Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain

The nuclear protein cyclophilin 33 (Cyp33) is a peptidyl-prolyl cis-trans isomerase that catalyzes cis-trans isomerization of the peptide bond preceding a proline and promotes folding and conformational changes in folded and unfolded proteins. The N-terminal RNA-recognition motif (RRM) domain of Cyp33 has been found to associate with the third plant homeodomain (PHD3) finger of the mixed lineage leukemia (MLL) proto-oncoprotein and a poly(A) RNA sequence. Here, we report a 1.9 A resolution crystal structure of the RRM domain of Cyp33 and describe the molecular mechanism of PHD3 and RNA recognition. The Cyp33 RRM domain folds into a five-stranded antiparallel beta-sheet and two alpha-helices. The RRM domain, but not the catalytic module of Cyp33, binds strongly to PHD3, exhibiting a 2 muM affinity as measured by isothermal titration calorimetry. NMR chemical shift perturbation (CSP) analysis and dynamics data reveal that the beta strands and the beta2-beta3 loop of the RRM domain are involved in the interaction with PHD3. Mutations in the PHD3-binding site or deletions in the beta2-beta3 loop lead to a significantly reduced affinity or abrogation of the interaction. The RNA-binding pocket of the Cyp33 RRM domain, mapped on the basis of NMR CSP and mutagenesis, partially overlaps with the PHD3-binding site, and RNA association is abolished in the presence of MLL PHD3. Full-length Cyp33 acts as a negative regulator of MLL-induced transcription and reduces the expression levels of MLL target genes MEIS1 and HOXA9. Together, these in vitro and in vivo data provide insight into the multiple functions of Cyp33 RRM and suggest a Cyp33-dependent mechanism for regulating the transcriptional activity of MLL

Small scale spatial variability of snow density and depth over complex alpine terrain: Implications for estimating snow water equivalent

This study analyzes spatial variability of snow depth and density from measurements made in February and April of 2010 and 2011 in three 1–2 km2 areas within a valley of the central Spanish Pyrenees. Snow density was correlated with snow depth and different terrain characteristics. Regression models were used to predict the spatial variability of snow density, and to assess how the error in computed densities might influence estimates of snow water equivalent (SWE). The variability in snow depth was much greater than that of snow density. The average snow density was much greater in April than in February. The correlations between snow depth and density were generally statistically significant but typically not very high, and their magnitudes and signs were highly variable among sites and surveys. The correlation with other topographic variables showed the same variability in magnitude and sign, and consequently the resulting regression models were very inconsistent, and in general explained little of the variance. Antecedent climatic and snow conditions prior to each survey help highlight the main causes of the contrasting relation shown between snow depth, density and terrain. As a consequence of the moderate spatial variability of snow density relative to snow depth, the absolute error in the SWE estimated from computed densities using the regression models was generally less than 15%. The error was similar to that obtained by relating snow density measurements directly to adjacent snow depths.This work was supported by research projects CGL2011-27536/HID: “Hidrologia nival en el Pirineo central español: variabilidad espacial, importancia hidrológica y su respuesta a la variabilidad y cambio climático”, financed by the Spanish Commission of Science and Technology, and FEDER; ACQWA (FP7-ENV- 2008-1-212250); the projects “La nieve en el Pirineo aragonés: Distribución especial y su respuesta a las condiciones climáticas” and “Efecto de los escenarios de cambio climático sobre la hidrología superficial y la gestión de embalses del Pirineo Aragonés”, financed by “Obra Social La Caixa”; and “Influencia del cambio climático en el turismo de nieve-CTTP1/10”, financed by the Comunidad de Trabajo de los Pirineos, CTP.Peer Reviewe

The Genus Striga (Scrophulariaceae) in Africa

Twenty-eight species and six subspecies of the hemiparasitic genus Striga Lour., witchweed, occur in Africa. Twenty-two species are endemic. Witchweeds occur throughout the continent with greatest diversity in the grasslands and savannas north of the equator. Striga gesnerioides (Willd.) Vatke and S. hermonthica (Del.) Benth. have developed host-specific strains that may have distinct morphotypes. me accord these no formal taxonomic status. Striga hermonthica and S. asiatica (L.) Kuntze, limited to agroecosystems, may be recently derived from non-ruderal species. Striga hirsuta Benth. and S. lutea Lour., sometimes treated as conspecific with S. asiatica, are recognized as distinct species restricted to natural ecosystems. Striga linearifolia Hepper, with its strongly bilabiate corolla and perennial habit, is considered as a subspecies of S. bilabiata (Thunb.) Kuntze. Striga baumannii Engl. and S. fulgens Hepper are excluded from the genus. Striga baumannii has tuberous roots and a ligneous calyx and may represent a distinct genus. Striga fulgens, with free petals, is aligned with Chascanum E. Mey. in the Verbenaceae

Enhancements in nocturnal surface ozone at urban sites in the UK

Analysis of diurnal patterns of surface ozone (O3) at multiple urban sites in the UK shows the occurrence of prominent nocturnal enhancements during the winter months (November–March). Whilst nocturnal surface ozone (NSO) enhancement events have been observed at other locations, this is the first time that such features have been demonstrated to occur in the UK and the second location globally. The observed NSO enhancement events in the UK were found to be so prevalent that they are clearly discernible in monthly diurnal cycles averaged over several years of data. Long-term (2000–2010) analysis of hourly surface ozone data from 18 urban background stations shows a bimodal diurnal variation during the winter months with a secondary nighttime peak around 0300 hours along with the primary daytime peak. For all but one site, the daily maxima NSO concentrations during the winter months exceeded 60 μg/m3 on >20 % of the nights. The highest NSO value recorded was 118 μg/m3. During the months of November, December, and January, the monthly averaged O3 concentrations observed at night (0300 h) even exceeded those observed in the daytime (1300 h). The analysis also shows that these NSO enhancements can last for several hours and were regional in scale, extending across several stations simultaneously. Interestingly, the urban sites in the north of the UK exhibited higher NSO than the sites in the south of the UK, despite their daily maxima being similar. In part, this seems to be related to the sites in the north typically having lower concentrations of nitrogen oxides

A Biopersistence Study following Exposure to Chrysotile Asbestos Alone or in Combination with Fine Particles

In designing a study to evaluate the inhalation biopersistence of a chrysotile asbestos that was used as a component of a joint-compound, a feasibility study was initiated to evaluate the short-term biopersistence of the chrysotile alone and of the chrysotile in combination witht the sanded reformulated joint-compound. Two groups of Wistar rats were exposed to either 7RF3 chrysotile (Group 2) or to 7RF3 chrysotile combined with aerosolized sanded joint-compound (Group 3). In addition, a control group was exposed to flltered-air. The chrysotile used in the Ready Mix joint compound is rapidly removed from the lung. The chrysotile alone exposure group had a clearance half-time of fibers L > 20 μm of 2.2 days; in the chrysotile plus sanded exposure group the clearance half-time of fibers L > 20 μm was 2.8 days. However, across all size ranges there was approximately an order of magnitude decrease in the mean number of fibers remaining in the lungs of Group 3 as compared to Group 2 despite similiar aerosol exposures. Histopathological examination showed that the chrysotile exposed lungs had the same appearance as the flltered-air controls. This study uniquely illustrates that additional concurrent exposure to an aerosol of the sanded joint-compound, with large numbers of fine-particles depositing in the lungs, accelerates the recruitment of macrophages, resulting in a tenfold decrease in the number of fibers remaining in the lung. The increased number of macrophages in the chrysotile/sanded joint exposure group was confirmed histologically, with this being the only exposure-related histological finding reported

The snow must go on: Ground ice encasement, snow compaction and absence of snow differently cause soil hypoxia, CO2 accumulation and tree seedling damage in boreal forest

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Agreeing to disagree:Deaf and hearing children's awareness of subject–verb number agreement

This study investigated deaf adolescents' implicit and explicit awareness of subject–verb number agreement. In Experiment 1, a self-paced reading task, the reading times of deaf and hearing children (matched for reading and chronological age, mean = 8;3 and 13;10 years) increased when sentences contained disagreeing subject–verb number markers. However, deaf adolescents' slowing occurred later in the sentence than it did in both groups of hearing children. The same deaf adolescents were unable to detect and correct subject–verb agreement errors in Experiment 2, whereas both groups of hearing children performed well on this task. Thus, deaf adolescents demonstrated implicit awareness of agreement in the absence of explicit knowledge. Moreover, this nascent awareness was below that expected on the basis of their (substantially delayed) reading ability. Therefore, grammatical difficulties could be a significant impediment to deaf children's literacy. Future research should examine whether this is a result of late or incomplete learning of English, bilingualism, or another factor

Cost-effectiveness of collaborative care for chronically ill patients with comorbid depressive disorder in the general hospital setting, a randomised controlled trial

Background. Depressive disorder is one of the most common disorders, and is highly prevalent in chronically ill patients. The presence of comorbid depression has a negative influence on quality of life, health care costs, self-care, morbidity, and mortality. Early diagnosis and well-organized treatment of depression has a positive influence on these aspects. Earlier research in the USA has reported good results with regard to the treatment of depression with a collaborative care approach and an antidepressant algorithm. In the UK 'Problem Solving Treatment' has proved to be feasible. However, in the general hospital setting this approach has not yet been evaluated. Methods/Design. CC: DIM (Collaborative Care: Depression Initiative in the Medical setting) is a two-armed randomised controlled trial with randomisation at patient level. The aim of the trial is to evaluate the treatment of depressive disorder in general hospitals in the Netherlands based on a collaborative care framework, including contracting, 'Problem Solving Treatment', antidepressant algorithm, and manual-guided self-help. 126 outpatients with diabetes mellitus, chronic obstructive pulmonary disease, or cardiovascular diseases will be randomised to either the intervention group or the control group. Patients will be included if they have been diagnosed with moderate to severe depression, based on the DSM-IV criteria in a two-step screening method. The intervention group will receive treatment based on the collaborative care approach; the control group will receive 'care as usual'. Baseline and follow-up measurements (after 3, 6, 9, and 12 months) will be performed by means of questionnaires. The primary outcome measure is severity of depressive symptoms, as measured with the PHQ-9. The secondary outcome measure is the cost-effectiveness of these treatments according to the TiC-P, the EuroQol and the SF-36. Discussion. Earlier research has indicated that depressive disorder is a chronic, mostly recurrent illness, which tends to cluster with physical comorbidity. Even though the treatment of depressive disorder based on the guidelines for depression is proven effective, these guidelines are often insufficiently adhered to. Collaborative care and 'Problem Solving Treatment' will be specifically tailored to patients with depressive disorders and evaluated in a general hospital setting in the Netherlands

Spontaneous regression of congenital epulis: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Congenital epulis is a rare lesion found on the alveolar process of a newborn child, diagnosed soon after birth. The lesion has a site predilection for the anterior maxillary alveolar process and a 9:1 sex predilection for females. Once diagnosed the traditional management of the lesion has been surgical excision under general anesthesia.</p> <p>Case presentation</p> <p>The purpose of this case report is to describe spontaneous regression of congenital epulis in a three week old healthy African American female child. She presented with a 1.5 cm bilobed sessile nodular lesion in the region of the right maxillary cuspid. The clinical impression was congenital epulis. Since the lesion was not interfering with feeding and respiration, a conservative approach was taken. The child was followed-up for 18 months, during which the lesion progressively regressed.</p> <p>Conclusions</p> <p>Conservative management prevented unnecessary surgery and anesthesia exposure in a neonate.</p

Expression Profile of Nuclear Receptors along Male Mouse Nephron Segments Reveals a Link between ERRβ and Thick Ascending Limb Function

The nuclear receptor family orchestrates many functions related to reproduction, development, metabolism, and adaptation to the circadian cycle. The majority of these receptors are expressed in the kidney, but their exact quantitative localization in this ultrastructured organ remains poorly described, making it difficult to elucidate the renal function of these receptors. In this report, using quantitative PCR on microdissected mouse renal tubules, we established a detailed quantitative expression map of nuclear receptors along the nephron. This map can serve to identify nuclear receptors with specific localization. Thus, we unexpectedly found that the estrogen-related receptor β (ERRβ) is expressed predominantly in the thick ascending limb (TAL) and, to a much lesser extent, in the distal convoluted tubules. In vivo treatment with an ERR inverse agonist (diethylstilbestrol) showed a link between this receptor family and the expression of the Na+,K+-2Cl− cotransporter type 2 (NKCC2), and resulted in phenotype presenting some similarities with the Bartter syndrom (hypokalemia, urinary Na+ loss and volume contraction). Conversely, stimulation of ERRβ with a selective agonist (GSK4716) in a TAL cell line stimulated NKCC2 expression. All together, these results provide broad information regarding the renal expression of all members of the nuclear receptor family and have allowed us to identify a new regulator of ion transport in the TAL segments