Evidence for conflict monitoring during speech recognition in noise.

During difficult tasks, conflict can benefit performance on a subsequent trial. One theory for such performance adjustments is that people monitor for conflict and reactively engage cognitive control. This hypothesis has been challenged because tasks that control for associative learning do not show such "cognitive control" effects. The current study experimentally controlled associative learning by presenting a novel stimulus on every trial of a picture-speech conflict task and found that performance adjustments still occur. Thirty-one healthy young adults listened to and repeated words presented in background noise while viewing pictures that were congruent or incongruent (i.e., phonological neighbors) with the word. Following conflict, participants had higher word recognition (+17% points) on incongruent but not congruent trials. This result was not attributable to posterror effects nor a speed-accuracy trade-off. An analysis of erroneous responses showed that participants made more phonologically related errors than nonrelated errors only on incongruent trials, demonstrating elevated phonological conflict when the picture was a neighbor of the target word. Additionally, postconflict improvements appear to be due to better resolution of phonological conflict in the mental lexicon rather than decreased attention to the picture or increased attention to the speech signal. Our findings provide new evidence for conflict monitoring and suggest that cognitive control helps resolve phonological conflict during speech recognition in noise.

An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.

Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1-GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.

Evidence for cortical adjustments to perceptual decision criteria during word recognition in noise.

Extensive increases in cingulo-opercular frontal activity are typically observed during speech recognition in noise tasks. This elevated activity has been linked to a word recognition benefit on the next trial, termed "adaptive control," but how this effect might be implemented has been unclear. The established link between perceptual decision making and cingulo-opercular function may provide an explanation for how those regions benefit subsequent word recognition. In this case, processes that support recognition such as raising or lowering the decision criteria for more accurate or faster recognition may be adjusted to optimize performance on the next trial. The current neuroimaging study tested the hypothesis that pre-stimulus cingulo-opercular activity reflects criterion adjustments that determine how much information to collect for word recognition on subsequent trials. Participants included middle-age and older adults (N = 30; age = 58.3 ± 8.8 years; m ± sd) with normal hearing or mild sensorineural hearing loss. During a sparse fMRI experiment, words were presented in multitalker babble at +3 dB or +10 dB signal-to-noise ratio (SNR), which participants were instructed to repeat aloud. Word recognition was significantly poorer with increasing participant age and lower SNR compared to higher SNR conditions. A perceptual decision-making model was used to characterize processing differences based on task response latency distributions. The model showed that significantly less sensory evidence was collected (i.e., lower criteria) for lower compared to higher SNR trials. Replicating earlier observations, pre-stimulus cingulo-opercular activity was significantly predictive of correct recognition on a subsequent trial. Individual differences showed that participants with higher criteria also benefitted the most from pre-stimulus activity. Moreover, trial-level criteria changes were significantly linked to higher versus lower pre-stimulus activity. These results suggest cingulo-opercular cortex contributes to criteria adjustments to optimize speech recognition task performance.

Unique patterns of hearing loss and cognition in older adults' neural responses to cues for speech recognition difficulty.

Older adults with hearing loss experience significant difficulties understanding speech in noise, perhaps due in part to limited benefit from supporting executive functions that enable the use of environmental cues signaling changes in listening conditions. Here we examined the degree to which 41 older adults (60.56-86.25 years) exhibited cortical responses to informative listening difficulty cues that communicated the listening difficulty for each trial compared to neutral cues that were uninformative of listening difficulty. Word recognition was significantly higher for informative compared to uninformative cues in a + 10 dB signal-to-noise ratio (SNR) condition, and response latencies were significantly shorter for informative cues in the + 10 dB SNR and the more-challenging + 2 dB SNR conditions. Informative cues were associated with elevated blood oxygenation level-dependent contrast in visual and parietal cortex. A cue-SNR interaction effect was observed in the cingulo-opercular (CO) network, such that activity only differed between SNR conditions when an informative cue was presented. That is, participants used the informative cues to prepare for changes in listening difficulty from one trial to the next. This cue-SNR interaction effect was driven by older adults with more low-frequency hearing loss and was not observed for those with more high-frequency hearing loss, poorer set-shifting task performance, and lower frontal operculum gray matter volume. These results suggest that proactive strategies for engaging CO adaptive control may be important for older adults with high-frequency hearing loss to optimize speech recognition in changing and challenging listening conditions.

Real-world experience with caplacizumab in the management of acute TTP.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Cognitive Persistence and Executive Function in the Multilingual Brain During Aging.

Researchers have debated the extent to which the experience of speaking more than two languages induces long-term neuroplasticity that protects multilinguals from the adverse cognitive effects of aging. In this review, I propose a novel theory that multilingualism affects cognitive persistence, the application of effort to improve performance on challenging tasks. I review recent evidence demonstrating that the cingulo-opercular network, consisting of the bilateral inferior frontal gyrus (IFG) and dorsal anterior cingulate cortex (dACC), supports cognitive persistence. I then show that this same network is involved in multilingual language control and changes with multilingual language experience. While both early and late multilinguals exhibit differences in the cingulo-opercular network compared to monolinguals, I find that early multilinguals have a pattern of decreased dACC activity and increased left IFG activity that may enable more efficient cognitive control, whereas late multilinguals show larger dACC responses to conflict that may be associated with higher cognitive persistence. I further demonstrate that multilingual effects on the cingulo-opercular network are present in older adults and have been implicated in the mitigation of cognitive symptoms in age-related neurodegenerative disorders. Finally, I argue that mixed results in the literature are due, in part, to the confound between cognitive persistence and ability in most executive function tasks, and I provide guidance for separating these processes in future research.

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

A Novel Communication Value Task Demonstrates Evidence of Response Bias in Cases with Presbyacusis.

Decision-making about the expected value of an experience or behavior can explain hearing health behaviors in older adults with hearing loss. Forty-four middle-aged to older adults (68.45 ± 7.73 years) performed a task in which they were asked to decide whether information from a surgeon or an administrative assistant would be important to their health in hypothetical communication scenarios across visual signal-to-noise ratios (SNR). Participants also could choose to view the briefly presented sentences multiple times. The number of these effortful attempts to read the stimuli served as a measure of demand for information to make a health importance decision. Participants with poorer high frequency hearing more frequently decided that information was important to their health compared to participants with better high frequency hearing. This appeared to reflect a response bias because participants with high frequency hearing loss demonstrated shorter response latencies when they rated the sentences as important to their health. However, elevated high frequency hearing thresholds did not predict demand for information to make a health importance decision. The results highlight the utility of a performance-based measure to characterize effort and expected value from performing tasks in older adults with hearing loss.

Cingulo-opercular activity affects incidental memory encoding for speech in noise.

Correctly understood speech in difficult listening conditions is often difficult to remember. A long-standing hypothesis for this observation is that the engagement of cognitive resources to aid speech understanding can limit resources available for memory encoding. This hypothesis is consistent with evidence that speech presented in difficult conditions typically elicits greater activity throughout cingulo-opercular regions of frontal cortex that are proposed to optimize task performance through adaptive control of behavior and tonic attention. However, successful memory encoding of items for delayed recognition memory tasks is consistently associated with increased cingulo-opercular activity when perceptual difficulty is minimized. The current study used a delayed recognition memory task to test competing predictions that memory encoding for words is enhanced or limited by the engagement of cingulo-opercular activity during challenging listening conditions. An fMRI experiment was conducted with twenty healthy adult participants who performed a word identification in noise task that was immediately followed by a delayed recognition memory task. Consistent with previous findings, word identification trials in the poorer signal-to-noise ratio condition were associated with increased cingulo-opercular activity and poorer recognition memory scores on average. However, cingulo-opercular activity decreased for correctly identified words in noise that were not recognized in the delayed memory test. These results suggest that memory encoding in difficult listening conditions is poorer when elevated cingulo-opercular activity is not sustained. Although increased attention to speech when presented in difficult conditions may detract from more active forms of memory maintenance (e.g., sub-vocal rehearsal), we conclude that task performance monitoring and/or elevated tonic attention supports incidental memory encoding in challenging listening conditions.

Cognitive persistence: Development and validation of a novel measure from the Wisconsin Card Sorting Test.

The Wisconsin Card Sorting Test (WCST) has long been used as a neuropsychological assessment of executive function abilities, in particular, cognitive flexibility or "set-shifting". Recent advances in scoring the task have helped to isolate specific WCST performance metrics that index set-shifting abilities and have improved our understanding of how prefrontal and parietal cortex contribute to set-shifting. We present evidence that the ability to overcome task difficulty to achieve a goal, or "cognitive persistence", is another important prefrontal function that is characterized by the WCST and that can be differentiated from efficient set-shifting. This novel measure of cognitive persistence was developed using the WCST-64 in an adult lifespan sample of 230 participants. The measure was validated using individual variation in cingulo-opercular cortex function in a sub-sample of older adults who had completed a challenging speech recognition in noise fMRI task. Specifically, older adults with higher cognitive persistence were more likely to demonstrate word recognition benefit from cingulo-opercular activity. The WCST-derived cognitive persistence measure can be used to disentangle neural processes involved in set-shifting from those involved in persistence.

Memory and language improvements following cognitive control training.

Cognitive control refers to adjusting thoughts and actions when confronted with conflict during information processing. We tested whether this ability is causally linked to performance on certain language and memory tasks by using cognitive control training to systematically modulate people's ability to resolve information-conflict across domains. Different groups of subjects trained on 1 of 3 minimally different versions of an n-back task: n-back-with-lures (High-Conflict), n-back-without-lures (Low-Conflict), or 3-back-without-lures (3-Back). Subjects completed a battery of recognition memory and language processing tasks that comprised both high- and low-conflict conditions before and after training. We compared the transfer profiles of (a) the High- versus Low-Conflict groups to test how conflict resolution training contributes to transfer effects, and (b) the 3-Back versus Low-Conflict groups to test for differences not involving cognitive control. High-Conflict training-but not Low-Conflict training-produced discernable benefits on several untrained transfer tasks, but only under selective conditions requiring cognitive control. This suggests that the conflict-focused intervention influenced functioning on ostensibly different outcome measures across memory and language domains. 3-Back training resulted in occasional improvements on the outcome measures, but these were not selective for conditions involving conflict resolution. We conclude that domain-general cognitive control mechanisms are plastic, at least temporarily, and may play a causal role in linguistic and nonlinguistic performance. (PsycINFO Database Record

Aging-Resilient Associations between the Arcuate Fasciculus and Vocabulary Knowledge: Microstructure or Morphology?

UNLABELLED: Vocabulary knowledge is one of the few cognitive functions that is relatively preserved in older adults, but the reasons for this relative preservation have not been well delineated. We tested the hypothesis that individual differences in vocabulary knowledge are influenced by arcuate fasciculus macrostructure (i.e., shape and volume) properties that remain stable during the aging process, rather than white matter microstructure that demonstrates age-related declines. Vocabulary was not associated with age compared to pronounced age-related declines in cognitive processing speed across 106 healthy adults (19.92-88.29 years) who participated in this neuroimaging experiment. Fractional anisotropy in the left arcuate fasciculus was significantly related to individual variability in vocabulary. This effect was present despite marked age-related differences in a T1-weighted/T2-weighted ratio (T1w/T2w) estimate of myelin that were observed throughout the left arcuate fasciculus and associated with age-related differences in cognitive processing speed. However, atypical patterns of arcuate fasciculus morphology or macrostructure were associated with decreased vocabulary knowledge. These results suggest that deterioration of tissue in the arcuate fasciculus occurs with normal aging, while having limited impact on tract organization that underlies individual differences in the acquisition and retrieval of lexical and semantic information. SIGNIFICANCE STATEMENT: Vocabulary knowledge is resilient to widespread age-related declines in brain structure that limit other cognitive functions. We tested the hypothesis that arcuate fasciculus morphology, which supports the development of reading skills that bolster vocabulary, could explain this relative preservation. We disentangled (1) the effects of age-related declines in arcuate microstructure (mean diffusivity; myelin content estimate) that predicted cognitive processing speed but not vocabulary, from (2) relatively stable arcuate macrostructure (shape/volume) that explained significant variance in an age-independent association between fractional anisotropy and vocabulary. This latter result may reflect differences in fiber trajectory and organization that are resilient to aging. We propose that developmental sculpting of the arcuate fasciculus determines acquisition, storage, and access of lexical information across the adult lifespan.

Is Listening in Noise Worth It? The Neurobiology of Speech Recognition in Challenging Listening Conditions.

This review examines findings from functional neuroimaging studies of speech recognition in noise to provide a neural systems level explanation for the effort and fatigue that can be experienced during speech recognition in challenging listening conditions. Neuroimaging studies of speech recognition consistently demonstrate that challenging listening conditions engage neural systems that are used to monitor and optimize performance across a wide range of tasks. These systems appear to improve speech recognition in younger and older adults, but sustained engagement of these systems also appears to produce an experience of effort and fatigue that may affect the value of communication. When considered in the broader context of the neuroimaging and decision making literature, the speech recognition findings from functional imaging studies indicate that the expected value, or expected level of speech recognition given the difficulty of listening conditions, should be considered when measuring effort and fatigue. The authors propose that the behavioral economics or neuroeconomics of listening can provide a conceptual and experimental framework for understanding effort and fatigue that may have clinical significance.

The effects of bilingualism on conflict monitoring, cognitive control, and garden-path recovery.

Bilinguals demonstrate benefits on non-linguistic tasks requiring cognitive control-the regulation of mental activity to resolve information-conflict during processing. This "bilingual advantage" has been attributed to the consistent management of two languages, yet it remains unknown if these benefits extend to sentence processing. In monolinguals, cognitive control helps detect and revise misinterpretations of sentence meaning. Here, we test if the bilingual advantage extends to parsing and interpretation by comparing bilinguals' and monolinguals' syntactic ambiguity resolution before and after practicing N-back, a non-syntactic cognitive-control task. Bilinguals outperformed monolinguals on a high-conflict but not a no-conflict version of N-back and on sentence comprehension, indicating that the advantage extends to language interpretation. Gains on N-back conflict trials also predicted comprehension improvements for ambiguous sentences, suggesting that the bilingual advantage emerges across tasks tapping shared cognitive-control procedures. Because the overall task benefits were observed for conflict and non-conflict trials, bilinguals' advantage may reflect increased cognitive flexibility.

Cingulo-Opercular Function During Word Recognition in Noise for Older Adults with Hearing Loss.

BACKGROUND/STUDY CONTEXT: Adaptive control, reflected by elevated activity in cingulo-opercular brain regions, optimizes performance in challenging tasks by monitoring outcomes and adjusting behavior. For example, cingulo-opercular function benefits trial-level word recognition in noise for normal-hearing adults. Because auditory system deficits may limit the communicative benefit from adaptive control, we examined the extent to which cingulo-opercular engagement supports word recognition in noise for older adults with hearing loss (HL). METHODS: Participants were selected to form groups with Less HL (n = 12; mean pure tone threshold, pure tone average [PTA] = 19.2 ± 4.8 dB HL [hearing level]) and More HL (n = 12; PTA = 38.4 ± 4.5 dB HL, 0.25-8 kHz, both ears). A word recognition task was performed with words presented in multitalker babble at +3 or +10 dB signal-to-noise ratios (SNRs) during a sparse acquisition fMRI experiment. The participants were middle-aged and older (ages: 64.1 ± 8.4 years) English speakers with no history of neurological or psychiatric diagnoses. RESULTS: Elevated cingulo-opercular activity occurred with increased likelihood of correct word recognition on the next trial (t(23) = 3.28, p = .003), and this association did not differ between hearing loss groups. During trials with word recognition errors, the More HL group exhibited higher blood oxygen level-dependent (BOLD) contrast in occipital and parietal regions compared with the Less HL group. Across listeners, more pronounced cingulo-opercular activity during recognition errors was associated with better overall word recognition performance. CONCLUSION: The trial-level word recognition benefit from cingulo-opercular activity was equivalent for both hearing loss groups. When speech audibility and performance levels are similar for older adults with mild to moderate hearing loss, cingulo-opercular adaptive control contributes to word recognition in noise.

8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors.

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aß1-40 at 60 mg/kg (PO).

Discovery of 2-pyridylureas as glucokinase activators.

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.

JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo.

Chronic myeloid leukemia (CML) stem cell survival is not dependent on BCR-ABL protein kinase and treatment with ABL tyrosine kinase inhibitors cures only a minority of CML patients, thus highlighting the need for novel therapeutic targets. The Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)5 pathway has recently been explored for providing putative survival signals to CML stem/progenitor cells (SPCs) with contradictory results. We investigated the role of this pathway using the JAK2 inhibitor, ruxolitinib (RUX). We demonstrated that the combination of RUX, at clinically achievable concentrations, with the specific and potent tyrosine kinase inhibitor nilotinib, reduced the activity of the JAK2/STAT5 pathway in vitro relative to either single agent alone. These effects correlated with increased apoptosis of CML SPCs in vitro and a reduction in primitive quiescent CML stem cells, including NOD.Cg-Prkdc(scid) IL2rg(tm1Wjl) /SzJ mice repopulating cells, induced by combination treatment. A degree of toxicity toward normal SPCs was observed with the combination treatment, although this related to mature B-cell engraftment in NOD.Cg-Prkdc(scid) IL2rg(tm1Wjl) /SzJ mice with minimal effects on primitive CD34(+) cells. These results support the JAK2/STAT5 pathway as a relevant therapeutic target in CML SPCs and endorse the current use of nilotinib in combination with RUX in clinical trials to eradicate persistent disease in CML patients.

Discovery of 7-tetrahydropyran-2-yl chromans: ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid ß-protein (Aß) in the central nervous system.

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aß1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aß1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

To adapt or not to adapt: the question of domain-general cognitive control.

What do perceptually bistable figures, sentences vulnerable to misinterpretation and the Stroop task have in common? Although seemingly disparate, they all contain elements of conflict or ambiguity. Consequently, in order to monitor a fluctuating percept, reinterpret sentence meaning, or say "blue" when the word RED is printed in blue ink, individuals must regulate attention and engage cognitive control. According to the Conflict Monitoring Theory (Botvinick, Braver, Barch, Carter, & Cohen, 2001), the detection of conflict automatically triggers cognitive control mechanisms, which can enhance resolution of subsequent conflict, namely, "conflict adaptation." If adaptation reflects the recruitment of domain-general processes, then conflict detection in one domain should facilitate conflict resolution in an entirely different domain. We report two novel findings: (i) significant conflict adaptation from a syntactic to a non-syntactic domain and (ii) from a perceptual to a verbal domain, providing strong evidence that adaptation is mediated by domain-general cognitive control.