Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion

Data-analysis strategies for image-based cell profiling

Image-based cell profiling is a high-throughput strategy for the quantification of phenotypic differences among a variety of cell populations. It paves the way to studying biological systems on a large scale by using chemical and genetic perturbations. The general workflow for this technology involves image acquisition with high-throughput microscopy systems and subsequent image processing and analysis. Here, we introduce the steps required to create high-quality image-based (i.e., morphological) profiles from a collection of microscopy images. We recommend techniques that have proven useful in each stage of the data analysis process, on the basis of the experience of 20 laboratories worldwide that are refining their image-based cell-profiling methodologies in pursuit of biological discovery. The recommended techniques cover alternatives that may suit various biological goals, experimental designs, and laboratories' preferences.Peer reviewe

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery.Chemistry and Chemical Biolog

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multi-fusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have “drug-like” properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (e.g., commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC50 = 20.1–68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.</p

Biogas Plants in Renewable Energy Systems—A Systematic Review of Modeling Approaches of Biogas Production

Biogas production is a relevant component in renewable energy systems. The paper addresses modeling approaches from an energy system, as well as from a process optimization, point of view. Model approaches of biogas production show different levels of detail. They can be classified as white, gray, and black box, or bottom-up and top-down approaches. On the one hand, biogas modeling can supply dynamic information on the anaerobic digestion process, e.g., to predict biogas yields or to optimize the anaerobic digestion process. These models are characterized by a bottom-up approach with different levels of detail: the comprehensive ADM1 (white box), simplifications and abstractions of AD models (gray box), or highly simplified process descriptions (black box). On the other hand, biogas production is included in energy system models. These models usually supply aggregated information on regional biogas potentials and greenhouse gas emissions. They are characterized by a top-down approach with a low level of detail. Most energy system models reported in literature are based on black box approaches. Considering the strengths and weaknesses of the integration of detailed and deeply investigated process models in energy system models reveals the opportunity to develop dynamic and fluctuating business models of biogas usage

Biogas Plants in Renewable Energy Systems—A Systematic Review of Modeling Approaches of Biogas Production

Biogas production is a relevant component in renewable energy systems. The paper addresses modeling approaches from an energy system, as well as from a process optimization, point of view. Model approaches of biogas production show different levels of detail. They can be classified as white, gray, and black box, or bottom-up and top-down approaches. On the one hand, biogas modeling can supply dynamic information on the anaerobic digestion process, e.g., to predict biogas yields or to optimize the anaerobic digestion process. These models are characterized by a bottom-up approach with different levels of detail: the comprehensive ADM1 (white box), simplifications and abstractions of AD models (gray box), or highly simplified process descriptions (black box). On the other hand, biogas production is included in energy system models. These models usually supply aggregated information on regional biogas potentials and greenhouse gas emissions. They are characterized by a top-down approach with a low level of detail. Most energy system models reported in literature are based on black box approaches. Considering the strengths and weaknesses of the integration of detailed and deeply investigated process models in energy system models reveals the opportunity to develop dynamic and fluctuating business models of biogas usage

Drivers and barriers for the development of cooperative business models in the biogas sector for the transformation of the energy system

The energy transition involves various challenges. One key aspect is the decentralization of power generation, which requires new actors. In order to integrate these into the system in the best possible way, there are various approaches e.g. in cooperation in citizens' initiatives or cooperatives (Dorniok, 2016). Cooperation in general can enable the implementation of certain business models or can increase profitability by the exploitation of economies of scale (Skovsgaard & Jacobsen, 2017; Theurl, 2010). Synergy effects result from the utilization of know-how, different technologies or resources of the partners involved to complement the own competencies and services (Eggers & Engelbrecht, 2005; Sander, 2009). Cooperation exists in various industries and enable the participating companies to compensate their size-related resource deficits (Glaister & Buckley, 1996; Todeva & Knoke, 2005). This creates the opportunity to develop innovations, open up new markets, exploit newly created economies of scale and share costs and risks (Franco & Haase, 2015). In agriculture, cooperation in the form of cooperatives have been of essential importance for a long time, especially with the aim of exploiting synergy effects (Bareille et al., 2017). In the field of renewable energy development, cooperation in form of citizen cooperatives make a significant contribution to the participation of citizens in political, social and financial aspects of the energy transition (Huybrechts & Mertens, 2014). Energy cooperatives are frequently discussed as a potential actor in the energy transition and are increasingly being established to advance the common interests of stakeholders. For example, the joint operation of decentralized power generation plants can involve new actors in the energy transition through regional cooperation (Walk, 2014). Existing biogas plants in Germany need new business models after the 20-year Renewable Energy Sources Act feed-in tariff expires. For continued operation, a business model innovation is needed, which can be realized based on the different technical utilization pathways. Cooperation can have a significant impact on the profitability of the different business models, especially by exploiting synergy effects (Karlsson et al., 2019). In addition, cooperation can help to ensure that existing plants continue to operate at all. Currently, the most widespread use of biogas in Germany is in the coupled generation of electricity and heat. Additionally, there is the possibility of upgrading biogas to biomethane or biogenic hydrogen path (Mertins & Wawer, 2022). Different options for cooperative business models that exist in the biogas utilization pathways are presented. The focus is on explaining the advantages of a joint approach compared to single-farm business models and identifying the relevant actors. Subsequently, drivers and barriers for the different cooperative business models are identified and classified based on 20 semi-structured interviews with plant operators in the administrative district of Osnabrück. The aim is to identify drivers and barriers for cooperative post-EEG operation. As a result, political instruments are to be found that make it possible to involve relevant actors and thus stimulate the best possible continued operation from the point of view of the energy system. The results are structured according to the PESTEL analysis. This assigns drivers and barriers to the categories political, economic, sociocultural, technological, ecological and legal (Kaufmann, 2021). The analysis of the interviews is supplemented and validated by a literature review. Drivers and barriers for cooperative business models are manifold and can vary mainly depending on the plant and the operator. Drivers • Political o Promotion of renewable energies: reduce dependence on fossil (Russian) fuels • Economic o Expectation of synergies (information sharing, shared risk, economies of scale) o Planning security (fixed supply or purchase contracts) o Access to new markets (not accessible by single-farm business models) o Cost savings by sharing infrastructure, technology o Positive return expectation • Sociocultural o Motivating, innovative environment o Lowers barriers to participation in new markets o Target-oriented partnerships o Better use of capacities and strengths o Strengthening regional value creation • Technological o Economies of scale (efficiency) o Available, mature technology o Storable, transportable gas o Well-developed infrastructure • Ecological o Increase in plant efficiency o Reduction of greenhouse gas emissions o Promotion of the circular economy by utilization of organic waste and agricultural residues o Improving soil quality (fermentation residues as fertilizer) Barriers • Political o Competition to other renewable energies • Economic o Uncertainty about future development of energy markets o Disagreements between the cooperation partners o Lack of flexibility due to longer-term contractual obligations o Allocation of profits • Sociocultural o Cooperation with current competitor o Cultural differences and lack of trust o Acceptance by the general public (e.g. overproduction of maize) • Technological o Different technology that is difficult to combine o Data protection • Ecological o Competition for agricultural land o Use of monocultures o Emissions from plant o Pollution from transport • Legal o Legal requirements and regulations o Unfavorable regulatory environment, e.g. long permitting process One finding is that uncertainty is a major barrier for plant operators. This includes uncertainty about regulatory frameworks and political requirements, as well as about the general development of the energy markets. In addition, social factors such as lack of reliability and disagreement about revenue sharing are a potential barrier. A key driver for the implementation of cooperative business models is the expectation of synergy effects. In addition, operators are driven by a positive expectation of returns and the responsibility for securing the energy supply in times of crisis. The drivers identified can now be used to develop strategies to advance cooperative business models. In particular, synergy effects should be exploited so that operators can benefit from cooperation. The advantages can also be highlighted and communicated to increase acceptance among the general public. Another important step is to reduce the barriers discussed above. In order to reduce social barriers in particular, it may be advisable to include an external partner in the cooperation, such as a municipal utility that operates an upgrading plant and concludes purchase agreements with the individual partners. In addition, it would be politically expedient to provide the operators with a clear framework for the future in order to reduce uncertainties. As a further aspect, knowledge transfer on new technologies and markets should take place