A novel role of TRIM28 B box domain in L1 retrotransposition and ORF2p-mediated cDNA synthesis.

The long interspersed element 1 (LINE-1 or L1) integration is affected by many cellular factors through various mechanisms. Some of these factors are required for L1 amplification, while others either suppress or enhance specific steps during L1 propagation. Previously, TRIM28 has been identified to suppress transposable elements, including L1 expression via its canonical role in chromatin remodeling. Here, we report that TRIM28 through its B box domain increases L1 retrotransposition and facilitates shorter cDNA and L1 insert generation in cultured cells. Consistent with the latter, we observe that tumor specific L1 inserts are shorter in endometrial, ovarian, and prostate tumors with higher TRIM28 mRNA expression than in those with lower TRIM28 expression. We determine that three amino acids in the B box domain that are involved in TRIM28 multimerization are critical for its effect on both L1 retrotransposition and cDNA synthesis. We provide evidence that B boxes from the other two members in the Class VI TRIM proteins, TRIM24 and TRIM33, also increase L1 retrotransposition. Our findings could lead to a better understanding of the host/L1 evolutionary arms race in the germline and their interplay during tumorigenesis.

Analysis of epigenetic features characteristic of L1 loci expressed in human cells.

Only a select few L1 loci in the human genome are expressed in any given cell line or organ, likely to minimize damage done to the genome. The epigenetic features and requirements of expressed L1 loci are currently unknown. Using human cells and comprehensive epigenetic analysis of individual expressed and unexpressed L1 loci, we determined that endogenous L1 transcription depends on a combination of epigenetic factors, including open chromatin, activating histone modifications, and hypomethylation at the L1 promoter. We demonstrate that the L1 promoter seems to require interaction with enhancer elements for optimal function. We utilize epigenetic context to predict the expression status of L1Hs loci that are poorly mappable with RNA-Seq. Our analysis identified a population of 'transitional' L1 loci that likely have greater potential to be activated during the epigenetic dysregulation seen in tumors and during aging because they are the most responsive to targeted CRISPR-mediated delivery of trans-activating domains. We demonstrate that an engineered increase in endogenous L1 mRNA expression increases Alu mobilization. Overall, our findings present the first global and comprehensive analysis of epigenetic status of individual L1 loci based on their expression status and demonstrate the importance of epigenetic context for L1 expression heterogeneity.

The latitudinal gradient in rates of evolution for bird beaks, a species interaction trait.

Where is evolution fastest? The biotic interactions hypothesis proposes that greater species richness creates more ecological opportunity, driving faster evolution at low latitudes, whereas the 'empty niches' hypothesis proposes that ecological opportunity is greater where diversity is low, spurring faster evolution at high latitudes. We tested these contrasting predictions by analysing rates of beak evolution for a global dataset of 1141 avian sister species. Rates of beak size evolution are similar across latitudes, with some evidence that beak shape evolves faster in the temperate zone, consistent with the empty niches hypothesis. The empty niches hypothesis is further supported by a meta-analysis showing that rates of trait evolution and recent speciation are generally faster in the temperate zone, whereas rates of molecular evolution are slightly faster in the tropics. Our results suggest that drivers of evolutionary diversification are either similar across latitudes or more potent in the temperate zone, thus calling into question multiple hypotheses that invoke faster tropical evolution to explain the latitudinal diversity gradient.

AVONET: morphological, ecological and geographical data for all birds.

Functional traits offer a rich quantitative framework for developing and testing theories in evolutionary biology, ecology and ecosystem science. However, the potential of functional traits to drive theoretical advances and refine models of global change can only be fully realised when species-level information is complete. Here we present the AVONET dataset containing comprehensive functional trait data for all birds, including six ecological variables, 11 continuous morphological traits, and information on range size and location. Raw morphological measurements are presented from 90,020 individuals of 11,009 extant bird species sampled from 181 countries. These data are also summarised as species averages in three taxonomic formats, allowing integration with a global phylogeny, geographical range maps, IUCN Red List data and the eBird citizen science database. The AVONET dataset provides the most detailed picture of continuous trait variation for any major radiation of organisms, offering a global template for testing hypotheses and exploring the evolutionary origins, structure and functioning of biodiversity.

Faster evolution of a premating reproductive barrier is not associated with faster speciation rates in New World passerine birds.

Why are speciation rates so variable across the tree of life? One hypothesis is that this variation is explained by how rapidly reproductive barriers evolve. We tested this hypothesis by conducting a comparative study of the evolution of bird song, a premating barrier to reproduction. Speciation in birds is typically initiated when geographically isolated (allopatric) populations evolve reproductive barriers. We measured the strength of song as a premating barrier between closely related allopatric populations by conducting 2339 field experiments to measure song discrimination for 175 taxon pairs of allopatric or parapatric New World passerine birds, and estimated recent speciation rates from molecular phylogenies. We found evidence that song discrimination is indeed an important reproductive barrier: taxon pairs with high song discrimination in allopatry did not regularly interbreed in parapatry. However, evolutionary rates of song discrimination were not associated with recent speciation rates. Evolutionary rates of song discrimination were also unrelated to latitude or elevation, but species with innate song (suboscines) evolved song discrimination much faster than species with learned song (oscines). We conclude that song is a key premating reproductive barrier in birds, but faster evolution of this reproductive barrier between populations does not consistently result in faster diversification between species.

Responsible agriculture must adapt to the wetland character of mid-latitude peatlands.

Drained, lowland agricultural peatlands are greenhouse gas (GHG) emission hotspots and a large but vulnerable store of irrecoverable carbon. They exhibit soil loss rates of ~2.0 cm yr-1 and are estimated to account for 32% of global cropland emissions while producing only 1.1% of crop kilocalories. Carbon dioxide emissions account for >80% of their terrestrial GHG emissions and are largely controlled by water table depth. Reducing drainage depths is, therefore, essential for responsible peatland management. Peatland restoration can substantially reduce emissions. However, this may conflict with societal needs to maintain productive use, to protect food security and livelihoods. Wetland agriculture strategies will, therefore, be required to adapt agriculture to the wetland character of peatlands, and balance GHG mitigation against productivity, where halting emissions is not immediately possible. Paludiculture may substantially reduce GHG emissions but will not always be viable in the current economic landscape. Reduced drainage intensity systems may deliver partial reductions in the rate of emissions, with smaller modifications to existing systems. These compromise systems may face fewer hurdles to adoption and minimize environmental harm until societal conditions favour strategies that can halt emissions. Wetland agriculture will face agronomic, socio-economic and water management challenges, and careful implementation will be required. Diversity of values and priorities among stakeholders creates the potential for conflict. Successful implementation will require participatory research approaches and co-creation of workable solutions. Policymakers, private sector funders and researchers have key roles to play but adoption risks would fall predominantly on land managers. Development of a robust wetland agriculture paradigm is essential to deliver resilient production systems and wider environmental benefits. The challenge of responsible use presents an opportunity to rethink peatland management and create thriving, innovative and green wetland landscapes for everyone's future benefit, while making a vital contribution to global climate change mitigation.

Montane species track rising temperatures better in the tropics than in the temperate zone.

Many species are responding to global warming by shifting their distributions upslope to higher elevations, but the observed rates of shifts vary considerably among studies. Here, we test the hypothesis that this variation is in part explained by latitude, with tropical species being particularly responsive to warming temperatures. We analyze two independent empirical datasets-shifts in species' elevational ranges, and changes in composition of forest inventory tree plots. Tropical species are tracking rising temperatures 2.1-2.4 times (range shift dataset) and 10 times (tree plot dataset) better than their temperate counterparts. Models predict that for a 100 m upslope shift in temperature isotherm, species at the equator have shifted their elevational ranges 93-96 m upslope, while species at 45° latitude have shifted only 37-42 m upslope. For tree plots, models predict that a 1°C increase in temperature leads to an increase in community temperature index (CTI), a metric of the average temperature optima of tree species within a plot, of 0.56°C at the equator but no change in CTI at 45° latitude (-0.033°C). This latitudinal gradient in temperature tracking suggests that tropical montane communities may be on an "escalator to extinction" as global temperatures continue to rise.

Evolutionary conservatism will limit responses to climate change in the tropics.

Rapid species turnover in tropical mountains has fascinated biologists for centuries. A popular explanation for this heightened beta diversity is that climatic stability at low latitudes promotes the evolution of narrow thermal tolerance ranges, leading to local adaptation, evolutionary divergence and parapatric speciation along elevational gradients. However, an emerging consensus from research spanning phylogenetics, biogeography and behavioural ecology is that this process rarely, if ever, occurs. Instead, closely related species typically occupy a similar elevational niche, while species with divergent elevational niches tend to be more distantly related. These results suggest populations have responded to past environmental change not by adapting and diverging in place, but instead by shifting their distributions to tightly track climate over time. We argue that tropical species are likely to respond similarly to ongoing and future climate warming, an inference supported by evidence from recent range shifts. In the absence of widespread in situ adaptation to new climate regimes by tropical taxa, conservation planning should prioritize protecting large swaths of habitat to facilitate movement.

Climate change causes upslope shifts and mountaintop extirpations in a tropical bird community.

Montane species worldwide are shifting upslope in response to recent temperature increases. These upslope shifts are predicted to lead to mountaintop extinctions of species that live only near mountain summits, but empirical examples of populations that have disappeared are sparse. We show that recent warming constitutes an "escalator to extinction" for birds on a remote Peruvian mountain-high-elevation species have declined in both range size and abundance, and several previously common mountaintop residents have disappeared from the local community. Our findings support projections that warming will likely drive widespread extirpations and extinctions of high-elevation taxa in the tropical Andes. Such climate change-driven mountaintop extirpations may be more likely in the tropics, where temperature seems to exert a stronger control on species' range limits than in the temperate zone. In contrast, we show that lowland bird species at our study site are expanding in range size as they shift their upper limits upslope and may thus benefit from climate change.

Adaptation and Latitudinal Gradients in Species Interactions: Nest Predation in Birds.

AbstractAre biotic interactions stronger in the tropics? Here, we investigate nest predation in birds, a canonical example of a strong tropical biotic interaction. Counter to expectations, daily rates of nest predation vary minimally with latitude. However, life-history traits that influence nest predation have diverged between latitudes. For example, tropical species have evolved a longer average nesting period, which is associated with reduced rates of nest attendance by parents. Daily nest mortality declines with nesting period length within regions, but tropical species have a higher intercept. Consequently, for the same nesting period length, tropical species experience higher daily nest predation rates than temperate species. The implication of this analysis is that the evolved difference in nesting period length between latitudes produces a flatter latitudinal gradient in daily nest predation than would otherwise be predicted. We propose that adaptation may frequently dampen geographic patterns in interaction rates.

Speciation and gene flow across an elevational gradient in New Guinea kingfishers.

Closely related species with parapatric elevational ranges are ubiquitous in tropical mountains worldwide. The gradient speciation hypothesis proposes that these series are the result of in situ ecological speciation driven by divergent selection across elevation. Direct tests of this scenario have been hampered by the difficulty inferring the geographic arrangement of populations at the time of divergence. In cichlids, sticklebacks and Timema stick insects, support for ecological speciation driven by other selective pressures has come from demonstrating parallel speciation, where divergence proceeds independently across replicated environmental gradients. Here, we take advantage of the unique geography of the island of New Guinea to test for parallel gradient speciation in replicated populations of Syma kingfishers that show extremely subtle differentiation across elevation and between historically isolated mountain ranges. We find that currently described high-elevation and low-elevation species have reciprocally monophyletic gene trees and form nuclear DNA clusters, rejecting this hypothesis. However, demographic modelling suggests selection has likely maintained species boundaries in the face of gene flow following secondary contact. We compile evidence from the published literature to show that although in situ gradient speciation in labile organisms such as birds appears rare, divergent selection and post-speciation gene flow may be an underappreciated force in the origin of elevational series and tropical beta diversity along mountain slopes.

Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling.

Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell's (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance.

Atypical Varicella-Zoster Kaposi Varicelliform Eruption in Sézary Syndrome.

Patients with mycosis fungoides experience considerable morbidity and mortality from secondary bacterial and viral infections. Staphylococcus aureus, ß-hemolytic streptococci, herpes simplex virus, and herpes zoster virus remain the most common infectious pathogens in this group of patients. With depressed cellular immunity and diminished skin barrier as the main precipitating risk factors, immunocompromised patients can often present with an atypical presentation of a common dermatologic condition. The case herein discusses a clinically atypical nonvesicular Kaposi varicelliform eruption secondary to a varicella-zoster virus in a patient with Sézary syndrome. Concurrent polypharmacy in these patients is also a risk factor for development of drug hypersensitivity reactions. However, given their immunocompromised status, first and foremost, a careful inspection should be made of every atypical skin eruption in search of an infectious etiology, and afterward, an appropriate treatment should be promptly initiated.

Inhibition of type 4 cyclic nucleotide phosphodiesterase blocks intracellular TLR signaling in chronic lymphocytic leukemia and normal hematopoietic cells.

A subset of chronic lymphocytic leukemia (CLL) BCRs interacts with Ags expressed on apoptotic cells, suggesting that CLL BCRs have the potential to internalize apoptotic cell RNA- or DNA-containing fragments with resultant activation of TLR7 or TLR9, respectively. By blocking cAMP degradation, type 4 cAMP phosphodiesterase (PDE4) inhibitors activate cAMP-mediated signaling and induce apoptosis in CLL cells. In this study, we show that autologous irradiated leukemic cells induce proliferation in CLL cells and that such proliferation is blocked by a TLR7/8/9 inhibitor, by DNase, and by the PDE4 inhibitor rolipram. Rolipram also inhibited CLL cell proliferation induced by synthetic TLR7 and TLR9 agonists, as well as TLR agonist-induced costimulatory molecule expression and TNF-a (but not IL-6 or IL-10) production. Whereas treatment with a TLR9 agonist protected IgH V region unmutated, but not mutated, CLL cells from apoptosis, PDE4 inhibitors augmented apoptosis in both subtypes, suggesting that cAMP-mediated signaling may abrogate a TLR9-mediated survival signal in prognostically unfavorable IGHV unmutated CLL cells. Rolipram inhibited both TLR7/8- and TLR9-induced IFN regulatory factor 5 and NF-kB p65 nuclear translocation. PDE4 inhibitors also blocked TLR signaling in normal human immune cells. In PBMC and CD14-positive monocytes, PDE4 inhibitors blocked IFN-a or TNF-a (but not IL-6) production, respectively, following stimulation with synthetic TLR agonists or RNA-containing immune complexes. These results suggest that PDE4 inhibitors may be of clinical utility in CLL or autoimmune diseases that are driven by TLR-mediated signaling.

Rapid upslope shifts in New Guinean birds illustrate strong distributional responses of tropical montane species to global warming.

Temperate-zone species have responded to warming temperatures by shifting their distributions poleward and upslope. Thermal tolerance data suggests that tropical species may respond to warming temperatures even more strongly than temperate-zone species, but this prediction has yet to be tested. We addressed this data gap by conducting resurveys to measure distributional responses to temperature increases in the elevational limits of the avifaunas of two geographically and faunally independent New Guinean mountains, Mt. Karimui and Karkar Island, 47 and 44 y after they were originally surveyed. Although species richness is roughly five times greater on mainland Mt. Karimui than oceanic Karkar Island, distributional shifts at both sites were similar: upslope shifts averaged 113 m (Mt. Karimui) and 152 m (Karkar Island) for upper limits and 95 m (Mt. Karimui) and 123 m (Karkar Island) for lower limits. We incorporated these results into a metaanalysis to compare distributional responses of tropical species with those of temperate-zone species, finding that average upslope shifts in tropical montane species match local temperature increases significantly more closely than in temperate-zone montane species. That tropical species appear to be strong responders has global conservation implications and provides empirical support to hitherto untested models that predict widespread extinctions in upper-elevation tropical endemics with small ranges.

Outcome Disparities in African American Compared with European American Women with ER+HER2- Tumors Treated within an Equal-Access Health Care System.

PURPOSE: Breast cancer mortality rates are higher for African American women (AAW) than for any other ethnic group in the United States. Recent reports suggest that outcome disparities between AAW and European American women (EAW) are present in the ER+HER2- subtype. To improve our understanding, pathological characteristics, mortality and molecular profiles from women treated within an equal-access health care system were evaluated. PROCEDURES: All AAW (n=90) and EAW (n=308) with ER+HER2- tumors were identified. Gene expression profiles were generated from primary breast tumors from 57 AAW and 181 EAW. Pathological characteristics, survival and gene expression analysis were evaluated using chi-square analysis, log-rank tests and ANOVA. RESULTS: Tumors from AAW were significantly more likely to be PR-, Ki67+ and of higher grade. Tumor stage, size and lymph node status did not differ significantly, nor did mortality rates (P=.879). At the molecular level, genes PSPHL and CRYBB2P1 were expressed at significantly higher levels in tumor tissues as well as normal stroma and blood from AAW. Polymorphisms controlling expression of each gene were identified with minor allele frequencies differing significantly between populations but not between cases and controls within each population. CONCLUSIONS: Survival disparities were not detected in patients with ER+HER2- tumors treated within an equal-access health care system and molecular differences in tumors were not causal. Thus, outcome disparities in AAW with ER+HER2- tumors are largely attributable to socioeconomic factors affecting access to screening and treatment, rather than reflecting underlying biological differences.

Competitive Interactions upon Secondary Contact Drive Elevational Divergence in Tropical Birds.

Tropical mountains harbor exceptionally high biodiversity, which is in part due to the marked elevational stratification of tropical biotas. However, the factors that influence the evolution of elevational distributions remain uncertain. I used a database of sister species of tropical montane birds from 41 families and three regions-the Neotropics, the Himalayas, and New Guinea-to test whether patterns of elevational divergence were consistent with (1) a stochastic process, (2) ecological sorting of elevational divergence that occurred in allopatry, or (3) elevational divergence driven by competitive interactions upon secondary contact. The stochastic and ecological sorting hypotheses predict that increased elevational divergence in sympatric sister species is explained by their greater evolutionary age, whereas the competitive interactions hypothesis predicts that elevational divergence is explained by geographical overlap. I found that genetic distances were unrelated to elevational divergence and that allopatric sister species occupied similar elevational distributions regardless of genetic distance in each region. Instead, sympatry was the only significant predictor of elevational divergence; regardless of evolutionary age, sympatric sister species had greater elevational divergence than allopatric sister species in each region, as predicted by the competitive interactions hypothesis. Importantly, this pattern occurred in all three geographic regions, which suggests that competition-driven elevational divergence upon secondary contact is a general process of community assembly in tropical montane avifaunas.

Response to comment on "Interspecific competition limits bird species' ranges on tropical mountains".

Xing et al. (1) create new variables and fit models to argue against the hypothesis that interspecific competition shapes species' elevational ranges. However, their key newly created variable is best interpreted as a proxy for the important variable of the interspecific competition hypothesis. Thus, their reanalysis uncovers the patterns we already described that are consistent with the interspecific competition hypothesis.