https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Microarrays can measure the expression of thousands of genes to identify changes in expression between different biological states. Methods are needed to determine the significance of these changes while accounting for the enormous number of genes. We describe a method, Significance Analysis of Microarrays (SAM), that assigns a score to each gene on the basis of change in gene expression relative to the standard deviation of repeated measurements. For genes with scores greater than an adjustable threshold, SAM uses permutations of the repeated measurements to estimate the percentage of genes identified by chance, the false discovery rate (FDR). When the transcriptional response of human cells to ionizing radiation was measured by microarrays, SAM identified 34 genes that changed at least 1.5-fold with an estimated FDR of 12%, compared with FDRs of 60 and 84% by using conventional methods of analysis. Of the 34 genes, 19 were involved in cell cycle regulation and 3 in apoptosis. Surprisingly, four nucleotide excision repair genes were induced, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation.

/pdf/significance-analysis-of-microarrays-applied-to-the-ionizing-10j4beasgw.pdf

Significance analysis of microarrays applied to the ionizing radiation response

The flowering plant Arabidopsis thaliana is an important model system for identifying genes and determining their functions. Here we report the analysis of the genomic sequence of Arabidopsis. The sequenced regions cover 115.4 megabases of the 125-megabase genome and extend into centromeric regions. The evolution of Arabidopsis involved a whole-genome duplication, followed by subsequent gene loss and extensive local gene duplications, giving rise to a dynamic genome enriched by lateral gene transfer from a cyanobacterial-like ancestor of the plastid. The genome contains 25,498 genes encoding proteins from 11,000 families, similar to the functional diversity of Drosophila and Caenorhabditis elegans--the other sequenced multicellular eukaryotes. Arabidopsis has many families of new proteins but also lacks several common protein families, indicating that the sets of common proteins have undergone differential expansion and contraction in the three multicellular eukaryotes. This is the first complete genome sequence of a plant and provides the foundations for more comprehensive comparison of conserved processes in all eukaryotes, identifying a wide range of plant-specific gene functions and establishing rapid systematic ways to identify genes for crop improvement.

/pdf/analysis-of-the-genome-sequence-of-the-flowering-plant-3vizsb52m2.pdf

Analysis of the genome sequence of the flowering plant Arabidopsis thaliana.

WAF1, a potential mediator of p53 tumor suppression

The study of fast and intricate enzyme reactions requires methods that have the speed and sophistication to match. Such an approach reveals the way in which proteins are tagged with ubiquitin for destruction.

Cell biology: Stairway to the proteasome.

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome–lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium “Targeting protein degradation: from small molecules to complex organelles.” The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.

/pdf/targeted-protein-degradation-from-small-molecules-to-complex-spc2mf20.pdf

Targeted protein degradation: from small molecules to complex organelles—a Keystone Symposia report

Low-complexity protein aggregates are a hallmark of neurodegeneration. High-resolution snapshots of the structure of one such aggregate offer an unprecedented view of how these proteins disrupt crucial cellular functions. Low-complexity protein aggregates are a hallmark of neurodegeneration. High-resolution snapshots of the structure of one such aggregate offer an unprecedented view of how these proteins disrupt crucial cellular functions.

Protein aggregates caught stalling

Defects in mitophagy, the selective recycling of mitochondria through autophagy, are linked to aging, sarcopenia, and neurodegenerative diseases. To therapeutically target mitophagy, the dynamics and molecular mechanisms in vivo must be understood. Here, we describe newly generated mitophagy biosensor zebrafish, reveal widespread basal mitophagy during normal development, and illuminate the dynamics and molecular mechanisms of mitophagy induced by physiological stresses—fasting and hypoxia. In fasted muscle, volumetric quantification of mitolysosome size uncovered organelle stress-response dynamics, and live, time-lapse imaging revealed mitophagy occurred via a piecemeal rather than wholesale process. Activating Hypoxiainducible factor through physiological hypoxia or chemical or genetic modulation also provoked mitophagy. Surprisingly, disruption of a single mitophagy receptor bnip3 mitigated the response. Disruption of bnip3la (nix) or fundc1, putative hypoxia-associated mitophagy receptors, or pink1 or prkn (Parkin) had no effect. This in vivo imaging study establishes fundamental dynamics of fasting-induced mitophagy and elucidates molecular mechanisms governing hypoxia-induced mitophagy.

/pdf/live-imaging-of-reporter-zebrafish-reveals-dynamics-and-3urkrx7a4m.pdf

Live imaging of reporter zebrafish reveals dynamics and molecular basis of physiological-stress induced mitophagy

Proper development of multicellular organisms from a single cell requires precise control of cellular proliferation, differentiation, and apoptosis. This multistep control involves a complex interplay between numerous genes regulating spatial and temporal aspects of development and proliferation. Defects in these control mechanisms can lead to developmental defects or tumor formation. Research performed over the past decade has brought us closer to an understanding of how a family of critical growth regulators, typified by the retinoblastoma (RB) tumor suppressor gene (Rb), function to control cell proliferation and differentiation.

J. Wade Harper

Papers

Cell biology: Stairway to the proteasome.

Targeted protein degradation: from small molecules to complex organelles—a Keystone Symposia report

Protein aggregates caught stalling

Live imaging of reporter zebrafish reveals dynamics and molecular basis of physiological-stress induced mitophagy

Retinoblastoma Protein in Growth Control and Differentiation