A tissue-specific, naturally occurring human SNF2L variant inactivates chromatin remodeling

Mammalian genomes encode two imitation switch family chromatin remodeling proteins, SNF2H and SNF2L. In the mouse, SNF2H is expressed ubiquitously, whereas SNF2L expression is limited to the brain and gonadal tissue. This pattern of SNF2L expression suggests a critical role for SNF2L in neuronal physiology. Indeed, SNF2L was shown to promote neurite outgrowth as well as regulate the human engrailed homeotic genes, important regulators of brain development. Here we identify a novel splice variant of human SNF2L we call SNF2L+13, which contains a nonconserved in-frame exon within the conserved catalytic core domain of SNF2L. SNF2L+13 retains the ability to incorporate into multiprotein complexes; however, it is devoid of enzymatic activity. Most interestingly, unlike mouse SNF2L, human SNF2L is expressed ubiquitously, and regulation is mediated by isoform variation. The human SNF2L+13 null variant is predominant in non-neuronal tissue, whereas the human wild type active SNF2L isoform is expressed in neurons. Thus, like the mouse, active human SNF2L is limited to neurons and a few other tissues.     

Prevalence of congenital hypothyroidism in Isfahan, Iran: results of a survey on 20,000 neonates

AIMS: To evaluate the prevalence of congenital hypothyroidism (CH) in a screening program performed for the first time in Isfahan, Iran. METHODS: From May 2002 to December 2002, T4 and TSH serum concentrations of 20,000 3- to 7-day-old newborns, born in all 17 hospitals of the city, were measured by radioimmunoassay and immunoradiometric assay, respectively. The newborns with abnormal screening results (TSH >20 mIU/l, T4 <6.5 microg/dl and based on the weight) were re-examined. RESULTS: Of 531 recalled subjects (recall rate 2.6%), 54 were confirmed to be hypothyroid, showing a prevalence of 1:370 for CH. CONCLUSION: Considering the high frequency of CH, the necessity of implementing a routine screening program in the healthcare system of Isfahan Province is emphasized.     

The role of JAGGED in shaping lateral organs

Position-dependent regulation of growth is important for shaping organs in multicellular organisms. We have characterized the role of JAGGED, a gene that encodes a protein with a single C(2)H(2) zinc-finger domain, in controlling the morphogenesis of lateral organs in Arabidopsis thaliana. Loss of JAGGED function causes organs to have serrated margins. In leaves, the blade region is most severely affected. In sepals, petals and stamens, the strongest defects are seen in the distal regions. By monitoring cell-cycle activity in developing petals with the expression of HISTONE 4, we show that JAGGED suppresses the premature differentiation of tissues, which is necessary for the formation of the distal region. The localization of defects overlaps with the expression domain of JAGGED, which is restricted to the growing regions of lateral organs. JAGGED expression is notably absent from the cryptic bract, the remnant of a leaf-like organ that subtends the flower in many species but does not normally develop in wild-type Arabidopsis. If misexpressed, JAGGED can induce the formation of bracts, suggesting that the exclusion of JAGGED from the cryptic bract is a cause of bractless flowers in Arabidopsis.     

High zinc sensitivity and pore formation in an invertebrate P2X receptor

To investigate fast purinergic signaling in invertebrates, we examined the functional properties of a P2X receptor subunit cloned from the parasitic platyhelminth Schistosoma mansoni. This purinoceptor (SmP2X) displays unambiguous homology of primary sequence with vertebrate P2X subunits. SmP2X subunits assemble into homomeric ATP-gated channels that exhibit slow activation kinetics and are blocked by suramin and PPADS but not TNP-ATP. SmP2X mediates the uptake of the dye YO-PRO-1 through the formation of large pores and can be blocked by submicromolar concentrations of extracellular Zn2+ ions (IC50 = 0.4 microM). The unique receptor phenotype defined by SmP2X suggests that slow kinetics, modulation by zinc and the ability to form large pores are ancestral properties of P2X receptors. The high sensitivity of SmP2X to zinc further reveals a zinc regulation requirement for the parasite's physiology that could potentially be exploited for therapeutic purposes.     

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 1

SAR studies for novel non-imidazole containing H(3) receptor antagonists with high potency and selectivity for rat H(3) receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.     

In vivo evaluation of [11C]TMI,a COX-2 selective PET tracer,in baboons

Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [¹¹C]TMI, a selective COX-2 inhibitor (Ki?≤?1?nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [¹¹C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [¹¹C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (V_T) estimates in the range of 3.2–7?(mL/cm³). We observed about 25% lower V_T values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [¹¹C]TMI binding. Our findings indicate that [¹¹C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases.     

Peroxo heteroligand vanadates(V): Synthesis,spectra-structure relationships,and stability toward decomposition

Effect of heteroligands (L) on the properties of vanadium peroxides was investigated by preparing a number of peroxovanadium complexes, which were characterized by analysis, IR, UV/V and NMR spectra. X-ray structures for some were obtained. The vanadates(V) contain the cation M(I)=Na, K, NH₄, Rb or Cs. Diperoxo complexes include M(I)[VO(O₂)₂L], where L=dipyridyl, o-phenanthroline; M(I)₃[VO(O₂)₂(C₂O₄)]; K₂[(nicotinic acid) {VO(O₂)₂}₂]H₂O;M(I)₄[O{VO(O₂)₂}₂ cystine]2H₂O; H₄[O{VO(O₂)₂(adenine)₂)₂]2H₂O; and K₂H₂[O{VO(O₂)₂(adenosine)}₂]2H₂O. Monoperoxo vanadates(V) correspond to the formula M(I)₂[VO(O₂)L]₂ for L=citrate and malate; M(I)₂[VO(O₂)L] for L=nitrilotriacetate; M(I)[VO(O₂)L] for L=iminodiacetate, tartrate and EDTA; and [HVO₂(O₂)(adenosine)]2H₂O. Syntheses of these heteroligand peroxovanadium compounds are sensitive to pH, temperature and the concentration of the components. The stability towards decomposition in solid state, mother-liquid and pure water solutions depends upon the heteroligand. Characteristic (V=O) and (O-O) stretching frequency bands in IR can be correlated with the corresponding bond lengths and the [peroxoV(V)] charge transfer bands in UV/V spectra. Intramolecular one-electron transfer in peroxo vanadates(V) can trigger the generation of radicals, and its dependency upon the nature of the heteroligand is discussed.