Is Rett syndrome a subtype of pervasive developmental disorders?

The author reviews the issue on whether Rett syndrome (RS) is a subtype of pervasive developmental disorders (PDDs). More than 200 articles of RS have been published in the last 10 years. Internal and external validities of RS have been established by several independent studies. There remains the question whether RS presents clinical features that meet the total criteria for PDDs. The available data seem to support the idea of classifying RS as a subtype of PDDs in the DSM-IV.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44607/1/10803_2005_Article_BF01046327.pd

Book reviews

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44602/1/10803_2005_Article_BF02216065.pd

Brief report: Haloperidol treatment of trichotillomania in a boy with autism and mental retardation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44605/1/10803_2005_Article_BF02207333.pd

Brief report: Violence in asperger syndrome, a critique

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44604/1/10803_2005_Article_BF02207331.pd

Selective Inhibition of Cysteine-Dependent Enzymes by Bioorthogonal Tethering

A general approach for the rapid and selective inhibition of enzymes in cells using a common tool compound would be of great value for research and therapeutic development. We previously reported a chemogenetic strategy that addresses this challenge for kinases, relying on bioorthogonal tethering of a pan inhibitor to a target kinase through a genetically encoded non-canonical amino acid. However, pan inhibitors are not available for many enzyme classes. Here, we expand the scope of the chemogenetic strategy to cysteine-dependent enzymes by bioorthogonal tethering of electrophilic warheads. For proof of concept, selective inhibition of two E2 ubiquitin-conjugating enzymes, UBE2L3 and UBE2D1, was demonstrated in biochemical assays. Further development and optimization of this approach should enable its use in cells as well as other cysteine-dependent enzymes, facilitating the investigation of their cellular function and validation as therapeutic targets

Brief report: A comparison of the diagnostic criteria for Asperger syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44608/1/10803_2005_Article_BF01046332.pd

Nuclear microenvironments modulate transcription from low-affinity enhancers

Transcription factors bind low-affinity DNA sequences for only short durations. It is not clear how brief, low-affinity interactions can drive efficient transcription. Here, we report that the transcription factor Ultrabithorax (Ubx) utilizes low-affinity binding sites in the Drosophila melanogaster shavenbaby (svb) locus and related enhancers in nuclear microenvironments of high Ubx concentrations. Related enhancers colocalize to the same microenvironments independently of their chromosomal location, suggesting that microenvironments are highly differentiated transcription domains. Manipulating the affinity of svb enhancers revealed an inverse relationship between enhancer affinity and Ubx concentration required for transcriptional activation. The Ubx cofactor, Homothorax (Hth), was co-enriched with Ubx near enhancers that require Hth, even though Ubx and Hth did not co-localize throughout the nucleus. Thus, microenvironments of high local transcription factor and cofactor concentrations could help low-affinity sites overcome their kinetic inefficiency. Mechanisms that generate these microenvironments could be a general feature of eukaryotic transcriptional regulation

Daytime HONO vertical gradients during SHARP 2009 in Houston, TX

Nitrous Acid (HONO) plays an important role in tropospheric chemistry as a precursor of the hydroxyl radical (OH), the most important oxidizing agent in the atmosphere. Nevertheless, the formation mechanisms of HONO are still not completely understood. Recent field observations found unexpectedly high daytime HONO concentrations in both urban and rural areas, which point to unrecognized, most likely photolytically enhanced HONO sources. Several gas-phase, aerosol, and ground surface chemistry mechanisms have been proposed to explain elevated daytime HONO, but atmospheric evidence to favor one over the others is still weak. New information on whether HONO formation occurs in the gas-phase, on aerosol, or at the ground may be derived from observations of the vertical distribution of HONO and its precursor nitrogen dioxide, NO<sub>2</sub>, as well as from its dependence on solar irradiance or actinic flux. <br><br> Here we present field observations of HONO, NO<sub>2</sub> and other trace gases in three altitude intervals (30–70 m, 70–130 m and 130–300 m) using UCLA's long path DOAS instrument, as well as in situ measurements of OH, NO, photolysis frequencies and solar irradiance, made in Houston, TX, during the Study of Houston Atmospheric Radical Precursor (SHARP) experiment from 20 April to 30 May 2009. The observed HONO mixing ratios were often ten times larger than the expected photostationary state with OH and NO. Larger HONO mixing ratios observed near the ground than aloft imply, but do not clearly prove, that the daytime source of HONO was located at or near the ground. Using a pseudo steady-state (PSS) approach, we calculated the missing daytime HONO formation rates, P<sub>unknown</sub>, on four sunny days. The NO<sub>2</sub>-normalized P<sub>unknown</sub>, P<sub>norm</sub>, showed a clear symmetrical diurnal variation with a maximum around noontime, which was well correlated with actinic flux (NO<sub>2</sub> photolysis frequency) and solar irradiance. This behavior, which was found on all clear days in Houston, is a strong indication of a photolytic HONO source. [HONO]/[NO<sub>2</sub>] ratios also showed a clear diurnal profile, with maxima of 2–3% around noon. PSS calculations show that this behavior cannot be explained by the proposed gas-phase reaction of photoexcited NO<sub>2</sub> (NO<sub>2</sub><sup>*</sup>) or any other gas-phase or aerosol photolytic process occurring at similar or longer wavelengths than that of HONO photolysis. HONO formation by aerosol nitrate photolysis in the UV also seems to be unlikely. <br><br> P<sub>norm</sub> correlated better with solar irradiance (average <i>R</i><sup>2</sup> = 0.85/0.87 for visible/UV) than with actinic flux (<i>R</i><sup>2</sup> = 0.76) on the four sunny days, clearly pointing to HONO being formed at the ground rather than on the aerosol or in the gas-phase. In addition, the observed [HONO]/[NO<sub>2</sub>] diurnal variation can be explained if the formation of HONO depends on solar irradiance, but not if it depends on the actinic flux. The vertical mixing ratio profiles, together with the stronger correlation with solar irradiance, support the idea that photolytically enhanced NO<sub>2</sub> to HONO conversion on the ground was the dominant source of HONO in Houston

Asperger syndrome and clumsiness

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44610/1/10803_2005_Article_BF01046112.pd

Par-4 Links Dopamine Signaling and Depression

SummaryProstate apoptosis response 4 (Par-4) is a leucine zipper containing protein that plays a role in apoptosis. Although Par-4 is expressed in neurons, its physiological role in the nervous system is unknown. Here we identify Par-4 as a regulatory component in dopamine signaling. Par-4 directly interacts with the dopamine D2 receptor (D2DR) via the calmodulin binding motif in the third cytoplasmic loop. Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy. To examine the importance of the Par-4/D2DR interaction in dopamine signaling in vivo, we used a mutant mouse lacking the D2DR interaction domain of Par-4, Par-4ΔLZ. Primary neurons from Par-4ΔLZ embryos exhibit an enhanced dopamine-cAMP-CREB signaling pathway, indicating an impairment in dopamine signaling in these cells. Remarkably, Par-4ΔLZ mice display significantly increased depression-like behaviors. Collectively, these results provide evidence that Par-4 constitutes a molecular link between impaired dopamine signaling and depression