Reconsidering the dynamics of reason: Response to Ferrari,Mormann, Nordmann,and Uebel

I address the points raised by the four commentators by indicating how I have been thinking about extending and expanding my perspective since Dynamics of Reason (2001). This involves reinterpreting the Kantian distinction between understanding and sensibility, and thereby rethinking the relativized a priori. I connect these ideas with experimental contexts and technology, as well as with the wider culture context. I suggest implications for the relationships among science, democracy, and religion—and eventually reconceptualizing Kant’s original Enlightenment project.     

Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm

The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems—PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine—to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G_S that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.     

Additive and synergistic inhibition of mammalian microsomal enzyme functions by piperonyl butoxide,safrole and other methylenedioxyphenyl derivatives

Zusammenfassung Piperonylbutoxyd, Methylendioxylanilin, Methyleugenol, Safranol und Vanillylamin bewirken eine additive Hemmung der Funktion mikrosomaler Enzyme in Mäusen, wenn sie zusammen in Dosen verabreicht werden, die einzeln inaktiv sind. Piperonylbutoxyd und Safranol induzieren synergistisch die Hemmung von Aminopyrenedemethylase-Aktivität. Es erfolgte keine synergistische Hemmung nach kombinierter Behandlung mit Pib. und hohen Dosen der strukturell verwandten, aber inaktiven Piperonylsäure.

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Supported by N.I.H. Grants No. C-6516 and No. Fr-05526.

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We thank Mrs.M. Sengupta and Mr.E. Greene for their technical assistance.     

A natural allele of Nxf1 suppresses retrovirus insertional mutations

Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) tremor mutation and the Eya1(BOR) model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between the mRNA export receptor and pre-mRNA processing. Population structure of the suppressive allele in wild Mus musculus castaneus suggests selective advantage. A congenic Mvb1(CAST) allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.     

Obesity in the new millennium

Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem. In addition to suffering poor health and an increased risk of illnesses such as hypertension and heart disease, obese people are often stigmatized socially. But major advances have now been made in identifying the components of the homeostatic system that regulates body weight, including several of the genes responsible for animal and human obesity. A key element of the physiological system is the hormone leptin, which acts on nerve cells in the brain (and elsewhere) to regulate food intake and body weight. The identification of additional molecules that comprise this homeostatic system will provide further insights into the molecular basis of obesity, and possibilities for new treatments.     

Positive after-image, PAI: early erasure by saccadic eye movement or Jendrassik manoeuvre

Positive after-images (PAIs) evoked by low intensity stroboscopic flash are erased by voluntary large amplitude saccadic eye movements. The duration of the PAI is shortened by a Jendrassik manoeuvre. The results suggest that muscle spindle afferent impulses conducted centrally are involved in the erasure phenomenon. The duration of the PAI is modifiable by drugs. The social implications of PAI are considered briefly.     

Scanning electron microscopy of antibody-dependent cell-mediated cytotoxicity of Friend leukemia virus-infected spleen cells

Summary Friend leukemia virus (FLV) infected splenocytes treated with rabbit anti-FLV serum and subsequently incubated with splenic lymphocytes from non-immune Balb/c mice were examined by scanning electron microscopy. Villous-covered lymphocytes adherred to the tumor cells and induced surface blebs, numerous membrane pores and eventual tumor cell lysis.