Search

Reports of programmed cell death (PCD) in phytoplankton raise questions about the ecological evolutionary role of cell death in these organisms. We induced PCD by nitrogen deprivation and unregulated cell death (non-PCD) in one strain of the green microalga

Heavy metals cross-select for antimicrobial resistance in laboratory experiments, but few studies have documented this effect in polluted soils. Moreover, despite decades of awareness of heavy metal contamination at the EPA Superfund site in North Birmingham, Alabama, this is the first analysis of the impact of this pollution on the soil microbiome.

Human tumor xenograft models do not replicate the human immune system and tumor microenvironment. We developed an improved humanized mouse model, derived from fresh cord blood CD34+ stem cells (CD34+ HSC), and combined it with lung cancer cell line–derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34+ HSCs could reconstitute detectable mature human leukocytes (hCD45+) in mice at four weeks without the onset of graft-versus-host disease (GVHD). Repopulated human T cells, B cells, natural killer (NK) cells, dendritic cells (DC), and myeloid-derived suppressor cells (MDSC) increased in peripheral blood, spleen, and bone marrow over time. Although cultured CD34+ HSCs labeled with luciferase could be detected in mice, the cultured HSCs did not develop into mature human immune cells by four weeks, unlike fresh CD34+ HSCs. Ex vivo, reconstituted T cells, obtained from the tumor-bearing humanized mice, secreted IFNγ upon treatment with phorbol myristate acetate (PMA) or exposure to human A549 lung tumor cells and mediated antigen-specific CTL responses, indicating functional activity. Growth of engrafted PDXs and tumor xenografts was not dependent on the human leukocyte antigen status of the donor. Treatment with the anti–PD-1 checkpoint inhibitors pembrolizumab or nivolumab inhibited tumor growth in humanized mice significantly, and correlated with an increased number of CTLs and decreased MDSCs, regardless of the donor HLA type. In conclusion, fresh CD34+HSCs are more effective than their expanded counterparts in humanizing mice, and do so in a shorter time. The Hu-PDX model provides an improved platform for evaluation of immunotherapy.

Legends to Figures S1-S7

Figure S1-S7

Hematoxylin and eosin staining showing conformity of grade between patient sample and respective established xenografts from both primary and metastatic sites.

Association between surgical specimen size and rate of PDX establishment.

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient-derived xenografts (PDX) in colorectal cancer are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target, and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 colorectal cancer patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2–82.6) vs. biopsy 35% (95% CI: 22.1%–50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modeling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of colorectal cancer patients. Mol Cancer Ther; 16(7); 1435–42. ©2017 AACR.

Purpose:Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies.Experimental Design:We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA).Results:A total of 153/206 (74.3%) were men; median age, 62 years (range, 18–91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1–13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%–55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20–38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04).Conclusions:This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

Supplementary Fig S3. Association of gene size and the differential expression of IFN-γ pathway in genes commonly mutated in MSS CRC

Supplementary Figure 2

Supplementary Table S1

Supplemental table 1

APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed β-catenin activation via up- or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in ApcΔ580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer–invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARD-mediated upregulation of other proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness.Significance:These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis.

Supplementary Figures S1-S7 - This file includes supplementary figures S1-S7: Figure S1. PPARD increased active β-catenin and its target gene (e.g. c-Myc and cyclin D1) expression levels in mouse IECs and human HCT116 colorectal cancer cells by western blot and qRT-PCR. Figure S2. PPARD and its ligand GW501516 promoted intestinal tumorigenesis in multiple APC mutant mouse models, shown by intestinal photographs and tumor number counts. Figure S3. Western blot and IHCs showing that PPARD increased BMP7/TAK1/active β-catenin expression levels in mouse IECs. Figure S4. IHC microphotographs and score results showing active β-catenin expression levels in 41 human paired colorectal adenomas (Adenoma), CRC tumor centers (Tumor center), and cancer invasive fronts (Invasive front). Figure S5. Western blot and IHC results showing that PPARD upregulated AKT1 but not AKT2 to increase p-rpS6 levels in mouse IECs and human HCT116 colorectal cancer cells. Figure S6. Immunofluorescence staining of rRNA, IHC microphotographs and IHC score results of CDK1 showing rRNA expression levels in mouse intestinal tissues from PD and ApcÎ"580-PD mice and their corresponding control littermates, and nuclear CDK1 expression levels in 41 human paired colorectal adenomas (Adenoma), CRC tumor centers (Tumor center), and cancer invasive fronts (Invasive front). Figure S7. Multiple human public database analyses showing PPARD and BMP7 genetic alterations in colon cancer patients, and comparison of the survival probability for the colon cancer patients with low and high expression of BMP7.

Reports of programmed cell death (PCD) in phytoplankton raise questions about the ecological evolutionary role of cell death in these organisms. We induced PCD by nitrogen deprivation and unregulated cell death (non-PCD) in one strain of the green microalga Ankistrodesmus densus and investigated the effects of the cell death supernatants on phylogenetically related co-occurring organisms using growth rates and maximum biomass as proxies of fitness. PCD-released materials from A. densus CCMA-UFSCar-3 significantly increased growth rates of two conspecific strains compared to healthy culture (HC) supernatants and improved the maximum biomass of all A. densus strains compared to related species. Although growth rates of non- A. densus with PCD supernatants were not statistically different from HC treatment, biomass gain was significantly reduced. Thus, the organic substances released by PCD, possibly nitrogenous compounds, could promote conspecific growth. These results support the argument that PCD may differentiate species or subtypes and increases inclusive fitness in this model unicellular chlorophyte. Further research, however, is needed to identify the responsible molecules and how they interact with cells to provide the PCD benefits.

The design of metal nanoparticle-modified polymer surfaces in a green and scalable way is both desirable and highly challenging. Herein, a new green low-temperature plasma-based

Heavy metals (HMs) are known to modify bacterial communities both in the laboratory and in situ. As a consequence, soils in HM contaminated sites like the U.S. Environmental Protection Agency (EPA) Superfund sites are predicted to have altered ecosystem functioning, with potential ramifications for the health of organisms, including humans, that live nearby. Further, several studies have shown that metal tolerant bacteria are often also resistant to antimicrobial agents (AMR), and therefore HM contaminated soils could potentially act as reservoirs that could disseminate AMR genes into human-associated pathogenic bacteria. To explore this possibility soil samples were collected from six public locations in the zip code 35207 (the home of the North Birmingham 35th Avenue Superfund site) and in six public areas in a neighboring reference zip code (35214). Sequencing of the V4 region of the bacterial 16S rRNA gene revealed that elevated concentrations of HMs As, Mn, Pb, and Zn reduced microbial diversity and altered community structure within each zip code. While there was no difference between zip codes in the proportion of total culturable microbes that survived antimicrobial or metal exposure, bacterial isolates with HMR almost always also exhibited AMR. Metagenomes inferred using PICRUST2 also predicted significantly higher mean relative frequencies in 35207 for several AMR genes related to both specific and broad-spectrum AMR phenotypes. Together, these results support the hypothesis that chronic HM pollution alters soil bacterial community structure in ecologically meaningful ways and may also select for bacteria with increased potential to contribute to AMR in human bacterial disease.

Many biological functions are leaky, and organisms that perform them contribute some of their products to a community "marketplace" in which nonperforming individuals may compete for them. Leaky functions are partitioned unequally in microbial communities, and the evolutionary forces determining which species perform them and which become beneficiaries are poorly understood. Here, we demonstrate that the market principle of comparative advantage determines the distribution of a leaky antibiotic resistance gene in an environment occupied by two "species"-strains of Escherichia coli growing on mutually exclusive resources and thus occupying separate niches. Communities comprised of antibiotic-resistant cells were rapidly invaded by sensitive cells of both types. While the two phenotypes coexisted stably for 500 generations, in 15/18 replicates, antibiotic sensitivity became fixed in one species. Fixation always occurred in the same species despite both species being genetically identical except for their niche-defining mutation. In the absence of antibiotic, the fitness cost of resistance was identical in both species. However, the intrinsic resistance of the species that ultimately became the sole helper was significantly lower, and thus its reward for expressing the resistance gene was higher. Opportunity cost of resistance, not absolute cost or efficiency of antibiotic removal, determined which species became the helper, consistent with the economic theory of comparative advantage. We present a model that suggests that this market-like dynamic is a general property of Black Queen systems and, in communities dependent on multiple leaky functions, could lead to the spontaneous development of an equitable and efficient division of labor.

We previously developed and assessed “The Art of Microbiology,” a course-based undergraduate research experience (CURE) which uses agar art to spur student experimentation, where we found student outcomes related to science persistence. However, these outcomes were not correlated with specific activities and gains were not reported from more than one class. In this study, we explored which of the three major activities in this CURE—agar art, experimental design, or poster presentations—affected student engagement and outcomes associated with improved understanding of the nature of science (NOS). The Art of Microbiology was studied in three microbiology teaching laboratories: at a research university with either the CURE developer (18 students) or a CURE implementer (39 students) and at a community college with a CURE implementer (25 students). Our quasi-experimental mixed methods study used pre/post-NOS surveys and semi-structured class-wide interviews. Community college students had lower baseline NOS responses but had gains in NOS similar to research university students post-CURE. We surveyed research university students following each major activity using the Assessing Student Perspective of Engagement in Class Tool (ASPECT) survey but did not find a correlation between NOS and activity engagement. Of the three activities, we found the highest engagement with agar art, especially in the CURE developer class. Interviewed students in all classes described agar art as a fun, relevant, and low-stakes assignment. This work contributes to the evidence supporting agar art as a curricular tool, especially in ways that can add research to classrooms in and beyond the research university.

Microalgal cultures are often maintained in xenic conditions, i.e., with associated bacteria, and many studies indicate that these communities both are complex and have significant impacts on the physiology of the target photoautotroph. Here, we investigated the structure and stability of microbiomes associated with a diverse sampling of diatoms during long-term maintenance in serial batch culture. We found that, counter to our initial expectation, evenness diversity increased with time since cultivation, driven by a decrease in dominance by the most abundant taxa in each culture. We also found that the site from which and time at which a culture was initially collected had a stronger impact on microbiome structure than the diatom species; however, some bacterial taxa were commonly present in most cultures despite having widely geographically separated collection sites. Our results support the conclusion that stochastic initial conditions (i.e., the local microbial community at the collection site) are important for the long-term structure of these microbiomes, but deterministic forces such as negative frequency dependence and natural selection exerted by the diatom are also at work. IMPORTANCE Natural microbial communities are extremely complex, with many more species coexisting in the same place than there are different resources to support them. Understanding the forces that allow this high level of diversity has been a central focus of ecological and evolutionary theory for many decades. Here, we used stock cultures of diatoms, which were maintained for years in continuous growth alongside populations of bacteria, as proxies for natural communities. We show that the bacterial communities remained relatively stable for years, and there is evidence that ecological forces worked to stabilize coexistence instead of favoring competition and exclusion. We also show evidence that, despite some important regional differences in bacterial communities, there was a globally present core microbiome potentially selected for in these diatom cultures. Understanding interactions between bacteria and diatoms is important both for basic ecological science and for practical science, such as industrial biofuel production.

Multi-region multi-sector energy-economic models are often used to analyze long-term scenarios of energy development, however, these models usually rely on a simplified representation of technological details in power generation. To strengthen this representation, we develop a method for modeling the economic competition between different advanced technologies in multi-region multi-sector dynamic energy-economic models based on a markup approach, which represents the measure of the cost of a technology relative to the price received for electricity generation. The markup includes capital costs, fixed and variable operating and maintenance (O&M) costs, fuel costs, and transmission and distribution (T&D) costs. For intermittent technologies, it also includes a backup requirement to make these technologies effectively dispatchable. For carbon capture and storage (CCS) technologies, it also includes the costs of CO2 capture, transportation and storage. We provide a standardized markup calculation for generation technologies for different regions of the world, including USA, China, India, EU, Japan and others. Then we analyze the sensitivity of the calculation to critical inputs, including capital costs, fuel costs, carbon prices and capacity factors. We provide a detailed calculation of the relative costs of the following technologies: new pulverized coal, new pulverized coal with CCS, natural gas combined cycle, natural gas with CCS, biomass-fueled plant, biomass with CCS, advanced nuclear, wind (for small and medium penetration levels), solar, wind with backup (for large penetration levels), co-firing of coal and biomass combined with CCS, and advanced CCS on natural gas. For illustration, we incorporate the markups into the MIT Economic Projection and Policy Analysis (EPPA) model, a global multi-sector multi-sector dynamic energy-economic model with a detailed representation of power generation technologies, and run several scenarios. Our analysis and results provide insight on the deployment of different low-carbon power generation technologies depending on assumptions about carbon policy stringency.

The establishment of an emissions trading scheme (ETS) in China creates the potential for a “least cost” solution for achieving the greenhouse gas (GHG) emissions reductions required for China to meet its Paris Agreement pledges. China has pledged to reduce CO 2 intensity by 60–65% in 2030 relative to 2005 and to stop the increase in absolute CO 2 emissions around 2030. In this series of studies, we enhance the MIT Economic Projection and Policy Analysis (EPPA) model to include the latest assessments of the costs of power generation technologies in China to evaluate the impacts of different potential ETS pathways on deployment of carbon capture and storage (CCS) technology. This paper reports the results from baseline scenarios where power generation prices are assumed to be homogeneous across the country for a given mode of generation. We find that there are different pathways where CCS might play an important role in reducing the emission intensity in China's electricity sector, especially for low carbon intensity targets consistent with the ultimate goals of the Paris Agreement. Uncertainty about the exact technology mix suggests that decision makers should be wary of picking winning technologies, and should instead seek to provide incentives for emission reductions. While it will be challenging to meet the CO 2 intensity target of 550 g/kWh for the electric power sector by 2020, multiple pathways exist for achieving lower targets over a longer timeframe. Our initial analysis shows that carbon prices of 35–40$/tCO 2 make CCS technologies on coal-based generation cost-competitive against other modes of generation and that carbon prices higher than 100$/tCO 2 favor a major expansion of CCS. The next step is to confirm these initial results with more detailed modeling that takes into account granularity across China's energy sector at the provincial level.

The authors gratefully acknowledge the financial support for this work provided by the MIT Joint Program on the Science and Policy of Global Change through a consortium of industrial sponsors and Federal grants. Suggestions and feedback from participants of the MIT EPPA meeting and Jamie Bartholomay are highly appreciated.

Integrated assessment models (IAMs) form a prime tool in informing about climate mitigation strategies. Diagnostic indicators that allow comparison across these models can help describe and explain differences in model projections. This increases transparency and comparability. Earlier, the IAM community has developed an approach to diagnose models (Kriegler (2015 Technol. Forecast. Soc. Change 90 45–61)). Here we build on this, by proposing a selected set of well-defined indicators as a community standard, to systematically and routinely assess IAM behaviour, similar to metrics used for other modeling communities such as climate models. These indicators are the relative abatement index, emission reduction type index, inertia timescale, fossil fuel reduction, transformation index and cost per abatement value. We apply the approach to 17 IAMs, assessing both older as well as their latest versions, as applied in the IPCC 6th Assessment Report. The study shows that the approach can be easily applied and used to indentify key differences between models and model versions. Moreover, we demonstrate that this comparison helps to link model behavior to model characteristics and assumptions. We show that together, the set of six indicators can provide useful indication of the main traits of the model and can roughly indicate the general model behavior. The results also show that there is often a considerable spread across the models. Interestingly, the diagnostic values often change for different model versions, but there does not seem to be a distinct trend.

In the wake of the COVID-19 pandemic, the general public has been subjected to an “information epidemic” or an “infodemic” leading to a plethora of invalid information. We decided to educate a non-majors biology class with an intent to help advance public health awareness related to COVID-19. This is particularly important for non-majors biology students who may only ever take one science classes as a part of their core curriculum. In the light of an unanticipated transition to an online platform, an E-service-learning module was introduced for this course. In the four-week service-learning module, which included expert-led lectures and an E-service-learning assignment, students created digital infographics to inform their peers and community about COVID-19 safety precautions and completed a required post-reflection assignment summarizing their learning gains. Out of 112 enrolled students, 87 consented to have their reflections analyzed for this study and 8 students chose to participate in additional one-on-one online interviews. We categorized post-reflection and interview data into four broad categories: responses related to the service-learning, guest lectures, information on COVID-19 virus or pandemic, and those about the broader implications of COVID-19. Our post-reflection data and interview data together reveal that while some students were appreciative of an opportunity to be involved in the process of educating the community via infographics, a majority of the students reported a greater range of learning gains from expert led-lectures. Continued research on E-service-learning should explore the degree to which this pedagogical tool can maximize student learning in an online classroom environment.

Reactive oxygen species (ROS) are omnipresent in the ocean, originating from both biological (e.g., unbalanced metabolism or stress) and non-biological processes (e.g. photooxidation of colored dissolved organic matter). ROS can directly affect the growth of marine organisms, and can also influence marine biogeochemistry, thus indirectly impacting the availability of nutrients and food sources. Microbial communities and evolution are shaped by marine ROS, and in turn microorganisms influence steady-state ROS concentrations by acting as the predominant sink for marine ROS. Through their interactions with trace metals and organic matter, ROS can enhance microbial growth, but ROS can also attack biological macromolecules, causing extensive modifications with deleterious results. Several biogeochemically important taxa are vulnerable to very low ROS concentrations within the ranges measured in situ, including the globally distributed marine cyanobacterium Prochlorococcus and ammonia-oxidizing archaea of the phylum Thaumarchaeota. Finally, climate change may increase the amount of ROS in the ocean, especially in the most productive surface layers. In this review, we explore the sources of ROS and their roles in the oceans, how the dynamics of ROS might change in the future, and how this change might impact the ecology and chemistry of the future ocean.

Course-based undergraduate research experiences (CUREs) often involve a component where the outcomes of student research are broadly relevant to outside stakeholders. We wanted to see if building courses around an environmental justice issue relevant to the local community would impact students’ sense of civic engagement and appreciation of the relevance of scientific research to the community. In this quasi-experimental study, we assessed civic engagement and scientific identity gains (N = 98) using pre- and post-semester surveys and open-ended interview responses in three different CUREs taught simultaneously at three different universities. All three CURES were focused on an environmental heavy metal pollution issue predominantly affecting African–Americans in Birmingham, Alabama. While we found increases in students’ sense of science efficacy and identity, our team was unable to detect meaningful changes in civic engagement levels, all of which were initially quite high. However, interviews suggested that students were motivated to do well in their research because the project was of interest to outside stakeholders. Our observations suggest that rather than directly influencing students’ civic engagement, the “broadly relevant” component of our CUREs engaged their pre-existing high levels of engagement to increase their engagement with the material, possibly influencing gains in science efficacy and science identity. Our observations are consistent with broader community relevance being an important component of CURE success, but do not support our initial hypothesis that CURE participation would influence students’ attitudes toward the civic importance of science.

Using the MIT Economic Projection and Policy Analysis (EPPA) model, we explore factors influencing carbon capture and storage (CCS) deployment in power generation and its role in mitigating carbon emissions. We find that in the 2∘C scenario with EPPA’s base-case technology cost and performance assumptions, CCS plays an important role in the second half of the century: by 2100 CCS is applied to almost 40% of world electricity production, with a third coming from coal with CCS and the other two-thirds from gas with CCS. Results on CCS deployment depend on the assumed fraction of carbon captured in CCS power plants, as emissions constraints get tighter and the carbon price rises. Adding options for higher capture fractions or offsetting uncaptured emissions leads to greater deployment of CCS than in the 2∘C base case. We provide a sensitivity analysis by making favorable assumptions for CCS, nuclear and renewables. We also explore regional differences in the deployment of CCS. We find that US and Europe mostly rely on gas CCS, whereas China relies on coal CCS and India pursues both options. We also assess how these projections align with assessment of CO2 storage potential, and find that storage potential is larger than storage demand at both global and regional scales. Ultimately, we find that under stringent mitigation scenarios, the power sector relies on a mix of technological options, and the conditions that favor a particular mix of technologies differ by region.

Activating mutations of the KRAS gene are one of the major genomic alterations associated with tumorigenesis of non-small cell lung cancer (NSCLC). Thus far, treatment of KRAS-mutant NSCLC remains an unmet medical need. We determined the in vivo treatment responses of 13 KRAS mutant and 14 KRAS wild type NSCLC patient-derived xenografts (PDXs) to agents that target known NSCLC vulnerabilities: the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, and the BCL-X(L)/BCL-2 inhibitor navitoclax. The results showed that the tumor regression rate after single agent therapy with KRT-232, trametinib and navitoclax was 11%, 10% and 0%, respectively. Combination therapies of trametinib plus KRT-232 and trametinib plus navitoclax led to improved partial response rates over single-agent activity in a subset of PDX models. Tumor regression was observed in 23% and 50% of PDXs after treatment with trametinib plus KRT-232 and trametinib plus navitoclax, respectively. The disease control rates in KRAS-mutant PDXs tested were 90%-100% after treatment with trametinib plus KRT-232 or plus navitoclax. A correlation analysis of treatment responses and genomic and proteomic biomarkers revealed that sensitivity to KRT-232 was significantly associated with TP53 wild-type or STK11 mutant genotypes (P

Anthropogenic CO2 emissions are projected to lower the pH of the ocean 0.3 units by 2100. Previous studies suggested that Prochlorococcus and Synechococcus, the numerically dominant phytoplankton in the oceans, have different responses to elevated CO2 that may result in a dramatic shift in their relative abundances in future oceans. Here we showed that the exponential growth rates of these two genera respond to future CO2 conditions in a manner similar to other cyanobacteria, but Prochlorococcus strains had significantly lower realized growth rates under elevated CO2 regimes due to poor survival after exposure to fresh culture media. Despite this, a Synechococcus strain was unable to outcompete a Prochlorococcus strain in co-culture at elevated CO2 . Under these conditions, Prochlorococcus' poor response to elevated CO2 disappeared, and Prochlorococcus' relative fitness showed negative frequency dependence, with both competitors having significant fitness advantages when initially rare. These experiments suggested that the two strains should be able to coexist indefinitely in co-culture despite sharing nearly identical nutritional requirements. We speculate that negative frequency dependence exists due to reductive Black Queen evolution that has resulted in a passively mutualistic relationship analogous to that connecting Prochlorococcus with the 'helper' heterotrophic microbes in its environment.

Benthic organisms may be exposed to polycyclic aromatic hydrocarbons (PAHs) in marine sediments as the result of oil spills. PAH photoinduced toxicity, which has been documented in a wide range of early life stage (ELS) aquatic biota, is a phenomenon by which ultraviolet (UV) radiation potentiates the toxicity of photodynamic PAHs (often leading to mortality). Fiddler crabs

We present estimates of carbon budgets for different levels of surface air temperature (SAT) increase from multiple 400-member ensembles of simulations with the MIT Earth System Model of intermediate complexity (MESM). Ensembles were carried out using distributions of climate parameters affecting climate system response to external forcing obtained by comparison of historical simulations with available observations.First, to evaluate MESM performance, we ran two ensembles: one with MESM forced by 1% per year increase in CO2 concentrations (and with non-CO2 greenhouse gases (GHG) at pre-industrial level) and the other with GHG concentrations from the RCP 8.5 scenario. Distributions of climate characteristics describing model response to increasing CO2 concentrations (e.g. TRC and TCRE) as well as values of carbon budgets of exceeding different SAT levels agree well with published estimates.Then we ran a number of ensembles with MESM driven by emissions produced by the MIT Economic Projection and Policy Analysis (EPPA) Model. Our results show that under stringent mitigation policy concerning non-CO2 GHGs, the SAT increase can be kept below 2°C relative to pre-industrial with 66% probability through the end of the 21st century without negative CO2 emissions. The SAT increase can also be restricted to 1.5°C with 50% probability if such policy is implemented immediately. If GHG emissions follow the path implied by the Paris Agreement pledges through 2030, then it would require either an unrealistically sharp drop in non-CO2 GHG emissions or negative CO2 emissions to stay below 1.5°C. Keeping the temperature increase below a chosen value (1.5°C or 2°C) beyond 2100 will most likely require negative CO2 emissions in part due to difficulties in restricting agricultural methane emissions.Further analysis shows that temperature change during the 21st century is also significantly affected by the assumption concerning decrease of SO2 emissions from energy-intensive industries. Implementation of technologies resulting in reduction of those emissions will decrease the probability of SAT staying below a given limit by about 7-12%. This will affect the time when negative CO2 emissions will become necessary to prevent temperature increase.

Efforts to estimate the physical and economic impacts of future climate change face substantial challenges. To enrich the currently popular approaches to impact analysis—which involve evaluation of a damage function or multi-model comparisons based on a limited number of standardized scenarios—we propose integrating a geospatially resolved physical representation of impacts into a coupled human-Earth system modeling framework. Large internationally coordinated exercises cannot easily respond to new policy targets and the implementation of standard scenarios across models, institutions and research communities can yield inconsistent estimates. Here, we argue for a shift toward the use of a self-consistent integrated modeling framework to assess climate impacts, and discuss ways the integrated assessment modeling community can move in this direction. We then demonstrate the capabilities of such a modeling framework by conducting a multi-sectoral assessment of climate impacts under a range of consistent and integrated economic and climate scenarios that are responsive to new policies and business expectations., Climate impact assessments usually rely on modeling approaches that are either comprehensive but inflexible and inefficient, or lacking sufficient detail. Here the authors describe a framework to assess multi-sectoral climate impacts and show its capability and timely responsiveness to new policies.

Carbon capture and storage (CCS) technology is an important option in the portfolio of emission mitigation solutions in scenarios that lead to deep reductions in greenhouse gas (GHG) emissions. We focus on CCS application in hard-to-abate sectors (cement industry, iron and steel, chemicals) and introduce industrial CCS options into the MIT Economic Projection and Policy Analysis (EPPA) model, a global multi-region multi-sector energy-economic model that provides a basis for the analysis of long-term energy deployment. We use the EPPA model to explore the potential for industrial CCS in different parts of the world, under the assumptions that CCS is the only mitigation option for deep GHG emission reductions in industry and that negative emission options are not available for other sectors of the economy. We evaluate CCS deployment in a scenario that limits the increase in average global surface temperature to 2 °C above preindustrial levels. When industrial CCS is not available, global costs of reaching the target are higher by 12% in 2075 and 71% in 2100 relative to the cost of achieving the policy with CCS. Overall, industrial CCS enables continued growth in the use of energy-intensive goods along with large reductions in global and sectoral emissions. We find that in scenarios with stringent climate policy, CCS in the industry sector is a key mitigation option, and our approach provides a path to projecting the deployment of industrial CCS across industries and regions.

Where positive externalities are structural inevitabilities of particular behaviors and strategies (e.g. “Black Queen (BQ) functions”), stable commensalism is both possible and likely even between individuals who would otherwise be in close competition, and the coexistence thus stabilized generates opportunity for the eventual development of mutual and collective benefit. Here we review examples of BQ functions in animal behavior, both in the natural world and in human economies, with a focus on how these functions encourage the evolution of specialization and division of labor. The non-human examples we consider range from microbial systems to vertebrate communities while the human examples consider economic agents ranging from foraging societies to superpowers. With these examples, we discuss four classes of BQ functions: (i) functions that protect against harmful things in the environment; (ii) functions that provide products with value added relative to their constituent parts; (iii) functions that provide structures that can be utilized by other organisms; and (iv) functions that yield information. We also explore a set of examples where BQ-stabilized commensal relationships developed into two-way exchange relationships in human systems: (i) the ancient mutualism between humans and dogs, (ii) the division of labor in human societies between sexes and age groups, and (iii) the dominance of Silicon Valley over other regional technology centers. We conclude that BQ functions are an underappreciated motivator of markets and communities and suggest future experimental evolution research encouraged by our perspective.

Prochlorococcus is a globally important marine cyanobacterium that lacks the gene catalase and relies on ‘helper’ bacteria such as Alteromonas to remove reactive oxygen species. Increasing atmospheric CO2 decreases the need for carbon concentrating mechanisms and photorespiration in phytoplankton, potentially altering their metabolism and microbial interactions even when carbon is not limiting growth. Here, Prochlorococcus (VOL4, MIT9312) was co-cultured with Alteromonas (strain EZ55) under ambient (400 p.p.m.) and elevated CO2 (800 p.p.m.). Under elevated CO2, Prochlorococcus had a significantly longer lag phase and greater apparent die-offs after transfers suggesting an increase in oxidative stress. Whole-transcriptome analysis of Prochlorococcus revealed decreased expression of the carbon fixation operon, including carboxysome subunits, corresponding with significantly fewer carboxysome structures observed by electron microscopy. Prochlorococcus co-culture responsive gene 1 had significantly increased expression in elevated CO2, potentially indicating a shift in the microbial interaction. Transcriptome analysis of Alteromonas in co-culture with Prochlorococcus revealed decreased expression of the catalase gene, known to be critical in relieving oxidative stress in Prochlorococcus by removing hydrogen peroxide. The decrease in catalase gene expression was corroborated by a significant ~6-fold decrease in removal rates of hydrogen peroxide from co-cultures. These data suggest Prochlorococcus may be more vulnerable to oxidative stress under elevated CO2 in part from a decrease in ecosystem services provided by heterotrophs like Alteromonas. This work highlights the importance of considering microbial interactions in the context of a changing ocean.

Public acceptance of evolution is conspicuously low in the United States. This is especially true in the American Southeast, where the famous “Scopes Monkey Trial” made the religious objections of rural Tennesseans to Darwin’s theory famous. In this piece I argue that disbelief in evolution in the Southeast is caused more by social factors than by scientific ones, and I present some efforts that I have successfully used to side-step these social issues in order to effectively teach evolutionary biology to diverse college students in Alabama. I close by calling on other educators to work to defuse the religious, political, and social minefields that separate academic biologists and the public in order to be more effective communicators and teachers of evolution.

Evolution innovates by repurposing existing genetic elements to produce new functions. However, the range of new functions and traits this evolutionary tinkering can produce is limited to those that are supported and enabled by the rest of the genome. The full complement of genes in a genome required for a novel trait to manifest constitutes the trait’s “deep” genetic basis. The deep genetic basis of novel traits can be very difficult to determine under most circumstances, leaving it understudied despite its critical importance. Novel traits that arise during highly tractable microbial evolution experiments present opportunities to correct this deficit. One such novel trait is aerobic growth on citrate (Cit+ ), which evolved in one of twelve populations in the Long-Term Evolution Experiment with Escherichia coli (LTEE). We sought to uncover the deep genetic basis of this trait by transforming 3,985 single gene knockout mutants from the Keio collection with a plasmid that can confer aerobic growth on citrate. In our preliminary screen, we identified 111 genes putatively necessary for expression of the Cit+ trait. Of these, ∼ 32% are involved in core metabolic pathways, including the TCA and glycolysis pathways. Another ∼ 22% encode a variety of transporter proteins. The remaining genes are either of unknown function or uncertain involvement with citrate metabolism. Our work demonstrates how novel traits that are built upon pre-existing functions can depend on the activity of a large number of genes, hinting at an unappreciated level of complexity in the evolution of relatively simple new functions.

This paper assesses the range of CO2 transport and storage costs and evaluates their impact on economy-wide modeling results of decarbonization pathways. Much analytic work has been dedicated to evaluating the cost and performance of various CO2 capture technologies, but less attention has been paid to evaluating the cost of CO2 transport and storage. Many integrated assessment modeling studies assume a combined cost for CO2 transport and storage that is uniform in all regions, commonly estimated at $10/tCO2. Realistically, the cost of CO2 transport and storage is not fixed at $10/tCO2 and varies across geographic, geologic, and institutional settings. We surveyed the literature to identify key sources of variability in transport and storage costs and developed a method to quantify and incorporate these elements into a cost range. We find that onshore pipeline transport and storage costs vary from $4 to 45/tCO2 depending on key sources of variability including transport distance, scale (i.e. quantity of CO2 transported and stored), monitoring assumptions, reservoir geology, and transport cost variability such as pipeline capital costs. Using the MIT Economic Projection and Policy Analysis (EPPA) model, we examined the impact of variability in transport and storage costs by applying a range of uniform costs in all regions in a future where global temperature rise is limited to 2°C. We then developed three modeling cases where transport and storage costs vary regionally. In these latter cases, global cumulative CO2 captured and stored through 2100 ranges from 290 to 377 Gt CO2, compared to 425 Gt CO2 when costs are assumed to be uniformly $10/t CO2 in all regions. We conclude that the widely used assumption of $10/tCO2 for the transport and storage of CO2 is reasonable in some regions, but not in others. Moreover, CCS deployment is more sensitive to transport and storage costs in some regions than others, particularly China. More analysis is needed to further quantify CO2 transport and storage costs at a regional level.

Anxiety can impact overall performance and persistence in college. Student response systems (SRSs), real-time active-learning technologies used to engage students and gauge their understanding, have been shown to elicit anxiety for some students. Kahoot! is an SRS technology that differs from others in that it involves gamification, the use of gamelike elements. Recent studies have explored the impact of active-learning strategies on student anxiety across different institutions, but there is little known about how Kahoot! impacts student perceived anxiety, especially in comparison with other active-learning strategies. In two complementary yet parallel studies of introductory biology courses at a western research-intensive institution (n = 694) and a southeastern research-intensive institution (n = 60), we measured students’ perceived anxiety. We then explored how students were influenced by nongraded Kahoot! play and other elements of instruction. Using previously developed and course-specific pre- and post-course surveys, we found students at both universities agreed that nongraded Kahoot! play caused less anxiety compared with other pedagogical practices, such as working in small groups or reading the textbook. After playing Kahoot!, lower-performing students demonstrated greater engagement and lower levels of anxiety compared with their peers, suggesting that Kahoot! may be a particularly engaging active-learning strategy for these students.