Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability

Although correlations between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established, the mechanisms underlying these connections remain poorly understood. Here, we used a mutant version of the transcription elongation factor TFIIS (TFIISmut), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII; it affects mRNA splicing and termination as well. Remarkably, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed light on the relationship between transcription stress and R-loops and suggest that different classes of R-loops may exist, potentially with distinct consequences for genome stability.Cancer Research UK FC001166UK Medical Research Council FC001166Wellcome Trust FC001166European Research Council 693327, ERC2014 AdG669898Ministerio de Economía y Competitividad BFU2013-42918-P, BFU2016-75058-

Gauging support for macroecological patterns in helminth parasites

© 2018 John Wiley & Sons Ltd Aim: To explore spatial patterns of helminth parasite diversity, and to investigate three main macroecological patterns – (a) latitude–diversity relationships, (b) positive scaling between parasite and host diversity, and (c) species–area relationships – using a largely underutilized global database of helminth parasite occurrence records. Location: Global. Methods: We examined the London Natural History Museum’s collection of helminth parasite occurrence records, consisting of over 18,000 unique host species and 27,000 unique helminth parasite species distributed across over 350 distinct terrestrial and aquatic localities. Results: We find support for latitudinal gradients in parasite diversity and a strong relationship between host and parasite diversity at the global scale. Helminth species diversity–area relationships were not detectable as a function of host body mass, but larger geographic areas supported higher parasite richness, potentially mediated through higher host richness. Main conclusions: Our findings indicate that helminth parasites may obey some of the macroecological relationships found in free-living species, suggesting that parasites may offer further support for the generality of these patterns, while offering interesting counterexamples for others. We conclude with a discussion of future directions and potential challenges in the newly emerging macroecology of infectious disease

Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody.

Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2-/-[Formula: see text] mice, or survive treatment with paclitaxel. Treatment of mice bearing breast cancer patient-derived xenografts (PDXs) with the humanized anti-ROR1 monoclonal antibody cirmtuzumab repressed expression of genes associated with breast cancer stemness, reduced activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1, and impaired the capacity of breast cancer PDXs to metastasize or reengraft Rag2-/-[Formula: see text] mice. Finally, treatment of PDX-bearing mice with cirmtuzumab and paclitaxel was more effective than treatment with either alone in eradicating breast cancer PDXs. These results indicate that targeting ROR1 may improve the response to chemotherapy of patients with breast cancer

Host species composition influences infection severity among amphibians in the absence of spillover transmission

Wildlife epidemiological outcomes can depend strongly on the composition of an ecological community, particularly when multiple host species are affected by the same pathogen. However, the relationship between host species richness and disease risk can vary with community context and with the degree of spillover transmission that occurs among co‐occurring host species. We examined the degree to which host species composition influences infection by Batrachochytrium dendrobatidis (Bd), a widespread fungal pathogen associated with amphibian population declines around the world, and whether transmission occurs from one highly susceptible host species to other co‐occurring host species. By manipulating larval assemblages of three sympatric amphibian species in the laboratory, we characterized the relationship between host species richness and infection severity, whether infection mediates growth and survivorship differently across various combinations of host species, and whether Bd is transmitted from experimentally inoculated tadpoles to uninfected tadpoles. We found evidence of a dilution effect where Bd infection severity was dramatically reduced in the most susceptible of the three host species (Anaxyrus boreas). Infection also mediated survival and growth of all three host species such that the presence of multiple host species had both positive (e.g., infection reduction) and negative (e.g., mortality) effects on focal species. However, we found no evidence that Bd infection is transmitted by this species. While these results demonstrate that host species richness as well as species identity underpin infection dynamics in this system, dilution is not the product of reduced transmission via fewer infectious individuals of a susceptible host species. We discuss various mechanisms, including encounter reduction and antagonistic interactions such as competition and opportunistic cannibalism that may act in concert to mediate patterns of infection severity, growth, and mortality observed in multihost communities.There are many ways in which infection can be influenced by species diversity. Here we show experimentally that the interactions between species in a multi‐host amphibian community drive the severity of infection by the amphibian chytrid fungus. We find no evidence that infection is transmitted between two host species in our study, suggesting that spillover infection is not a cause of dilution effects in this system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111214/1/ece31385.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111214/2/ece31385-sup-0001-FigureS1.pd

Population fluctuations and synanthropy explain transmission risk in rodent-borne zoonoses

Publisher Copyright: © 2022, The Author(s).Population fluctuations are widespread across the animal kingdom, especially in the order Rodentia, which includes many globally important reservoir species for zoonotic pathogens. The implications of these fluctuations for zoonotic spillover remain poorly understood. Here, we report a global empirical analysis of data describing the linkages between habitat use, population fluctuations and zoonotic reservoir status in rodents. Our quantitative synthesis is based on data collated from papers and databases. We show that the magnitude of population fluctuations combined with species’ synanthropy and degree of human exploitation together distinguish most rodent reservoirs at a global scale, a result that was consistent across all pathogen types and pathogen transmission modes. Our spatial analyses identified hotspots of high transmission risk, including regions where reservoir species dominate the rodent community. Beyond rodents, these generalities inform our understanding of how natural and anthropogenic factors interact to increase the risk of zoonotic spillover in a rapidly changing world.Peer reviewe

A Comparison of the Intrinsic Shapes of Two Different Types of Dwarf Galaxies: Blues Compact Dwarfs and Dwarf Ellipticals

We measure the apparent shapes for a sample of 62 blue compact dwarf galaxies (BCDs), and compare them with the apparent shapes for a sample of 80 dwarf elliptical galaxies (dEs). The BCDs are flatter, on average, than the dEs, but the difference is only marginally significant. We then use both non-parametric and parametric techniques to determine possible distributions of intrinsic shapes for the BCDs. The hypothesis that BCDs are oblate spheroids can be ruled out with a high confidence level ($> 99$), but the hypothesis that they are prolate spheroids cannot be excluded. The apparent shapes of BCDs are totally consistent with the hypothesis that they are triaxial ellipsoids. If the intrinsic axis ratios, $\beta$ and $\gamma$, are distributed according to a Gaussian with means $\beta_0$ and $\gamma_0$ and standard deviation $\sigma$, we find the best-fitting distribution for BCDs has $(\beta_0,\gamma_0,\sigma)= (0.66,0.55,0.16)$, while that for dEs has $(\beta_0,\gamma_0,\sigma)= (0.85,0.64,0.24)$. Our results are consistent with the hypothesis that BCDs have a close evolutionary relation with dEs.Comment: total 23 pages, 9 figures, and 1 Table, submitted to ApJ on Sep 19 1997. Email addresses: [email protected], [email protected], [email protected], [email protected], [email protected]

Resonant-Cavity-Induced Phase Locking and Voltage Steps in a Josephson Array

We describe a simple dynamical model for an underdamped Josephson junction array coupled to a resonant cavity. From numerical solutions of the model in one dimension, we find that (i) current-voltage characteristics of the array have self-induced resonant steps (SIRS), (ii) at fixed disorder and coupling strength, the array locks into a coherent, periodic state above a critical number of active Josephson junctions, and (iii) when $N_a$ active junctions are synchronized on an SIRS, the energy emitted into the resonant cavity is quadratic with $N_a$. All three features are in agreement with a recent experiment [Barbara {\it et al}, Phys. Rev. Lett. {\bf 82}, 1963 (1999)]}.Comment: 4 pages, 3 eps figures included. Submitted to PRB Rapid Com