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This study determined the extent to which working memory (WM) played a moderating and/or mediating role in word-problem-solving (WPS) instructional outcomes between children with and without math difficulties (MD). A randomized pretest-posttest control group study investigated the effects of 8-week strategy instruction in one of four treatment conditions on WPS accuracy of third graders with MD ( N  = 136) when compared to children with ( N  = 28) and without MD ( N  = 43). Comparisons were made of three strategy conditions that included overt cues (e.g. underlining key sentences, filling in diagrams), another treatment condition that removed the overt cues (material-only), and two control conditions (children with and without MD). Four important findings emerged. First, posttest WM significantly predicted posttest WPS, computation, and schema accuracy independent of pretest and treatment conditions. Second, posttest WM mediated posttest WPS treatment outcomes when the control conditions included children without MD. Third, strategy conditions that included overt cues (e.g. crossing out irrelevant sentences) decreased WM demands compared to the Materials-Only condition (without overt cues) for children with MD. Finally, incremental attention allocation training within treatment conditions improved posttest WM in children with MD but not posttest WPS. Results indicated that WPS differences between children with and without MD across treatment conditions were mediated by posttest WM performance.

Given the rapid growth in educational policies targeting educators' knowledge of dyslexia, this study explored the technical adequacy of a common instrument for measuring that knowledge. The responses of 1141 preservice teachers were scored in three ways: polytomously with the original 4-point Likert scale, dichotomously as true-false, and dichotomously as though the options were multiple choice. An exploratory factor analysis suggested at least one-third of the items needed to be removed. Confirmatory factor analyses suggested a one-factor model with polytomous scoring had the best fit to the data, but only six items loaded. All models demonstrated unacceptable internal consistency reliability (<0.70). Because no technically adequate version of the measure was identified, questions remain about basing policy on scores from these instruments. However, the findings indicated ways this type of measure might be improved., (© 2024 John Wiley & Sons Ltd.)

The purposes of the current study were to examine the effects of cognitive and reading skills (i.e., working memory [WM], oral language development [OLD], and reading skills) on second language (L2) writing performance as well as the changes in these relationships across different grades among Spanish-speaking children learning English. A battery of measures assessing English and Spanish WM, OLD, reading skills, and English writing were administered to 494 English learners in Grades 1 to 3. Path analysis was conducted for each grade separately in both English and Spanish models. The findings indicated that the relationships between English writing performance and English cognitive and reading skills became stronger as the grades increased. However, the relationships between English writing and the Spanish cognitive and reading determinants were mixed, indicating a statistically significant relationship with Spanish WM and reading skills for Grade 2 and 3 students but not with OLD across all grades. Implications for L2 writing development are discussed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This single-center retrospective study evaluated patients who underwent treatment of a primary or secondary hepatic malignancy with injection of glass or resin yttrium-90 ( 90 Y) microspheres with a corresponding hybrid angiography-computed tomography (angio-CT) and 90 Y positron emission tomography (PET). Volumetric contours were defined by three independent observers and were used to calculate relative tumoral enhancement at angio-CT. This parameter was compared with the tumor-to-normal (T/N) activity ratio predicted by technetium-99m macro-aggregated albumin ( 99m Tc-MAA) single photon emission computed tomography (SPECT) and microsphere activity distribution by 90 Y PET. A similar correlation was observed for the enhancement ratio at angio-CT with observed microsphere distribution at 90 Y PET (r=0.34) to that predicted by 99m Tc-MAA SPECT (r=0.32). The enhancement ratio on angio-CT performed as well as 99m Tc-MAA in the prediction of 90 Y PET activity distribution. The technique could not be readily applied to tumors with large areas of hypoattenuation (necrosis) on angio-CT. With refinement and further study, this technique could be used as a quantitative adjunct to standard-of-care  99m Tc-MAA SPECT for dosimetry calculations and prediction of microsphere distribution to maximize tumor response and minimize hepatotoxicity., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Campbell et al.)

Interim and summative assessments often are used to make decisions about student writing skills and needs for instruction, but the extent to which different raters and score types might introduce bias for some groups of students is largely unknown. To evaluate this possibility, we analyzed interim writing assessments and state summative test data for 2,621 students in Grades 3-11. Both teachers familiar with students and researchers unaware of students' identifying characteristics evaluated the interim assessments with analytic rubrics. Teachers assigned higher scores on the interim assessments than researchers. Female students had higher scores than males, and English learners (ELs), students eligible for free or reduced-price school lunch (FRL), and students eligible for special education (SPED) had lower scores than other students. These differences were smaller with researcher compared to teacher ratings. Across grade levels, interim assessment scores were similarly predictive of state rubric scores, scale scores, and proficiency designations across student groups. However, students identified as Hispanic, FRL, EL, or SPED had lower scale scores and a lower likelihood of reaching proficiency on the state exam. For this reason, these students' risk of unsuccessful performance on the state exam would be greater than predicted when based on interim assessment scores. These findings highlight the potential importance of masking student identities when evaluating writing to reduce scoring bias and suggest that the written composition portions of high-stakes writing examinations may be less biased against historically marginalized groups than the multiple choice portions of these exams. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

To explore potential pandemic-related learning gaps on expressive writing skills, predominantly Hispanic (≈50%) and White (≈30%) primary-grade students responded to grade-specific writing prompts in the fall semesters before and after school closures. Responses were evaluated with an analytic rubric consisting of five traits (focus, organization, development, grammar, mechanics), each scored on a 1-4 scale. Data first were analyzed descriptively and, after propensity score weighting, with ordinal response models (for analytic scores) and generalized linear mixed effects models (for composite scores). Compared to first graders in 2019 ( n  = 310), those in 2020 ( n  = 203) scored significantly lower overall as well as on all rubric criteria and were more likely to write unintelligible responses. Second graders in 2020 ( n  = 194) performed significantly lower than those in 2019 ( n  = 328) in some traits but not all, and there was a widening gap between students who did/not score proficiently. A three-level longitudinal model analyzing the sample of students moving from first to second grade in fall 2020 ( n  = 90) revealed significant improvements, but students still performed significantly lower than second graders in the previous year. Implications for student resiliency and instructional planning are discussed., (© 2023 Elsevier Inc. All rights reserved.)

Teacher preparation for problem-solving instruction is essential to meeting the math needs of English learners (ELs) with math learning disabilities (MLD) in U.S. public schools. In investigating this instruction with Hispanic ELs with MLD, this study focused on how professional development supported one special educator's implementation of effective practices for both academic language and problem-solving instruction. The professional development prepared the teacher for instructional and cooperative learning phases that faded prompting as students achieved independence in applying the problem-solving strategy. A multiple-baseline design was used to assess nine third-grade Hispanic ELs with MLD. As compared with the baseline phase, instructional scaffolding increased word problem solving for all the participants. All students' level of probe performance was maintained during follow-up sessions. The results suggest the intervention facilitated improved math problem-solving performance.

Kindergarten students commonly receive a limited amount of exposure to scientific concepts and informational texts. The present study used a multiple probe design across participants to determine the effects of shared reading instruction on three kindergarten students' science-related vocabulary acquisition in a virtual classroom during the Covid-19 pandemic. The interventionist delivered explicit vocabulary instruction by reading aloud a science picture book and intentionally pausing to define, explain, and discuss vocabulary words that were unfamiliar to young students. Researcher-developed vocabulary probes were administered every fifth instructional session and measured specific words taught during instruction. Results of virtual shared reading instruction indicate positive effects (Tau- U  = 0.222-0.933) on kindergarten students' science vocabulary learning. Students, their instructor, and caregivers all perceived the shared reading instruction as beneficial for science vocabulary development. These findings suggest explicit science vocabulary instruction during shared reading is beneficial to students and feasible for teachers to implement in a virtual classroom., Supplementary Information: The online version contains supplementary material available at 10.1007/s10643-021-01288-w., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

Purpose The study aimed to evaluate the adverse event (AE) and hepatotoxicity profile, including radioembolization induced liver disease (REILD), following repeat radioembolization (RE) to the same or overlapping vascular territories in patients with hepatocellular carcinoma (HCC) and limited functional hepatic reserve/cirrhosis. Methods Nine patients (seven male and two female; median age, 66 years) with cirrhosis and HCC who underwent repeat RE (cycle 1 and cycle 2) between January 2012 and August 2019 were included. Patient demographics, clinical and treatment history, and pertinent laboratory values were recorded at baseline and post-treatment time points over a period of four months. Post-RE AE/hepatotoxicity was assessed, organized by type and frequency, and graded by severity according to the National Cancer Institute common terminology criteria for adverse events, version 5.0 (CTCAE v5.0). To assess rudimentary comparisons for post-RE hepatotoxicity vs. factors of interest, Spearman's rank correlation/rho was calculated, and all relevant plots were constructed. Kaplan-Meier analysis was performed along with associated median survival time. All statistical analyses were performed with Stata v16.1. Results Following cycle 1, 22 objective AE were identified according to CTCAE v.5 (17 grade I, four grade II, and one grade III), with grade I, II, and III AE experienced by 78%, 33%, and 11% of patients, respectively. Following cycle 2, 19 objective AE were identified according to CTCAE v.5 (11 grade I, seven grade II, and one grade III), with grade I, II, and III AE experienced by 89%, 56%, and 11% of patients, respectively. A single patient developed REILD after cycle 1, which progressed to fatal REILD following cycle 2. Following cycle 2, an additional patient advanced from less severe hepatotoxicity to REILD. Following cycle 2, positive correlations between the higher model for end-stage liver disease (MELD; rho=0.70) and Child-Pugh (rho=0.74) scores and degree of post-RE hepatotoxicity/REILD appear to emerge. Post-repeat RE median overall survival was 12.5 months. Conclusion Post-RE hepatotoxicity following repeat RE to the same or overlapping vascular territories in patients with limited functional hepatic reserve/cirrhosis is a common occurrence with variable severity ranging from transient laboratory derangement to fatal REILD. Lack of a consensus REILD definition and grading scale results in non-uniform reporting of incidence as well as clinical and laboratory features of the disease process. Strides aimed at improving clinical characterization, forming a more complete diagnostic definition, and establishing a uniform grading system with respect to REILD are of particular importance and would ultimately improve repeat RE patient selection and risk management., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Reed et al.)

Many middle-school students struggle with basic reading skills. One reason for this might be a lack of automaticity in word-level lexical processes. To investigate this, we used a novel backward masking paradigm, in which a written word is either covered with a mask or not. Participants (N = 444 [after exclusions]; nfemale = 264, nmale = 180) were average to struggling middle-school students from an urban area in Eastern Iowa that were all native speakers of English and were roughly equally from grades 6, 7, and 8 (average age: 13 years). Two-hundred-fifty-five students qualified for free or reduced-price lunch, a proxy for economic disadvantage. Participants completed different masked and unmasked task versions where they read a word and selected a response (e.g., a pictured referent). This was related to standardized measures of decoding, fluency, and reading comprehension. Decoding was uniquely predicted by knowledge (unmasked performance), whereas fluency was uniquely predicted by automaticity (masked performance). Automaticity was stable across two testing points. Thus, automaticity should be considered an individually reliable marker/reading trait that uniquely predicts some skills in average to struggling middle-school students. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

In applying a methods-oriented approach to evaluation, this study interpreted the effectiveness of a summer reading program from three different stakeholder perspectives: practitioners from the school district, the funding agency supporting the program, and the policymakers considering mandating summer school. Archival data were obtained on 2330 students reading below benchmark in Grades 2-5. After propensity score matching participants to peers who did not attend the summer program, the final sample consisted of 630 students. Pre-to-posttest growth models revealed positive effects in Grades 2-4 (standardized slopes of .40-.54), but fifth graders demonstrated negligible improvement (standardized slope of .15). The standardized mean differences of propensity score matched treatment and control group students indicated null effects in all grade levels (d = -.13 to .05). Achieving proficient reading performance also was not attributable to summer school participation. Findings underscore the importance of operationalizing effectiveness in summative evaluation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Clathrin-mediated endocytosis (CME) occurs via the formation of clathrin-coated vesicles from clathrin-coated pits (CCPs). Clathrin is recruited to CCPs through interactions between the AP2 complex and its N-terminal domain, which in turn recruits endocytic accessory proteins. Inhibitors of CME that interfere with clathrin function have been described, but their specificity and mechanisms of action are unclear. Here we show that overexpression of the N-terminal domain with (TDD) or without (TD) the distal leg inhibits CME and CCP dynamics by perturbing clathrin interactions with AP2 and SNX9. TDD overexpression does not affect clathrin-independent endocytosis or, surprisingly, AP1-dependent lysosomal trafficking from the Golgi. We designed small membrane-permeant peptides that encode key functional residues within the four known binding sites on the TD. One peptide, Wbox2, encoding residues along the W-box motif binding surface, binds to SNX9 and AP2 and potently and acutely inhibits CME., (© 2020 Chen et al.)

Children with weak decoding skills often struggle to learn multisyllabic words during reading instruction. The primary purpose of this study was to investigate the extent to which initial response to morphological awareness instruction, along with specific language and cognitive variables (i.e., phonological awareness, rapid naming, orthographic knowledge/awareness, verbal comprehension, working memory), predicts responsiveness to morphological awareness instruction for third-grade students who were at risk for reading disabilities. Thirty-nine third-grade students with decoding deficits were assessed on five independent variables identified as critical predictors of future performance on morphological tasks. A series of regression analyses showed that initial response to instruction, compared to other cognitive and language variables, predicted the most variance in students' morphological skills with prefixes. Furthermore, two cognitive variables, verbal working memory and comprehension, were predictive of performance on morphological tasks after accounting for initial response to instruction. Findings from this study suggest that students with decoding deficits may benefit from morphological instruction and those who demonstrate low response to initial morphological instruction or have weak verbal comprehension and verbal working memory abilities could be risk for failing to acquire morphological instruction as expected.

A study by Tóth, Kocsis, Háden, Szerafin, Shinn-Cunningham, and Winkler [Neuroimage 141, 108 - 119 (2016)] reported that spatial cues (such as interaural differences or ITDs) that differentiate the perceived sound source directions of a target tone sequence (figure) from simultaneous distracting tones (background) did not improve the ability of participants to detect the target sequence. The present study aims to investigate more systematically whether spatially separating a complex auditory "figure" from the background auditory stream may enhance the detection of a target in a cluttered auditory scene. Results of the presented experiment suggest that the previous negative results arose because of the specific experimental conditions tested. Here the authors find that ITDs provide a clear benefit for detecting a target tone sequence amid a mixture of other simultaneous tone bursts.

To improve oral reading fluency rate and promote its generalization to unpracticed texts, this study investigated a Varied Practice approach that involved passages with a high proportion of overlapping words (M = 85% unique word overlap). Fourth graders were randomly assigned either to the Varied Practice treatment (n = 405), where they read three different passages one time each, or the Repeated Reading comparison (n = 422), in which they read the same passage three times each. Both groups read with a partner for about 20 min, 3-4 times per week, over an average 12 weeks (30 total sessions). Results indicated that students in Varied Practice demonstrated significantly better fluency outcomes than students in Repeated Reading, but both groups demonstrated growth near the 90th percentile. Results of a quantile regression revealed that low-to-middle achievers benefited from Varied Practice the most. Overall, the findings suggest fluency approaches rooted in statistical learning hold promise as an alternative to approaches focused on practicing words in redundant contexts., (Copyright © 2019 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.)

Actin assembly supplies the structural framework for cell morphology and migration. Beyond structure, this actin framework can also be engaged to drive biochemical signaling programs. Here, we describe how the hyperactivation of Rac1 via the P29S mutation (Rac1 P29S ) in melanoma hijacks branched actin network assembly to coordinate proliferative cues that facilitate metastasis and drug resistance. Upon growth challenge, Rac1 P29S -harboring melanoma cells massively upregulate lamellipodia formation by dendritic actin polymerization. These extended lamellipodia form a signaling microdomain that sequesters and phospho-inactivates the tumor suppressor NF2/Merlin, driving Rac1 P29S cell proliferation in growth suppressive conditions. These biochemically active lamellipodia require cell-substrate attachment but not focal adhesion assembly and drive proliferation independently of the ERK/MAPK pathway. These data suggest a critical link between cell morphology and cell signaling and reconcile the dichotomy of Rac1's regulation of both proliferation and actin assembly by revealing a mutual signaling axis wherein actin assembly drives proliferation in melanoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Studies of auditory looming bias have shown that sources increasing in intensity are more salient than sources decreasing in intensity. Researchers have argued that listeners are more sensitive to approaching sounds compared with receding sounds, reflecting an evolutionary pressure. However, these studies only manipulated overall sound intensity; therefore, it is unclear whether looming bias is truly a perceptual bias for changes in source distance, or only in sound intensity. Here we demonstrate both behavioral and neural correlates of looming bias without manipulating overall sound intensity. In natural environments, the pinnae induce spectral cues that give rise to a sense of externalization; when spectral cues are unnatural, sounds are perceived as closer to the listener. We manipulated the contrast of individually tailored spectral cues to create sounds of similar intensity but different naturalness. We confirmed that sounds were perceived as approaching when spectral contrast decreased, and perceived as receding when spectral contrast increased. We measured behavior and electroencephalography while listeners judged motion direction. Behavioral responses showed a looming bias in that responses were more consistent for sounds perceived as approaching than for sounds perceived as receding. In a control experiment, looming bias disappeared when spectral contrast changes were discontinuous, suggesting that perceived motion in distance and not distance itself was driving the bias. Neurally, looming bias was reflected in an asymmetry of late event-related potentials associated with motion evaluation. Hence, both our behavioral and neural findings support a generalization of the auditory looming bias, representing a perceptual preference for approaching auditory objects., Competing Interests: The authors declare no conflict of interest.

α-Tocopherol (TOC) is a widely used supplement known for its role as an antioxidant. Previously, we have shown that TOC elicits adaptive responses by upregulating the ERK/CREB/HO-1 pathway, which depends on its concentration in cultured renal proximal tubule cells (RPTCs). This suggests that high-dose TOC (hTOC) may elicit adverse effects via inflicting oxidative stress. Since the pro-oxidant p66shc is a major mediator of oxidant injury in various models of renal toxicants, we tested the hypothesis that hTOC elicits renal toxicity through activation of p66shc and consequent oxidative stress. RPTCs (NRK52E) were treated with high-dose TOC (hTOC; 400 nM) in cells where expression or mitochondrial cytochrome c-binding of p66shc was manipulated by genetic means. Intracellular production of reactive oxygen species (ROS), mitochondrial depolarization, and cell viability was also determined. Additionally, activation of the pro-survival ERK/CREB/HO-1 signaling and the p66shc promoter was determined via reporter luciferase assays. hTOC decreased cell viability via increasing ROS-dependent mitochondrial depolarization and suppressing the pro-survival ERK/CREB/HO-1 pathway via transcriptional activation of p66shc. Conversely, either knockdown of p66shc, mutation of its mitochondrial cytochrome c-binding site, or overexpression of ERK or HO-1 ameliorated adverse effects of hTOC and restored the pro-survival signaling. The pro-oxidant p66shc plays dual role in toxicity of high-dose TOC: it provokes oxidative stress and suppresses adaptive responses.

The critical initiation phase of clathrin-mediated endocytosis (CME) determines where and when endocytosis occurs. Heterotetrameric adaptor protein 2 (AP2) complexes, which initiate clathrin-coated pit (CCP) assembly, are activated by conformational changes in response to phosphatidylinositol-4,5-bisphosphate (PIP2) and cargo binding at multiple sites. However, the functional hierarchy of interactions and how these conformational changes relate to distinct steps in CCP formation in living cells remains unknown. We used quantitative live-cell analyses to measure discrete early stages of CME and show how sequential, allosterically regulated conformational changes activate AP2 to drive both nucleation and subsequent stabilization of nascent CCPs. Our data establish that cargoes containing Yxxφ motif, but not dileucine motif, play a critical role in the earliest stages of AP2 activation and CCP nucleation. Interestingly, these cargo and PIP2 interactions are not conserved in yeast. Thus, we speculate that AP2 has evolved as a key regulatory node to coordinate CCP formation and cargo sorting and ensure high spatial and temporal regulation of CME., (© 2017 Kadlecova et al.)

Ikarugamycin (IKA) is a previously discovered antibiotic, which has been shown to inhibit the uptake of oxidized low-density lipoproteins in macrophages. Furthermore, several groups have previously used IKA to inhibit clathrin-mediated endocytosis (CME) in plant cell lines. However, detailed characterization of IKA has yet to be performed. Consequently, we performed biochemistry and microscopy experiments to further characterize the effects of IKA on CME. We show that IKA has an IC50 of 2.7 μm in H1299 cells and acutely inhibits CME, but not other endocytic pathways, in a panel of cell lines. Although long-term incubation with IKA has cytotoxic effects, the short-term inhibitory effects on CME are reversible. Thus, IKA can be a useful tool for probing routes of endocytic trafficking., Competing Interests: The authors declare no conflicts of interests., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nicotine (NIC) exposure augments free fatty acid (FFA) deposition and oxidative stress, with a concomitant increase in the expression of the pro-oxidant p66shc. In addition, a decrease in the antioxidant manganese superoxide dismutase (MnSOD) has been observed in the kidneys of mice fed a high‑fat diet. The present study aimed to determine whether the pro‑oxidant p66shc mediates NIC‑dependent increases in renal oxidative stress by augmenting the production of reactive oxygen species (ROS) and suppressing the FFA‑induced antioxidant response in cultured NRK52E renal proximal tubule cells. Briefly, NRK52E renal proximal tubule cells were treated with 200 µM NIC, 100 µM oleic acid (OA), or a combination of NIC and OA. The expression levels of p66shc and MnSOD were modulated according to genetic methods. ROS production and cell injury, in the form of lactate dehydrogenase release, were subsequently detected. Promoter activity of p66shc and MnSOD, as well as forkhead box (FOXO)‑dependent transcription, was investigated using reporter luciferase assays. The results demonstrated that NIC exacerbated OA‑mediated intracellular ROS production and cell injury through the transcriptional activation of p66shc. NIC also suppressed OA‑mediated induction of the antioxidant MnSOD promoter activity through p66shc‑dependent inactivation of FOXO activity. Overexpression of p66shc and knockdown of MnSOD had the same effect as treatment with NIC on OA‑mediated lipotoxicity. These data may be used to generate a therapeutic means to ameliorate renal lipotoxicity in obese smokers.

Introduction: Life expectancy of an obese smoker is 13 years less than a normal weight smoker, which could be linked to the increased renal risk imposed by smoking. Both smoking-through nicotine (NIC)-and obesity-by free fatty acid overload-provoke oxidative stress in the kidney, which ultimately results in development of chronic kidney injury. Their combined renal risk, however, is virtually unknown. We tested the hypothesis that chronic NIC exposure worsens renal oxidative stress in mice on high-fat diet (HFD) by altering the balance between expression of pro-oxidant and antioxidant genes., Methods: Nine-week-old male C57Bl/6J mice consumed normal diet (ND) or HFD and received either NIC (200 μg/ml) or vehicle (2% saccharine) in their drinking water. Body weight, plasma clinical parameters, renal lipid deposition, markers of renal oxidative stress and injury, as well as renal expression of the pro-oxidant p66shc and the antioxidant MnSOD were determined after 12 weeks., Results: NIC significantly augmented levels of circulating free fatty acid, as well as lipid deposition, oxidative stress and sublethal injury in the kidneys of mice on HFD. In addition, NIC exposure suppressed HFD-mediated induction of MnSOD while increased expression of p66shc in the kidney., Conclusions: Tobacco smoking or the increasingly popular E-cigarettes-via NIC exposure-could worsen obesity-associated lipotoxicity in the kidney. Hence, our findings could help to develop strategies that mitigate adverse effects of NIC on the obese kidney., Implications: Life expectancy of an obese smoker is 13 years less than a normal weight smoker, which could be linked to the increased renal risk imposed by smoking. NIC-the main component of tobacco smoke, E-cigarettes and replacement therapies-links smoking to renal injury via oxidative stress, which could superimpose renal oxidative stress caused by obesity. Our results substantiate this scenario using a mouse model of diet induced obesity and NIC exposure and imply the augmented long-term renal risk in obese smokers. Also, our study may help to develop strategies that mitigate adverse effects of NIC on the obese kidney., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This research synthesis was conducted to understand the effectiveness of interventions designed to improve learning from informational text for students with learning disabilities in elementary school (K-5). The authors identified 18 studies through a comprehensive search. The interventions were evaluated to determine treatment effects and to understand implementation and methodological variables that influenced outcomes. Moderate to large effect sizes on researcher-developed measures for cognitive strategy interventions were reported. Interventions that utilized graphic organizers as study guides to support social studies learning were also associated with improved outcomes. The findings are considered within the context of limited implementation of standardized measures. The authors extend findings from previous research by reporting a paucity of interventions to enhance higher-level cognitive and comprehension skills. The majority of reviewed studies targeted fact acquisition and main idea identification, and overall encouraging findings were noted for these skills. Implications for future research are discussed., (© Hammill Institute on Disabilities 2014.)

This study examined the contributions of vocabulary and spelling to the reading comprehension of students in grades 6-10 who were and were not classified as English language learners. Results indicate that vocabulary accounted for greater between-grade differences and unique variance (Δ R 2 = .11 to .31) in comprehension as compared to spelling (Δ R 2 = .01 to .09). However, the contribution of spelling to comprehension was higher in the upper grade levels included in this cross-sectional analysis and functioned as a mediator of the impact of vocabulary knowledge at all levels. The direct effect of vocabulary was strong but lower in magnitude at each successive grade level from .58 in grade 6 to .41 in grade 10 while the indirect effect through spelling increased in magnitude at each successive grade level from .09 in grade 6 to .16 in grade 10. There were no significant differences between the language groups in the magnitude of the indirect impact, suggesting both groups of students relied more on both sources of lexical information in higher grades as compared to students in lower grades.

Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen-deuterium exchange coupled with mass spectrometry revealed global nucleotide- and membrane-binding-dependent conformational changes, as well as the existence of an allosteric relay element in the α2(S) helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a 'closed' conformation docked near the stalk to an 'open' conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross-linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self-assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy-causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin-catalyzed membrane fission., (© 2016 The Authors.)

A temporally acute binaural system can help to resolve inherent fluctuations in binaural information that are often present in complex auditory scenes. Using a broadband noise stimulus that rapidly alternates between two different values of interaural time difference (ITD), the ability of the binaural system to hear the lateral position resulting from one of the ITD values was investigated. Results show that listeners are able to accurately lateralize brief noise tokens of only 3-7 ms in duration. In two subsequent experiments, the role of an amplitude modulation (AM) imposed on the ITD-switching stimulus used in the first experiment was tested. For wideband stimuli, the temporal position of the ITD target relative to the phase of the AM did not influence absolute lateralization or detection performance. When the stimuli were narrowband, however, detection of the ITD target was best when temporally positioned in the rising portion of the AM. These experiments illustrate that the auditory system is capable of making accurate lateral estimates of very brief moments of ITD information. Furthermore, for these instantaneous changes in ITD information, the stimulus bandwidth can influence the role of envelope cues for the readout of binaural information.

The majority of everyday listening situations involve a complex mixture of multiple sound sources. Assuming a spectro-temporally sparse target signal, e.g., speech, the binaural cues in these complex listening environments do not simply result from a single sound source, but are often rapidly switching between the most dominant sources at any given moment. To investigate the perception of rapidly switching interaural time difference (ITD) cues, a noise stimulus that periodically alternates between two different values of ITD was created. This stimulus appears to evoke a purely binaural percept of modulation, which is the focus of the studies presented here. Results indicate that listeners can reliably discriminate this ITD-switching stimulus from a stimulus composed of stationary ITD cues. Frequency discrimination of this ITD-switching stimulus was tested in a separate experiment, which showed that listeners are generally able to discriminate a 50% change in modulation frequency for reference rates below 16 Hz. The final study investigated if modulation masking exists between the monaural and binaural auditory pathways. Although a statistically significant increase in modulation detection thresholds was observed when both types of modulations were presented together, the increase was relatively small, indicating only a weak interaction.

The interaural level difference (ILD) of a lateralized target source may be effectively reduced when the target is presented together with background noise containing zero ILD. It is not certain whether listeners perceive a position congruent with the reduced ILD or the actual target ILD in a lateralization task. Two sets of behavioral experiments revealed that many listeners perceived a position at or even larger than that corresponding to the presented target ILD when a temporal onset/offset asynchrony between the broadband target and the broadband background noise was present. When no temporal asynchrony was present, however, the perceived lateral position indicated a dependency on the coherence of the background noise for several listeners. With interaurally correlated background noise, listeners reported a reduced ILD resulting from the combined target and background noise stimulus. In contrast, several of the listeners made a reasonable estimate of the position corresponding to the target ILD for interaurally uncorrelated, broadband, background noise. No obvious difference in performance was seen between low- or high-frequency stimuli. Extension of a weighting template to the output of a standard equalization-cancellation model was shown to remove a lateral bias on the predicted target ILD resulting from the presence of background noise. Provided that an appropriate weighting template is applied based on knowledge of the background noise coherence, good prediction of the behavioral data is possible.

A synthesis of the extant research on peer-mediated reading and math interventions for students in regular or alternative education settings with academic difficulties and disabilities in Grades 6 to 12 (ages 11-18) is presented. Interventions conducted between 2001 and 2012 targeting reading and math were included if they measured effects on at least one academic outcome measure. A total of 13 intervention studies were synthesized in which 10 studies employed an experimental or quasi-experimental design and three studies used a single-case design. Findings from the 13 studies revealed mostly moderate to high effects favoring peer mediation, particularly when implementing a peer-mediated feedback component. In addition, findings suggest such interventions have social validity among adolescents and teachers. More rigorous research on secondary peer-mediated math interventions, peer-mediated interventions in alternative settings, and effective ways to pair dyads to incorporate a structured feedback component is warranted. Implications for peer-mediated instruction for academically struggling adolescents are discussed., (© Hammill Institute on Disabilities 2013.)

Smoking and obesity increases renal oxidative stress via nicotine (NIC) or free fatty acid such as oleic acid (OA) but decreases levels of the vitamin E-derivative α-tocopherol (TOC), which has shown to stimulate the antioxidant system such as heme oxygenase-1 (HO-1). Hence, we hypothesized that supplementation of TOC may protect renal proximal tubules from NIC- or OA-mediated oxidative stress by upregulating the HO-1 gene. NIC- or OA-dependent production of reactive oxygen species (ROS) was determined in the presence or absence of various pharmacologic or genetic inhibitors that modulate HO-1 activation and enhancer elements in the HO-1 promoter such as the antioxidant response element (ARE) and the cAMP-response element (CRE) in renal proximal tubule cells (NRK52E). Activity of the HO-1 promoter, the ARE and the CRE was determined in luciferase assays. We found that pre- or posttreatment with TOC attenuated NIC- or OA-dependent ROS production that required HO-1 activation. TOC activated the HO-1 promoter via the CRE but not the ARE enhancer through the extracellular signal-regulated kinase (ERK) and protein kinase A (PKA). Consequently, inhibitors of ERK, PKA, or CRE activation mitigated beneficial effects of TOC on NIC- or OA-mediated ROS production. Hence, vitamin E supplementation-via induction of the cytoprotective HO-1-may help to reduce renal oxidative stress imposed by smoking or obesity.

Background/aim: Gender-associated dimorphism in renal oxidative stress may be related to the protective effects of estrogens or the adverse effects of testosterone. Signal transducer and activator of transcription-3 (STAT3)-dependent transcription is vital in renal antioxidant responses, which may be differentially regulated by sex hormones., Materials and Methods: Renal proximal tubule cells were treated with 400 μM H2O2 in the presence or absence of 100 nM dihydrotestosterone (DHT), 100 nM 17β-estradiol (E2) or dominant-negative STAT3 (dnSTAT3). Production of reactive oxygen species (ROS), phosphorylation/transcriptional activation of STAT3 and promoter activity of the STAT3-regulated antioxidant gene (MnSOD) were determined., Results: After treatment with H2O2, DHT decreased tyrosine phosphorylation/transcriptional activity of STAT3 and promoter activity of MnSOD while E2 increased them. Consequently, DHT augmented while E2 attenuated ROS production. Effects of dnSTAT3 were similar to DHT., Conclusion: Sex hormones may influence renal oxidative stress through differential regulation of STAT3-dependent antioxidant responses., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Although curriculum based measures of oral reading (CBM-R) have strong technical adequacy, there is still a reason to believe that student performance may be influenced by factors of the testing situation, such as errors examiners make in administering and scoring the test. This study examined the construct-irrelevant variance introduced by examiners using a cross-classified multilevel model. We sought to determine the extent of variance in student CBM-R scores attributable to examiners and, if present, the extent to which it was moderated by students' grade level and English learner (EL) status. Fit indices indicated that a cross-classified random effects model (CCREM) best fits the data with measures nested within students, students nested within schools, and examiners crossing schools. Intraclass correlations of the CCREM revealed that roughly 16% of the variance in student CBM-R scores was associated between examiners. The remaining variance was associated with the measurement level, 3.59%; between students, 75.23%; and between schools, 5.21%. Results were moderated by grade level but not by EL status. The discussion addresses the implications of this error for low-stakes and high-stakes decisions about students, teacher evaluation systems, and hypothesis testing in reading intervention research., (Published by Elsevier Ltd.)

Teacher read-alouds (TRA) are common in middle and high school content area classes. Because the practice of reading the textbook out loud to students is often used out of concern about students' ability to understand and learn from text when reading silently (SR), this randomized controlled trial was designed to experimentally manipulate text reading while blocking on all other instructional elements to determine the relative effects on learning content. Predominantly Spanish-English bilingual twelfth-graders ( n = 123) were randomly assigned to either a TRA or SR condition and provided 1 week of high quality instruction in US history. Daily lessons included teaching key terms in the passage, previewing text headings, and conducting comprehension checks. Results of immediate, 1-week delayed, and 1-month delayed assessments of content learning revealed no significant differences between the two groups. Students were also asked to rate the method of reading they believed best helped them understand and remember information. Students in the SR condition more consistently agreed that reading silently was beneficial. Findings suggest low performing adolescents of different linguistic backgrounds can learn content as well when reading appropriately challenging text silently as when the teacher reads the text aloud to them.

Background/aim: Acute renal injury (AKI) is more prevalent in males than in females perhaps due to adverse effects of testosterone. The oxidant sensor p66shc is regulated by testosterone, hence may be responsible for the aforementioned gender disparity., Materials and Methods: Wild-type or p66shc-knockdown renal proximal tubule cells were treated with 400 μM H2O2 in the presence or absence of 100 nM dihydrotestosterone (DHT); the production of reactive oxygen species and cell injury were determined. The impact of DHT on p66shc expression and promoter activity as well as gender-dependent expression of p66shc in the mouse kidney was also determined., Results: DHT increased H2O2-dependent oxidative stress and injury via p66shc and expression of p66shc via promoter activation. Renal expression of p66shc was higher in male compared to female kidneys., Conclusion: Higher sensitivity of the male kidney to AKI may be due to the testosterone-dependent increase in p66shc expression.

Background: Chronic nicotine (Ch-NIC) exposure exacerbates ischemia/reperfusion (I/R)-induced oxidative stress and acute kidney injury (AKI), and mitochondrial production of reactive oxygen species (ROS) in cultured renal proximal tubule cells (RPTCs). Because Ser36-phosphorylated p66shc modulates mitochondrial ROS production and injury of RPTCs, we hypothesized that Ch-NIC exacerbates AKI by increasing stress-induced phosphorylation of p66shc., Methods: We first tested whether Ch-NIC augments I/R-AKI-induced expression and phosphorylation of p66shc in vivo. We then examined whether knocking down p66shc, or impairing its Ser36 phosphorylation or binding to cytochrome c, alters the effects of Ch-NIC on oxidative stress (H₂O₂)-induced production of ROS, mitochondrial depolarization and injury in RPTCs in vitro., Results: We found that Ch-NIC increased the expression of p66shc in the control and ischemic kidneys, but only increased its Ser36 phosphorylation after renal I/R. Knocking down p66shc or impairing phosphorylation of its Ser36 residue, via the S36A mutation (but not the phosphomimetic S36D mutation), blunted Ch-NIC + H2O2-dependent ROS production, mitochondrial depolarization and injury in RPTCs. Additionally, Ch-NIC + H2O2-dependent binding of p66shc to mitochondrial cytochrome c was attenuated by S36A mutation of p66shc, and impairing cytochrome c binding (via W134F mutation) abolished ROS production, mitochondrial depolarization and injury, while ectopic overexpression of p66shc (which mimics Ch-NIC treatment) augmented oxidant injury. We determined that Ch-NIC stimulates the p66shc promoter through p53- and epigenetic modification (promoter hypomethylation)., Conclusions: Ch-NIC worsens oxidative stress-dependent acute renal injury by increasing expression and consequent oxidative stress-dependent Ser36 phosphorylation of p66shc. Thus, targeting this pathway may have therapeutic relevance in preventing/ameliorating tobacco-related kidney injury.

Background/aims: Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease. Pathologic consequences of obesity include non-esterified fatty acid-induced oxidative stress and consequent injury. Since the serine36-phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells., Methods: Renal proximal tubule cells were used and treated with OA: ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c binding-deficient cells., Results: We found that OA increased ROS production via the mitochondria - and to a less extent via the NADPH oxidase - resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA-dependent lipotoxicity., Conclusion: These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity., (Copyright © 2013 S. Karger AG, Basel.)

Background/aim: Cisplatin nephrotoxicity includes early activation of the pro-apoptotic p66Shc and disorganization of the actin cytoskeleton, integrity which is regulated by heat-shock protein-27 (Hsp27). Here we determined the potential role of p66Shc in abrogating the Hsp27 function., Materials and Methods: Effects of p66Shc knockdown and Hsp27 overexpression on F-actin stress fibers after cisplatin treatment were visualized by phalloidin staining. Binding of p66Shc to Hsp27 after cisplatin treatment was determined by immunoprecipitation in cell and tissue lysates. The role of p66Shc and its Ser36 phosphorylation in Hsp27 binding was assessed by overexpressing it or mutating its Ser36 residue., Results: Knockdown of p66Shc and overexpression of Hsp27 ameliorated cisplatin-mediated collapse of the actin cytoskeleton. Further studies revealed that p66Shc binds Hsp27 after treatment with cisplatin that requires Ser36 phosphorylation of p66Shc., Conclusion: We propose a novel function of p66Shc that, through interacting with Hsp27, accelerates cisplatin-dependent disruption of the actin cytoskeleton.

In this study, the authors examined the validity of a holistically scored retell within a confirmatory factor analysis framework by comparing the fit of a three-factor model of reading with the data from a diverse sample of seventh and eighth graders. The final model demonstrated adequate fit, χ(2)(32) = 97.316; comparative fit index = .96; Tucker-Lewis index = .94; and root mean square error of approximation = .08. Retell's chi-square difference, Δχ(2)(1) = 16.652, p < .001, and factor loading (.250, p < .001) were higher for the comprehension construct. Similarly, retell's correlation to comprehension measures (r = .155-.257, p < .01) was stronger than its relationship to measures of fluency (r = .158-.183, p < .01) or word identification (r = .132, p < .05). However, retell had a large residual variance (.938) and low interrater reliability (κ = .37), suggesting that improvements to the instrument are needed. Despite overall latent differences, retell did not demonstrate differential item functioning.

Previous data from our group have demonstrated (Arany I, Grifoni S, Clark JS, Csongradi, Maric C, Juncos LA. Am J Physiol Renal Physiol 301: F125-F133, 2011) that chronic nicotine (NIC) exposure exacerbates acute renal ischemic injury (AKI) in mice that could increase the risk for development and progression of chronic kidney disease (CKD). It has been shown that proximal tubules of the kidney can acquire characteristics that may compromise structural recovery and favor development of inflammation and fibrosis following injury. Chronic NIC exposure can amplify this epithelial process although the mechanism is not identified. Recently, the unphosphorylated form of signal transducer and activator of transcription-3 (U-STAT3) has emerged as a noncanonical mediator of inflammation and fibrosis that may be responsible for the effects of chronic NIC. We found that levels of transforming growth factor β-1 (TGF-β1), α-smooth muscle actin (α-SMA), fibronectin, monocyte chemotactic protein-1 (MCP-1), and expression of U-STAT3 were increased in the ischemic kidneys of NIC-exposed mice. Chronic NIC exposure also increased TGF-β1-dependent F-actin reorganization, vimentin, fibronectin, and α-SMA expression as well as promoter activity of α-SMA and MCP-1 without significant loss of epithelial characteristics (E-cadherin) in cultured renal proximal tubule cells. Importantly, transduction of cells with a U-STAT3 mimetic (Y705F-STAT3) augmented stress fiber formation and also amplified NIC+TGF-β1-induced expression of α-SMA, vimentin, fibronectin, as well as promoter activity of α-SMA and MCP-1. Our results reveal a novel, chronic NIC-exposure-related and U-STAT3-dependent mechanism as mediator of a sustained transcription of genes that are linked to remodeling and inflammation in the kidney during injury. This process may facilitate progression of AKI to CKD. The obtained data may lead to devising therapeutic methods to specifically enhance the protective and/or inhibit adverse effects of STAT3 in the kidney.

This study examined whether the type of prompt or the method of passage reading had an effect on the retell performance of 6th-8th graders randomly assigned to one of four retell testing conditions. Both the type of prompt and the use of follow-up prompting were significantly related to the percentage of predetermined idea units retold. Effect sizes were approximately moderate ( d = .44-.62) when one change was made to the prompt but were strong ( d = .96-1.05) with a combination of changes. The addition of silent reading did not significantly improve performance.

The purpose of this narrative synthesis is to determine the reliability and validity of retell protocols for assessing reading comprehension of students in grades K-12. Fifty-four studies were systematically coded for data related to the administration protocol, scoring procedures, and technical adequacy of the retell component. Retell was moderately correlated with standardized measures of reading comprehension and, with older students, had a lower correlation with decoding and fluency. Literal information was retold more frequently than inferential, and students with learning disabilities or reading difficulties needed more supports to demonstrate adequate recall. Great variability was shown in the prompting procedures, but scoring methods were more consistent across studies. The influences of genre, background knowledge, and organizational features were often specific to particular content, texts, or students. Overall, retell has not yet demonstrated adequacy as a progress monitoring instrument.

The lack of a mouse model has hampered an understanding of the pathogenesis and immunity of Marburg hemorrhagic fever (MHF), the disease caused by marburgvirus (MARV), and has created a bottleneck in the development of antiviral therapeutics. Primary isolates of the filoviruses, i.e., ebolavirus (EBOV) and MARV, are not lethal to immunocompetent adult mice. Previously, pathological, virologic, and immunologic evaluation of a mouse-adapted EBOV, developed by sequential passages in suckling mice, identified many similarities between this model and EBOV infections in nonhuman primates. We recently demonstrated that serially passaging virus recovered from the liver homogenates of MARV-infected immunodeficient (SCID) mice was highly successful in reducing the time to death in these mice from 50 to 70 days to 7 to 10 days after challenge with the isolate MARV-Ci67, -Musoke, or -Ravn. In this study, we extended our findings to show that further sequential passages of MARV-Ravn in immunocompetent mice caused the MARV to kill BALB/c mice. Serial sampling studies to characterize the pathology of mouse-adapted MARV-Ravn revealed that this model is similar to the guinea pig and nonhuman primate MHF models. Infection of BALB/c mice with mouse-adapted MARV-Ravn caused uncontrolled viremia and high viral titers in the liver, spleen, lymph node, and other organs; profound lymphopenia; destruction of lymphocytes within the spleen and lymph nodes; and marked liver damage and thrombocytopenia. Sequencing the mouse-adapted MARV-Ravn strain revealed differences in 16 predicted amino acids from the progenitor virus, although the exact changes required for adaptation are unclear at this time. This mouse-adapted MARV strain can now be used to develop and evaluate novel vaccines and therapeutics and may also help to provide a better understanding of the virulence factors associated with MARV.

Alzheimer's disease (AD) is characterized by large numbers of senile plaques in the brain that consist of fibrillar aggregates of 40- and 42-residue amyloid-beta (Abeta) peptides. However, the degree of dementia in AD correlates better with the concentration of soluble Abeta species assayed biochemically than with histologically determined plaque counts, and several investigators now propose that soluble aggregates of Abeta are the neurotoxic agents that cause memory deficits and neuronal loss. These endogenous aggregates are minor components in brain extracts from AD patients and transgenic mice that express human Abeta, but several species have been detected by gel electrophoresis in sodium dodecylsulfate (SDS) and isolated by size exclusion chromatography (SEC). Endogenous Abeta aggregation is stimulated at cellular interfaces rich in lipid rafts, and anionic micelles that promote Abeta aggregation in vitro may be good models of these interfaces. We previously found that micelles formed in dilute SDS (2 mM) promote Abeta(1-40) fiber formation by supporting peptide interaction on the surface of a single micelle complex. In contrast, here we report that monomeric Abeta(1-42) undergoes an immediate conversion to a predominant beta-structured conformation in 2 mM SDS which does not proceed to amyloid fibrils. The conformational change is instead rapidly followed by the near quantitative conversion of the 4 kDa monomer SDS gel band to 8-14 kDa bands consistent with dimers through tetramers. Removal of SDS by dialysis gave a shift in the predominant SDS gel bands to 30-60 kDa. While these oligomers resemble the endogenous aggregates, they are less stable. In particular, they do not elute as discrete species on SEC, and they are completed disaggregated by boiling in 1% SDS. It appears that endogenous oligomeric Abeta aggregates are stabilized by undefined processes that have not yet been incorporated into in vitro Abeta aggregation procedures.

The filoviruses, Ebola (EBOV) and Marburg (MARV), cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by performing 9 sequential passages in progressively older mice (suckling to adult). Evaluation of this model identified many similarities between infection in mice and nonhuman primates, including viral tropism for antigen-presenting cells, high viral titers in the spleen and liver, and an equivalent mean time to death. Existence of the EBOV mouse model has increased our understanding of host responses to filovirus infections and likely has accelerated the development of countermeasures, as it is one of the only hemorrhagic fever viruses that has multiple candidate vaccines and therapeutics. Here, we demonstrate that serially passaging liver homogenates from MARV-infected severe combined immunodeficient (scid) mice was highly successful in reducing the time to death in scid mice from 50-70 days to 7-10 days after MARV-Ci67, -Musoke, or -Ravn challenge. We performed serial sampling studies to characterize the pathology of these scid mouse-adapted MARV strains. These scid mouse-adapted MARV models appear to have many similar properties as the MARV models previously developed in guinea pigs and nonhuman primates. Also, as shown here, the scid-adapted MARV mouse models can be used to evaluate the efficacy of candidate antiviral therapeutic molecules, such as phosphorodiamidate morpholino oligomers or antibodies.

A number of hypotheses regarding how anti-Abeta antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Abeta immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Abeta levels after a single peripheral dose of anti-Abeta antibodies to both wild-type (WT) and young non-Abeta depositing APP and BRI-Abeta42 mice. The rapid rise in plasma Abeta observed after antibody (Ab) administration is attributable to prolongation of the half-life of Abeta bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Abeta, we find no evidence that total brain Abeta levels are significantly altered. Surprisingly, cerebral spinal fluid Abeta levels transiently rise, and when Ab:Abeta complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Abeta, these data provide a framework to evaluate proposed mechanisms of Abeta attenuation mediated by peripheral administration of an anti-Abeta monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Abeta or targeting a low abundance aggregation intermediate.

Alzheimer's disease (AD) is characterized by the presence of large numbers of fibrillar amyloid deposits in the form of senile plaques in the brain. The fibrils in senile plaques are composed of 40- and 42-residue amyloid-beta (Abeta) peptides. Several lines of evidence indicate that fibrillar Abeta and especially soluble Abeta aggregates are important in the pathogenesis of AD, and many laboratories have investigated soluble Abeta aggregates generated from monomeric Abeta in vitro. Of these in vitro aggregates, the best characterized are called protofibrils. They are composed of globules and short rods, show primarily beta-structure by circular dichroism (CD), enhance the fluorescence of bound thioflavin T, and readily seed the growth of long fibrils. However, one difficulty in correlating soluble Abeta aggregates formed in vitro with those in vivo is the high probability that cellular interfaces affect the aggregation rates and even the aggregate structures. Reports that focus on the features of interfaces that are important in Abeta aggregation have found that amphiphilic interactions and micellar-like Abeta structures may play a role. We previously described the formation of Abeta(1-40) aggregates at polar-nonpolar interfaces, including those generated at microdroplets formed in dilute hexafluoro-2-propanol (HFIP). Here we compared the Abeta(1-40) aggregates produced on sodium dodecyl sulfate (SDS) micelles, which may be a better model of biological membranes with phospholipids that have anionic headgroups. At both HFIP and SDS interfaces, changes in peptide secondary structure were observed by CD immediately when Abeta(1-40) was introduced. With HFIP, the change involved an increase in predominant beta-structure content and in fluorescence with thioflavin T, while with SDS, a partial alpha-helical conformation was adopted that gave no fluorescence. However, in both systems, initial amorphous clustered aggregates progressed to soluble fibers rich in beta-structure over a roughly 2 day period. Fiber formation was much faster than in the absence of an interface, presumably because of the close intermolecular proximity of peptides at the interfaces. While these fibers resembled protofibrils, they failed to seed the aggregation of Abeta(1-40) monomers effectively.

The deposition of aggregated amyloid-beta (Abeta) peptides in the brain as senile plaques is a pathological hallmark of Alzheimer's disease (AD). Several lines of evidence indicate that fibrillar and, in particular, soluble aggregates of these 40- and 42-residue peptides are important in the etiology of AD. Recent studies also stress that amyloid aggregates are polymorphic and that a single polypeptide can fold into multiple amyloid conformations. Here we review our recent reports that Abeta(1-40) in vitro can form soluble aggregates with predominant beta-structures that differ in stability and morphology. One class of aggregates involved soluble Abeta protofibrils, prepared by vigorous overnight agitation of monomeric Abeta(1-40) in low ionic strength buffers. These aggregates were quite stable and disaggregated to only a limited extent on dilution. A second class of soluble Abeta aggregates was generated at polar-nonpolar interfaces. Aggregation in a two-phase system of buffer over chloroform occurred more rapidly than in buffer alone. In buffered 2% hexafluoroisopropanol (HFIP), microdroplets of HFIP were formed and the half-time for aggregation was less than 10 minutes. Like Abeta protofibrils, these interfacial aggregates showed increased thioflavin T fluorescence and were rich in beta-structure by circular dichroism. However, electron microscopy and atomic force microscopy revealed very different morphologies. The HFIP aggregates formed initial globular clusters that progressed over several days to soluble fibrous aggregates. When diluted out of HFIP these aggregates initially were very unstable and disaggregated completely within 2 minutes. However, their stability increased as they progressed to fibers. It is important to determine whether similar interfacial Abeta aggregates are produced in vivo.