Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation

Aberrant Expression of Pseudogene-Derived lncRNAs as an Alternative Mechanism of Cancer Gene Regulation in Lung Adenocarcinoma

Transcriptome sequencing has led to the widespread identification of long non-coding RNAs (lncRNAs). Subsequently, these genes have been shown to hold functional importance in human cellular biology, which can be exploited by tumors to drive the hallmarks of cancer. Due to the complex tertiary structure and unknown binding motifs of lncRNAs, there is a growing disparity between the number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical components of cancer pathways that could serve as novel therapeutic intervention points. Pseudogenes are non-coding DNA sequences that are defunct relatives of their protein-coding parent genes but retain high sequence similarity. Interestingly, certain lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans particularly because of this sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that aberrant expression of lncRNAs overlapping pseudogene loci provides an alternative mechanism of cancer gene deregulation. Using RNA-sequencing data from two cohorts of lung adenocarcinoma, each paired with patient-matched non-malignant lung samples, we discovered 104 deregulated pseudogene-derived lncRNAs. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) had lncRNA protein-coding parent gene expression that was significantly associated with survival. Here, we uncover evidence to suggest the lncRNA-pseudogene-protein-coding gene axis as a prominent mechanism of cancer gene regulation in lung adenocarcinoma, and highlights the clinical utility of exploring the non-coding regions of the cancer transcriptome

Justifying the Special Theory of Relativity with Unconceived Methods

Many realists argue that present scientific theories will not follow the fate of past scientific theories because the former are more successful than the latter. Critics object that realists need to show that present theories have reached the level of success that warrants their truth. I reply that the special theory of relativity has been repeatedly reinforced by unconceived scientific methods, so it will be reinforced by infinitely many unconceived scientific methods. This argument for the special theory of relativity overcomes the critics’ objection, and has advantages over the no-miracle argument and the selective induction for it

In Defense of the Epistemic Imperative

Sample (2015) argues that scientists ought not to believe that their theories are true because they cannot fulfill the epistemic obligation to take the diachronic perspective on their theories. I reply that Sample’s argument imposes an inordinately heavy epistemic obligation on scientists, and that it spells doom not only for scientific theories but also for observational beliefs and philosophical ideas that Samples endorses. I also delineate what I take to be a reasonable epistemic obligation for scientists. In sum, philosophers ought to impose on scientists only an epistemic standard that they are willing to impose on themselves

Human Cancer Long Non-Coding RNA Transcriptomes

Once thought to be a part of the ‘dark matter’ of the genome, long non-coding RNAs (lncRNAs) are emerging as an integral functional component of the mammalian transcriptome. LncRNAs are a novel class of mRNA-like transcripts which, despite no known protein-coding potential, demonstrate a wide range of structural and functional roles in cellular biology. However, the magnitude of the contribution of lncRNA expression to normal human tissues and cancers has not been investigated in a comprehensive manner. In this study, we compiled 272 human serial analysis of gene expression (SAGE) libraries to delineate lncRNA transcription patterns across a broad spectrum of normal human tissues and cancers. Using a novel lncRNA discovery pipeline we parsed over 24 million SAGE tags and report lncRNA expression profiles across a panel of 26 different normal human tissues and 19 human cancers. Our findings show extensive, tissue-specific lncRNA expression in normal tissues and highly aberrant lncRNA expression in human cancers. Here, we present a first generation atlas for lncRNA profiling in cancer

Pointing to visible and invisible targets

We investigated how the visibility of targets influenced the type of point used to provide directions. In Study 1 we asked 605 passersby in three localities for directions to well-known local landmarks. When that landmark was in plain view behind the requester, most respondents pointed with their index fingers, and few respondents pointed more than once. In contrast, when the landmark was not in view, respondents pointed initially with their index fingers, but often elaborated with a whole-hand point. In Study 2, we covertly filmed the responses from 157 passersby we approached for directions, capturing both verbal and gestural responses. As in Study 1, few respondents produced more than one gesture when the target was in plain view and initial points were most likely to be index finger points. Thus, in a Western geographical context in which pointing with the index finger is the dominant form of pointing, a slight change in circumstances elicited a preference for pointing with the whole hand when it was the second or third manual gesture in a sequence

Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described &lt;10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation

A compilation of observation[s] from moored current meters, thermographs, and wind instrument. Vol. 4. Peru continental shelf March-April 1969

A summary of moored instrument measurements over the continental shelf of Peru is presented. Measurements of variables were made in an upwelling zone between Pisco and San Juan, from 28 March to 9 April, 1969. Time series of temperature and horizontal current and wind velocities were obtained at several depths and locations by an array of moored, recording instruments. Supplementary hydrographic and drogue measurements were also made

Taking a Proposal Seriously : Orientations to Agenda and Agency in Support Workers’ Responses to Client Proposals

While joint decision-making is regularly launched by a proposal, it is the recipients’ responses that crucially influence the proposal outcome. This chapter examines how support workers respond to the proposals made by clients during rehabilitation group meetings at the Clubhouse. Drawing on a collection of 180 client-initiated proposal sequences, the paper describes two dilemmas that the support workers face when seeking to take client proposals “seriously.” The first concerns the meeting’s agenda and consists of a tension between providing recognition for the individual client and encouraging collective participation. The second dilemma has to do with agency and consists of a tension between focusing on the client as the originator of the proposal and avoiding treating him or her alone accountable for it. The analysis of these dilemmas contributes to a deeper understanding of group decision-making, in general, while these findings have specific relevance in mental health rehabilitation.While joint decision-making is regularly launched by a proposal, it is the recipients’ responses that crucially influence the proposal outcome. This chapter examines how support workers respond to the proposals made by clients during rehabilitation group meetings at the Clubhouse. Drawing on a collection of 180 client-initiated proposal sequences, the paper describes two dilemmas that the support workers face when seeking to take client proposals “seriously.” The first concerns the meeting’s agenda and consists of a tension between providing recognition for the individual client and encouraging collective participation. The second dilemma has to do with agency and consists of a tension between focusing on the client as the originator of the proposal and avoiding treating him or her alone accountable for it. The analysis of these dilemmas contributes to a deeper understanding of group decision-making, in general, while these findings have specific relevance in mental health rehabilitation.Peer reviewe

The plight of the sense-making ape

This is a selective review of the published literature on object-choice tasks, where participants use directional cues to find hidden objects. This literature comprises the efforts of researchers to make sense of the sense-making capacities of our nearest living relatives. This chapter is written to highlight some nonsensical conclusions that frequently emerge from this research. The data suggest that when apes are given approximately the same sense-making opportunities as we provide our children, then they will easily make sense of our social signals. The ubiquity of nonsensical contemporary scientific claims to the effect that humans are essentially--or inherently--more capable than other great apes in the understanding of simple directional cues is, itself, a testament to the power of preconceived ideas on human perception