of promoters into two groups: high CG promoters, mostly ubiquitously active, and low CG promoters, mostly cell line–specific. Computational models trained on the binding potential of transcriptional factor (TF) binding motifs could predict promoter activities in both high and low CG groups: average area under the receiver operating characteristic curve (AUC) of the models was 91% and exceeded the AUC of CG content by an average of 23%. Known relationships, for example, between HNF4A and hepatocytes, were recapitulated in the corresponding cell lines, in this case the liver-derived cell line HepG2. Half of the associations between tissue-specific TFs and cell line–specific promoters were new. Our study underscores the importance of collecting functional information from complementary assays and conditions to understand biology in a systematic framework.

�� ��� I. Scholars have called the nineteenth century a “bourgeois epoch,” as members of Germany’s middle classes shaped the transformation of the emerging nation- state into an economic and industrial power and acquired greater authority in civil society. 1 Already by the middle of the century, members of the bourgeoisie began proclaiming themselves and their class the victors of history and the shapers of the future. Middle- class writers created a narrative of ascent that erased the political failure of 1848, established common values in place of confessional, cultural, and economic differences, and celebrated bourgeois ingenuity and entrepreneurship. At the root of this vision was a hegemonic conceptualization of bourgeois masculinity. 2 Gustav Freytag’s Soll und Haben (1855) and Wilhelm Riehl’s Deutsche Arbeit (1861), for instance, celebrated the manly virtues of productivity, strength, and self- discipline and elevated the bourgeois work ethic to a quasi- religious virtue. The resulting achievements of bourgeois men not only legitimated the bourgeoisie’s social, cultural, economic, and moral supremacy over the idle aristocracy and the undisciplined working classes, but also justifi ed the “patriarchal dividend” that ensured male preeminence in the family and society. 3 By the 1880s, however, this narrative of achievement, unity, and patriarchal hegemony was under threat. The consequences of industrialization, urbanization, and modernization, including the growing stratifi cation among the bourgeoisie, the increasing assertiveness of women, and an emerging consumer and leisure culture, joined other factors in demythologizing the ideals of bourgeois society and culture. Theodor Fontane’s novels Frau Jenny Treibel (1892) and Mathilde Mohring (1891 / 1895 / 1896) refl ect these changing circumstances and constitute critical assessments of the foundational components of bourgeois self- identity, from the moral legitimacy of bourgeois social and cultural hegemony to the predominant role of patriarchy. Fontane worked on

background: Preimplantation genetic screening (PGS) has been used in an attempt to determine embryonic aneuploidy. Techniques that use new molecular methods to determine the karyotype of an embryo are expanding the scope of PGS. methods: We introduce a new method for PGS, termed ‘parental support’, which leverages microarray measurements from parental DNA to ‘clean’ single-cell microarray measurements on embryonic cells and explicitly computes confidence in each copy number call. The method distinguishes mitotic and meiotic copy errors and determines parental source of aneuploidy. results: Validation with 459 single cells of known karyotype indicated that per-cell false-positive and false-negative rates are roughly equivalent to the ‘gold standard’ metaphase karyotype. The majority of the cells were run in parallel with a clinical commercial PGS service. Computed confidences were conservative and roughly concordant with accuracy. To examine ploidy in human embryos, the method was then applied to 26 disaggregated, cryopreserved, cleavage-stage embryos for a total of 134 single blastomeres. Only 23.1% of the embryos were euploid, though 46.2% of embryos were mosaic euploid. Mosaicism affected 57.7% of the embryos. Counts of mitotic and meiotic errors were roughly equivalent. Maternal meiotic trisomy predominated over paternal trisomy, and maternal meiotic trisomies were negatively predictive of mosaic euploid embryos. conclusions: We have performed a major preclinical validation of a new method for PGS and found that the technology performs approximately as well as a metaphase karyotype. We also directly measured the mechanism of aneuploidy in cleavage-stage human embryos and found high rates and distinct patterns of mitotic and meiotic aneuploidy.

Molecular interactions between protein complexes and DNA carry out essential gene regulatory functions. Uncovering such interactions by means of chromatin-immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) has recently become the focus of intense interest. We here introduce QuEST (Quantitative Enrichment of Sequence Tags), a powerful statistical framework based on the Kernel Density Estimation approach, which utilizes ChIP-Seq data to determine positions where protein complexes come into contact with DNA. Using QuEST, we discovered several thousand binding sites for the human transcription factors SRF, GABP and NRSF at an average resolution of about 20 base-pairs. MEME-based motif analyses on the QuEST-identified sequences revealed DNA binding by cofactors of SRF, providing evidence that cofactor binding specificity can be obtained from ChIP-Seq data. By combining QuEST analyses with gene ontology (GO) annotations and expression data, we illustrate how general functions of transcription factors can be inferred.

Transcriptional coexpression of interacting gene products is required for complex molecular processes; however, the function and evolution of cis-regulatory elements that orchestrate coexpression remain largely unexplored. We mutagenized 19 regulatory elements that drive coexpression of Ciona muscle genes and obtained quantitative estimates of the cis-regulatory activity of the 77 motifs that comprise these elements. We found that individual motif activity ranges broadly within and among elements, and among different instantiations of the same motif type. The activity of orthologous motifs is strongly constrained, although motif arrangement, type, and activity vary greatly among the elements of different co-regulated genes. Thus, the syntactical rules governing this regulatory function are flexible but become highly constrained evolutionarily once they are established in a particular element.

In vivo protein-DNA interactions connect each transcription factor with its direct targets to form a gene network scaffold. To map these protein-DNA interactions comprehensively across entire mammalian genomes, we developed a large-scale chromatin immunoprecipitation assay (ChIPSeq) based on direct ultrahigh-throughput DNA sequencing. This sequence census method was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST, for repressor element–1 silencing transcription factor) to 1946 locations in the human genome. The data display sharp resolution of binding position [±50 base pairs (bp)], which facilitated our finding motifs and allowed us to identify noncanonical NRSF-binding motifs. These ChIPSeq data also have high sensitivity and specificity [ROC (receiver operator characteristic) area ≥ 0.96] and statistical confidence ( P –4 ), properties that were important for inferring new candidate interactions. These include key transcription factors in the gene network that regulates pancreatic islet cell development.

The treatment of owner-occupied housing in the Consumer Price Index has long been a subject of confusion and consternation. Thus, a session to explore the issues was organized at the National Association for Business Economics Annual Meeting in Chicago on September 26, 2005.Business Economics (2006) 41, 59–68; doi:10.2145/20060108