Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2)

Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus. We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED. Mutations in SLC4A11, which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay.     

Enabling Political Legitimacy and Conceptual Integration for Climate Change Adaptation Research within an Agricultural Bureaucracy: a Systemic Inquiry

The value of using systems approaches, for situations framed as ‘super wicked’, is examined from the perspective of research managers and stakeholders in a state-based climate change adaptation (CCA) program (CliChAP). Polycentric drivers influencing the development of CCA research pre-2010 in Victoria, Australia are reflected on, using Soft Systems Methodology (SSM) to generate a boundary critique of CCA research as a human activity system. We experienced the complexity of purpose with research practices pulling in different directions, reflected on the appropriateness of agricultural bureaucracies’ historical new public management (NPM) practices, and focused on realigning management theory with emerging demands for adaptation research skills and capability. Our analysis conceptualised CliChAP as a subsystem, generating novelty in a wider system, concerned with socio-ecological co-evolution. Constraining/enabling conditions at the time dealing with political legitimacy and conceptual integration were observed as potential catalysts for innovation in research management towards better handling of uncertainty as a social process using systemic thinking in practice (StiP).

     

Reframing Cognitive Behaviour Theory from a Systems Perspective

The author has worked with Cognitive Behaviour Theory for many years. His interest in systems theory prompted him to explore CBT from a systems perspective. This led to six observations that are then explored. This paper therefore begins by looking at the linearity of CBT and how feedback loops might be better incorporated. Next, the nature of perception is explored with ideas from Maturana and others. The third aspect investigates core beliefs and how they impact at all steps of the decision-making process. Fourthly, an examination of thoughts and emotional revealed other ways we make sense of the world and challenges the idea that thinking precedes emotion. The next aspect looks at CBT’s assumption of the individual as a separate being rather than a systems view which sees a person highly interconnected and finally that CBT focuses on making sense of the present moment rather than predictions we make of likely future outcomes. This is then all brought together in a diagram reframing CBT, highlighting the centrality of awareness to all cognitive processes and a number of leverage points where change might emerge.     

Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma

Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.     

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.     

Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.     

Is Newton a ‘radical empiricist’ about method?

Recently, some Newton scholars have argued that Newton is an empiricist about metaphysics—that ideally, he wants to let advances in physical theory resolve either some or all metaphysical issues. But while proponents of this interpretation are using ‘metaphysics’ in a very broad sense, to include the ‘principles that enable our knowledge of natural phenomena’, attention has thus far been focused on Newton’s approach to ontological, not epistemological or methodological, issues. In this essay, I therefore consider whether Newton wants to let physical theory bear on the very ‘principles that enable our knowledge’. By examining two kinds of argument in the Principia, I contend that Newton can be considered a methodological empiricist in a substantial respect. I also argue, however, that he cannot be a ‘radical empiricist’—that he does not and cannot convert all methodological issues into empirical issues.