Exact Level And Power Of Permutation, Bootstrap, And Asymptotic Tests Of Trend

We develop computational tools that can evaluate the exact size and power of three tests of trend (e.g., permutation, bootstrap and asymptotic) without resorting to large-sample theory or simulations. We then use these tools to compare the operating characteristics of the three tests. It is seen that the bootstrap test is ultra-conservative relative to the other two tests and as a result suffers from a severe deterioration in power. The power of the asymptotic test is uniformly larger than that of the other two tests, but it fails to preserve the Type I error for most of the range of the baseline response probability. The permutation test, being exact, is guaranteed to preserve the Type I error throughout the range of the baseline response probability. The price paid for this guarantee is a loss of power relative to the asymptotic test. The power loss is, however, small in most situations

Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease

Metapopulation Viability of Swamp Rabbits in Southern Illinois: Potential Impacts of Habitat Change

Swamp rabbits (Sylvilagus aquaticus) in southern Illinois exist as a metapopulation due to fragmentation of the bottomland hardwood forests in which they live. This fragmentation makes their persistence in Illinois uncertain. We used population viability analysis (PVA) to estimate the probability of persistence of the swamp rabbit metapopulation in Illinois, using a habitat suitability map we created and life history parameters drawn from the literature. We varied the parameters used in our PVA from 50% to 150% of the initial value to compare their effects on extinction risk and to direct future management and research. We tested the effects of potential habitat loss and fragmentation by 1) removing patches individually and in groups from the analysis and by 2) adding 60, 120, and 180 m to the edge of all patches. We also tested the potential effect of dispersal corridors by increasing dispersal between connected patches. Under baseline conditions, the model suggests a 0% chance of quasiextinction (90% metapopulation decline) of swamp rabbits within 25 (or even 50) years. Changes in fecundity values and the effects of catastrophic flooding had the greatest effect on extinction risk, and changes in no other parameter yielded any appreciable impact. Removing the largest patches from the population increased the 25- year risk of extinction to 4%, whereas any other modifications to the habitat did not change the extinction risk. We suggest that managers focus on sustaining habitat quality, particularly upland habitats adjacent to occupied bottomland hardwood forests to improve the likelihood of swamp rabbit persistence in Illinois

enoLOGOS: a versatile web tool for energy normalized sequence logos

enoLOGOS is a web-based tool that generates sequence logos from various input sources. Sequence logos have become a popular way to graphically represent DNA and amino acid sequence patterns from a set of aligned sequences. Each position of the alignment is represented by a column of stacked symbols with its total height reflecting the information content in this position. Currently, the available web servers are able to create logo images from a set of aligned sequences, but none of them generates weighted sequence logos directly from energy measurements or other sources. With the advent of high-throughput technologies for estimating the contact energy of different DNA sequences, tools that can create logos directly from binding affinity data are useful to researchers. enoLOGOS generates sequence logos from a variety of input data, including energy measurements, probability matrices, alignment matrices, count matrices and aligned sequences. Furthermore, enoLOGOS can represent the mutual information of different positions of the consensus sequence, a unique feature of this tool. Another web interface for our software, C2H2-enoLOGOS, generates logos for the DNA-binding preferences of the C2H2 zinc-finger transcription factor family members. enoLOGOS and C2H2-enoLOGOS are accessible over the web at

EFBAT: exact family-based association tests

Background: Family-based association tests are important tools for investigating genetic risk factors of complex diseases. These tests are especially valuable for being robust to population structure. We introduce a tool, EFBAT, which performs exact family-based tests of association for X-chromosome and autosomal biallelic markers. Results: The program EFBAT extends a network algorithm previously applied to autosomal markers to include the X-chromosome and to perform tests of association under the null hypotheses "no association, no linkage" and "no association in the presence of linkage" under additive, dominant and recessive genetic models. These tests are valid regardless of patterns of missing familial data. Conclusion: The general framework for performing exact family-based association tests has been usefully extended to the X-chromosome, particularly for the hypothesis of "no association in the presence of linkage" and for different genetic models

NICER X-ray Observations of Eta Carinae During its Most Recent Periastron Passage

We report high-precision X-ray monitoring observations in the 0.4-10 keV band of the luminous, long-period colliding-wind binary Eta Carinae up to and through its most recent X-ray minimum/periastron passage in February 2020. Eta Carinae reached its observed maximum X-ray flux on 7 January 2020, at a flux level of $3.30 \times 10^{-10}$ ergs s$^{-1}$ cm$^{-2}$, followed by a rapid plunge to its observed minimum flux, $0.03 \times 10^{-10}$ ergs s$^{-1}$ cm$^{-2}$ near 17 February 2020. The NICER observations show an X-ray recovery from minimum of only $\sim$16 days, the shortest X-ray minimum observed so far. We provide new constraints of the "deep" and "shallow" minimum intervals. Variations in the characteristic X-ray temperature of the hottest observed X-ray emission indicate that the apex of the wind-wind "bow shock" enters the companion's wind acceleration zone about 81 days before the start of the X-ray minimum. There is a step-like increase in column density just before the X-ray minimum, probably associated with the presence of dense clumps near the shock apex. During recovery and after, the column density shows a smooth decline, which agrees with previous $N_{H}$ measurements made by SWIFT at the same orbital phase, indicating that changes in mass-loss rate are only a few percent over the two cycles. Finally, we use the variations in the X-ray flux of the outer ejecta seen by NICER to derive a kinetic X-ray luminosity of the ejecta of $\sim 10^{41}$ ergs s$^{-1}$ near the time of the "Great Eruption'

Eta Carinae: an evolving view of the central binary, its interacting winds and its foreground ejecta

FUV spectra of Eta Car, recorded across two decades with HST/STIS, document multiple changes in resonant lines caused by dissipating extinction in our line of sight. The FUV flux has increased nearly ten-fold which has led to increased ionization of the multiple shells within the Homunculus and photo-destruction of molecular hydrogen. Comparison of observed resonant line profiles with CMFGEN model profiles allows separation of wind-wind collision and shell absorptions from the primary wind, P Cygni profiles.The dissipating occulter preferentially obscured the central binary and interacting winds relative to the very extended primary wind. We are now able to monitor changes in the colliding winds with orbital phase. High velocity transient absorptions occurred across the most recent periastron passage, indicating acceleration of the primary wind by the secondary wind which leads to a downstream, high velocity bowshock that is newly generated every orbital period. There is no evidence of changes in the properties of the binary winds.Comment: 36 pages, 22 figures, accepted Astrophysical Journa