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The quality of interventions for children with autism has improved thanks in part to the widespread dissemination of evidence-based practices (EBPs); however, teachers still report challenges developing focused interventions targeting the core challenges of students with autism. Tested in three randomized trials, COMPASS is a consultation-based implementation strategy that prioritizes shared decision-making in the development of goals and intervention plans using an evidence-based practice in psychology approach. To successfully train COMPASS consultants, a 16-item Intervention Plan Quality Scale (IPQS) was developed and tested with a set of nine school-based COMPASS-trained consultants who provided a total of 28 consultations. Results revealed that the IPQS had acceptable reliability and concurrent validity and was successful in helping consultant trainees develop high-quality plans over four feedback sessions. Overall, the IPQS was helpful for fidelity monitoring and appears to partially mediate child goal attainment outcomes through teacher adherence implementing the intervention plans.

Little is known about differences in dosage or feedback that make teacher coaching effective in relation to teacher and student outcomes. This study builds upon previous research on the Collaborative Model for Promoting Competence and Success (COMPASS) to understand the impact of different types (face-to-face coaching vs. emailed feedback) and dosages (one vs. two or four) of performance feedback compared to receiving no feedback following an initial consultation during which intervention plans were developed. Findings suggest that teacher adherence and student goal-attainment outcomes depend on dosage, not type of coaching. Specifically, having two or four opportunities for performance feedback was significantly better than having none or only one opportunity. Ratings of teacher adherence and student goal attainment delivered via emailed feedback or face-to-face coaching were similar, which may have important implications for cost and efficiency. While preliminary, the results are promising and warrant further research. Implications are also discussed.

School-based service providers must understand how to best measure academic skill development given its key role in improving long-term outcomes for individuals with autism spectrum disorder (ASD). Curriculum-based measurement (CBM), which has applications for foundational academic skill areas of reading, writing, and mathematics, may be one way to determine academic intervention targets and progress monitor academic skills for students with ASD, but the extent of the literature base is unknown. Results of this scoping review regarding use of CBM with autistic students indicated few studies, overall. Studies had a wide range of sample sizes and primarily focused on intervention, using CBM as progress or outcome measures. Numerous demographic characteristics and study elements were absent from the literature. Future directions for this area of research and the implications for assessment in response to instruction for students with ASD are presented.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but research in humans has been constrained by the difficulty of examining hippocampal function during early development. In the present study, we assessed 48 2-year-olds with a novel paradigm in which participants completed two games on a tablet that required remembering associations between unique characters, the places they visited, and the temporal order with which they did so. At the completion of each game, a unique, novel song played. Toddlers remembered spatial locations better than temporal order during an immediate test, after a 20-minute delay, and after a week delay. After the last behavioral session, toddlers underwent an fMRI task during natural nocturnal sleep evaluating hippocampal activation in response to learned and novel songs. We found that the extent of hippocampal activation for learned songs compared to novel songs during sleep was correlated with memory for temproal order across all time delays, but not with memory for spatial locations. The results confirm that that the functional contribution of the hippocampus to early memory can be assessed during sleep and suggest that assessment of temporal aspects of memory in the current task best capture this contribution.

Although individuals with autism spectrum disorder (ASD) have been often shown to display similar memory performance on semantic memory tasks compared to typically developing (TD) children, there is ongoing debate about whether and how their ability to remember specific past events (i.e., episodic memory) is impaired. We assessed a sample of 62 children with ASD and 72 TD children, ranging in age between 8 and 12 years on 2 memory tasks. Participants encoded a series of images and their association with either where they appeared on the screen (item-space association task) or with the color of an image's border (item-color association task). Children with ASD showed worse memory in the item-space association task compared to their TD peers, but comparable memory for the item-color association task. These differences persisted when age, intellectual quotient, and general item recognition memory were accounted for statistically. We interpret these results in light of evidence for specific deficits along the dorsal stream affecting processing of spatiotemporal information in ASD. Autism Res 2020, 13: 1985-1997. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Episodic memory requires the ability to bind contextual details (such as color, location, etc.) to an item or event in order to remember the past with specific detail. Here, we compared children with autism spectrum disorder (ASD) and typically developing (TD) children on tasks examining episodic memory. Children with ASD recalled more poorly previously seen items and their associated space-related details, but they performed comparably to TD children on color details. We discuss the possible mechanisms that contribute to worse spatial processing/recall in ASD.

The autophagy-initiating human ULK complex consists of the kinase ULK1/2, FIP200, ATG13, and ATG101. Hydrogen-deuterium exchange mass spectrometry was used to map their mutual interactions. The N-terminal 640 residues (NTD) of FIP200 interact with the C-terminal IDR of ATG13. Mutations in these regions abolish their interaction. Negative stain EM and multiangle light scattering showed that FIP200 is a dimer, while a single molecule each of the other subunits is present. The FIP200NTD is flexible in the absence of ATG13, but in its presence adopts the shape of the letter C ∼20 nm across. The ULK1 EAT domain interacts loosely with the NTD dimer, while the ATG13:ATG101 HORMA dimer does not contact the NTD. Cryo-EM of the NTD dimer revealed a structural similarity to the scaffold domain of TBK1, suggesting an evolutionary similarity between the autophagy-initiating TBK1 kinase and the ULK1 kinase complex.

Acadience Reading (AR) is a screener for early detection of reading problems in elementary students. Limited research exists, however, on its technical adequacy for evaluation of English Learners (ELs). In this study, we tested the long-term predictive validity and diagnostic accuracies of AR and examined the differences between native English-speaking and EL students. A sample of 305 students (94 ELs, 31% of the sample) completed AR at three time points in kindergarten and the statewide reading test in third grade. Hierarchical regression models confirmed good long-term validity for AR with end of the school year scores outperforming the other two time-points and EL status along with ethnic background not playing a significant role. Findings also revealed that AR at the end of the school year provided moderate long-term diagnostic accuracy for students well below benchmark. Implications for research and practice as well as limitations of the study are discussed.

Episodic memory, or the ability to remember past events with specific detail, is central to the human experience and is related to learning and adaptive functioning in a variety of domains. In typically developing children, episodic memory emerges during infancy and improves during early childhood and beyond. Developmental processes within the hippocampus are hypothesized to be primarily responsible for both the early emergence and persistence of episodic memory in late infancy and early childhood. However, these hypotheses are based on non-human models. In-vivo investigations in early human development of hippocampal processes have been significantly limited by methodological challenges in acquiring neuroimaging data, particularly task-related functional neuroimaging data, from infants and toddlers. Recent studies in adults have shown neural activity in the brain regions supporting episodic memory during slow-wave sleep using functional magnetic resonance imaging (fMRI), and fMRI has been increasingly utilized in infancy and early childhood to address other research questions. We review initial evidence and present preliminary data showing the promise of this approach for examining hippocampal contribution to how infants and toddlers remember individual events, and their association with information about the context in which the event occurred. Overall, our review, integrated with the presentation of some preliminary data provides insight on leveraging sleep to gain new perspectives on early memory functioning.

The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagAGDP:RagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo-electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.

Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the proautophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryoelectron microscopy was used to visualize a 2-step PI3KC3-C1 activation pathway driven by NRFB2 MIT domain binding. Binding of a single NRBF2 MIT domain bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes.

Gram-negative pathogens expressing serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all β-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low μM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 μg/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery.

Aim: Maintaining biodiversity in the face of land use and climate change is a paramount challenge, particularly when distributions of many species remain incompletely known. Emerging technologies help address this data deficiency by facilitating the collection of spatially explicit data for multiple species from multiple taxa. In this study, we combine acoustic and visual sensor surveys to inform conservation and land use planning in an area experiencing rapid climate and land use change. Location: Mojave Desert, California, United States. Methods: We deployed camera traps and acoustic detectors at 210 sites between March and July 2016. We identified photographic detections of mammals and acoustic recordings of songbirds to the species level and used multispecies occupancy models to estimate and evaluate species' occupancy probabilities. We then extrapolated model results to the region and forecasted how projected climate and land use changes might affect species' occupancy probabilities in 50 years. Lastly, we identified areas with high conservation value (i.e., high relative species richness) now and in 50 years, and related the distributions of these areas to land use designations. Results: We detected 15 mammal and 68 songbird species. At the community level, occupancy decreased with increasing temperatures and distances to woodlands. We forecasted that occupancy probabilities and areas with high conservation value would decline in 50 years due to projected increases in maximum temperatures and identified that up to 43%, 24% and 27% of land designated for renewable energy development, recreation and military activities, respectively, encompassed these high value areas. Main conclusions: Cooler areas close to woodlands and water are of high conservation value to mammals and songbirds in the Mojave. These areas will become increasingly limited with changing climate, however, making their protection from human disturbance imperative. We encourage continued use of visual and acoustic sensors across large spatial, temporal and taxonomic scales as tools to inform land use and wildlife conservation.

Macroautophagy/autophagy is an evolutionarily conserved degradation system with fundamental biological functions. The activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complexes and the subsequent production of phosphatidylinositol 3-phosphate (PtdIns3P) are pivotal to autophagy. Using a combination of structural biology, biochemistry, and biophysics, we revealed how the non-catalytic subunit BECN1 serves as a membrane-binding switch in the regulation of PtdIns3K complexes and autophagy.

This study investigates factors that influenced the science, technology, engineering and mathematics (STEM) subject enrolment decisions of Year 12 students in Australia. Structural equation modelling (SEM) is used to develop a model using Programme for International Student Assessment (PISA) and Longitudinal Surveys of Australian Youth (LSAY) data with participating students (N = 7442) from 356 schools. An adapted version of the theory of planned behaviour (TPB), a behavioural prediction model, is used as the guiding conceptual framework. Students' demographic background, attitudes towards science and achievement in science and mathematics at age 15 are used as predictors for subsequent enrolment in STEM subjects in Year 12. Gender, socio-economic status (SES) and immigrant status (native vs. non-native) are shown to be contributing factors. The personal value of science, enjoyment of science, self-concept in science and achievement (mathematics and science) are mediating factors in the model. These findings provide schools, policymakers and educational advisors with a greater understanding of the factors that influence Australian students' decisions of whether to enrol in a STEM subject at Year 12. Evidence provided allows key stakeholders to take a more targeted approach to enhance STEM participation for students from varying demographic backgrounds.

Membrane targeting of the BECN1-containing class III PI 3-kinase (PI3KC3) complexes is pivotal to the regulation of autophagy. The interaction of PI3KC3 complex II and its ubiquitously expressed inhibitor, Rubicon, was mapped to the first β sheet of the BECN1 BARA domain and the UVRAG BARA2 domain by hydrogen-deuterium exchange and cryo-EM. These data suggest that the BARA β sheet 1 unfolds to directly engage the membrane. This mechanism was confirmed using protein engineering, giant unilamellar vesicle assays, and molecular simulations. Using this mechanism, a BECN1 β sheet-1 derived peptide activates both PI3KC3 complexes I and II, while HIV-1 Nef inhibits complex II. These data reveal how BECN1 switches on and off PI3KC3 binding to membranes. The observations explain how PI3KC3 inhibition by Rubicon, activation by autophagy-inducing BECN1 peptides, and inhibition by HIV-1 Nef are mediated by the switchable ability of the BECN1 BARA domain to partially unfold and insert into membranes.

The neural correlates distinguishing youth with Autism Spectrum Disorder (ASD-) and ASD with co-occurring Attention Deficit Hyperactivity Disorder (ASD+) are poorly understood despite significant phenotypic and prognostic differences. Paired-pulse transcranial magnetic stimulation (TMS) measures, including intracortical facilitation (ICF), short interval cortical inhibition (SICI), and cortical silent period (CSP) were measured in an age matched cohort of youth with ASD- (n = 20), ASD + (n = 29), and controls (TDC) (n = 24). ASD- and ASD+ groups did not differ by IQ or social functioning; however, ASD+ had significantly higher inattention and hyperactivity ratings. ICF (higher ratio indicates greater facilitation) in ASD+ (Mean 1.0, SD 0.19) was less than ASD- (Mean 1.3, SD 0.36) or TDC (Mean 1.2, SD 0.24) (F2,68 = 6.5, p = 0.003; post-hoc tests, ASD+ vs either TDC or ASD-, p ≤ 0.05). No differences were found between groups for SICI or age corrected active/resting motor threshold (AMT/RMT). Across all ASD youth (ASD- and ASD+), ICF was inversely correlated with worse inattention (Conners-3 Inattention (r = -0.41; p

CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived noncovalent inhibitor of CTX-M-9. Here, we present the biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while it exhibited some low-level inhibition of other serine β-lactamases. Complex crystal structures with the CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active-site residues on the β3 strand. In vitro pharmacokinetic studies revealed drug-like properties and positive prospects for further optimization. These studies suggest that tetrazole-based compounds can provide novel chemotypes for future serine β-lactamase inhibitor discovery.

The purpose of this paper is to introduce educators to three types of applets that are compatible with smartphones, tablets, and desktop computers: screencasting applets, graphing calculator applets, and student response applets. The applets discussed can be seamlessly and effectively integrated into classrooms to help facilitate lectures, collect assessment data, and provide students with additional instructional support. While three specific applets will be discussed, there are many applets available, each with diverse features, varying capabilities, and different price points. In addition to discussing various applications of each type of applet, the authors will share their experiences with using these technologies in the classroom and disclose some tricks-of-the-trade.

Attempts to alter intestinal dysbiosis via administration of probiotics have consistently shown that colonization with the administered microbes is transient. This study sought to determine whether provision of an initial course of Bifidobacterium longum subsp. infantis (B. infantis) would lead to persistent colonization of the probiotic organism in breastfed infants. Mothers intending to breastfeed were recruited and provided with lactation support. One group of mothers fed B. infantis EVC001 to their infants from day 7 to day 28 of life (n = 34), and the second group did not administer any probiotic (n = 32). Fecal samples were collected during the first 60 postnatal days in both groups. Fecal samples were assessed by 16S rRNA gene sequencing, quantitative PCR, mass spectrometry, and endotoxin measurement. B. infantis-fed infants had significantly higher populations of fecal Bifidobacteriaceae, in particular B. infantis, while EVC001 was fed, and this difference persisted more than 30 days after EVC001 supplementation ceased. Fecal milk oligosaccharides were significantly lower in B. infantis EVC001-fed infants, demonstrating higher consumption of human milk oligosaccharides by B. infantis EVC001. Concentrations of acetate and lactate were significantly higher and fecal pH was significantly lower in infants fed EVC001, demonstrating alterations in intestinal fermentation. Infants colonized by Bifidobacteriaceae at high levels had 4-fold-lower fecal endotoxin levels, consistent with observed lower levels of Gram-negative Proteobacteria and Bacteroidetes. IMPORTANCE The gut microbiome in early life plays an important role for long-term health and is shaped in large part by diet. Probiotics may contribute to improvements in health, but they have not been shown to alter the community composition of the gut microbiome. Here, we found that breastfed infants could be stably colonized at high levels by provision of B. infantis EVC001, with significant changes to the overall microbiome composition persisting more than a month later, whether the infants were born vaginally or by caesarean section. This observation is consistent with previous studies demonstrating the capacity of this subspecies to utilize human milk glycans as a nutrient and underscores the importance of pairing a probiotic organism with a specific substrate. Colonization by B. infantis EVC001 resulted in significant changes to fecal microbiome composition and was associated with improvements in fecal biochemistry. The combination of human milk and an infant-associated Bifidobacterium sp. shows, for the first time, that durable changes to the human gut microbiome are possible and are associated with improved gut function.

BackgroundAngelman syndrome (AS) is a rare neurological disorder characterized by severe developmental disability, communication impairment, elevated seizure risk, and motor system abnormalities.AimsThe aims of this study were to determine the feasibility of social scene eye tracking and pupillometry measures in individuals with AS and to compare the performance of AS participants to individuals with idiopathic Autism Spectrum Disorder (ASD) and typically developing controls (TDC).Methods and proceduresIndividuals with AS and age- and gender- matched controls completed a social eye tracking paradigm. Neurobehavioral characterization of AS participants was completed via a battery of psychological testing and caregiver behavioral evaluations.Outcomes and resultsEight of seventeen recruited AS participants completed the eye tracking paradigm. Compared to TDC, AS subjects demonstrated significantly less preference for social scenes than geometric shapes. Additionally, AS subjects showed less pupil dilation, compared to TDC, when viewing social scenes versus geometric shapes. There was no statistically significant difference found between AS and ASD subjects in either social eye tracking or pupillometry.Conclusions and implicationsThe use of eye tracking and pupillometry may represent an innovative measure for quantifying AS-associated impairments in social salience.

Autophagy is the process of cellular self-eating by a double-membrane organelle, the autophagosome. A range of signaling processes converge on two protein complexes to initiate autophagy: the ULK1 (unc51-like autophagy activating kinase 1) protein kinase complex and the PI3KC3-C1 (class III phosphatidylinositol 3-kinase complex I) lipid kinase complex. Some 90% of the mass of these large protein complexes consists of noncatalytic domains and subunits, and the ULK1 complex has essential noncatalytic activities. Structural studies of these complexes have shed increasing light on the regulation of their catalytic and noncatalytic activities in autophagy initiation. The autophagosome is thought to nucleate from vesicles containing the integral membrane protein Atg9 (autophagy-related 9), COPII (coat protein complex II) vesicles, and possibly other sources. In the wake of reconstitution and super-resolution imaging studies, we are beginning to understand how the ULK1 and PI3KC3-C1 complexes might coordinate the nucleation and fusion of Atg9 and COPII vesicles at the start of autophagosome biogenesis.

The class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) is central to autophagy initiation. We previously reported the V-shaped architecture of the four-subunit version of PI3KC3-C1 consisting of VPS (vacuolar protein sorting) 34, VPS15, BECN1 (Beclin 1), and ATG (autophagy-related) 14. Here we show that a putative fifth subunit, nuclear receptor binding factor 2 (NRBF2), is a tightly bound component of the complex that profoundly affects its activity and architecture. NRBF2 enhances the lipid kinase activity of the catalytic subunit, VPS34, by roughly 10-fold. We used hydrogen-deuterium exchange coupled to mass spectrometry and negative-stain electron microscopy to map NRBF2 to the base of the V-shaped complex. NRBF2 interacts primarily with the N termini of ATG14 and BECN1. We show that NRBF2 is a homodimer and drives the dimerization of the larger PI3KC3-C1 complex, with implications for the higher-order organization of the preautophagosomal structure.

The FOCUS (Fundamentals of Conceptual Understanding and Success) Co-Requisite Model Intervention (FOCUS Intervention) for College Algebra was developed as part of the Developmental Education Demonstration Projects (DEDP) in Texas. The program was designed to use multiple services, courses, and best practices to support student completion of a credit-bearing mathematics course. The curriculum design and instructional strategies of the College Algebra FOCUS band are described and examples are included to expand on the richness of the model. Using repeated measures of students' mathematics proficiency and baseline comparison group data of students' course grades, we present evidence linking the FOCUS Intervention with increased mathematics proficiency, fewer course withdrawals, and improved course grades.

Human rights education is advanced as a method for promoting social responsibility, with an emphasis on promoting ideals of "global citizenship" among undergraduate students. At the same time, the practice of learning communities is widespread on college campuses for retaining freshmen and promoting student success. However, there is limited research on the effectiveness of combining these approaches. In response to this literature gap, this article first provides an overview of key concepts--social responsibility, human rights education, and learning communities--and outlines how these terms are currently understood within higher education. Second, the methods and initial findings of a longitudinal study within Webster University's Social Engagement Learning Community focus on gauging and assessing human rights knowledge and social engagement. Initial findings suggest that most freshmen respondents lack basic human rights knowledge and an activist orientation, yet their empathy and perspective-taking abilities provide foundations for building awareness of human rights issues and social responsibility. Lastly, recommendations are outlined for addressing learning goals related to identity awareness, helping students step outside of their "comfort zones," and promoting awareness and solutions.