Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma

The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with “low”, “intermediate”, and “high” immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-κB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-κB pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma. Significance: These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival

Phytoplankton Cell Size Reduction in Response to Warming Mediated by Nutrient Limitation

Shrinking of body size has been proposed as one of the universal responses of organisms to global climate warming. Using phytoplankton as an experimental model system has supported the negative effect of warming on body-size, but it remains controversial whether the size reduction under increasing temperatures is a direct temperature effect or an indirect effect mediated over changes in size selective grazing or enhanced nutrient limitation which should favor smaller cell-sizes. Here we present an experiment with a factorial combination of temperature and nutrient stress which shows that most of the temperature effects on phytoplankton cell size are mediated via nutrient stress. This was found both for community mean cell size and for the cell sizes of most species analyzed. At the highest level of nutrient stress, community mean cell size decreased by 46% per degrees C, while it decreased only by 4.7% at the lowest level of nutrient stress. Individual species showed qualitatively the same trend, but shrinkage per degrees C was smaller. Overall, our results support the hypothesis that temperature effects on cell size are to a great extent mediated by nutrient limitation. This effect is expected to be exacerbated under field conditions, where higher temperatures of the surface waters reduce the vertical nutrient transport

Best practices in heterotrophic high-cell-density microalgal processes: achievements, potential and possible limitations

Microalgae of numerous heterotrophic genera (obligate or facultative) exhibit considerable metabolic versatility and flexibility but are currently underexploited in the biotechnological manufacturing of known plant-derived compounds, novel high-value biomolecules or enriched biomass. Highly efficient production of microalgal biomass without the need for light is now feasible in inexpensive, well-defined mineral medium, typically supplemented with glucose. Cell densities of more than 100 g l−1 cell dry weight have been achieved with Chlorella, Crypthecodinium and Galdieria species while controlling the addition of organic sources of carbon and energy in fedbatch mode. The ability of microalgae to adapt their metabolism to varying culture conditions provides opportunities to modify, control and thereby maximise the formation of targeted compounds with non-recombinant microalgae. This review outlines the critical aspects of cultivation technology and current best practices in the heterotrophic high-cell-density cultivation of microalgae. The primary topics include (1) the characteristics of microalgae that make them suitable for heterotrophic cultivation, (2) the appropriate chemical composition of mineral growth media, (3) the different strategies for fedbatch cultivations and (4) the principles behind the customisation of biomass composition. The review confirms that, although fundamental knowledge is now available, the development of efficient, economically feasible large-scale bioprocesses remains an obstacle to the commercialisation of this promising technology

Population genomics reveals that an anthropophilic population of Aedes aegypti\textit{Aedes aegypti} mosquitoes in West Africa recently gave rise to American and Asian populations of this major disease vector

$\textbf{BACKGROUND}$: The mosquito $\textit{Aedes aegypti}$ is the main vector of dengue, Zika, chikungunya and yellow fever viruses. This major disease vector is thought to have arisen when the African subspecies $\textit{Ae. aegypti}$ formosus evolved from being zoophilic and living in forest habitats into a form that specialises on humans and resides near human population centres. The resulting domestic subspecies, $\textit{Ae. aegypti aegypti}$, is found throughout the tropics and largely blood-feeds on humans. $\textbf{RESULTS}$: To understand this transition, we have sequenced the exomes of mosquitoes collected from five populations from around the world. We found that $\textit{Ae. aegypti}$ specimens from an urban population in Senegal in West Africa were more closely related to populations in Mexico and Sri Lanka than they were to a nearby forest population. We estimate that the populations in Senegal and Mexico split just a few hundred years ago, and we found no evidence of $\textit{Ae. aegypti aegypti}$ mosquitoes migrating back to Africa from elsewhere in the tropics. The out-of-Africa migration was accompanied by a dramatic reduction in effective population size, resulting in a loss of genetic diversity and rare genetic variants. $\textbf{CONCLUSIONS}$: We conclude that a domestic population of $\textit{Ae. aegypti}$ in Senegal and domestic populations on other continents are more closely related to each other than to other African populations. This suggests that an ancestral population of $\textit{Ae. aegypti }$evolved to become a human specialist in Africa, giving rise to the subspecies $\textit{Ae. aegypti aegypti}$. The descendants of this population are still found in West Africa today, and the rest of the world was colonised when mosquitoes from this population migrated out of Africa. This is the first report of an African population of Ae. aegypti aegypti mosquitoes that is closely related to Asian and American populations. As the two subspecies differ in their ability to vector disease, their existence side by side in West Africa may have important implications for disease transmission.This work was funded by European Research Council grant Drosophila Infection 281668 to FMJ, a KAUST AEA award to FMJ and AP, a Medical Research Council Centenary Award to WJP and a National Institutes of Health Ruth L. Kirschstein National Research Service Award to JC

qsubsec: A lightweight template system for defining Sun Grid Engine workflows

The Sun Grid Engine (SGE) high-performance computing batch queueing system is commonly used in bioinformatics analysis. Creating re-usable scripts for the SGE is a common challenge. The qsubsec template language and interpreter described here allow researchers to easily create generic template definitions that encapsulate a particular computational job, effectively separating the process logic from the specific run details. At submission time, the generic template is filled in with specific values. This system provides an intermediate level between simple scripting and complete workflow management tools

fqtools: An efficient software suite for modern FASTQ file manipulation

Summary: Many Next Generation Sequencing analyses involve the basic manipulation of input sequence data before downstream processing (for example searching for specific sequences, format conversion or basic file statistics). The rapidly increasing data volumes involved in NGS make any dataset manipulation a time-consuming and error-prone process. I have developed fqtools; a fast and reliable FASTQ file manipulation suite that can process the full set of valid FASTQ files, including those with multi-line sequences, whilst identifying invalid files. Fqtools is faster than similar tools, and is designed for use in automatic processing pipelines

Oncolytic virus treatment differentially affects the CD56 dim and CD56 bright NK cell subsets in vivo and regulates a spectrum of human NK cell activity

Natural killer (NK) cells protect against intracellular infection and cancer. These properties are exploited in oncolytic virus (OV) therapy, where antiviral responses enhance anti-tumour immunity. We have analysed the mechanism by which reovirus, an oncolytic dsRNA virus, modulates human NK cell activity. Reovirus activates NK cells in a type I interferon (IFN-I) dependent manner, inducing STAT1 and STAT4 signalling in both CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cell subsets. Gene expression profiling revealed the dominance of IFN-I responses and identified induction of genes associated with NK cell cytotoxicity and cell cycle progression, with distinct responses in the CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ subsets. However, reovirus treatment inhibited IL-15 induced NK cell proliferation in an IFN-I dependent manner and was associated with reduced AKT signalling. In vivo, human CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cells responded with similar kinetics to reovirus treatment, but CD56ᵇʳⁱᵍʰᵗ NK cells were transiently lost from the peripheral circulation at the peak of the IFN-I response, suggestive of their redistribution to secondary lymphoid tissue. Coupled with the direct, OV-mediated killing of tumour cells, the activation of both CD56ᵈⁱᵐ and CD56ᵇʳⁱᵍʰᵗ NK cells by antiviral pathways induces a spectrum of activity that includes the NK cell-mediated killing of tumour cells and modulation of adaptive responses via the trafficking of IFN-γ expressing CD56ᵇʳⁱᵍʰᵗ NK cells to lymph nodes