VNP20009 is a very effective anti-cancer agent and can specifically target tumors and inhibit tumor growth. It was assumed that the tumor targeting ability of VNP20009 correlated to its anticancer capacity. However, our observation contradicted to this assumption. Three VNP20009 mutant strains (ΔslyA, ΔSTM3120 and ΔhtrA) with reduced fitness in normal tissues and unchanged fitness in tumors partially or completely lost their anti-cancer capacities. The genes slyA, STM3120 and htrA were required for survival within macrophages and were indispensable for tumor microenvironment remodeling by VNP20009. The infiltration of immune cells occurred less in the tumors of mice infected with the mutant strains. In addition, the mRNA levels of TNF-α and IL-1β were significantly decreased in the tumors of mice treated with the mutant strains. Our results indicate that the immune responses elicited by bacteria rather than the bacterial titer in tumors play a “decisive” role in VNP20009-mediated bacterial cancer therapy, which provides a novel perspective for the underlying mechanism of bacterial cancer therapy.

Quiescin sulfhydryl oxidase 1 (QSOX1) is a highly conserved disulfide bond-generating enzyme that is overexpressed in diverse tumor types. Its enzymatic activity promotes the growth and invasion of tumor cells and alters extracellular matrix composition. In a nude mouse-human tumor xenograft model, tumors containing shRNA for QSOX1 grew significantly more slowly than controls, suggesting that QSOX1 supports a proliferative phenotype in vivo. High throughput screening experiments identified ebselen as an in vitro inhibitor of QSOX1 enzymatic activity. Ebselen treatment of pancreatic and renal cancer cell lines stalled tumor growth and inhibited invasion through Matrigel in vitro. Daily oral treatment with ebselen resulted in a 58% reduction in tumor growth in mice bearing human pancreatic tumor xenografts compared to controls. Mass spectrometric analysis of ebselen-treated QSOX1 mechanistically revealed that C165 and C237 of QSOX1 covalently bound to ebselen. This report details the anti-neoplastic properties of ebselen in pancreatic and renal cancer cell lines. The results here offer a “proof-of-principle” that enzymatic inhibition of QSOX1 may have clinical relevancy.

Clear cell renal cell carcinomas (ccRCCs) harbor frequent mutations in epigenetic modifiers including SETD2, the H3K36me3 writer. We profiled DNA methylation (5mC) across the genome in cell line-based models of SETD2 inactivation and SETD2 mutant primary tumors because 5mC has been linked to H3K36me3 and is therapeutically targetable. SETD2 depleted cell line models (long-term and acute) exhibited a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 centered across intergenic regions adjacent to low expressing genes, which became upregulated upon dysregulation of the epigenome. Poised enhancers of developmental genes were prominent hypermethylation targets. SETD2 mutant primary ccRCCs, papillary renal cell carcinomas, and lung adenocarcinomas all demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype and advanced grade. These findings collectively demonstrate that SETD2 mutations drive tumorigenesis by coordinated disruption of the epigenome and transcriptome,and they have important implications for future therapeutic strategies targeting chromatin regulator mutant tumors.

Emerging infectious diseasespose a significant threat to global health, but predicting disease outcomes for particular species can be complicated when pathogen virulence varies across space, time, or hosts. The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) has caused worldwide declines in frog populations. Not only do Bd isolates from wild populations vary in virulence, but virulence shifts can occur over short timescales when Bd is maintained in the laboratory. We leveraged changes in Bd virulence over multiple generations of passage to better understand mechanisms of pathogen virulence. We conducted whole-genome resequencing of two samples of the same Bd isolate, differing only in passage history, to identify genomic processes associated with virulence attenuation. The isolate with shorter passage history (and greater virulence) had greater chromosome copy numbers than the isolate maintained in culture for longer, suggesting that virulence attenuation may be associated with loss of chromosome copies. Our results suggest that genomic processes proposed as mechanisms for rapid evolution in Bd are correlated with virulence attenuation in laboratory culture within a single lineage of Bd. Moreover, these genomic processes can occur over extremely short timescales. On a practical level, our results underscore the importance of immediately cryo-archiving new Bd isolates and using fresh isolates, rather than samples cultured in the laboratory for long periods, for laboratory infection experiments. Finally, when attempting to predict disease outcomes for this ecologically important pathogen, it is critical to consider existing variation in virulence among isolates and the potential for shifts in virulence over short timescales.

Physical fitness has been long associated with maintenance and improvement of motor performance as we age. In particular, measures of psychomotor speed and motor dexterity tend to be higher in physically fit aging adults as compared to their sedentary counterparts. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS), we explored the patterns of neural activity that may, in part, account for differences between individuals of varying physical fitness levels. In this study, we enrolled both sedentary and physically fit middle age (40–60) and younger (18–30) adults and measured upper extremity motor performance during behavioral testing. In a follow-up session, we employed TMS and fMRI to assess levels of interhemispheric communication during unimanual tasks. Results show that increased physical fitness is associated with better upper extremity motor performance on distal dexterity assessments and increased levels of interhemispheric inhibition in middle age adults. Further, the functional correlates of changes of ipsilateral activity appears to be restricted to the aging process as younger adults of varying fitness levels do not differ in hemispheric patterns of activity or motor performance. We conclude that sedentary aging confers a loss of interhemispheric inhibition that is deleterious to some aspects of motor function, as early as midlife, but these changes can be mediated by chronic engagement in aerobic exercise.

Enhancement algorithms are typically applied to video content to increase their appeal to viewers. Such algorithms are readily available in the literature and are already widely applied in, for example, commercially available TVs. On the contrary, not much research has been done on enhancing stereoscopic 3D video content. In this paper, we present research focused on the effect of applying enhancement algorithms used for 2D content on 3D side-by-side content. We evaluate both offline enhancement of video content based on proprietary enhancement algorithms and real-time enhancement in the TVs. This is done using stereoscopic TVs with active shutter glasses, viewed both in their 2D and 3D viewing mode. The results of this research show that 2D enhancement algorithms are a viable first approach to enhance 3D content. In addition to video quality degradation due to the loss of spatial resolution as a consequence of the 3D video format, brightness reduction inherent to polarized or shutter glasses similarly degrades video quality. We illustrate the benefit of providing brightness enhancement for stereoscopic displays.

Human populations differ reliably in the degree to which people favor family, friends, and community members over strangers and outsiders. In the last decade, researchers have begun to propose several economic and evolutionary hypotheses for these cross-population differences in parochialism. In this paper, we outline major current theories and review recent attempts to test them. We also discuss the key methodological challenges in assessing these diverse economic and evolutionary theories for cross-population differences in parochialism.

Recent studies provide compelling evidence for the idea that creative thinking draws upon two kinds of processes linked to distinct physiological features, and stimulated under different conditions. In short, the fast system-I produces intuition whereas the slow and deliberate system-II produces reasoning. System-I can help see novel solutions and associations instantaneously, but is prone to error. System-II has other biases, but can help checking and modifying the system-I results. Although thinking is the core business of science, the accepted ways of doing our work focus almost entirely on facilitating system-II. We discuss the role of system-I thinking in past scientific breakthroughs, and argue that scientific progress may be catalyzed by creating conditions for such associative intuitive thinking in our academic lives and in education. Unstructured socializing time, education for daring exploration, and cooperation with the arts are among the potential elements. Because such activities may be looked upon as procrastination rather than work, deliberate effort is needed to counteract our systematic bias.

A number of emerging dynamic traffic analysis applications, such as regional or statewide traffic assignment, require a theoretically rigorous and computationally efficient model to describe the propagation and dissipation of system congestion with bottleneck capacity constraints. An open-source light-weight dynamic traffic assignment (DTA) package, namely DTALite, has been developed to allow a rapid utilization of advanced dynamic traffic analysis capabilities. This paper describes its three major modeling components: (1) a light-weight dynamic network loading simulator that embeds Newell’s simplified kinematic wave model; (2) a mesoscopic agent-based DTA procedure to incorporate driver’s heterogeneity; and (3) an integrated traffic assignment and origin–destination demand calibration system that can iteratively adjust path flow volume and distribution to match the observed traffic counts. A number of real-world test cases are described to demonstrate the effectiveness and performance of the proposed models under different network and data availability conditions.

Coordinated drilling efforts are an important method to investigate active tectonics and magmatic processes related to faults and volcanoes. The US National Science Foundation (NSF) recently sponsored a series of workshops to define the nature of future continental drilling efforts. As part of this series, we convened a workshop to explore how continental scientific drilling can be used to better understand active tectonic and magmatic processes. The workshop, held in Park City, Utah, in May 2013, was attended by 41 investigators from seven countries. Participants were asked to define compelling scientific justifications for examining problems that can be addressed by coordinated programs of continental scientific drilling and related site investigations. They were also asked to evaluate a wide range of proposed drilling projects, based on white papers submitted prior to the workshop.

Participants working on faults and fault zone processes highlighted two overarching topics with exciting potential for future scientific drilling research: (1) the seismic cycle and (2) the mechanics and architecture of fault zones. Recommended projects target fundamental mechanical processes and controls on faulting, and range from induced earthquakes and earthquake initiation to investigations of detachment fault mechanics and fluid flow in fault zones. Participants working on active volcanism identified five themes: the volcano eruption cycle; eruption sustainability, near-field stresses, and system recovery; eruption hazards; verification of geophysical models; and interactions with other Earth systems. Recommended projects address problems that are transferrable to other volcanic systems, such as improved methods for identifying eruption history and constraining the rheological structure of shallow caldera regions. Participants working on chemical geodynamics identified four major themes: large igneous provinces (LIPs), ocean islands, continental hotspot tracks and rifts, and convergent plate margins (subduction zones).

This workshop brought together a diverse group of scientists with a broad range of scientific experience and interests. A particular strength was the involvement of both early-career scientists, who will initiate and carry out these new research programs, and more senior researchers with many years of experience in scientific drilling and active tectonics research. Each of the themes and questions outlined above has direct benefits to society, including improving hazard assessment, direct monitoring of active systems for early warning, renewable and non-renewable resource and energy exploitation, and predicting the environmental impacts of natural hazards, emphasizing the central role that scientific drilling will play in future scientific and societal developments.