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Published in "Language Learning" in 1995, Munro and Derwing's* investigation of foreign accent, comprehensibility, and intelligibility in second language (L2) speech instigated significant change in L2 pronunciation research (Levis, 2020). A key finding was that despite the presence of a foreign accent, listeners could indeed comprehend L2 speech. Within their framework, comprehension of L2 speech was assessed along two dimensions. The first, intelligibility, was an assessment of actual listener comprehension, measured through listener transcriptions of a given utterance. The second, comprehensibility, was a scalar measure of how easy to understand listeners perceived an utterance to be. While these two measures of listener comprehension (i.e., understanding) have been shown to correlate, they have also been shown to measure different forms of understanding (Derwing & Munro, 2015). This means that while increased intelligibility can be associated with increased comprehensibility, it is still common for listeners to accurately transcribe nonnative speech while simultaneously indicating the speech to be hard to understand (i.e., evidence indicates that intelligibility outpaces comprehensibility in the development of L2 pronunciation). Research published in the 25 years since has repeatedly demonstrated that accentedness, comprehensibility, and intelligibility are partially independent dimensions of L2 speech (Munro & Derwing, 2020). Whereas Munro and Derwing's (2011) research timeline attended to the concepts of accent and broad intelligibility (i.e., inclusive of both actual and ease of understanding), the past decade has seen an increased scholarly emphasis specifically on the global speech dimension of "comprehensibility." Given this increased scholarly interest, our timeline is presented with the goal of tracing the post-Munro and Derwing (1995) development of L2 speech comprehensibility research.

In this Brief Report, we describe an evaluation of and revisions to a rubric adapted from the Jacobs et al.'s (1981) ESL COMPOSITION PROFILE, with four rubric categories and 20-point rating scales, in the context of an intensive English program writing placement test. Analysis of 4 years of rating data (2016–2021, including 434 essays) using many-facet Rasch measurement demonstrated that the 20-point rating scales of the Jacobs et al. rubric functioned poorly due to (a) questionably small distinctions in writing quality between successive score categories and (b) the presence of several disordered categories. We reanalyzed the score data after collapsing the 20-point scales into 4-point scales to simulate a revision to the rubric. This reanalysis appeared promising, with well-ordered and distinct score categories, and only a trivial decrease in person separation reliability. After implementing this revision to the rubric, we examined data from recent administrations (2022–2023, including 93 essays) to evaluate scale functioning. As in the simulation, scale categories were well-ordered and distinct in operational rating. Moreover, no raters demonstrated exceedingly poor fit using the revised rubric. Findings hold implications for other programs adopting/adapting the PROFILE or a similar rubric. [ABSTRACT FROM AUTHOR]

Introduction: Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Results: Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages. [ABSTRACT FROM AUTHOR]

We present ZeroEGGS, a neural network framework for speech‐driven gesture generation with zero‐shot style control by example. This means style can be controlled via only a short example motion clip, even for motion styles unseen during training. Our model uses a Variational framework to learn a style embedding, making it easy to modify style through latent space manipulation or blending and scaling of style embeddings. The probabilistic nature of our framework further enables the generation of a variety of outputs given the input, addressing the stochastic nature of gesture motion. In a series of experiments, we first demonstrate the flexibility and generalizability of our model to new speakers and styles. In a user study, we then show that our model outperforms previous state‐of‐the‐art techniques in naturalness of motion, appropriateness for speech, and style portrayal. Finally, we release a high‐quality dataset of full‐body gesture motion including fingers, with speech, spanning across 19 different styles. Our code and data are publicly available at https://github.com/ubisoft/ubisoft‐laforge‐ZeroEGGS. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03–0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4–2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39–0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis. [ABSTRACT FROM AUTHOR]

Author(s): Angeles Pulido [1]; Linjiang Chen [2]; Tomasz Kaczorowski [2]; Daniel Holden [2]; Marc A. Little [2]; Samantha Y. Chong [2]; Benjamin J. Slater [2]; David P. McMahon [1]; Baltasar [...], Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metalorganic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energystructurefunction maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energystructurefunction maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties.

The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo. Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R) -[11C]NR2B-Me, (R) -[18F]OF-Me-NB1, and (S) -[18F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was <2% for (R) -[11C]NR2B-Me and (R) -[18F]OF-Me-NB1 and higher for (S) -[18F]OF-NB1 (15%). All radiotracers showed good brain uptake and distribution throughout grey matter, with substantial (>68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20–40 mL/cm3 for (R) -[11C]NR2B-Me, 8–16 mL/cm3 for (R) -[18F]OF-Me-NB1, and 15–35 mL/cm3 for (S) -[18F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2–3 for (R) -[11C]NR2B-Me and (S) -[18F]-OF-NB1, and 0.5-1 for (R) -[18F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S) -[18F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation. [ABSTRACT FROM AUTHOR]

Purpose: GluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer's disease, and Parkinson's disease. (R)-[18F]OF-Me-NB1 was reported to be more specific and selective than (S)-[18F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF–Me-NB1 in nonhuman primates. Methods: The radiosynthesis of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 started from 18F-fluorination of the boronic ester precursor, followed by removal of the acetyl protecting group. PET scans in two rhesus monkeys were conducted on the Focus 220 scanner. Blocking studies were performed after treatment of the animals with the GluN2B antagonist Co101,244 or the sigma-1 receptor antagonist FTC-146. One-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method with arterial input function were used to obtain the regional volume of distribution (VT, mL/cm3). Occupancy values by the two blockers were obtained by the Lassen plot. Regional non-displaceable binding potential (BPND) was calculated from the corresponding baseline VT and the VND derived from the occupancy plot of the Co101,244 blocking scans. Results: (R)- and (S)-[18F]OF-Me-NB1 were produced in > 99% radiochemical and enantiomeric purity, with molar activity of 224.22 ± 161.69 MBq/nmol at the end of synthesis (n = 10). Metabolism was moderate, with ~ 30% parent compound remaining for (R)-[18F]OF-Me-NB1 and 20% for (S)-[18F]OF-Me-NB1 at 30 min postinjection. Plasma free fraction was 1–2%. In brain regions, both (R)- and (S)-[18F]OF-Me-NB1 displayed fast uptake with slower clearance for the (R)- than (S)-enantiomer. For (R)-[18F]OF-Me-NB1, both the 1TC model and MA1 method gave reliable estimates of regional VT values, with MA1 VT (mL/cm3) values ranging from 8.9 in the cerebellum to 12.8 in the cingulate cortex. Blocking with 0.25 mg/kg of Co101,244 greatly reduced the uptake of (R)-[18F]OF-Me-NB1 across all brain regions, resulting in occupancy of 77% and VND of 6.36, while 0.027 mg/kg of FTC-146 reduced specific binding by 30%. Regional BPND, as a measure of specific binding signals, ranged from 0.40 in the cerebellum to 1.01 in the cingulate cortex. Conclusions: In rhesus monkeys, (R)-[18F]OF-Me-NB1 exhibited fast kinetics and heterogeneous uptake across brain regions, while the (S)-enantiomer displayed a narrower dynamic range of uptake across regions. A Blocking study with a GluN2B antagonist indicated binding specificity. The value of BPND was > 0.5 in most brain regions, suggesting good in vivo specific binding signals. Taken together, results from the current study demonstrated the potential of (R)-[18F]OF-Me-NB1 as a useful radiotracer for imaging the GluN2B receptors. [ABSTRACT FROM AUTHOR]

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer–induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents. A silent modulator for AD: The loss of synapses observed in patients with Alzheimer's disease (AD) contributes to the progressive cognitive impairments. Although microglia activity has been shown to participate in synaptic loss, the mechanisms mediating the process are not completely elucidated. Now, Spurrier et al. evaluated the role of metabotropic glutamate receptor 5 (mGluR5) on synaptic loss and showed that oral administration of an mGluR5 silent allosteric modulator (SAM) restored synaptic density and reduced phosphorylated TAU accumulation in mouse models of AD. Mechanistically, the treatment reversed gene expression changes induced in AD mice and prevented synaptic localization of the complement protein C1Q. The results suggest that SAMs targeting mGluR5 could be an effective approach for limiting AD-related synaptic loss. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the synaptic vesicle glycoprotein 2A (SV2A) changes in the whole central nervous system (CNS) under pathophysiological conditions, a high affinity SV2A PET radiotracer with improved in vivo stability is desirable to minimize the potential confounding effect of radiometabolites. The aim of this study was to develop such a PET tracer based on the molecular scaffold of UCB-A, and evaluate its pharmacokinetics, in vivo stability, specific binding, and nonspecific binding signals in nonhuman primate brains, in comparison with [11C]UCB-A, [11C]UCB-J, and [18F]SynVesT-1. Methods: The racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) and its two enantiomers were synthesized and assayed for in vitro binding affinities to human SV2A. We synthesized the enantiopure [18F]SDM-16 using the corresponding enantiopure arylstannane precursor. Nonhuman primate brain PET scans were performed on FOCUS 220 scanners. Arterial blood was drawn for the measurement of plasma free fraction (fP), radiometabolite analysis, and construction of the plasma input function. Regional time-activity curves (TACs) were fitted with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Nondisplaceable binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. Results: SDM-16 was synthesized in 3 steps with 44% overall yield and has the highest affinity (Ki = 0.9 nM) to human SV2A among all reported SV2A ligands. [18F]SDM-16 was prepared in about 20% decay-corrected radiochemical yield within 90 min, with greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in monkey brains and was metabolically more stable than the other SV2A PET tracers. The fP of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test–retest variability (TRV) was 7 ± 3%, and averaged absolute TRV (aTRV) was 14 ± 7% for the analyzed brain regions. Conclusion: We have successfully synthesized a novel SV2A PET tracer [18F]SDM-16, which has the highest SV2A binding affinity and metabolical stability among published SV2A PET tracers. The [18F]SDM-16 brain PET images showed superb contrast between gray matter and white matter. Moreover, [18F]SDM-16 showed high specific and reversible binding in the NHP brains, allowing for the reliable and sensitive quantification of SV2A, and has potential applications in the visualization and quantification of SV2A beyond the brain. [ABSTRACT FROM AUTHOR]