The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer.

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model. We have identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients. Overall, these findings support the clinical evaluation of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer.

Listening to Yourself and Watching Your Tongue: Distinct Abilities and Brain Regions for Monitoring Semantic and Phonological Speech Errors.

Despite the many mistakes we make while speaking, people can effectively communicate because we monitor our speech errors. However, the cognitive abilities and brain structures that support speech error monitoring are unclear. There may be different abilities and brain regions that support monitoring phonological speech errors versus monitoring semantic speech errors. We investigated speech, language, and cognitive control abilities that relate to detecting phonological and semantic speech errors in 41 individuals with aphasia who underwent detailed cognitive testing. Then, we used support vector regression lesion symptom mapping to identify brain regions supporting detection of phonological versus semantic errors in a group of 76 individuals with aphasia. The results revealed that motor speech deficits as well as lesions to the ventral motor cortex were related to reduced detection of phonological errors relative to semantic errors. Detection of semantic errors selectively related to auditory word comprehension deficits. Across all error types, poor cognitive control related to reduced detection. We conclude that monitoring of phonological and semantic errors relies on distinct cognitive abilities and brain regions. Furthermore, we identified cognitive control as a shared cognitive basis for monitoring all types of speech errors. These findings refine and expand our understanding of the neurocognitive basis of speech error monitoring.

Do People With Apraxia of Speech and Aphasia Improve or Worsen Across Repeated Sequential Word Trials?

PURPOSE: During motor speech examinations for suspected apraxia of speech (AOS), clients are routinely asked to repeat words several times sequentially. The purpose of this study was to understand the task in terms of the relationship among consecutive attempts. We asked to what extent phonemic accuracy changes across trials and whether the change is predicted by AOS diagnosis and sound production severity. METHOD: One hundred thirty-three participants were assigned to four diagnostic groups based on quantitative metrics (aphasia plus AOS, aphasia-only, and aphasia with two borderline speech profiles). Each participant produced four multisyllabic words 5 times consecutively. These productions were audio-recorded and transcribed phonetically and then summarized as the proportion of target phonemes that was produced accurately. Nonparametric statistics were used to analyze percent change in accuracy from the first to the last production based on diagnostic group and a broad measure of speech sound accuracy. RESULTS: Accuracy on the repeated words deteriorated across trials for all groups, showing reduced accuracy from the first to the last repetition for 62% of participants. Although diagnostic groups differed on the broad measure of speech sound accuracy, severity classification based on this measure did not determine degree of deterioration on the repeated words task. DISCUSSION: Responding to a request to say multisyllabic words 5 times sequentially is challenging for people with aphasia with and without AOS, and as such, performance is prone to errors even with mild impairment. For most, the task does not encourage self-correction. Instead, it promotes errors, regardless of diagnosis, and is, therefore, useful for screening purposes.

Aphasia severity is modulated by race and lesion size in chronic survivors: A retrospective study.

INTRODUCTION: In stroke survivors with aphasia (SWA), differences in behavioral language performance have been observed between Black and White Americans. These racial differences in aphasia outcomes may reflect biological stroke severity, disparities in access to care, potential assessment bias, or interactions between these factors and race. Understanding the origin of disparities in aphasia outcomes is critical to any efforts to promote health equity among SWA. In this study, we explore aphasia outcomes by examining the relationship between race, socioeconomic status, and neurological factors in SWA. METHOD: Eighty-five chronic left-hemisphere SWA (31 Black, 54 White) participated in the study. The primary aphasia outcome measure was the Western Aphasia Battery-Revised (WAB-R). Lesion size was measured based on manual lesion segmentations. FLAIR and T2 images were scored for severity of white matter disease. Independent sample t-tests were used to determine differences by race in education, age, income, aphasia severity, white matter disease, and lesion size. A linear regression model was used to explore factors that predicted aphasia severity on the WAB-R. RESULT: Level of education and estimated income differed by race in our sample. For predictors of aphasia severity, the regression model revealed a significant effect of lesion size on WAB Aphasia Quotient and an interaction of race x lesion size, such that Black and White participants with small lesions had similar WAB scores, but in individuals with larger lesions, Black participants had lower WAB scores than White participants. CONCLUSION: We suggest two explanations for the difference between Black and White SWA in the relationship between lesion size and aphasia severity. First, the impact of disparities in access to rehabilitation after stroke may be more evident when a stroke is larger and causes significant aphasia. Additionally, an assessment bias in aphasia outcome measures may be more evident with increasing severity of aphasia. Future studies should further discern the drivers of observed disparities in aphasia outcomes in order to identify opportunities to improve equity in aphasia care.

Distinguishing semantic control and phonological control and their role in aphasic deficits: A task switching investigation.

People use cognitive control across many contexts in daily life, yet it remains unclear how cognitive control is used in contexts involving language. Distinguishing language-specific cognitive control components may be critical to understanding aphasia, which can co-occur with cognitive control deficits. For example, deficits in control of semantic representations (i.e., semantic control), are thought to contribute to semantic deficits in aphasia. Conversely, little is known about control of phonological representations (i.e., phonological control) in aphasia. We developed a switching task to investigate semantic and phonological control in 32 left hemisphere stroke survivors with aphasia and 37 matched controls. We found that phonological and semantic control were related, but dissociate in the presence of switching demands. People with aphasia exhibited group-wise impairment at phonological control, although individual impairments were subtle except in one case. Several individuals with aphasia exhibited frank semantic control impairments, and these individuals had relative deficits on other semantic tasks. The present findings distinguish semantic control from phonological control, and confirm that semantic control impairments contribute to semantic deficits in aphasia.

Absence of Perilesional Neuroplastic Recruitment in Chronic Poststroke Aphasia.

BACKGROUND AND OBJECTIVES: A prominent theory proposes that neuroplastic recruitment of perilesional tissue supports aphasia recovery, especially when language-capable cortex is spared by smaller lesions. This theory has rarely been tested directly and findings have been inconclusive. We tested the perilesional plasticity hypothesis using 2 fMRI tasks in 2 groups of patients with previous aphasia diagnosis. METHODS: Two cohorts totaling 82 patients with chronic left-hemisphere stroke with previous aphasia diagnosis and 82 control participants underwent fMRI using either a naming task or a reliable semantic decision task. Individualized perilesional tissue was defined by dilating anatomical lesions and language regions were defined using meta-analyses. Mixed modeling examined differences in activity between groups. Relationships with lesion size and aphasia severity were examined. RESULTS: Patients exhibited reduced activity in perilesional language tissue relative to controls in both tasks. Although a few cortical regions exhibited greater activity irrespective of distance from the lesion, or only when distant from the lesion, no regions exhibited increased activity only when near the lesion. Larger lesions were associated with reduced language activity irrespective of distance from the lesion. Using the reliable fMRI task, reduced language activity was related to aphasia severity independent of lesion size. DISCUSSION: We found no evidence for neuroplastic recruitment of perilesional tissue in aphasia beyond its typical role in language. Rather, our findings are consistent with alternative hypotheses that changes in left-hemisphere activation during recovery relate to normalization of language network dysfunction and possibly recruitment of alternate cortical processors. These findings clarify left-hemisphere neuroplastic mechanisms supporting language recovery after stroke.

Transgenerational Genetic Effects Help Explain Latitudinal Variation in Seed Mass and Germination Timing in Plantago lanceolata.

We know little about the underlying genetic control of phenotypic patterns of seed traits across large-scale geographic and environmental gradients. Such knowledge is important for understanding the evolution of populations within species and for improving species conservation. Therefore, to test for genetic variation in Plantago lanceolata, we made reciprocal crosses between northern and southern genotypes that span the species' range in Europe. The results provide evidence of transgenerational genetic effects on seed mass and germination timing. Northern mothers produced larger seeds with delayed germination, in contrast to southern mothers, which produced smaller seeds with accelerated germination. A maternal latitude affected both the seed coat, solely maternal tissue, and embryo/endosperm tissues. Thus, latitudinal variation in seed size and germination timing can be explained, in part, by the direct influence of maternal genotype, independent of zygotic genes that parents pass directly to the embryo and endosperm. Data suggest that researchers exploring the existence and evolution of large-scale geographic variation within species test for transgenerational genetic effects. In addition, data suggest that transgenerational control of seed traits should be considered when developing procedures designed to facilitate species conservation and restoration.

Structural disconnection of the posterior medial frontal cortex reduces speech error monitoring.

Optimal performance in any task relies on the ability to detect and correct errors. The anterior cingulate cortex and the broader posterior medial frontal cortex (pMFC) are active during error processing. However, it is unclear whether damage to the pMFC impairs error monitoring. We hypothesized that successful error monitoring critically relies on connections between the pMFC and broader cortical networks involved in executive functions and the task being monitored. We tested this hypothesis in the context of speech error monitoring in people with post-stroke aphasia. Diffusion weighted images were collected in 51 adults with chronic left-hemisphere stroke and 37 age-matched control participants. Whole-brain connectomes were derived using constrained spherical deconvolution and anatomically-constrained probabilistic tractography. Support vector regressions identified white matter connections in which lost integrity in stroke survivors related to reduced error detection during confrontation naming. Lesioned connections to the bilateral pMFC were related to reduce error monitoring, including many connections to regions associated with speech production and executive function. We conclude that connections to the pMFC support error monitoring. Error monitoring in speech production is supported by the structural connectivity between the pMFC and regions involved in speech production, comprehension, and executive function. Interactions between pMFC and other task-relevant processors may similarly be critical for error monitoring in other task contexts.

Two types of phonological reading impairment in stroke aphasia.

Alexia is common in the context of aphasia. It is widely agreed that damage to phonological and semantic systems not specific to reading causes co-morbid alexia and aphasia. Studies of alexia to date have only examined phonology and semantics as singular processes or axes of impairment, typically in the context of stereotyped alexia syndromes. However, phonology, in particular, is known to rely on subprocesses, including sensory-phonological processing, motor-phonological processing, and sensory-motor integration. Moreover, many people with stroke aphasia demonstrate mild or mixed patterns of reading impairment that do not fit neatly with one syndrome. This cross-sectional study tested whether the hallmark symptom of phonological reading impairment, the lexicality effect, emerges from damage to a specific subprocess of phonology in stroke patients not selected for alexia syndromes. Participants were 30 subjects with left-hemispheric stroke and 37 age- and education-matched controls. A logistic mixed-effects model tested whether post-stroke impairments in sensory phonology, motor phonology, or sensory-motor integration modulated the effect of item lexicality on patient accuracy in reading aloud. Support vector regression voxel-based lesion-symptom mapping localized brain regions necessary for reading and non-orthographic phonological processing. Additionally, a novel support vector regression structural connectome-symptom mapping method identified the contribution of both lesioned and spared but disconnected, brain regions to reading accuracy and non-orthographic phonological processing. Specifically, we derived whole-brain structural connectomes using constrained spherical deconvolution-based probabilistic tractography and identified lesioned connections based on comparisons between patients and controls. Logistic mixed-effects regression revealed that only greater motor-phonological impairment related to lower accuracy reading aloud pseudowords versus words. Impaired sensory-motor integration was related to lower overall accuracy in reading aloud. No relationship was identified between sensory-phonological impairment and reading accuracy. Voxel-based and structural connectome lesion-symptom mapping revealed that lesioned and disconnected left ventral precentral gyrus related to both greater motor-phonological impairment and lower sublexical reading accuracy. In contrast, lesioned and disconnected left temporoparietal cortex is related to both impaired sensory-motor integration and reduced overall reading accuracy. These results clarify that at least two dissociable phonological processes contribute to the pattern of reading impairment in aphasia. First, impaired sensory-motor integration, caused by lesions disrupting the left temporoparietal cortex and its structural connections, non-selectively reduces accuracy in reading aloud. Second, impaired motor-phonological processing, caused at least partially by lesions disrupting left ventral premotor cortex and structural connections, selectively reduces sublexical reading accuracy. These results motivate a revised cognitive model of reading aloud that incorporates a sensory-motor phonological circuit.

An Exploratory Study of Cerebellar Transcranial Direct Current Stimulation in Individuals With Chronic Stroke Aphasia.

BACKGROUND: Aphasia is a common, debilitating consequence of stroke, and speech therapy is often inadequate to achieve a satisfactory outcome. Neuromodulation techniques have emerged as a potential augmentative treatment for improving aphasia outcomes. Most studies have targeted the cerebrum, but there are theoretical and practical reasons that stimulation over the cerebral hemispheres might not be ideal. On the other hand, the right cerebellum is functionally and anatomically linked to major language areas in the left hemisphere, making it a promising alternative target site for stimulation. OBJECTIVE: To provide preliminary effect sizes for the ability of a short course of anodal transcranial direct current stimulation (tDCS) targeted over the right cerebellum to enhance language processing in individuals with chronic poststroke aphasia. METHOD: Ten individuals received five sessions of open-label anodal tDCS targeting the right cerebellum. The effects of the tDCS were compared with the effects of sham tDCS on 14 controls from a previous clinical trial. In total, 24 individuals with chronic poststroke aphasia participated in the study. Behavioral testing was conducted before treatment, immediately following treatment, and at the 3-month follow-up. RESULTS: Cerebellar tDCS did not significantly enhance language processing measured either immediately following treatment or at the 3-month follow-up. The effect sizes of tDCS over sham treatment were generally nil or small, except for the mean length of utterance on the picture description task, for which medium to large effects were observed. CONCLUSION: These results may provide guidance for investigators who are planning larger trials of tDCS for individuals with chronic poststroke aphasia.

Multiple modes of selection can influence the role of phenotypic plasticity in species' invasions: Evidence from a manipulative field experiment.

In exploring the roles of phenotypic plasticity in the establishment and early evolution of invading species, little empirical attention has been given to the importance of correlational selection acting upon suites of functionally related plastic traits in nature. We illustrate how this lack of attention has limited our ability to evaluate plasticity's role during invasion and also, the costs and benefits of plasticity. We addressed these issues by transplanting clones of European-derived Plantago lanceolata L. genotypes into two temporally variable habitats in the species' introduced range in North America. Phenotypic selection analyses were performed for each habitat to estimate linear, quadratic, and correlational selection on phenotypic trait values and plasticities in the reproductive traits: flowering onset and spike and scape lengths. Also, we measured pairwise genetic correlations for our "colonists." Results showed that (a) correlational selection acted on trait plasticity after transplantation, (b) selection favored certain combinations of genetically correlated and uncorrelated trait values and plasticities, and (c) using signed, instead of absolute, values of plasticity in analyses facilitated the detection of correlational selection on trait value-plasticity combinations and their adaptive value. Based on our results, we urge future studies on species invasions to (a) measure correlational selection and (b) retain signed values of plasticity in order to better discriminate between adaptive and maladaptive plasticity.

Domains of Health-Related Quality of Life Are Associated With Specific Deficits and Lesion Locations in Chronic Aphasia.

BACKGROUND: Health-related quality of life (HRQL) in stroke survivors is related to numerous factors, but more research is needed to delineate factors related to HRQL in people with aphasia. OBJECTIVE: To examine the relationship between HRQL and demographic factors, impairment-based measures, and lesion characteristics in chronic aphasia. METHODS: A total of 41 left-hemisphere stroke survivors with aphasia underwent cognitive testing and magnetic resonance imaging. To address relationships with demographic and impairment-based measures, test scores were entered into a principal component analysis (PCA) and multiple linear regression was performed for overall and domain (physical, communication, psychosocial) scores of the Stroke and Aphasia Quality of Life Scale (SAQOL-39g). Independent variables included factor scores from the PCA, motricity, lesion volume, depressed mood, and demographic variables. To address relationships with lesion location, multivariate support vector regression lesion-symptom mapping (SVR-LSM) was used to localize lesions associated with SAQOL-39g scores. RESULTS: The PCA yielded 3 factors, which were labeled Language Production, Nonlinguistic Cognition, and Language Comprehension. Multiple linear regression revealed that depression symptoms predicted lower SAQOL-39g average and domain scores. Lower motricity scores predicted lower SAQOL-39g average and physical scores, and lower Language Production factor scores predicted lower communication scores. SVR-LSM demonstrated that basal ganglia lesions were associated with lower physical scores, and inferior frontal lesions were associated with lower psychosocial scores. CONCLUSIONS: HRQL in chronic left-hemisphere stroke survivors with aphasia relates to lesion location, depression symptoms, and impairment-based measures. This information may help identify individuals at risk for specific aspects of low HRQL and facilitate targeted interventions to improve well-being.

Bacterial efflux inhibitors are widely distributed in land plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Secondary metabolites play a critical role in plant defense against disease and are of great importance to ethnomedicine. Bacterial efflux pumps are active transport proteins that bacterial cells use to protect themselves against multiple toxic compounds, including many antimicrobials. Efflux pump inhibitors from plants can block these efflux pumps, increasing the potency of antimicrobial compounds. This study demonstrates that efflux pump inhibition against the Gram-positive bacterial pathogen Staphylococcus aureus is widespread in extracts prepared from individual species throughout the land plant lineage. It therefore suggests a general mechanism by which plants used by indigenous species may be effective as a topical treatment for some bacterial infections. AIM OF THE STUDY: The goal of this research was to evaluate the distribution of efflux pump inhibitors in nine plant extracts with an ethnobotanical use suggestive of an antimicrobial function for the presence of efflux pump inhibitory activity against Staphylococcus aureus. MATERIALS AND METHODS: Plants were collected, dried, extracted, and vouchers submitted to the Herbarium of the University of North Carolina Chapel Hill (NCU). The extracts were analyzed by quantitative mass spectrometry (UPLC-MS) to determine the presence and concentration of flavonoids with known efflux pump inhibitory activity. A mass spectrometry-based assay was employed to measure efflux pump inhibition for all extracts against Staphylococcus aureus. The assay relies on UPLC-MS measurement of changes in ethidium concentration in the spent culture broth when extracts are incubated with bacteria. RESULTS: Eight of these nine plant extracts inhibited toxic compound efflux at concentrations below the MIC (minimum inhibitory concentration) value for the same extract. The most active extracts were those prepared from Osmunda claytoniana L. and Pinus strobes L., which both demonstrated IC50 values for efflux inhibition of 19 ppm. CONCLUSIONS: Our findings indicate that efflux pump inhibitors active against Staphylococcus aureus are common in land plants. By extension, this activity is likely to be important in many plant-derived antimicrobial extracts, including those used in traditional medicine, and evaluation of efflux pump inhibition may often be valuable when studying natural product efficacy.

Effects of age and left hemisphere lesions on audiovisual integration of speech.

Neuroimaging studies have implicated left temporal lobe regions in audiovisual integration of speech and inferior parietal regions in temporal binding of incoming signals. However, it remains unclear which regions are necessary for audiovisual integration, especially when the auditory and visual signals are offset in time. Aging also influences integration, but the nature of this influence is unresolved. We used a McGurk task to test audiovisual integration and sensitivity to the timing of audiovisual signals in two older adult groups: left hemisphere stroke survivors and controls. We observed a positive relationship between age and audiovisual speech integration in both groups, and an interaction indicating that lesions reduce sensitivity to timing offsets between signals. Lesion-symptom mapping demonstrated that damage to the left supramarginal gyrus and planum temporale reduces temporal acuity in audiovisual speech perception. This suggests that a process mediated by these structures identifies asynchronous audiovisual signals that should not be integrated.

Two reproductive traits show contrasting genetic architectures in Plantago lanceolata.

In many species, temperature-sensitive phenotypic plasticity (i.e., an individual's phenotypic response to temperature) displays a positive correlation with latitude, a pattern presumed to reflect local adaptation. This geographical pattern raises two general questions: (a) Do a few large-effect genes contribute to latitudinal variation in a trait? (b) Is the thermal plasticity of different traits regulated pleiotropically? To address the questions, we crossed individuals of Plantago lanceolata derived from northern and southern European populations. Individuals naturally exhibited high and low thermal plasticity in floral reflectance and flowering time. We grew parents and offspring in controlled cool- and warm-temperature environments, mimicking what plants would encounter in nature. We obtained genetic markers via genotype-by-sequencing, produced the first recombination map for this ecologically important nonmodel species, and performed quantitative trait locus (QTL) mapping of thermal plasticity and single-environment values for both traits. We identified a large-effect QTL that largely explained the reflectance plasticity differences between northern and southern populations. We identified multiple smaller-effect QTLs affecting aspects of flowering time, one of which affected flowering time plasticity. The results indicate that the genetic architecture of thermal plasticity in flowering is more complex than for reflectance. One flowering time QTL showed strong cytonuclear interactions under cool temperatures. Reflectance and flowering plasticity QTLs did not colocalize, suggesting little pleiotropic genetic control and freedom for independent trait evolution. Such genetic information about the architecture of plasticity is environmentally important because it informs us about the potential for plasticity to offset negative effects of climate change.

Dissociable Mechanisms of Verbal Working Memory Revealed through Multivariate Lesion Mapping.

Two maintenance mechanisms with separate neural systems have been suggested for verbal working memory: articulatory-rehearsal and non-articulatory maintenance. Although lesion data would be key to understanding the essential neural substrates of these systems, there is little evidence from lesion studies that the two proposed mechanisms crucially rely on different neuroanatomical substrates. We examined 39 healthy adults and 71 individuals with chronic left-hemisphere stroke to determine if verbal working memory tasks with varying demands would rely on dissociable brain structures. Multivariate lesion-symptom mapping was used to identify the brain regions involved in each task, controlling for spatial working memory scores. Maintenance of verbal information relied on distinct brain regions depending on task demands: sensorimotor cortex under higher demands and superior temporal gyrus (STG) under lower demands. Inferior parietal cortex and posterior STG were involved under both low and high demands. These results suggest that maintenance of auditory information preferentially relies on auditory-phonological storage in the STG via a nonarticulatory maintenance when demands are low. Under higher demands, sensorimotor regions are crucial for the articulatory rehearsal process, which reduces the reliance on STG for maintenance. Lesions to either of these regions impair maintenance of verbal information preferentially under the appropriate task conditions.

Brain structures and cognitive abilities important for the self-monitoring of speech errors.

The brain structures and cognitive abilities necessary for successful monitoring of one's own speech errors remain unknown. We aimed to inform self-monitoring models by examining the neural and behavioral correlates of phonological and semantic error detection in individuals with post-stroke aphasia. First, we determined whether detection related to other abilities proposed to contribute to monitoring according to various theories, including naming ability, fluency, word-level auditory comprehension, sentence-level auditory comprehension, and executive function. Regression analyses revealed that fluency and executive scores were independent predictors of phonological error detection, while a measure of word-level comprehension related to semantic error detection. Next, we used multivariate lesion-symptom mapping to determine lesion locations associated with reduced error detection. Reduced overall error detection related to damage to a region of frontal white matter extending into dorsolateral prefrontal cortex (DLPFC). Detection of phonological errors related to damage to the same areas, but the lesion-behavior association was stronger, suggesting the localization for overall error detection was driven primarily by phonological error detection. These findings demonstrate that monitoring of different error types relies on distinct cognitive functions, and provide causal evidence for the importance of frontal white matter tracts and DLPFC for self-monitoring of speech.

Localization of Phonological and Semantic Contributions to Reading.

Reading involves the rapid extraction of sound and meaning from print through a cooperative division of labor between phonological and lexical-semantic processes. Whereas lesion studies of patients with stereotyped acquired reading deficits contributed to the notion of a dissociation between phonological and lexical-semantic reading, the neuroanatomical basis for effects of lexicality (word vs pseudoword), orthographic regularity (regular vs irregular spelling-sound correspondences), and concreteness (concrete vs abstract meaning) on reading is underspecified, particularly outside the context of strong behavioral dissociations. Support vector regression lesion-symptom mapping (LSM) of 73 left hemisphere stroke survivors (male and female human subjects) not preselected for stereotyped dissociations revealed the differential contributions of specific cortical regions to reading pseudowords (ventral precentral gyrus), regular words (planum temporale, supramarginal gyrus, ventral precentral and postcentral gyrus, and insula), and concrete words (pars orbitalis and pars triangularis). Consistent with the primary systems view of reading being parasitic on language-general circuitry, our multivariate LSM analyses revealed that phonological decoding depends on perisylvian areas subserving sound-motor integration and that semantic effects on reading depend on frontal cortex subserving control over concrete semantic representations that aid phonological access from print. As the first study to localize the differential cortical contributions to reading pseudowords, regular words, and concrete words in stroke survivors with variable reading abilities, our results provide important information on the neurobiological basis of reading and highlight the insights attainable through multivariate, process-based approaches to alexia.SIGNIFICANCE STATEMENT Whereas fMRI evidence for neuroanatomical dissociations between phonological and lexical-semantic reading is abundant, evidence from modern lesion studies establishing the differential contributions of specific brain regions to specific reading processes is lacking. Our application of multivariate lesion-symptom mapping revealed that effects of lexicality, orthographic regularity, and concreteness on reading differentially depend on areas subserving auditory-motor integration and semantic control. Phonological decoding of print relies on a dorsal perisylvian network supporting auditory and articulatory representations, with unfamiliar words relying especially on articulatory mapping. In tandem with this dorsal decoding system, anterior inferior frontal gyrus may coordinate control over concrete semantic representations that support mapping of print to sound, which is a novel potential mechanism for semantic influences on reading.

Natural selection contributes to geographic patterns of thermal plasticity in Plantago lanceolata.

A long-standing debate in evolutionary biology concerns the relative importance of different evolutionary forces in explaining phenotypic diversification at large geographic scales. For example, natural selection is typically assumed to underlie divergence along environmental gradients. However, neutral evolutionary processes can produce similar patterns. We collected molecular genetic data from 14 European populations of Plantago lanceolata to test the contributions of natural selection versus neutral evolution to population divergence in temperature-sensitive phenotypic plasticity of floral reflectance. In P. lanceolata, reflectance plasticity is positively correlated with latitude/altitude. We used population pairwise comparisons between neutral genetic differentiation (F ST and Jost's D) and phenotypic differentiation (P ST) to assess the contributions of geographic distance and environmental parameters of the reproductive season in driving population divergence. Data are consistent with selection having shaped large-scale geographic patterns in thermal plasticity. The aggregate pattern of P ST versus F ST was consistent with divergent selection. F ST explained thermal plasticity differences only when geographic distance was not included in the model. Differences in the extent of cool reproductive season temperatures, and not overall temperature variation, explained plasticity differences independent of distance. Results are consistent with the hypothesis that thermal plasticity is adaptive where growing seasons are shorter and cooler, that is, at high latitude/altitude.

Behavioral Effects of Chronic Gray and White Matter Stroke Lesions in a Functionally Defined Connectome for Naming.

BACKGROUND: In functional magnetic resonance imaging studies, picture naming engages widely distributed brain regions in the parietal, frontal, and temporal cortices. However, it remains unknown whether those activated areas, along with white matter pathways between them, are actually crucial for naming. OBJECTIVE: We aimed to identify nodes and pathways implicated in naming in healthy older adults and test the impact of lesions to the connectome on naming ability. METHODS: We first identified 24 cortical nodes activated by a naming task and reconstructed anatomical connections between these nodes using probabilistic tractography in healthy adults. We then used structural scans and fractional anisotropy (FA) maps in 45 patients with left hemisphere stroke to assess the relationships of node and pathway integrity to naming, phonology, and nonverbal semantic ability. RESULTS: We found that mean FA values in 13 left hemisphere white matter tracts within the dorsal and ventral streams and 1 interhemispheric tract significantly related to naming scores after controlling for lesion size and demographic factors. In contrast, lesion loads in the cortical nodes were not related to naming performance after controlling for the same variables. Among the identified tracts, the integrity of 4 left hemisphere ventral stream tracts related to nonverbal semantic processing and 1 left hemisphere dorsal stream tract related to phonological processing. CONCLUSIONS: Our findings reveal white matter structures vital for naming and its subprocesses. These findings demonstrate the value of multimodal methods that integrate functional imaging, structural connectivity, and lesion data to understand relationships between brain networks and behavior.