Ectopic Expression of Zmiz1 Induces Cutaneous Squamous Cell Malignancies in a Mouse Model of Cancer

Cutaneous squamous cell carcinoma (SCC) is the second most common form of cancer in the human population, yet the underlying genetic mechanisms contributing to the disease are not well understood. We recently identified Zmiz1 as a candidate oncogene in nonmelanoma skin cancer through a transposon mutagenesis screen. Here we show that transposon-induced mutations in Zmiz1 drive expression of a truncated transcript that is similar to an alternative endogenous ZMIZ1 transcript found to be overexpressed in human SCCs relative to normal skin. We also describe an original mouse model of invasive keratoacanthoma driven by skin-specific expression of the truncated Zmiz1 transcript. Unlike most mouse models, Zmiz1-induced skin tumors develop rapidly and in the absence of promoting agents such as phorbol esters. In addition, we found that the alternative Zmiz1 isoform has greater protein stability than its full-length counterpart. Finally, we provide evidence that ZMIZ1 is overexpressed in a significant percentage of human breast, ovarian, and colon cancers in addition to human SCCs, suggesting that ZMIZ1 may play a broader role in epithelial cancers

Seroprevalence of Zika virus in wild African green monkeys and baboons

ABSTRACT Zika virus (ZIKV) has recently spread through the Americas and has been associated with a range of health effects, including birth defects in children born to women infected during pregnancy. Although the natural reservoir of ZIKV remains poorly defined, the virus was first identified in a captive “sentinel” macaque monkey in Africa in 1947. However, the virus has not been reported in humans or nonhuman primates (NHPs) in Africa outside Gabon in over a decade. Here, we examine ZIKV infection in 239 wild baboons and African green monkeys from South Africa, the Gambia, Tanzania, and Zambia using combinations of unbiased deep sequencing, quantitative reverse transcription-PCR (qRT-PCR), and an antibody capture assay that we optimized using serum collected from captive macaque monkeys exposed to ZIKV, dengue virus, and yellow fever virus. While we did not find evidence of active ZIKV infection in wild NHPs in Africa, we found variable ZIKV seropositivity of up to 16% in some of the NHP populations sampled. We anticipate that these results and the methodology described within will help in continued efforts to determine the prevalence, natural reservoir, and transmission dynamics of ZIKV in Africa and elsewhere. IMPORTANCE Zika virus (ZIKV) is a mosquito-borne virus originally discovered in a captive monkey living in the Zika Forest of Uganda, Africa, in 1947. Recently, an outbreak in South America has shown that ZIKV infection can cause myriad health effects, including birth defects in the children of women infected during pregnancy. Here, we sought to investigate ZIKV infection in wild African primates to better understand its emergence and spread, looking for evidence of active or prior infection. Our results suggest that up to 16% of some populations of nonhuman primate were, at some point, exposed to ZIKV. We anticipate that this study will be useful for future studies that examine the spread of infections from wild animals to humans in general and those studying ZIKV in primates in particular. Podcast: A podcast concerning this article is available

Structural Determinants of RGS-RhoGEF Signaling Critical to Entamoeba histolytica Pathogenesis

SummaryG protein signaling pathways, as key components of physiologic responsiveness and timing, are frequent targets for pharmacologic intervention. Here, we identify an effector for heterotrimeric G protein α subunit (EhGα1) signaling from Entamoeba histolytica, the causative agent of amoebic colitis. EhGα1 interacts with this effector and guanosine triphosphatase-accelerating protein, EhRGS-RhoGEF, in a nucleotide state-selective fashion. Coexpression of EhRGS-RhoGEF with constitutively active EhGα1 and EhRacC leads to Rac-dependent spreading in Drosophila S2 cells. EhRGS-RhoGEF overexpression in E. histolytica trophozoites leads to reduced migration toward serum and lower cysteine protease activity, as well as reduced attachment to, and killing of, host cells. A 2.3 Å crystal structure of the full-length EhRGS-RhoGEF reveals a putative inhibitory helix engaging the Dbl homology domain Rho-binding surface and the pleckstrin homology domain. Mutational analysis of the EhGα1/EhRGS-RhoGEF interface confirms a canonical “regulator of G protein signaling” domain rather than a RhoGEF-RGS (“rgRGS”) domain, suggesting a convergent evolution toward heterotrimeric and small G protein cross-talk

A flexible, open, and interactive digital platform to support online and blended experiential learning environments: Thinglink and thin sections

Abstract. This study investigates the potential value of, and provides a method for, the creation of flexible, digital, and asynchronous platforms to create student-centred materials for use in an online and/or blended learning environment. We made use of Thinglink to create a “virtual microscope” resource for geology and associated courses in higher education. This is achieved through the dissemination of a simple learning resource comprising interactive imagery and audio. The visual analysis of rocks under the microscope, termed thin-section petrography, is a fundamental component in geology programmes in higher education, with key skills which are transferable with other fields such as material science, biology, and forensic science. However, learning environments and activities in this field are often dictated by the requirement for access to microscope facilities and supplementary resources which are highly variable in their academic level, availability, design, and scale, ranging from traditional textbooks to online resources. A resource was created which allows individuals to experience some of the aspects of petrographic microscopy in a digital manner. In particular, specific features of the materials observed and how microscopes work were included. The resource was disseminated to a population of learners and educators, who provided responses to a questionnaire. Responses were overwhelmingly positive and indicate considerable interest from learner and teacher alike. Critical areas for improvement include the need for clarity in the user interface and the inclusion of a recorded human voice rather than automated text narration. This study highlights the need for, and benefits of, interactive online learning resources in petrology and associated fields. This type of resource has positive implications for the flexibility, inclusivity, and accessibility of teaching materials. Such resources may prove particularly valuable when distance learning is unavoidable (e.g. the COVID-19 crisis) and/or hybrid, blended learning environments are being deployed. The method and platform used in this study are highly transferable to other subject areas (or other areas of the geosciences)

Comparative analysis of the complete genome sequence of the California MSW strain of myxoma virus reveals potential host adaptations

Myxomatosis is a rapidly lethal disease of European rabbits that is caused by myxoma virus (MYXV). The introduction of a South American strain of MYXV into the European rabbit population of Australia is the classic case of host-pathogen coevolution following cross-species transmission. The most virulent strains of MYXV for European rabbits are the Californian viruses, found in the Pacific states of the United States and the Baja Peninsula, Mexico. The natural host of Californian MYXV is the brush rabbit, Sylvilagus bachmani. We determined the complete sequence of the MSW strain of Californian MYXV and performed a comparative analysis with other MYXV genomes. The MSW genome is larger than that of the South American Lausanne (type) strain of MYXV due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the M156R, M154L, M153R, M152R, and M151R genes and part of the M150R gene from the right-hand (RH) end of the genome at the left-hand (LH) TIR. Despite the extreme virulence of MSW, no novel genes were identified; five genes were disrupted by multiple indels or mutations to the ATG start codon, including two genes, M008.1L/R and M152R, with major virulence functions in European rabbits, and a sixth gene, M000.5L/R, was absent. The loss of these gene functions suggests that S. bachmani is a relatively recent host for MYXV and that duplication of virulence genes in the TIRs, gene loss, or sequence variation in other genes can compensate for the loss of M008.1L/R and M152R in infections of European rabbits.This work was funded in part by grant R01 AI093804 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. E.C.H. was supported by an NHMRC Australia Fellowship, and D.C.T. was supported by an ARC Future Fellowship

Population structure and phylogeography of the Gentoo Penguin (Pygoscelis papua) across the Scotia Arc

Climate change, fisheries' pressure on penguin prey, and direct human disturbance of wildlife have all been implicated in causing large shifts in the abundance and distribution of penguins in the Southern Ocean. Without mark-recapture studies, understanding how colonies form and, by extension, how ranges shift is challenging. Genetic studies, particularly focused on newly established colonies, provide a snapshot of colonization and can reveal the extent to which shifts in abundance and occupancy result from changes in demographic rates (e.g., reproduction and survival) or migration among suitable patches of habitat. Here, we describe the population structure of a colonial seabird breeding across a large latitudinal range in the Southern Ocean. Using multilocus microsatellite genotype data from 510 Gentoo penguin (Pygoscelis papua) individuals from 14 colonies along the Scotia Arc and Antarctic Peninsula, together with mitochondrial DNA data, we find strong genetic differentiation between colonies north and south of the Polar Front, that coincides geographically with the taxonomic boundary separating the subspecies P. p. papua and P. p. ellsworthii. Using a discrete Bayesian phylogeographic approach, we show that southern Gentoos expanded from a possible glacial refuge in the center of their current range, colonizing regions to the north and south through rare, long-distance dispersal. Our findings show that this dispersal is important for new colony foundation and range expansion in a seabird species that ordinarily exhibits high levels of natal philopatry, though persistent oceanographic features serve as barriers to movement

Atmospheric Circulation of Eccentric Hot Neptune GJ436b

GJ436b is a unique member of the transiting extrasolar planet population being one of the smallest and least irradiated and possessing an eccentric orbit. Because of its size, mass and density, GJ436b could plausibly have an atmospheric metallicity similar to Neptune (20-60 times solar abundances), which makes it an ideal target to study the effects of atmospheric metallicity on dynamics and radiative transfer in an extrasolar planetary atmosphere. We present three-dimensional atmospheric circulation models that include realistic non-gray radiative transfer for 1, 3, 10, 30, and 50 times solar atmospheric metallicity cases of GJ436b. Low metallicity models (1 and 3 times solar) show little day/night temperature variation and strong high-latitude jets. In contrast, higher metallicity models (30 and 50 times solar) exhibit day/night temperature variations and a strong equatorial jet. Spectra and light curves produced from these simulations show strong orbital phase dependencies in the 50 times solar case and negligible variations with orbital phase in the 1 times solar case. Comparisons between the predicted planet/star flux ratio from these models and current secondary eclipse measurements support a high metallicity atmosphere (30-50 times solar abundances) with disequilibrium carbon chemistry at play for GJ436b. Regardless of the actual atmospheric composition of GJ436b, our models serve to illuminate how metallicity influences the atmospheric circulation for a broad range of warm extrasolar planets.Comment: 25 pages, 13 figure

Evaluation of a New Balloon Catheter for Difficult Calcified Lesions in Infrainguinal Arterial Disease: Outcome of a Multicenter Registry

The purpose of this study was to assess the technical performance and immediate procedure outcome of a new balloon catheter in the treatment of calcified lesions in infrainguinal arterial disease. Seventy-five patients with infrainguinal arterial disease were prospectively entered into the registry. The catheter (ReeKross Clearstream, Ireland) is a 5- to 6-Fr balloon catheter with a rigid shaft intended for enhanced pushability. Only technical procedural outcome was recorded. Treated calcified lesions (range: 5–30 cm), assessed angiographically, were located in the superficial femoral, popliteal, and crural arteries. In 67 patients the lesion was an occlusion. Guidewire passage occurred subintimally in 68 patients. In 24 patients a standard balloon catheter was chosen as first treatment catheter: 5 failed to cross the lesion, 8 balloons ruptured, and in 11 patients there was an inadequate dilatation result. In only one of the five patients did subsequent use of the ReeKross catheter also fail in lesion crossing. The ReeKross was successful as secondary catheter in the other 23 cases. In 50 patients the ReeKross was used as primary catheter. In total the ReeKross crossed the lesions in 74 patients. After passage and dilatation with this catheter in 73 patients (1 failed true-lumen reentry), 19 had >30% residual lesions, of which 11 were not treated and 8 were successfully stented. No ReeKross balloons ruptured. We conclude that in the treatment of difficult calcified lesions in arterial stenotic or occlusive disease, the choice of a high-pushability angioplasty catheter, with more calcification-resistant balloon characteristics, like the ReeKross, warrants consideration