Molecular and physiological basis of Saccharomyces cerevisiae tolerance to adverse lignocellulose-based process conditions

Lignocellulose-based biorefineries have been gaining increasing attention to substitute current petroleum-based refineries. Biomass processing requires a pretreatment step to break lignocellulosic biomass recalcitrant structure, which results in the release of a broad range of microbial inhibitors, mainly weak acids, furans, and phenolic compounds. Saccharomyces cerevisiae is the most commonly used organism for ethanol production; however, it can be severely distressed by these lignocellulose-derived inhibitors, in addition to other challenging conditions, such as pentose sugar utilization and the high temperatures required for an efficient simultaneous saccharification and fermentation step. Therefore, a better understanding of the yeast response and adaptation towards the presence of these multiple stresses is of crucial importance to design strategies to improve yeast robustness and bioconversion capacity from lignocellulosic biomass. This review includes an overview of the main inhibitors derived from diverse raw material resultants from different biomass pretreatments, and describes the main mechanisms of yeast response to their presence, as well as to the presence of stresses imposed by xylose utilization and high-temperature conditions, with a special emphasis on the synergistic effect of multiple inhibitors/stressors. Furthermore, successful cases of tolerance improvement of S. cerevisiae are highlighted, in particular those associated with other process-related physiologically relevant conditions. Decoding the overall yeast response mechanisms will pave the way for the integrated development of sustainable yeast cell--based biorefineries.This study was supported by the Portuguese Foundation for Science and Technology (FCT) by the strategic funding of UID/BIO/04469/2013 unit, MIT Portugal Program (Ph.D. grant PD/BD/128247/ 2016 to Joana T. Cunha), Ph.D. grant SFRH/BD/130739/2017 to Carlos E. Costa, COMPETE 2020 (POCI-01-0145-FEDER-006684), BioTecNorte operation (NORTE-01-0145-FEDER-000004), YeasTempTation (ERA-IB-2-6/0001/2014), and MultiBiorefinery project (POCI-01-0145-FEDER-016403). Funding by the Institute for Bioengineering and Biosciences (IBB) from FCT (UID/BIO/04565/2013) and from Programa Operacional Regional de Lisboa 2020 (Project N. 007317) was also receiveinfo:eu-repo/semantics/publishedVersio

Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells

Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single-cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell-derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of datasets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors

Spatial Clustering of HIV Prevalence in Atlanta, Georgia and Population Characteristics Associated with Case Concentrations

We assessed prevalent HIV cases in Atlanta to examine case distribution trends and population characteristics at the census tract level that may be associated with clustering effects. We calculated cluster characteristics (area and internal HIV prevalence) via Kuldorff's spatial scan method. Subsequent logistic regression analyses were performed to analyze sociodemographics associated with inclusion in a cluster. Organizations offering voluntary HIV testing and counseling services were identified and we assessed average travel time to access these services. One large cluster centralized in downtown Atlanta was identified that contains 60% of prevalent HIV cases. The prevalence rate within the cluster was 1.34% compared to 0.32% outside the cluster. Clustered tracts were associated with higher levels of poverty (OR = 1.19), lower density of multi-racial residents (OR = 1.85), injection drug use (OR = 1.99), men having sex with men (OR = 3.01), and men having sex with men and IV drug use (OR = 1.6). Forty-two percent (N = 11) of identified HIV service providers in Atlanta are located in the cluster with an average travel time of 13 minutes via car to access these services (SD = 9.24). The HIV epidemic in Atlanta is concentrated in one large cluster characterized by poverty, men who have sex with men (MSM), and IV drug usage. Prevention efforts targeted to the population living in this area as well as efforts to address the specific needs of these populations may be most beneficial in curtailing the epidemic within the identified cluster