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Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.

The reliability and validity of traditional taxonomies are limited by arbitrary boundaries between psychopathology and normality, often unclear boundaries between disorders, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. These taxonomies went beyond evidence available on the structure of psychopathology and were shaped by a variety of other considerations, which may explain the aforementioned shortcomings. The Hierarchical Taxonomy Of Psychopathology (HiTOP) model has emerged as a research effort to address these problems. It constructs psychopathological syndromes and their components/subtypes based on the observed covariation of symptoms, grouping related symptoms together and thus reducing heterogeneity. It also combines co-occurring syndromes into spectra, thereby mapping out comorbidity. Moreover, it characterizes these phenomena dimensionally, which addresses boundary problems and diagnostic instability. Here, we review the development of the HiTOP and the relevant evidence. The new classification already covers most forms of psychopathology. Dimensional measures have been developed to assess many of the identified components, syndromes, and spectra. Several domains of this model are ready for clinical and research applications. The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies. It also provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response. This can greatly improve the utility of the diagnosis of mental disorders. The new classification remains a work in progress. However, it is developing rapidly and is poised to advance mental health research and care significantly as the relevant science matures.

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because a review of the recent literature indicates that they are still not universally honored.We focus on verbally mediated measures; thus, for example, we do not address the development of behavioral observation scales. Moreover, our primary focus is on self-report measures, because these constitute the majority (67%) of our reference sample. Nonetheless, most of the basic principles we articulate are applicable to interview-based measures and rating scales designed to be completed by clinicians, parents, teachers, spouses, peers, and so forth.Before proceeding further, it is interesting to examine the new measures comprising our Psychological Assessment sample. This examination sample offers a glimpse at why scale development continues unabated, as well as the nature of the unmet needs these scale developers are seeking to fill. First, not surprisingly given this journal's focus, more than half (61%) of the scales assess some aspect of psychopathology, personality, or adjustment. The next most common categories are measures of attitudes and interpersonal relations (20% and 15%, respectively). The remaining scales assess a miscellany of behaviors, abilities, response validity, trauma experience, and so forth. In all categories, most new scales apparently tap relatively narrow constructs, such as suicidality, fear of intimacy, We wish to acknowledge the helpful comments of Jane Loevinger on a previous version of this article.

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH-or FHdeficient cells, HIF activation is due to HIF1␣ stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIF␣ prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, ␣-ketoglutarate. We designed and synthesized cell-permeating ␣-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate-or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular ␣-ketoglutarate. Introduction of ␣-ketoglutarate derivatives restores normal PHD activity and HIF1␣ levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.Under normal oxygenation conditions (normoxia), hypoxiainducible factor alpha (HIF␣) proteins (HIF1␣ and/or HIF2␣), which are the formation-limiting units of the HIF transcription factor heteromer, are constantly both synthesized and degraded, a process that maintains them in high availability but at a very low steady state (4, 25). The high turnover of HIF␣ is mediated by HIF␣ prolyl hydroxylases (PHD1 to -3, also known as EglN1 to -3 and HPH1 to -3). PHDs hydroxylate proline residues on the oxygen-dependent degradation (ODD) domain of HIF␣, generating docking sites for pVHL-part of an E3 ubiquitin ligase complex that targets HIF␣ for degradation (21,22). To catalyze proline hydroxylation, PHDs convert molecular oxygen and ␣-ketoglutarate to carbon dioxide and succinate (22). Although PHDs depend on oxygen for activity, their affinity for oxygen is low (K m ϭ 230 to 250 M), making them good oxygen sensors (11). Under hypoxia, prolyl hydroxylation of HIF␣ and its consequent interaction with pVHL are prevented, and HIF␣ proteins are stabilized (21). Stabilized HIF␣ units bind to the HIF␤ unit, setting off HIF transcription activity. Thus, HIF is physiologically activated by hypoxia, and its downstream targets respond accordingly by increasing angiogenesis and glycolysis.The aberrant stabilization of HIF␣ under normoxic conditions is termed pseudohypoxia. Pseudohypoxia is probably a major cause of tumors associated with VHL mutations (15). Pseudohypoxia was also shown recently in tumor cells with mutations in fumarate hydratase (FH) or in any of three of the four subunits of succinate dehydrogenase (SDH), SDHB, SDHC, or SDHD (5,8,9,19,20,28). Both FH and SDH are mitochondrial proteins; SDH forms complex II of the electron transport chain, and both SDH and FH are enzymes of the tricarboxylic acid (TCA) cycle. In addition, SDH and FH are also bona fide tumor suppressors. Dysfunction of either of these TCA cycle enzymes causes pseudohypoxia, leading to the enhanced neovasculari...

Metabolomics is an emerging field of postgenomic biology concerned with comprehensive analysis of small molecules in biological systems. However, difficulties associated with the identification of detected metabolites currently limit its application. Here we demonstrate that a retention time prediction model can improve metabolite identification on a hydrophilic interaction chromatography (HILIC)-high-resolution mass spectrometry metabolomics platform. A quantitative structure retention relationship (QSRR) model, incorporating six physicochemical variables in a multiple-linear regression based on 120 authentic standard metabolites, shows good predictive ability for retention times of a range of metabolites (cross-validated R(2) = 0.82 and mean squared error = 0.14). The predicted retention times improved metabolite identification by removing 40% of the false identifications that occurred with identification by accurate mass alone. The importance of this procedure was demonstrated by putative identification of 690 metabolites in extracts of the protozoan parasite Trypanosoma brucei, thus allowing identified metabolites to be mapped onto an organism-wide metabolic network, providing opportunities for future studies of cellular metabolism from a global systems biology perspective.