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Aneuploidy is a cellular state with an unbalanced chromosome number that deviates from the usual euploid status. During evolution, elaborate cellular mechanisms have evolved to maintain the correct chromosome content over generations. The rare errors often lead to cell death, cell cycle arrest, or impaired proliferation. At the same time, aneuploidy can provide a growth advantage under selective conditions in a stressful, frequently changing environment. This is likely why aneuploidy is commonly found in cancer cells, where it correlates with malignancy, drug resistance, and poor prognosis. To understand this “aneuploidy paradox”, model systems have been established and analyzed to investigate the consequences of aneuploidy. Most of the evidence to date has been based on models with chromosomes gains, but chromosome losses and recurrent monosomies can also be found in cancer. We summarize the current models of chromosome loss and our understanding of its consequences, particularly in comparison to chromosome gains.

Summary Heterodimeric complexes incorporating the lipase‐like proteins EDS1 with PAD4 or SAG101 are central hubs in plant innate immunity. EDS1 functions encompass signal relay from TIR domain‐containing intracellular NLR‐type immune receptors (TNLs) towards RPW8‐type helper NLRs (RNLs) and, in Arabidopsis thaliana , bolstering of signaling and resistance mediated by cell‐surface pattern recognition receptors (PRRs). Increasing evidence points to the activation of EDS1 complexes by small molecule binding. We used CRISPR/Cas‐generated mutant lines and agroinfiltration‐based complementation assays to interrogate functions of EDS1 complexes in Nicotiana benthamiana . We did not detect impaired PRR signaling in N. benthamiana lines deficient in EDS1 complexes or RNLs. Intriguingly, in assays monitoring functions of Sl EDS1‐ Nb EDS1 complexes in N. benthamiana , mutations within the Sl EDS1 catalytic triad could abolish or enhance TNL immunity. Furthermore, nuclear EDS1 accumulation was sufficient for N. benthamiana TNL (Roq1) immunity. Reinforcing PRR signaling in Arabidopsis might be a derived function of the TNL/EDS1 immune sector. Although Solanaceae EDS1 functionally depends on catalytic triad residues in some contexts, our data do not support binding of a TNL‐derived small molecule in the triad environment. Whether and how nuclear EDS1 activity connects to membrane pore‐forming RNLs remains unknown.

Aneuploidy, a hallmark of cancer, leads to widespread changes in chromosome copy number, altering the abundance of hundreds or thousands of proteins. However, evidence suggests that levels of proteins encoded on affected chromosomes are often buffered toward their abundances observed in diploid cells. Despite its prevalence, the molecular mechanisms driving this protein dosage compensation remain largely unknown. It is unclear whether all proteins are buffered to a similar degree, what factors determine buffering, and whether dosage compensation varies across different cell lines or tumor types. Moreover, its potential adaptive advantage and therapeutic relevance remain unexplored. Here, we established a novel approach to quantify protein dosage buffering in a gene copy number-dependent manner, showing that dosage compensation is widespread but variable in cancer cell lines and tumor samples. By developing multifactorial machine learning models, we identify mean gene dependency, protein complex participation, haploinsufficiency, and mRNA decay as key predictors of buffering. We also show that dosage compensation can affect oncogenic potential and that higher buffering correlates with reduced proteotoxic stress and increased drug resistance. These findings highlight protein dosage compensation as a crucial regulatory mechanism and a potential therapeutic target in aneuploid cancers.

Aneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performed in vitro evolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors required for adaptation to aneuploidy in vitro and in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosome impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://gdc.cancer.gov/about-data/publications/PanCan-CellOfOrigin* https://proteomic.datacommons.cancer.gov/pdc/cptac-pancancer* https://www.gsea-msigdb.org/gsea/downloads_archive.jsp* https://maayanlab.cloud/Enrichr/#libraries

- Heterodimeric complexes incorporating the lipase-like proteins EDS1 with PAD4 or SAG101 are central hubs in plant innate immunity. EDS1 functions encompass signal relay from TIR domain-containing intracellular NLR-type immune receptors (TNLs) towards RPW8-type helper NLRs (RNLs) and, in A. thaliana, bolstering of signaling and resistance mediated by cell-surface pattern recognition receptors (PRRs). Biochemical activities underlying these mechanistic frameworks remain unknown. - We used CRISPR/Cas-generated mutant lines and agroinfiltration-based complementation assays to interrogate functions of EDS1 complexes in N. benthamiana. - We do not detect impaired PRR signaling in N. benthamiana lines deficient in EDS1 complexes or RNLs. Intriguingly, mutations within the catalytic triad of Solanaceae EDS1 can abolish or enhance TNL immunity in N. benthamiana. Furthermore, nuclear EDS1 accumulation is sufficient for N. benthamiana TNL (Roq1) immunity. - Reinforcing PRR signaling in Arabidopsis might be a derived function of the TNL/EDS1 immune sector. Dependency of Solanaceae but not A. thaliana EDS1 on catalytic triad residues raises the possibility that a TNL-derived small molecule binds to the Solanaceae EDS1 lipase-like domain, and that EDS1 lipase-like domain pocket contributions to TNL immune responses vary between lineages. Whether and how nuclear EDS1 activity connects to membrane pore-forming RNLs remains unknown. Competing Interest Statement The authors have declared no competing interest.

Summary Genome editing by RNA-guided nucleases, such as SpCas9, has been used in numerous different plant species. However, to what extent multiple independent loci can be targeted simultaneously by multiplexing has not been well-documented. Here, we developed a toolkit, based on a highly intron-optimized zCas9i gene, which allows assembly of nuclease constructs expressing up to 32 sgRNAs. We used this toolkit to explore the limits of multiplexing in two major model species, and report on isolation of transgene-free octuple Nicotiana benthamiana and duodecuple (12x) Arabidopsis thaliana mutant lines in a single generation (T1 and T2, respectively). We developed novel counter-selection markers for N. benthamiana, most importantly Sl-FAST2, comparable to the well-established Arabidopsis seed fluorescence marker, and FCY-UPP, based on production of toxic 5-fluorouracyl in presence of a precursor. Targeting eight genes with an array of nine different sgRNAs and relying on FCY-UPP for selection of non-transgenic T1, we identified N. benthamiana mutant lines with astonishingly high efficiencies: All analyzed plants carried mutations in all genes (~112/116 target sites edited). Furthermore, we targeted 12 genes by an array of 24 sgRNAs in A. thaliana. Efficiency was significantly lower in A. thaliana, and our results indicate Cas9 availability is the limiting factor in such higher order multiplexing applications. We identify a duodecuple mutant line by a combination of phenotypic screening and amplicon sequencing. The resources and results presented provide new perspectives for how multiplexing can be used to generate complex genotypes or to functionally interrogate groups of candidate genes. Competing Interest Statement The authors have declared no competing interest.

CUPERTINO, Calif. - Tandem Computers Inc., a provider of computer hardware to the banking industry, is repositioning its products as data warehousing tools. The so-called fault-tolerant computers that Tandem makes historically have been used for transaction processing. Because the hardware is designed to avoid down time at all costs, it is used heavily by automated teller machine networks and other financial organizations that handle large volumes of real-time transactions. REDWOOD SHORES, Calif. - Cybercash Inc. is offering a Macintosh- compatible version of Wallet, its secure on-line payment software, for free over the Internet.

Urban expansion often occurs on croplands. However, there is little scientific understanding of how global patterns of future urban expansion will affect the world’s cultivated areas. Here, we combine spatially explicit projections of urban expansion with datasets on global croplands and crop yields. Our results show that urban expansion will result in a 1.8–2.4% loss of global croplands by 2030, with substantial regional disparities. About 80% of global cropland loss from urban expansion will take place in Asia and Africa. In both Asia and Africa, much of the cropland that will be lost is more than twice as productive as national averages. Asia will experience the highest absolute loss in cropland, whereas African countries will experience the highest percentage loss of cropland. Globally, the croplands that are likely to be lost were responsible for 3–4% of worldwide crop production in 2000. Urban expansion is expected to take place on cropland that is 1.77 times more productive than the global average. The loss of cropland is likely to be accompanied by other sustainability risks and threatens livelihoods, with diverging characteristics for different megaurban regions. Governance of urban area expansion thus emerges as a key area for securing livelihoods in the agrarian economies of the Global South.

Just when bankers may be thinking it is safe to go on-line, First Virtual Holdings Inc. says it has evidence of a significant threat to the security of electronic payments over the Internet. Officials of San Diego-based First Virtual - which makes one of several competing systems for clearing Internet payments - went on a national press tour to demonstrate so-called \"sniffer\" software that can intercept credit card numbers as they are typed on a keyboard. Because the program is not a computer virus, it operates with great stealth and is unaffected by antivirus techniques, according to First Virtual engineers. They see it as evidence that their formula for electronic payments - relying on secure electronic mail connections away from the Internet - is superior to those that rely on data encryption.

The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ~100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.