Publications by authors named "Zachary Miller"

119 Publications

Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease.

J Med Chem 2021 Aug 26;64(15):10934-10950. Epub 2021 Jul 26.

Department of Pharmaceutical Sciences, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536-0596, United States.

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 () effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 () also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00291DOI Listing
August 2021

Dissociating nouns and verbs in temporal and perisylvian networks: Evidence from neurodegenerative diseases.

Cortex 2021 Sep 2;142:47-61. Epub 2021 Jun 2.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Naming of nouns and verbs can be selectively impaired in neurological disorders, but the specificity of the neural and cognitive correlates of such dissociation remains unclear. Functional imaging and stroke research sought to identify cortical regions selectively recruited for nouns versus verbs, yet findings are inconsistent. The present study investigated this issue in neurodegenerative diseases known to selectively affect different brain networks, thus providing new critical evidence of network specificity. We examined naming performances on nouns and verbs in 146 patients with different neurodegenerative syndromes (Primary Progressive Aphasia - PPA, Alzheimer's disease - AD, and behavioral variant Frontotemporal Dementia - FTD) and 30 healthy adults. We then correlated naming scores with MRI-derived cortical thickness values as well as with performances in semantic and syntactic tasks, across all subjects. Results indicated that patients with the semantic variant PPA named significantly fewer nouns than verbs. Instead, nonfluent/agrammatic PPA patients named fewer verbs than nouns. Across all subjects, performance on nouns (adjusted for verbs) specifically correlated with cortical atrophy in left anterior temporal regions, and performance on verbs (adjusted for nouns) with atrophy in left inferior and middle frontal, inferior parietal and posterior temporal regions. Furthermore, lower lexical-semantic abilities correlated with deficits in naming both nouns and verbs, while lower syntactic abilities only correlated with naming verbs. Our results show that different neural and cognitive mechanisms underlie naming of specific grammatical categories in neurodegenerative diseases. Importantly, our findings showed that verb processing depends on a widespread perisylvian networks, suggesting that some regions might be involved in processing different types of action knowledge. These findings have important implications for early differential diagnosis of neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.cortex.2021.05.006DOI Listing
September 2021

Functional and morphological correlates of developmental dyslexia: A multimodal investigation of the ventral occipitotemporal cortex.

J Neuroimaging 2021 Sep 11;31(5):962-972. Epub 2021 Jun 11.

Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

Background And Purpose: The ventral occipitotemporal cortex (vOT) is a region crucial for reading acquisition through selective tuning to printed words. Developmental dyslexia is a disorder of reading with underlying neurobiological bases often associated with atypical neural responses to printed words. Previous studies have discovered anomalous structural development and function of the vOT in individuals with dyslexia. However, it remains unclear if or how structural abnormalities relate to functional alterations.

Methods: In this study, we acquired structural, functional (words and faces processing), and diffusion MRI data from 26 children with dyslexia (average age = 10.4 ± 2.0 years) and 14 age-matched typically developing readers (average age = 10.4 ± 1.6 years). Morphological indices of local gyrification, neurite density (i.e., dendritic arborization structure), and orientation dispersion (i.e., dendritic arborization orientation) were analyzed within the vOT region that showed preferential activation in typically developing readers for words (as compared to face stimuli).

Results: The two cohorts diverged significantly in both functional and structural measures. Compared to typically developing controls, children with dyslexia did not show selectivity for words in the left vOT (contrast: words > false fonts). This lack of tuning to printed words was associated with greater neurite dispersion heterogeneity in the dyslexia cohort, but similar neurite density. These group differences were not present in the homologous contralateral area, the right vOT.

Conclusions: Our findings provide new insight into the neurobiology of the lack of vOT word tuning in dyslexia by linking behavior, alterations in functional activation, and neurite organization.
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http://dx.doi.org/10.1111/jon.12892DOI Listing
September 2021

An oropharyngeal device for airway management of conscious and semiconscious patients: A randomized clinical trial.

J Am Coll Emerg Physicians Open 2021 Apr 29;2(2):e12440. Epub 2021 Apr 29.

University of Vermont Burlington Vermont USA.

Objective: No oropharyngeal devices exist for use in conscious and semiconscious trauma patients during emergency evacuation, transport, or resuscitation. We aimed to test the hypotheses that the ManMaxAirway (MMA) is better tolerated than the standard Guedel-style device in awake volunteers and that it produces a jaw thrust and improves air flow.

Methods: This was a randomized cross-over study of healthy volunteers with either the MMA or standard device. The primary outcome of tolerability was defined as maintaining the device in place for 60 seconds. Secondary outcomes included respiratory system function and jaw thrust. Resistance to airflow through the device lumen was measured in situ and when placed in subjects in the pulmonary laboratory alone. Jaw thrust was quantified as displacement between the mandibular condyle and condylar fossa apex relative to baseline visualized with magnetic resonance imaging (MRI).

Results: We enrolled 19 subjects. Of these, a convenience sample of 5 individuals was selected for MRI; the remaining individuals (n = 14) were randomized for the cross-over study. All 14 subjects were able to maintain the MMA for 60 seconds compared with 2/14 (14%) with the standard device (odds ratio, 145; 95% confidence interval, 6.3-3314). Subjects reported that the experimental device was more comfortable and its placement did not trigger the gag reflex. Airway resistance produced by the MMA in an oscillatory flow model was nearly an order of magnitude lower than that of the standard device (experimental vs standard, 8 Hz-0.092 vs 0.786 cmH0·s/L; 15 Hz-0.193 vs 1.321 cmH0·s/L). Rapid induction of the gag reflex precluded further measurements with the standard device. Forced oscillation pulmonary testing in conscious volunteers with and without the MMA demonstrated that the device decreased respiratory system resistance to airflow and reduced respiratory elastance (31% ± 8% and 44% ± 13.4%, respectively;  < 0.05). MRIs of the subjects (n = 5) with the MMA in place showed a significant jaw thrust compared with baseline (7 ± 1 mm).

Conclusions: The MMA proved well tolerated in conscious subjects, resulting in an opening of the anatomic airway and a decreased resistance to airflow.
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http://dx.doi.org/10.1002/emp2.12440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082718PMC
April 2021

Joint analysis of days to flowering reveals independent temperate adaptations in maize.

Heredity (Edinb) 2021 Jun 22;126(6):929-941. Epub 2021 Apr 22.

USDA-ARS, Ithaca, NY, USA.

Domesticates are an excellent model for understanding biological consequences of rapid climate change. Maize (Zea mays ssp. mays) was domesticated from a tropical grass yet is widespread across temperate regions today. We investigate the biological basis of temperate adaptation in diverse structured nested association mapping (NAM) populations from China, Europe (Dent and Flint) and the United States as well as in the Ames inbred diversity panel, using days to flowering as a proxy. Using cross-population prediction, where high prediction accuracy derives from overall genomic relatedness, shared genetic architecture, and sufficient diversity in the training population, we identify patterns in predictive ability across the five populations. To identify the source of temperate adapted alleles in these populations, we predict top associated genome-wide association study (GWAS) identified loci in a Random Forest Classifier using independent temperate-tropical North American populations based on lines selected from Hapmap3 as predictors. We find that North American populations are well predicted (AUC equals 0.89 and 0.85 for Ames and USNAM, respectively), European populations somewhat well predicted (AUC equals 0.59 and 0.67 for the Dent and Flint panels, respectively) and that the Chinese population is not predicted well at all (AUC is 0.47), suggesting an independent adaptation process for early flowering in China. Multiple adaptations for the complex trait days to flowering in maize provide hope for similar natural systems under climate change.
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http://dx.doi.org/10.1038/s41437-021-00422-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178344PMC
June 2021

Cortically constrained shape recognition: Automated white matter tract segmentation validated in the pediatric brain.

J Neuroimaging 2021 Jul 20;31(4):758-772. Epub 2021 Apr 20.

Department of Neurology, University of California, UCSF Memory and Aging Center, Sandler Neurosciences Center, San Francisco, California, USA.

Background And Purpose: Manual segmentation of white matter (WM) bundles requires extensive training and is prohibitively labor-intensive for large-scale studies. Automated segmentation methods are necessary in order to eliminate operator dependency and to enable reproducible studies. Significant changes in the WM landscape throughout childhood require flexible methods to capture the variance across the span of brain development.

Methods: Here, we describe a novel automated segmentation tool called Cortically Constrained Shape Recognition (CCSR), which combines two complementary approaches: (1) anatomical connectivity priors based on FreeSurfer-derived regions of interest and (2) shape priors based on 3-dimensional streamline bundle atlases applied using RecoBundles. We tested the performance and repeatability of this approach by comparing volume and diffusion metrics of the main language WM tracts that were both manually and automatically segmented in a pediatric cohort acquired at the UCSF Dyslexia Center (n = 59; 25 females; average age: 11 ± 2; range: 7-14).

Results: The CCSR approach showed high agreement with the expert manual segmentations: across all tracts, the spatial overlap between tract volumes showed an average Dice Similarity Coefficient (DSC) of 0.76, and the fractional anisotropy (FA) on average had a Lin's Concordance Correlation Coefficient (CCC) of 0.81. The CCSR's repeatability in a subset of this cohort achieved a DSC of 0.92 on average across all tracts.

Conclusion: This novel automated segmentation approach is a promising tool for reproducible large-scale tractography analyses in pediatric populations and particularly for the quantitative assessment of structural connections underlying various clinical presentations in neurodevelopmental disorders.
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http://dx.doi.org/10.1111/jon.12854DOI Listing
July 2021

Comorbid neuropathological diagnoses in early versus late-onset Alzheimer's disease.

Brain 2021 Aug;144(7):2186-2198

Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

Co-pathologies play an important role in the expression of the Alzheimer's disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer's disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer's disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer's disease (median age of onset = 55 years, 44 females) and 48 with late-onset Alzheimer's disease (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer's disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer's disease pathological diagnosis in 98% of patients with early-onset Alzheimer's disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer's disease (median = 2 versus 3, Mann-Whitney Z = 3.00, P = 0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer's disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P = 0.33; Lewy body disease: 49% versus 42%, P = 0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer's disease (22% versus 6%, P = 0.02). In contrast, LATE (35% versus 8%, P < 0.001), hippocampal sclerosis (15% versus 3%, P = 0.02), argyrophilic grain disease (58% versus 41%, P = 0.052), and vascular brain injury (65% versus 39%, P = 0.004) were more common in late than in early onset Alzheimer's disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI -2.5 to -0.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-Alzheimer's disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer's disease with potentially significant implications for clinical practice and clinical trials design.
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http://dx.doi.org/10.1093/brain/awab099DOI Listing
August 2021

Acceptability factors for wildlife approach in park and protected area settings.

J Environ Manage 2021 May 4;286:112276. Epub 2021 Mar 4.

Department of Recreation, Park and Tourism Management, The Pennsylvania State University, 801 Ford Building, State College, PA, 16802, USA. Electronic address:

Human-wildlife conflicts are a challenge in parks and protected areas around the world. Facilitating quality wildlife viewing experiences that minimize negative impacts to people and animals is often complicated by distance-related human behaviors. The purpose of this study was to examine how people's distance-related norms varied as a function of proximity from wildlife, wildlife species, and physical landscape features. By using virtual reality technology and simulations, this study assessed how physical landscape features (i.e., an open field, deadfall, and a paved road) impact wildlife viewing norms and also compared norms among three different wildlife species (i.e., bison, bear, and elk). Data were analyzed with repeated measures ANOVA to explore how these factors influenced acceptability ratings of distances between people and wildlife. Results revealed a significant interaction between distance to wildlife and landscape features. Recommendations for improving the management of humanwildlife conflicts and future research directions are discussed.
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http://dx.doi.org/10.1016/j.jenvman.2021.112276DOI Listing
May 2021

Observing COVID-19 related behaviors in a high visitor use area of Arches National Park.

PLoS One 2021 22;16(2):e0247315. Epub 2021 Feb 22.

Department of Environment and Society, Utah State University, Logan, Utah, United States of America.

Introduction: Visitation to parks and protected areas is a common COVID-19 coping strategy promoted by state and national public health officials and political leadership. Crowding and congestions in parks has been a perennial problem and the ability to socially distance within them is an unproven assumption. Is it possible to socially distance in a busy national park that has been designed to concentrate use?

Methodology/principal Findings: An observational study was conducted in July 2020 at the outside foyer of the Visitor Center of Arches National Park. Motion sensor cameras were placed to record one-minute videos when a person entered the field of view. Number of groups, group size, facial coverings and encounters within 6 feet (1.83 meters) of other groups were recorded. Groups were smaller on average than recorded in previous studies. Approximately 61% of the visitors wore masks. Most groups (69%) were able to experience the visitor center with no intergroup encounters. We model the probability of intergroup encounters and find as group size and number of groups increases, the probability of encounters rises. With four groups present, the probability of one or more encounters ranges from 19% to 40% for common group sizes, while if eight groups are present, the probability of one or more encounters increases from 34% to 64% for common group sizes.

Conclusions/significance: Under conditions in which park visitors have the physical space to avoid close encounters with other groups they are taking advantage of the opportunity. Visitors are minimizing group size, wearing masks, and remaining socially distant. However, encounters increase as the number or the size of the groups increases. In other areas of the parks this ability to avoid encounters may not be as possible. We recommend that park managers continue to appeal for compliance with CDC guidelines, especially the wearing of masks and encouraging visitors to split up into small groups when visiting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247315PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899324PMC
March 2021

Prevalence and Risk Factors for Food Insecurity Among Low-Income US Military Veterans.

Public Health Rep 2021 Sep-Oct;136(5):618-625. Epub 2021 Jan 21.

IMPAQ International, LLC, Washington, DC, USA.

Objective: Ensuring access to sufficient foods at all times is critical to veterans' health and well-being. Food insecurity has not been well explored in the veteran population. We examined the prevalence and predictors of food insecurity among low-income veterans, because the highest rates of food insecurity are among low-income households. We also examined rates of Supplemental Nutrition Assistance Program (SNAP) participation among subgroups at the highest risk of food insecurity.

Methods: We used univariate analyses and 2011-2017 National Health Interview Survey (NHIS) data on veterans aged ≥21 with family incomes <200% of the federal poverty level to estimate the prevalence of food insecurity. We used bivariate analyses to identify correlates of food insecurity and estimate SNAP participation rates among subgroups of low-income veterans. Percentages were weighted using NHIS survey weights.

Results: Of 5146 low-income veterans, 22.5% reported being food insecure in the previous month. Food insecurity was significantly associated with being aged <65 (33.0% aged 45-64 and 29.7% aged 21-44) compared with 15.0% and 6.4% among veterans aged 65-74 and ≥75, respectively ( < .001); unemployed compared with employed or not in the labor force (39.4%, 22.7%, and 20.2%, respectively; < .001); in fair or poor health compared with good, very good, or excellent heath (31.8% vs 18.2%; < .001); and having experienced serious psychological distress in the past month (56.3%) compared with not having experienced such distress (19.7%; < .001). Although overall SNAP participation among low-income veterans was estimated to be 27.0%, participation rates were highest among veterans who had experienced serious psychological distress (44.1%), were unemployed (39.2%), and were renting their home (39.0%).

Conclusions: Some low-income veterans are at greater risk of food insecurity than other veterans. Postseparation programs, civilian support services, and veterans' health providers should be aware of the characteristics that place veterans at highest risk of food insecurity.
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http://dx.doi.org/10.1177/0033354920974662DOI Listing
January 2021

Mutualism Wildlife Value Orientations Predict Support for Messages About Distance-Related Wildlife Conflict.

Environ Manage 2021 05 18;67(5):920-929. Epub 2021 Jan 18.

Department of Recreation, Park and Tourism Management, The Pennsylvania State University, State College, PA, USA.

Wildlife value orientations (WVOs) are used to address human-wildlife conflicts by developing value-framed messaging. However, little is known about whether WVOs (i.e., mutualism, domination) are useful in distance-related wildlife safety communication strategies. This study explores the predictive ability of mutualism and domination value orientations on study participants' levels of agreement with distance-related safety messages. Distance-related wildlife safety messages were crafted to appeal to the four WVO typologies (i.e., traditionalist, mutualist, pluralist, and distanced). Undergraduate students were asked to rate their levels of agreement with a series of distance-related messages. Confirmatory factor analyses were used to create domination and mutualism dimension scores. Multiple regressions predicted levels of agreement with each of the messages from domination and mutualism. Study results indicated that in this sample of undergraduate student participants, only mutualism values predicted distance-related wildlife safety message agreement. This information can be used to help frame communications about distance-related wildlife issues.
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http://dx.doi.org/10.1007/s00267-020-01414-1DOI Listing
May 2021

Validation of an online version of the Trier Social Stress Test in a study of adolescents.

Psychoneuroendocrinology 2021 03 14;125:105111. Epub 2020 Dec 14.

Institute of Child Development, University of Minnesota - Twin Cities, 51 E. River Road, Minneapolis, MN 55455, USA.

Introduction: The Trier Social Stress Test (TSST) is the most widely used protocol for activating a stress response of the hypothalamic-pituitary-adrenocortical (HPA) axis and other stress-mediating systems. A number of variants of the TSST exist, including ones for children, groups, and virtual reality. All of these versions, though, require in-person assessment. The COVID-19 pandemic has made in-person assessment impossible or extremely difficult and potentially dangerous. The purpose of this study was to validate a completely remote, online, version of the TSST for children.

Method: A sample of 68 (27 female) 15- and 16-year old participants were administered the TSST-Online (TSST-OL) during the late afternoon hours (3-6 p.m. start time). The participants, judges (one male, one female), and experimenter (female) all joined the assessment from their own homes via the online platform, ZOOM™. Two sessions were conducted, one to obtain consent, explain procedures, work with the family to arrange the computer and room set-up for the TSST-OL and one within two weeks to conduct the procedure. The participants were trained to take their own saliva samples and a saliva sampling kit was mailed to the home in between the first and second session. The samples were then mailed to the researchers within a day of collection. The participant was observed during saliva collection to determine correct procedures were followed. Salivary cortisol, salivary α-amylase and self-reports of stress were measured multiple times over the second session.

Results: rmANOVAs yielded a significant effect of trials, for cortisol, F(1.37,90.46) = 15.13, p = .001, sAA, F(2.75,146.68) = 6.91, p = .001, and self-rated stress, F(3.43,222.69) = 118.73, p = .001. There were no significant sex by trials interactions for any measure, although females reported more stress than males, F(1,65) = 9.14, p = .004. For cortisol, from baseline to expected peak (30 min after the onset of speech preparation), the Cohen's effect size was d = 0.57. Using 1.5 nmol/l (or 0.54 μg/dl) as the criterion for a response (Miller, Plessow, Kirschaum, & Stalder, 2013), 63% of the participants produced a significant increase in cortisol.

Conclusions: The responses to the TSST-OL are consistent with in-person responses among children and adolescents (see recent meta-analysis (Seddon et al., 2020). The protocol is a viable way of assessing reactivity of the HPA axis and other stress systems without needing to bring the participant into the research laboratory. This method will be useful during periods of widespread infection. It should also work to study populations who all live too far from the research laboratory to be assessed in person.
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http://dx.doi.org/10.1016/j.psyneuen.2020.105111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904651PMC
March 2021

The phantom chorus: birdsong boosts human well-being in protected areas.

Proc Biol Sci 2020 12 16;287(1941):20201811. Epub 2020 Dec 16.

Biological Sciences Department, California Polytechnic State University, San Luis Obispo, CA, USA.

Spending time in nature is known to benefit human health and well-being, but evidence is mixed as to whether biodiversity or perceptions of biodiversity contribute to these benefits. Perhaps more importantly, little is known about the sensory modalities by which humans perceive biodiversity and obtain benefits from their interactions with nature. Here, we used a 'phantom birdsong chorus' consisting of hidden speakers to experimentally increase audible birdsong biodiversity during 'on' and 'off' (i.e. ambient conditions) blocks on two trails to study the role of audition in biodiversity perception and self-reported well-being among hikers. Hikers exposed to the phantom chorus reported higher levels of restorative effects compared to those that experienced ambient conditions on both trails; however, increased restorative effects were directly linked to the phantom chorus on one trail and indirectly linked to the phantom chorus on the other trail through perceptions of avian biodiversity. Our findings add to a growing body of evidence linking mental health to nature experiences and suggest that audition is an important modality by which natural environments confer restorative effects. Finally, our results suggest that maintaining or improving natural soundscapes within protected areas may be an important component to maximizing human experiences.
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http://dx.doi.org/10.1098/rspb.2020.1811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779501PMC
December 2020

Enhanced visceromotor emotional reactivity in dyslexia and its relation to salience network connectivity.

Cortex 2021 01 20;134:278-295. Epub 2020 Nov 20.

Department of Neurology, University of California, UCSF Memory and Aging Center, Sandler Neurosciences Center, San Francisco, CA, USA; Department of Psychiatry, University of California, San Francisco, CA, USA. Electronic address:

Dyslexia is a neurodevelopmental disorder mainly defined by reading difficulties. During reading, individuals with dyslexia exhibit hypoactivity in left-lateralized language systems. Lower activity in one brain circuit can be accompanied by greater activity in another, and, here, we examined whether right-hemisphere-based emotional reactivity may be elevated in dyslexia. We measured emotional reactivity (i.e., facial behavior, physiological activity, and subjective experience) in 54 children ages 7-12 with (n = 32) and without (n = 22) dyslexia while they viewed emotion-inducing film clips. Participants also underwent task-free functional magnetic resonance imaging. Parents of children with dyslexia completed the Behavior Assessment System for Children, which assesses real-world behavior. During film viewing, children with dyslexia exhibited significantly greater reactivity in emotional facial behavior, skin conductance level, and respiration rate than those without dyslexia. Across the sample, greater emotional facial behavior correlated with stronger connectivity between right ventral anterior insula and right pregenual anterior cingulate cortex (p<.05), key salience network hubs. In children with dyslexia, greater emotional facial behavior related to better real-world social skills and higher anxiety and depression. Our findings suggest there is heightened visceromotor emotional reactivity in dyslexia, which may lead to interpersonal strengths as well as affective vulnerabilities.
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http://dx.doi.org/10.1016/j.cortex.2020.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880083PMC
January 2021

Association of and Clinical Variability in Alzheimer Disease With the Pattern of Tau- and Amyloid-PET.

Neurology 2021 02 1;96(5):e650-e661. Epub 2020 Dec 1.

From the Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences (R.L.J., A.V.V., O.H.L.-V., L.E., L.I., D.N.S.-M., T.M., Z.A.M., D.C.P., J.P., A.S., M.L.G.-T., H.J.R., B.L.M., G.D.R.), and Department of Radiology and Biomedical Imaging (G.D.R.), University of California, San Francisco; Department of Diagnostic Imaging (O.H.L.-V.), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Molecular Biophysics and Integrated Bioimaging Division (S.L.B., M.J., W.J.J., G.D.R.), Lawrence Berkeley National Laboratory; and Helen Wills Neuroscience Institute (W.J.J., G.D.R.), University of California Berkeley.

Objective: To assess whether Alzheimer disease (AD) clinical presentation and relate to the burden and topography of β-amyloid (Aβ) and tau pathologies using in vivo PET imaging.

Methods: We studied 119 Aβ-positive symptomatic patients aged 48-95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with posterior cortical atrophy (PCA). Pittsburgh compound B (PiB)-Aβ and flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), , and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the Clinical Dementia Rating Sum of Boxes.

Results: PiB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or . Flortaucipir-PET was commonly elevated in temporoparietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other AD. Cortical flortaucipir-PET binding was higher in younger patients across phenotypes ( = -0.63, 95% confidence interval [CI] -0.72, -0.50), especially in parietal and dorsal prefrontal cortices. The presence of was associated with a focal medial temporal flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR, 95% CI 0.091, 0.530).

Conclusions: Clinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and are not only risk factors for AD but also seem to affect disease expression by promoting a more medial temporal lobe-predominant pattern of tau pathology.
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http://dx.doi.org/10.1212/WNL.0000000000011270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884991PMC
February 2021

SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses.

Cell 2020 11 8;183(5):1325-1339.e21. Epub 2020 Oct 8.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
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http://dx.doi.org/10.1016/j.cell.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543886PMC
November 2020

A sorghum practical haplotype graph facilitates genome-wide imputation and cost-effective genomic prediction.

Plant Genome 2020 03 25;13(1):e20009. Epub 2020 Mar 25.

Institute for Genomic Diversity, Cornell University, Ithaca, NY, 14853, USA.

Successful management and utilization of increasingly large genomic datasets is essential for breeding programs to accelerate cultivar development. To help with this, we developed a Sorghum bicolor Practical Haplotype Graph (PHG) pangenome database that stores haplotypes and variant information. We developed two PHGs in sorghum that were used to identify genome-wide variants for 24 founders of the Chibas sorghum breeding program from 0.01x sequence coverage. The PHG called single nucleotide polymorphisms (SNPs) with 5.9% error at 0.01x coverage-only 3% higher than PHG error when calling SNPs from 8x coverage sequence. Additionally, 207 progenies from the Chibas genomic selection (GS) training population were sequenced and processed through the PHG. Missing genotypes were imputed from PHG parental haplotypes and used for genomic prediction. Mean prediction accuracies with PHG SNP calls range from .57-.73 and are similar to prediction accuracies obtained with genotyping-by-sequencing or targeted amplicon sequencing (rhAmpSeq) markers. This study demonstrates the use of a sorghum PHG to impute SNPs from low-coverage sequence data and shows that the PHG can unify genotype calls across multiple sequencing platforms. By reducing input sequence requirements, the PHG can decrease the cost of genotyping, make GS more feasible, and facilitate larger breeding populations. Our results demonstrate that the PHG is a useful research and breeding tool that maintains variant information from a diverse group of taxa, stores sequence data in a condensed but readily accessible format, unifies genotypes across genotyping platforms, and provides a cost-effective option for genomic selection.
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http://dx.doi.org/10.1002/tpg2.20009DOI Listing
March 2020

Verbal Semantics and the Left Dorsolateral Anterior Temporal Lobe: A Longitudinal Case of Bilateral Temporal Degeneration.

Aphasiology 2020 4;34(7):865-885. Epub 2019 Sep 4.

Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.

Background: Semantic variant primary progressive aphasia (svPPA), a clinical syndrome characterized by loss of semantic knowledge, is associated with neurodegeneration that starts in the anterior temporal lobe (ATL) and gradually spreads towards posterior temporal and medial frontal areas. At the earliest stages, atrophy may be predominantly lateralized to either the left or right ATL, leading to different clinical profiles with greatest impairment of word comprehension or visual/social semantics, respectively.

Methods & Procedures: We report the in-depth longitudinal investigation of cognitive and neuroanatomical features of JB, an unusual case of ATL neurodegeneration with relative sparing of left lateral ATL regions.

Outcomes & Results: Over the course of nine years, neurodegeneration progressed to involve bilateral temporo-lateral and frontal regions, resulting in a relatively symmetric and diffuse frontotemporal atrophy pattern. In parallel, JB developed greater behavioral, cognitive, and language impairments, as well as signs of motor neuron disease at her last evaluation. Episodic memory and socio-emotional processing deficits arose, likely secondary to semantic verbal deficits, while visuospatial processing, executive function, and non-semantic language abilities remained largely unaffected throughout the course of the disease.

Conclusions: The details of this rare case of early medial more than lateral ATL degeneration are consistent with a bilateral organization of the semantic system and, crucially, with a functional dissociation between medial paralimbic and lateral neocortical temporal regions. Cases of frontotemporal dementia (FTD) such as JB, who initially do not meet current clinical criteria for svPPA and instead present with some features of behavioral variant FTD, highlight the need for specific criteria for the right temporal variant of FTD that we propose could be called semantic variant FTD.
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http://dx.doi.org/10.1080/02687038.2019.1659935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529336PMC
September 2019

DSTYK Promotes Metastasis and Chemoresistance EMT in Colorectal Cancer.

Front Pharmacol 2020 2;11:1250. Epub 2020 Sep 2.

Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.

Objective: Tumor metastasis and resistance to chemotherapy are two critical factors that contribute to the high death rate of colorectal cancer (CRC) patients. Metastasis is facilitated by the epithelial-mesenchymal transition (EMT) of tumor cells, which has emerged not only as a fundamental process during metastasis, but is also a key process leading to chemoresistance of cancer cells. However, the underlying mechanisms of EMT in CRC cell remain unknown. Here, we aim to assess the role of dual serine/threonine and tyrosine protein kinase (DSTYK) in CRC metastasis and chemoresistance.

Methods: To study the role of DSTYK in TGF-β-induced EMT, we employed techniques including Crispr/Cas9 knockout (KO) to generate DSTYK KO cell lines, RT-PCR to detect the mRNA expression, immunofluorescence analyses, and western blots to detect protein levels of DSTYK in the following 4 cell lines: control LS411N-TβRII and LS411N-TβRII/DSTYK KO, control LS513 and LS513/DSTYK KO cells, treated with/without TGF-β. The effects of DSTYK on apoptosis were investigated by MTT assays, flow cytometry assays, and TUNEL assays. The expression of DSTYK in CRC patients and its correlation with EMT markers were determined by bioinformatics analysis. For analysis, both xenograft and orthotopic tumor mouse models were employed to investigate the function of DSTYK in chemoresistance and metastasis of tumors.

Results: In this study, we demonstrate that the novel kinase DSTYK promotes both TGF-β-induced EMT and the subsequent chemoresistance in CRC cells. DSTYK KO significantly attenuates TGF-β-induced EMT and chemoresistance in CRC cells. According to the Gene Expression Omnibus (GEO) database, the expression of DSTYK is not only positively correlated to the expression of TGF-β, but proportional to the death rate of CRC patients as well. Evidently, the expression of DSTYK in the metastatic colorectal cancer samples from patients was significantly higher than that of primary colorectal cancer samples. Further, we demonstrate in mouse models that chemotherapeutic drug treatment suppresses the growth of DSTYK KO tumors more effectively than control tumors.

Conclusion: Our findings identify DSTYK as a novel protein kinase in regulating TGF-β-mediated EMT and chemoresistance in CRC cells, which defines DSTYK as a potential therapeutic target for CRC therapy.
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http://dx.doi.org/10.3389/fphar.2020.01250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493073PMC
September 2020

Effects of bilingualism on age at onset in two clinical Alzheimer's disease variants.

Alzheimers Dement 2020 12 3;16(12):1704-1713. Epub 2020 Sep 3.

Department of Neurology, Memory and Aging Center, University of California, San Francisco, California, USA.

Introduction: The effect of bilingualism on age at onset has yet to be examined within different clinical variants of Alzheimer's disease.

Methods: We reviewed the research charts of 287 well-characterized participants with either amnestic Alzheimer's dementia or logopenic variant primary progressive aphasia (lvPPA) and identified bilingual speakers based on regular use of two or more languages and/or ability to communicate with native speakers in two or more languages. We evaluated whether bilingual speakers demonstrated a delay in age of symptom onset relative to monolingual speakers while controlling for other variables known to influence cognitive reserve.

Results: A 5-year delay in age at symptom onset was observed for bilingual relative to monolingual speakers with lvPPA. This delay in onset was not observed in the amnestic Alzheimer's dementia cohort.

Discussion: Bilingualism may serve as a unique cognitive reserve variable in lvPPA, but not in amnestic Alzheimer's dementia.
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http://dx.doi.org/10.1002/alz.12170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902304PMC
December 2020

Tracheal Squamous Cell Carcinoma Treated with Tracheal Resection and Anastomosis in a Cat.

Case Rep Vet Med 2020 7;2020:8818660. Epub 2020 Aug 7.

Metropolitan Veterinary Hospital, Akron, OH, USA.

A 10-year-old male castrated domestic shorthair cat presented for a suspected tracheal mass. Radiographs confirmed an intraluminal tracheal mass. Tracheal resection and anastomosis of 5 tracheal rings was performed with minimal, mild intraoperative complications and no postoperative complications. Histopathology of the tracheal mass revealed a diagnosis of squamous cell carcinoma (SCC) with incomplete margins both cranially and caudally. Further treatment, including surgical revision, radiation therapy, or chemotherapy, was recommended. At the time of publication, no further treatment has been initiated, and a scheduled consultation with the oncologist has been canceled. The cat is doing well at home with no reported signs of recurrence 120 days postoperatively. This is the first report of a cat with a tracheal SCC to be treated with a tracheal resection and anastomosis and only the third feline tracheal SCC to be treated in the veterinary literature.
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http://dx.doi.org/10.1155/2020/8818660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429769PMC
August 2020

Taking the sublexical route: brain dynamics of reading in the semantic variant of primary progressive aphasia.

Brain 2020 08;143(8):2545-2560

Department of Radiology and Biomedical Imaging, University of California San Francisco, USA.

Reading aloud requires mapping an orthographic form to a phonological one. The mapping process relies on sublexical statistical regularities (e.g. 'oo' to |uː|) or on learned lexical associations between a specific visual form and a series of sounds (e.g. yacht to/jɑt/). Computational, neuroimaging, and neuropsychological evidence suggest that sublexical, phonological and lexico-semantic processes rely on partially distinct neural substrates: a dorsal (occipito-parietal) and a ventral (occipito-temporal) route, respectively. Here, we investigated the spatiotemporal features of orthography-to-phonology mapping, capitalizing on the time resolution of magnetoencephalography and the unique clinical model offered by patients with semantic variant of primary progressive aphasia (svPPA). Behaviourally, patients with svPPA manifest marked lexico-semantic impairments including difficulties in reading words with exceptional orthographic to phonological correspondence (irregular words). Moreover, they present with focal neurodegeneration in the anterior temporal lobe, affecting primarily the ventral, occipito-temporal, lexical route. Therefore, this clinical population allows for testing of specific hypotheses on the neural implementation of the dual-route model for reading, such as whether damage to one route can be compensated by over-reliance on the other. To this end, we reconstructed and analysed time-resolved whole-brain activity in 12 svPPA patients and 12 healthy age-matched control subjects while reading irregular words (e.g. yacht) and pseudowords (e.g. pook). Consistent with previous findings that the dorsal route is involved in sublexical, phonological processes, in control participants we observed enhanced neural activity over dorsal occipito-parietal cortices for pseudowords, when compared to irregular words. This activation was manifested in the beta-band (12-30 Hz), ramping up slowly over 500 ms after stimulus onset and peaking at ∼800 ms, around response selection and production. Consistent with our prediction, svPPA patients did not exhibit this temporal pattern of neural activity observed in controls this contrast. Furthermore, a direct comparison of neural activity between patients and controls revealed a dorsal spatiotemporal cluster during irregular word reading. These findings suggest that the sublexical/phonological route is involved in processing both irregular and pseudowords in svPPA. Together these results provide further evidence supporting a dual-route model for reading aloud mediated by the interplay between lexico-semantic and sublexical/phonological neurocognitive systems. When the ventral route is damaged, as in the case of neurodegeneration affecting the anterior temporal lobe, partial compensation appears to be possible by over-recruitment of the slower, serial attention-dependent, dorsal one.
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http://dx.doi.org/10.1093/brain/awaa212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447517PMC
August 2020

Gas-Phase Protonation Thermodynamics of Biological Lipids: Experiment, Theory, and Implications.

Anal Chem 2020 08 19;92(15):10365-10374. Epub 2020 Jul 19.

Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403-1253, United States.

Phospholipids are important to cellular function and are a vital structural component of plasma and organelle membranes. These membranes isolate the cell from its environment, allow regulation of the internal concentrations of ions and small molecules, and host diverse types of membrane proteins. It remains extremely challenging to identify specific membrane protein-lipid interactions and their relative strengths. Native mass spectrometry, an intrinsically gas-phase method, has recently been demonstrated as a promising tool for identifying endogenous protein-lipid interactions. However, to what extent the identified interactions reflect solution- versus gas-phase binding strengths is not known. Here, the "Extended" Kinetic Method and computations at three different levels of theory are used to experimentally and theoretically determine intrinsic gas-phase basicities (GB, Δ for deprotonation of the protonated base) and proton affinities (PA, Δ for deprotonation of the protonated base) of six lipids representing common phospholipid types. Gas-phase acidities (Δ and Δ for deprotonation) of neutral phospholipids are also evaluated computationally and ranked experimentally. Intriguingly, it is found that two of these phospholipids, sphingomyelin and phosphatidylcholine, have the highest GB of any small, monomeric biomolecules measured to date and are more basic than arginine. Phosphatidylethanolamine and phosphatidylserine are found to be similar in GB to basic amino acids lysine and histidine, and phosphatidic acid and phosphatidylglycerol are the least basic of the six lipid types studied, though still more basic than alanine. Kinetic Method experiments and theory show that the gas-phase acidities of these phospholipids are high but less extreme than their GB values, with phosphatidylserine and phosphatidylglycerol being the most acidic. These results indicate that sphingomyelin and phosphatidylcholine lipids can act as charge-reducing agents when dissociated from native membrane protein-lipid complexes in the gas phase and provide a straightforward model to explain the results of several recent native mass spectrometry studies of protein-lipid complexes.
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http://dx.doi.org/10.1021/acs.analchem.0c00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074629PMC
August 2020

LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease.

J Med Chem 2020 04 30;63(7):3763-3783. Epub 2020 Mar 30.

Department of Pharmaceutical Sciences, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536-0596, United States.

The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 () (IC: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1α production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00416DOI Listing
April 2020

Temporal variant of frontotemporal dementia in C9orf72 repeat expansion carriers: two case studies.

Brain Imaging Behav 2020 Apr;14(2):336-345

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132, Milan, Italy.

The temporal variant of frontotemporal dementia (tv-FTD) is a progressive neurodegenerative disease with a complex clinical picture mainly characterized by behavioral and language disorders. In this work, we describe clinical, genetic, neuroanatomical and neuropathological (only in one case) features of two patients with tv-FTD carrying C9orf72 repeat expansion. The first patient (AB) presented with a 1-year disease duration showing focal right anterior temporal lobe (ATL) atrophy on magnetic resonance imaging (MRI). The second patient (BC) came to medical attention 13 years after disease onset and showed a prominent bilateral ATL involvement. Both patients showed naming deficits, impairment in identifying known faces and proper names, and personality changes with new onset behavioral rigidity, and progressing language difficulties to single-word and sentence comprehension difficulties. They were classified as tv-FTD. Clinical, cognitive and MRI follow-up were performed. As cognitive impairment progressed, MRI atrophy worsened in ATL and frontotemporal areas in both patients. Both cases had clear family histories of neurological and/or psychiatric disease. Genetic testing revealed a C9orf72 hexanucleotide repeat expansion in both cases. BC passed away after 15 years of disease and autopsy showed the expected TDP-type B pathology. These genetic cases of tv-FTD highlight the susceptibility of ATL to C9orf72-related pathology and emphasize the importance of genetical testing in FTD-spectrum disorders, regardless of the clinical phenotype.
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http://dx.doi.org/10.1007/s11682-019-00253-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467111PMC
April 2020

Language and spatial dysfunction in Alzheimer disease with white matter thorn-shaped astrocytes.

Neurology 2020 03 30;94(13):e1353-e1364. Epub 2020 Jan 30.

From the Memory and Aging Center (E.d.P.F.R., A.L.N., C.P., A.J.E., S.S., I.E.A., H.J.R., J.K., B.L.M., W.W.S., M.L.G.-T., Z.M., L.T.G.), Weill Institute for Neurosciences, and Department of Biostatistics and Epidemiology (L.T.G.), University of California, San Francisco; Global Brain Health Institute based at University of California (E.d.P.F.R., L.T.G.), San Francisco; Trinity College (E.d.P.F.R., L.T.G.), Dublin, Ireland; Department of Neurology (E.d.P.F.R.), Federal University of Minas Gerais, Belo Horizonte, Brazil; Department of Integrative Biology (A.J.E.), University of California, Berkeley; and Department of Pathology (L.T.G.), Lim-22, Lim-66, University of Sao Paulo Medical School, Sao Paulo, Brazil.

Objectives: Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations.

Methods: We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing.

Results: WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains.

Conclusions: The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.
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http://dx.doi.org/10.1212/WNL.0000000000008937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274917PMC
March 2020

Publisher Correction: Predicting coexistence in experimental ecological communities.

Nat Ecol Evol 2020 Feb;4(2):281

Department of Ecology & Evolution, University of Chicago, Chicago, IL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41559-020-1098-5DOI Listing
February 2020

Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET.

Sci Transl Med 2020 01;12(524)

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.
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http://dx.doi.org/10.1126/scitranslmed.aau5732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035952PMC
January 2020

Task-Free Functional Language Networks: Reproducibility and Clinical Application.

J Neurosci 2020 02 18;40(6):1311-1320. Epub 2019 Dec 18.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94158.

Intrinsic connectivity networks (ICNs) identified through task-free fMRI (tf-fMRI) offer the opportunity to investigate human brain circuits involved in language processes without requiring participants to perform challenging cognitive tasks. In this study, we assessed the ability of tf-fMRI to isolate reproducible networks critical for specific language functions and often damaged in primary progressive aphasia (PPA). First, we performed whole-brain seed-based correlation analyses on tf-fMRI data to identify ICNs anchored in regions known for articulatory, phonological, and semantic processes in healthy male and female controls (HCs). We then evaluated the reproducibility of these ICNs in an independent cohort of HCs, and recapitulated their functional relevance with a meta-analysis on task-based fMRI. Last, we investigated whether atrophy in these ICNs could inform the differential diagnosis of nonfluent/agrammatic, semantic, and logopenic PPA variants. The identified ICNs included a dorsal articulatory-phonological network involving inferior frontal and supramarginal regions; a ventral semantic network involving anterior middle temporal and angular gyri; a speech perception network involving superior temporal and sensorimotor regions; and a network between posterior inferior temporal and intraparietal regions likely linking visual, phonological, and attentional processes for written language. These ICNs were highly reproducible across independent groups and revealed areas consistent with those emerging from task-based meta-analysis. By comparing ICNs' spatial distribution in HCs with patients' atrophy patterns, we identified ICNs associated with each PPA variant. Our findings demonstrate the potential use of tf-fMRI to investigate the functional status of language networks in patients for whom activation studies can be methodologically challenging. We showed that a single, short, task-free fMRI acquisition is able to identify four reproducible and relatively segregated intrinsic left-dominant networks associated with articulatory, phonological, semantic, and multimodal orthography-to-phonology processes, in HCs. We also showed that these intrinsic networks relate to syndrome-specific atrophy patterns in primary progressive aphasia. Collectively, our results support the application of task-free fMRI in future research to study functionality of language circuits in patients for whom tasked-based activation studies might be methodologically challenging.
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http://dx.doi.org/10.1523/JNEUROSCI.1485-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002153PMC
February 2020

Predicting coexistence in experimental ecological communities.

Nat Ecol Evol 2020 01 16;4(1):91-100. Epub 2019 Dec 16.

Department of Ecology & Evolution, University of Chicago, Chicago, IL, USA.

The study of experimental communities is fundamental to the development of ecology. Yet, for most ecological systems, the number of experiments required to build, model or analyse the community vastly exceeds what is feasible using current methods. Here, we address this challenge by presenting a statistical approach that uses the results of a limited number of experiments to predict the outcomes (coexistence and species abundances) of all possible assemblages that can be formed from a given pool of species. Using three well-studied experimental systems-encompassing plants, protists, and algae with grazers-we show that this method predicts the results of unobserved experiments with high accuracy, while making no assumptions about the dynamics of the systems. These results demonstrate a fundamentally different way of building and quantifying experimental systems, requiring far fewer experiments than traditional study designs. By developing a scalable method for navigating large systems, this work provides an efficient approach to studying highly diverse experimental communities.
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http://dx.doi.org/10.1038/s41559-019-1059-zDOI Listing
January 2020
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