Initiating change at the local level: Delivery of Educational Services to Students with Moderate to Severe Handicapping Conditions

This article describes program initiat1ves undertaken by a rural educational cooperative In an effort to bridge the gap between current best practices and local educational program opportunities for school-aged students with moderate, severe, and profound handicapping conditions. It compares previous program characteristics with current practices in areas such educational placement, student groupings, curriculum, community-based Instruction, therapeutic services, end post-school preparation. Factors which influenced major program changes are discussed

Cloning of nitroalkane oxidase from Fusarium oxysporum identifies a new member of the acyl-CoA dehydrogenase superfamily

The flavoprotein nitroalkane oxidase (NAO) from Fusarium oxysporum catalyzes the oxidation of nitroalkanes to the respective aldehydes with production of nitrite and hydrogen peroxide. The sequences of several peptides from the fungal enzyme were used to design oligonucleotides for the isolation of a portion of the NAO gene from an F. oxysporum genomic DNA preparation. This sequence was used to clone the cDNA for NAO from an F. oxysporum cDNA library. The sequence of the cloned cDNA showed that NOA is a member of the acyl-CoA dehydrogenase (ACAD) superfamily. The members of this family share with NAO a mechanism that is initiated by proton removal from carbon, suggesting a common chemical reaction for this superfamily. NAO was expressed in Escherichia coli and the recombinant enzyme was characterized. Recombinant NAO has identical kinetic parameters to enzyme isolated from F. oxysporum but is isolated with oxidized FAD rather than the nitrobutyl-FAD found in the fungal enzyme. NAO purified from E. coli or from F. oxysporum has no detectable ACAD activity on short- or medium-chain acyl CoAs, and medium-chain acyl-CoA dehydrogenase and short-chain acyl-CoA dehydrogenase are unable to catalyze oxidation of nitroalkanes

Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation

BACKGROUND: The relationship between lung and joint inflammation in rheumatoid arthritis is poorly understood. Lung inflammation with resultant protein citrullination may trigger anti-citrullinated protein antibodies, inflammation, and arthritis. Alternatively, lung and joint inflammation may be two manifestations of a single underlying pathology. The lung has increased citrullination and TNF-alpha levels are high in rheumatoid arthritis; however, it is unknown if TNF-alpha can induce lung protein citrullination. The citrullinating enzyme peptidylarginine deiminase 4 (PAD4) exacerbates TNF-alpha-induced arthritis, but a role for PAD4 in lung citrullination and TNF-alpha-induced lung inflammation has not been explored. Our aim was to use TNF-alpha-overexpressing mice to clarify the intersection of TNF-alpha, citrullination, PAD4, arthritis, and lung inflammation. METHODS: Lung protein citrullination in wild-type mice, mice that overexpress TNF-alpha systemically (TNF(+)), TNF(+)PAD4(+/+), and TNF(+)PAD4(-/-) mice was quantified by both gel electrophoresis using a citrulline probe and western blot. Hematoxylin and eosin (HandE)-stained lung sections from TNF(+)PAD4(+/+) and TNF(+)PAD4(-/-) mice were scored for lung inflammation. HandE-stained ankle joint sections from mice that overexpress TNF-alpha only in the lungs were assessed for arthritis. RESULTS: TNF(+) mice have increased lung protein citrullination. TNF(+)PAD4(-/-) mice do not have significantly reduced lung protein citrullination, but do have decreased lung inflammation compared to TNF(+)PAD4(+/+) mice. Mice that overexpress TNF-alpha only in the lungs do not develop arthritis. CONCLUSIONS: PAD4 exacerbates lung inflammation downstream of TNF-alpha without having a major role in generalized protein citrullination in inflamed lungs. Also, TNF-alpha-induced lung inflammation is not sufficient to drive murine arthritis

Herschel observations of interstellar chloronium

Using the Herschel Space Observatory's Heterodyne Instrument for the Far-Infrared (HIFI), we have observed para-chloronium (H2Cl+) toward six sources in the Galaxy. We detected interstellar chloronium absorption in foreground molecular clouds along the sight-lines to the bright submillimeter continuum sources Sgr A (+50 km/s cloud) and W31C. Both the para-H2-35Cl+ and para-H2-37Cl+ isotopologues were detected, through observations of their 1(11)-0(00) transitions at rest frequencies of 485.42 and 484.23 GHz, respectively. For an assumed ortho-to-para ratio of 3, the observed optical depths imply that chloronium accounts for ~ 4 - 12% of chlorine nuclei in the gas phase. We detected interstellar chloronium emission from two sources in the Orion Molecular Cloud 1: the Orion Bar photodissociation region and the Orion South condensation. For an assumed ortho-to-para ratio of 3 for chloronium, the observed emission line fluxes imply total beam-averaged column densities of ~ 2.0E+13 cm-2 and ~ 1.2E+13 cm-2, respectively, for chloronium in these two sources. We obtained upper limits on the para-H2-35Cl+ line strengths toward H2 Peak 1 in the Orion Molecular cloud and toward the massive young star AFGL 2591. The chloronium abundances inferred in this study are typically at least a factor ~10 larger than the predictions of steady-state theoretical models for the chemistry of interstellar molecules containing chlorine. Several explanations for this discrepancy were investigated, but none has proven satisfactory, and thus the large observed abundances of chloronium remain puzzling.Comment: Accepted for publication in the Astrophysical Journa

On the Universality of CP Violation in Delta F = 1 Processes

We show that new physics which breaks the left-handed SU(3)_Q quark flavor symmetry induces contributions to CP violation in Delta F = 1 couplings which are approximately universal, in that they are not affected by flavor rotations between the up and the down mass bases. (Only the short distance contributions are universal, while observables are also affected by hadronic matrix elements.) Therefore, such flavor violation cannot be aligned, and is constrained by the strongest bound from either the up or the down sectors. We use this result to show that the bound from eps'/eps prohibits an SU(3)_Q breaking explanation of the recent LHCb evidence for CP violation in D meson decays. Another consequence of this universality is that supersymmetric alignment models with a moderate mediation scale are consistent with the data, and are harder to probe via CP violating observables. With current constraints, therefore, squarks need not be degenerate. However, future improvements in the measurement of CP violation in D-Dbar mixing will start to probe alignment models.Comment: 10 pages, 2 figures. Clarifications and references adde

Use of Genomic DNA as an Indirect Reference for Identifying Gender-Associated Transcripts in Morphologically Identical, but Chromosomally Distinct, Schistosoma mansoni Cercariae

BACKGROUND: The use of DNA microarray technology to study global Schistosoma gene expression has led to the rapid identification of novel biological processes, pathways or associations. Implementation of standardized DNA microarray protocols across laboratories would assist maximal interpretation of generated datasets and extend productive application of this technology. METHODOLOGY/PRINCIPAL FINDINGS: Utilizing a new Schistosoma mansoni oligonucleotide DNA microarray composed of 37,632 elements, we show that schistosome genomic DNA (gDNA) hybridizes with less variation compared to complex mixed pools of S. mansoni cDNA material (R = 0.993 for gDNA compared to R = 0.956 for cDNA during ‘self versus self’ hybridizations). Furthermore, these effects are species-specific, with S. japonicum or Mus musculus gDNA failing to bind significantly to S. mansoni oligonucleotide DNA microarrays (e.g R = 0.350 when S. mansoni gDNA is co-hybridized with S. japonicum gDNA). Increased median fluorescent intensities (209.9) were also observed for DNA microarray elements hybridized with S. mansoni gDNA compared to complex mixed pools of S. mansoni cDNA (112.2). Exploiting these valuable characteristics, S. mansoni gDNA was used in two-channel DNA microarray hybridization experiments as a common reference for indirect identification of gender-associated transcripts in cercariae, a schistosome life-stage in which there is no overt sexual dimorphism. This led to the identification of 2,648 gender-associated transcripts. When compared to the 780 gender-associated transcripts identified by hybridization experiments utilizing a two-channel direct method (co-hybridization of male and female cercariae cDNA), indirect methods using gDNA were far superior in identifying greater quantities of differentially expressed transcripts. Interestingly, both methods identified a concordant subset of 188 male-associated and 156 female-associated cercarial transcripts, respectively. Gene ontology classification of these differentially expressed transcripts revealed a greater diversity of categories in male cercariae. Quantitative real-time PCR analysis confirmed the DNA microarray results and supported the reliability of this platform for identifying gender-associated transcripts. CONCLUSIONS/SIGNIFICANCE: Schistosome gDNA displays characteristics highly suitable for the comparison of two-channel DNA microarray results obtained from experiments conducted independently across laboratories. The schistosome transcripts identified here demonstrate, for the first time, that gender-associated patterns of expression are already well established in the morphologically identical, but chromosomally distinct, cercariae stage

Search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓

A search for the lepton-flavor-violating decays Bs0→e±μ∓ and B0→e±μ∓ is performed with a data sample, corresponding to an integrated luminosity of 1.0  fb-1 of pp collisions at √s=7  TeV, collected by the LHCb experiment. The observed number of Bs0→e±μ∓ and B0→e±μ∓ candidates is consistent with background expectations. Upper limits on the branching fractions of both decays are determined to be B(Bs0→e±μ∓)101  TeV/c2 and MLQ(B0→e±μ∓)>126  TeV/c2 at 95% C.L., and are a factor of 2 higher than the previous bounds

Development of a complex intervention to test the effectiveness of peer support in type 2 diabetes

BACKGROUND: Diabetes is a chronic illness which requires the individual to assume responsibility for their own care with the aim of maintaining glucose and blood pressure levels as close to normal as possible. Traditionally self management training for diabetes has been delivered in a didactic setting. In recent times alternatives to the traditional delivery of diabetes care have been investigated, for example, the concept of peer support which emphasises patient rather than professional domination. The aim of this paper is to describe the development of a complex intervention of peer support in type 2 diabetes for a randomised control trial in a primary care setting. METHODS: The Medical Research Council (MRC) framework for the development and evaluation of complex interventions for randomised control trials (RCT) was used as a theoretical guide to designing the intervention. The first three phases (Preclinical Phase, Phase 1, Phase 2) of this framework were examined in depth. The Preclinical Phase included a review of the literature relating to type 2 diabetes and peer support. In Phase 1 the theoretical background and qualitative data from 4 focus groups were combined to define the main components of the intervention. The preliminary intervention was conducted in Phase 2. This was a pilot study conducted in two general practices and amongst 24 patients and 4 peer supporters. Focus groups and semi structured interviews were conducted to collect additional qualitative data to inform the development of the intervention. RESULTS: The four components of the intervention were identified from the Preclinical Phase and Phase 1. They are: 1. Peer supporters; 2. Peer supporter training; 3. Retention and support for peer supporters; 4. Peer support meetings. The preliminary intervention was implemented in the Phase 2. Findings from this phase allowed further modeling of the intervention, to produce the definitive intervention. CONCLUSION: The MRC framework was instrumental in the development of a robust intervention of peer support of type 2 diabetes in primary care. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42541690

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function