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<jats:title>Hierarchy and Representation</jats:title> <jats:p> Neuronal representations of objects are elaborated through the hierarchy of occipitotemporal cortical areas, and the recognition of a feature as “novel” is commonly thought to emerge and become prevalent at a cortical area because of local signal processing. <jats:bold> Hirabayashi <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6142" page="191" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1236927">191</jats:related-article> ) tested another possibility—that a feature representation becomes prevalent in a given area because a microcircuit creates a small number of precursor representations in a prior area in the cortical hierarchy, and the representations then become prevalent through proliferation in the subsequent area. In support of this notion, critical microcircuits for object association were observed using multiple single-unit recordings in two areas of the macaque temporal cortex. </jats:p>

<jats:p>Many scientific tasks—including studying the composition of blood and sequencing DNA—depend on being able to separate the parts from the whole. Only then can a scientist begin to understand how the pieces build up a process. To separate a sample into its components, scientists have been continually improving traditional approaches as well as developing new ones. In some cases, the improvements speed up separations; in others, advanced techniques provide new forms of separation that improve the efficiency of the processes. Though technologies are growing increasingly sophisticated, they are also becoming easier to use.</jats:p>

<jats:p>The core techniques used in toxicology studies have remained largely unchanged for over 40 years. It is acknowledged in the pharmaceutical industry that more predictive, earlier tests need to be established in order to prevent unsafe drugs progressing into the clinic and to stop potentially effective therapeutics being excluded from development. This recognition is driving the development of more relevant, specific, and reliable toxicology models and tests to improve drug safety and reduce the cost of development. In particular, the use of stem-cell–derived models can provide an opportunity to develop a transformative, integrated drug toxicity surveillance system.</jats:p>

<jats:p>Listen to stories on how autonomic nerves contribute to early prostate cancer development, the hazards of human-made earthquakes, and shiny beetles.</jats:p>

<jats:p>A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.</jats:p>

<jats:sec> <jats:title>Introduction</jats:title> <jats:p>Ribosome biogenesis is commonly up-regulated to satisfy the increased anabolic demands associated with malignant transformation and tumor growth. Many different oncogenic signaling pathways converge on the ribosome to increase translational flux. Despite the detailed understanding of ribosome regulation in cancer, it is not clear whether the net translational activity of the ribosome can itself regulate transcriptional programs that support and promote the malignant state.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>To investigate the transcriptional effects of modulating translational activity in malignant cells, we used integrated chemical and genetic approaches, including a gene signature–based genetic and chemical screen of more than 600,000 gene expression profiles (LINCS database) and an independent, reporter-based chemical screen of more than 300,000 compounds. A lead compound was tested in several cell-lines unified by their increased dependence on HSF1 activation for growth and survival, and in an in vivo cancer model.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> Inhibiting translation led to large changes in the transcriptome. The single most enriched category consisted of genes regulated by the heat-shock transcription factor, HSF1. The most down-regulated mRNA was <jats:italic>HSPA8</jats:italic> , which encodes the constitutive HSP70 chaperone that helps to fold nascent polypeptides. The expression of many other genes that HSF1 coordinates to support cancer were also strongly affected. HSF1 protein levels were unchanged, but HSF1 DNA occupancy was nearly eliminated. Inhibition of the HSF1-regulated gene expression program is thus a dominant transcriptional effect elicited by inhibiting protein translation. </jats:p> <jats:p>Using a gene signature of HSF1 inactivation to query the LINCS database revealed a strong connection between HSF1 inactivation and perturbations that inhibit protein translation, including a broad spectrum of chemical and genetic interventions that target the ribosome, eukaryotic initiation factors (eIFs), aminoacyl tRNA synthetases, and upstream signaling/regulatory pathways that control translation.</jats:p> <jats:p>Our high-throughput small-molecule screen identified rocaglamide A, an inhibitor of translation initiation, was the strongest inhibitor of HSF1 activation. An analog of this compound, RHT, increased thioredoxin-interacting protein (TXNIP) mRNA and protein levels and decreased glucose uptake and lactate production. Cell-based cancer models characterized by high dependence on HSF1 activation for growth and survival were highly sensitive to RHT, as were cells derived from diverse hematopoietic malignancies. RHT had a strong antitumor effect—with marked inhibition of HSF1 activity and glucose uptake—against xenografted acute myeloid leukemia cells.</jats:p> </jats:sec> <jats:sec> <jats:title>Discussion</jats:title> <jats:p>The ribosome functions as a central information hub in malignant cells: Translational flux conveys information about the cell’s metabolic status to regulate the transcriptional programs that support it. Multiple unbiased chemical and genetic approaches establish HSF1 as a prime transducer of this information, centrally poised to regulate the transcription of genes that support protein folding, biomass expansion, anabolic metabolism, cellular proliferation, and survival. Targeting translation initiation may offer a strategy for reversing HSF1 activation, disabling metabolic and cytoprotective pathways in malignant cells.</jats:p> <jats:boxed-text content-type="abstract-figure" orientation="portrait" position="float"> <jats:caption> <jats:p content-type="abstract-graphic"> <jats:inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="341_1238303_Fa.jpeg" /> </jats:p> <jats:p content-type="abstract-caption"> <jats:bold>HSF1 at the crossroads of protein translation and metabolism.</jats:bold> ( <jats:bold>Left</jats:bold> ) Cancers activate an HSF1-regulated transcriptional program to adapt to the anabolic demands of relentless biomass expansion. Glucose uptake increases, and expression of TXNIP, an inhibitor of glucose uptake, drops. ( <jats:bold>Right</jats:bold> ) Down-regulating translation with rocaglate scaffold initiation inhibitors reverses cancer-associated HSF1 activation. Glucose uptake drops as TXNIP levels rise. </jats:p> </jats:caption> </jats:boxed-text> </jats:sec>

<jats:sec> <jats:title>Background</jats:title> <jats:p>Acceptorless dehydrogenation (AD) reactions can result not only in simple removal of hydrogen gas from various substrates but also, importantly, in surprisingly efficient and environmentally benign (“green”) synthetic methodologies when intermediates resulting from the initial dehydrogenation process undergo further reactions.</jats:p> </jats:sec> <jats:sec> <jats:title>Advances</jats:title> <jats:p>Traditionally, dehydrogenation/oxidation reactions of organic compounds have been performed using stoichiometric amounts of inorganic oxidants, in addition to employing various additives, cocatalysts, and catalytic systems that result in generation of copious stoichiometric, often toxic, waste. Catalytic transfer hydrogenation methods, in which stoichiometric amounts of sacrificial organic acceptor compounds are used, also generate stoichiometric amounts of organic waste. Recent developments in catalysis by metal complexes have resulted in acceptorless dehydrogenation reactions that release hydrogen gas and in related reactions in which dehydrogenation is followed by in situ consumption of the generated hydrogen equivalents and no net hydrogen gas is liberated. These reactions circumvent the need for conventional oxidants or sacrificial acceptors and provide an assortment of applications in organic synthesis, including several methods based on further reactivity of the dehydrogenated intermediate compounds. Moreover, the evolved hydrogen gas is valuable in itself.</jats:p> </jats:sec> <jats:sec> <jats:title>Outlook</jats:title> <jats:p>Further development of new ADs for green, efficient chemical synthesis is expected to be greatly influenced by fundamental organometallic chemistry as a basis for catalyst design. Such processes are highly desirable and are expected to gradually displace elaborate conventional laboratory and industrial synthetic methods. They may also provide opportunities for hydrogen storage cycles, because the dehydrogenation reactions can be reversed under hydrogen pressure using the same catalyst. In general, AD and related dehydrogenative coupling reactions have the potential for redirecting synthetic strategies to the use of sustainable resources, devoid of toxic reagents and deleterious side reactions, with no waste generation.</jats:p> </jats:sec>