Specific Learning Disabilities: Response to Intervention

The content included in the current chapter centers around the screening and identification of students who experience learning challenges in an educational setting in the United States of America. The specific learning challenges discussed will focus on students who may have a specific learning disability (SLD). Legislation that brought about concepts such as response to intervention (RTI) is discussed in detail. The various levels of intensity of interventions, or tiers, provided to students are explained by more than one discipline. The new regulations guiding access to special education services are based on the identification, intervention, and close monitoring of student progress. The overarching goal of RTI is to provide support to students who may be experiencing difficulty, before they experience failure by falling too far behind their peers

Low zinc status and absorption exist in infants with jejunostomies or ileostomies which persists after intestinal repair.

There is very little data regarding trace mineral nutrition in infants with small intestinal ostomies. Here we evaluated 14 infants with jejunal or ileal ostomies to measure their zinc absorption and retention and biochemical zinc and copper status. Zinc absorption was measured using a dual-tracer stable isotope technique at two different time points when possible. The first study was conducted when the subject was receiving maximal tolerated feeds enterally while the ostomy remained in place. A second study was performed as soon as feasible after full feeds were achieved after intestinal repair. We found biochemical evidence of deficiencies of both zinc and copper in infants with small intestinal ostomies at both time points. Fractional zinc absorption with an ostomy in place was 10.9% ± 5.3%. After reanastamosis, fractional zinc absorption was 9.4% ± 5.7%. Net zinc balance was negative prior to reanastamosis. In conclusion, our data demonstrate that infants with a jejunostomy or ileostomy are at high risk for zinc and copper deficiency before and after intestinal reanastamosis. Additional supplementation, especially of zinc, should be considered during this time period

How to Stay Curious while avoiding Noisy TVs using Aleatoric Uncertainty Estimation

When extrinsic rewards are sparse, artificial agents struggle to explore an environment. Curiosity, implemented as an intrinsic reward for prediction errors, can improve exploration but it is known to fail when faced with action-dependent noise sources (‘noisy TVs’). In an attempt to make exploring agents robust to noisy TVs, we present a simple solution: aleatoric mapping agents (AMAs). AMAs are a novel form of curiosity that explicitly ascertain which state transitions of the environment are unpredictable, even if those dynamics are induced by the actions of the agent. This is achieved by generating separate forward predictions for the mean and aleatoric uncertainty of future states, with the aim of reducing intrinsic rewards for those transitions that are unpredictable. We demonstrate that in a range of environments AMAs are able to circumvent actiondependent stochastic traps that immobilise conventional curiosity driven agents. Furthermore, we demonstrate empirically that other common exploration approaches—previously thought to be immune to agent-induced randomness—can be trapped by stochastic dynamics. Code to reproduce our experiments is provided

Randomised trials conducted using cohorts : a scoping review

Acknowledgements We thank Margaret Sampson, MLIS, PhD, AHIP (Children’s Hospital of Eastern Ontario, Ottawa, Canada) for developing the search strategies on behalf of the CONSORT team. We thank Dr Philippa Fibert, St Mary’s University, Twickenham, London for her help in screening publications for inclusion.Peer reviewe

Ab initio structure search and in situ 7Li NMR studies of discharge products in the Li-S battery system.

The high theoretical gravimetric capacity of the Li-S battery system makes it an attractive candidate for numerous energy storage applications. In practice, cell performance is plagued by low practical capacity and poor cycling. In an effort to explore the mechanism of the discharge with the goal of better understanding performance, we examine the Li-S phase diagram using computational techniques and complement this with an in situ (7)Li NMR study of the cell during discharge. Both the computational and experimental studies are consistent with the suggestion that the only solid product formed in the cell is Li2S, formed soon after cell discharge is initiated. In situ NMR spectroscopy also allows the direct observation of soluble Li(+)-species during cell discharge; species that are known to be highly detrimental to capacity retention. We suggest that during the first discharge plateau, S is reduced to soluble polysulfide species concurrently with the formation of a solid component (Li2S) which forms near the beginning of the first plateau, in the cell configuration studied here. The NMR data suggest that the second plateau is defined by the reduction of the residual soluble species to solid product (Li2S). A ternary diagram is presented to rationalize the phases observed with NMR during the discharge pathway and provide thermodynamic underpinnings for the shape of the discharge profile as a function of cell composition.Fellowship support to KAS from the ConvEne IGERT Program of the National Science Foundation (DGE 0801627) is gratefully acknowledged. AJM acknowledges the support from the Winton Programme for the Physics of Sus-tainability. PDM and DSW thank the UK-EPSRC for financial support. This research made use of the shared experimental facilities of the Materials Research Laboratory (MRL), sup-ported by the MRSEC Program of the NSF under Award No. DMR 1121053. The MRL is a member of the NSF-funded Mate-rials Research Facilities Network (www.mrfn.org). CPG and ML thank the U.S. DOE Office of Vehicle Technologies (Con-tract No. DE-AC02-05CH11231) and the EU ERC (via an Ad-vanced Fellowship to CPG) for funding.This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/ja508982p

BLAST Observations of the South Ecliptic Pole field: Number Counts and Source Catalogs

We present results from a survey carried out by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST) on a 9 deg^2 field near the South Ecliptic Pole at 250, 350 and 500 {\mu}m. The median 1{\sigma} depths of the maps are 36.0, 26.4 and 18.4 mJy, respectively. We apply a statistical method to estimate submillimeter galaxy number counts and find that they are in agreement with other measurements made with the same instrument and with the more recent results from Herschel/SPIRE. Thanks to the large field observed, the new measurements give additional constraints on the bright end of the counts. We identify 132, 89 and 61 sources with S/N>4 at 250, 350, 500 {\mu}m, respectively and provide a multi-wavelength combined catalog of 232 sources with a significance >4{\sigma} in at least one BLAST band. The new BLAST maps and catalogs are available publicly at http://blastexperiment.info.Comment: 25 pages, 6 figures, 4 tables, Accepted by ApJS. Maps and catalogs available at http://blastexperiment.info

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multisubstrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structureguided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of similar to 500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A

CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey

<p>Abstract</p> <p>Background</p> <p><it>CRP </it>gene polymorphisms are associated with serum C-reactive protein concentrations and may play a role in chronic kidney disease (CKD) progression. We recently reported an association between the gene variant rs2808630 and CKD progression in African Americans with hypertensive kidney disease. This association has not been studied in other ethnic groups.</p> <p>Methods</p> <p>We used data from 5955 participants from Phase 2 of The Third National Health and Nutrition Examination Survey (1991-1994) to study the association between <it>CRP </it>polymorphisms and CKD prevalence in a population-based sample. The primary outcome was CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min or the presence of albuminuria. Secondary outcomes were the presence of albuminuria (any degree) and continuous eGFR. Six single nucleotide polymorphisms (SNPs) from the <it>CRP </it>gene, rs2808630, rs1205, rs3093066, rs1417938, rs3093058, and rs1800947, were evaluated.</p> <p>Results</p> <p><it>CRP </it>rs2808630 AG compared to the referent AA genotype was associated with CKD in non-Hispanic blacks (n = 1649, 293 of whom had CKD) with an adjusted odds ratio (OR) of 3.09 (95% CI 1.65-5.8; p = 0.001). For the secondary outcomes, rs2808630 AG compared to the referent AA genotype was associated with albuminuria with an adjusted OR of 3.07 (95% CI 1.59-5.94; p = 0.002), however not with eGFR. There was no association between the SNPs and CKD, albuminuria or eGFR in non-Hispanic whites or Mexicans Americans.</p> <p>Conclusions</p> <p>In this cross-sectional study, the 3' flanking <it>CRP </it>gene variant rs2808630 was associated with CKD, mainly through its association with albuminuria in the non-Hispanic blacks. Despite not finding an association with eGFR, our results support our previous study demonstrating an association between <it>CRP </it>gene variant rs2808630 and CKD progression in a longitudinal cohort of African American with hypertensive kidney disease.</p

Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer

The dysferlinopathies comprise a group of untreatable muscle disorders including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment syndrome, and rigid spine syndrome. As with other forms of muscular dystrophy, adeno-associated virus (AAV) gene transfer is a particularly auspicious treatment strategy, however the size of the DYSF cDNA (6.5 kb) negates packaging into traditional AAV serotypes known to express well in muscle (i.e. rAAV1, 2, 6, 8, 9). Potential advantages of a full cDNA versus a mini-gene include: maintaining structural-functional protein domains, evading protein misfolding, and avoiding novel epitopes that could be immunogenic. AAV5 has demonstrated unique plasticity with regards to packaging capacity and recombination of virions containing homologous regions of cDNA inserts has been implicated in the generation of full-length transcripts. Herein we show for the first time in vivo that homologous recombination following AAV5.DYSF gene transfer leads to the production of full length transcript and protein. Moreover, gene transfer of full-length dysferlin protein in dysferlin deficient mice resulted in expression levels sufficient to correct functional deficits in the diaphragm and importantly in skeletal muscle membrane repair. Intravascular regional gene transfer through the femoral artery produced high levels of transduction and enabled targeting of specific muscle groups affected by the dysferlinopathies setting the stage for potential translation to clinical trials. We provide proof of principle that AAV5 mediated delivery of dysferlin is a highly promising strategy for treatment of dysferlinopathies and has far-reaching implications for the therapeutic delivery of other large genes