Publications by authors named "Meredith Brown"

52 Publications

Correction for Clarke et al., "Transforming Growth Factor β Depletion Is the Primary Determinant of Smad Signaling Kinetics".

Mol Cell Biol 2021 Jul 23;41(8):e0025521. Epub 2021 Jul 23.

Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.00255-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300775PMC
July 2021

Syllable Inference as a Mechanism for Spoken Language Understanding.

Top Cogn Sci 2021 04 29;13(2):351-398. Epub 2021 Mar 29.

Department of Communicative Sciences and Disorders, Michigan State University, East Lansing, Michigan, USA.

A classic problem in spoken language comprehension is how listeners perceive speech as being composed of discrete words, given the variable time-course of information in continuous signals. We propose a syllable inference account of spoken word recognition and segmentation, according to which alternative hierarchical models of syllables, words, and phonemes are dynamically posited, which are expected to maximally predict incoming sensory input. Generative models are combined with current estimates of context speech rate drawn from neural oscillatory dynamics, which are sensitive to amplitude rises. Over time, models which result in local minima in error between predicted and recently experienced signals give rise to perceptions of hearing words. Three experiments using the visual world eye-tracking paradigm with a picture-selection task tested hypotheses motivated by this framework. Materials were sentences that were acoustically ambiguous in numbers of syllables, words, and phonemes they contained (cf. English plural constructions, such as "saw (a) raccoon(s) swimming," which have two loci of grammatical information). Time-compressing, or expanding, speech materials permitted determination of how temporal information at, or in the context of, each locus affected looks to, and selection of, pictures with a singular or plural referent (e.g., one or more than one raccoon). Supporting our account, listeners probabilistically interpreted identical chunks of speech as consistent with a singular or plural referent to a degree that was based on the chunk's gradient rate in relation to its context. We interpret these results as evidence that arriving temporal information, judged in relation to language model predictions generated from context speech rate evaluated on a continuous scale, informs inferences about syllables, thereby giving rise to perceptual experiences of understanding spoken language as words separated in time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tops.12529DOI Listing
April 2021

An Accessible Laparoscope for Surgery in Low- and Middle- Income Countries.

Ann Biomed Eng 2021 Jul 8;49(7):1657-1669. Epub 2021 Mar 8.

Duke Global Health Institute, Durham, NC, USA.

Laparoscopic surgery is the standard of care in high-income countries for many procedures in the chest and abdomen. It avoids large incisions by using a tiny camera and fine instruments manipulated through keyhole incisions, but it is generally unavailable in low- and middle-income countries (LMICs) due to the high cost of installment, lack of qualified maintenance personnel, unreliable electricity, and shortage of consumable items. Patients in LMICs would benefit from laparoscopic surgery, as advantages include decreased pain, improved recovery time, fewer wound infections, and shorter hospital stays. To address this need, we developed an accessible laparoscopic system, called the ReadyView laparoscope for use in LMICs. The device includes an integrated camera and LED light source that can be displayed on any monitor. The ReadyView laparoscope was evaluated with standard optical imaging targets to determine its performance against a state-of-the-art commercial laparoscope. The ReadyView laparoscope has a comparable resolving power, lens distortion, field of view, depth of field, and color reproduction accuracy to a commercially available endoscope, particularly at shorter, commonly-used working distances (3-5 cm). Additionally, the ReadyView has a cooler temperature profile, decreasing the risk for tissue injury and operating room fires. The ReadyView features a waterproof design, enabling sterilization by submersion, as commonly performed in LMICs. A custom desktop software was developed to view the video on a laptop computer with a frame rate greater than 30 frames per second and to white balance the image, which is critical for clinical use. The ReadyView laparoscope is capable of providing the image quality and overall performance needed for laparoscopic surgery. This portable low-cost system is well suited to increase access to laparoscopic surgery in LMICs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10439-020-02707-6DOI Listing
July 2021

HDAC inhibitors improve CRISPR-mediated HDR editing efficiency in iPSCs.

Sci China Life Sci 2021 Sep 6;64(9):1449-1462. Epub 2021 Jan 6.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

Genome-edited human induced pluripotent stem cells (iPSCs) hold great promise for therapeutic applications. However, low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and homology-directed repair (HDR)-edited iPSC lines, particularly for silent genes. This is partially due to chromatin compaction, inevitably limiting Cas9 access to the target DNA. Among the six HDAC inhibitors we examined, vorinostat, or suberoylanilide hydroxamic acid (SAHA), led to the highest HDR efficiency at both open and closed loci, with acceptable toxicity. HDAC inhibitors equally increased non-homologous end joining (NHEJ) editing efficiencies (∼50%) at both open and closed loci, due to the considerable HDAC inhibitor-mediated increase in Cas9 and sgRNA expression. However, we observed more substantial HDR efficiency improvement at closed loci relative to open chromatin (2.8 vs. 1.7-fold change). These studies provide a new strategy for HDR-editing of silent genes in iPSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11427-020-1855-4DOI Listing
September 2021

Early Troponin I Levels in Newborns Undergoing Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy and Residual Encephalopathy at Discharge.

Am J Perinatol 2020 Dec 7. Epub 2020 Dec 7.

Division of Neonatology, Department of Pediatrics, Bernard & Millie Duker Children's Hospital, Albany Medical Center, Albany, New York.

Objective:  Elevation of serum troponin I has been reported in newborns with hypoxic ischemic encephalopathy (HIE), but it is diagnostic and prognostic utility for newborn under 6 hours is not clear. Study the predictive value of early serum troponin I levels in newborns with HIE undergoing therapeutic hypothermia (TH) for persistent residual encephalopathy (RE) at discharge.

Study Design:  Retrospective chart review of newborns admitted with diagnosis of HIE to neonatal intensive care unit (NICU) for TH over a period of 3 years. Troponin levels were drawn with the initial set of admission laboratories while initiating TH. Newborns were followed up during hospital course and stratified into three groups based on predischarge examination and their electrical encephalography and cranial MRI findings: Group 1: no RE, Group 2: mild-to-moderate RE, and Group 3: severe RE or needing assisted medical technology or death. Demographic and clinical characteristics including troponin I levels were compared in each group.

Results:  Out of 104 newborns who underwent TH, 65 infants were in Group 1, 26 infants in Group 2, and 13 newborns in Group 3. All groups were comparable in demographic characteristics. There was a significant elevation of serum troponin in group 2 (mild-to-moderate RE) and group 3 (severe RE) as compared with group 1 (no RE). Receiver operator curve analysis for any RE (groups 2 and 3) compared with group 1 (no RE as control) had 0.88 (0.81-0.95) area under curve,  < 0.001. A cut-off level of troponin I ≥0.12 µg/L had a sensitivity of 77% and specificity of 78% for diagnosis of any RE, positive predictive value of 68%, and a negative predictive value of 84%.

Conclusion:  In newborns undergoing TH for HIE, the elevation of troponin within 6 hours of age predicts high risk of having RE at discharge.

Key Points: · Troponin I elevation is a biomarker of myocardial ischemia in adults and children.. · Myocardial ischemia may be part of multi-organ injury in neonatal HIE.. · Early elevation of troponin I level may correlate with the severity of neonatal HIE and predict residual encephalopathy in newborn at discharge from initial hospitalization..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1721497DOI Listing
December 2020

Limiting Self-Renewal of the Basal Compartment by PKA Activation Induces Differentiation and Alters the Evolution of Mammary Tumors.

Dev Cell 2020 12 28;55(5):544-557.e6. Epub 2020 Oct 28.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. Electronic address:

Differentiation therapy utilizes our understanding of the hierarchy of cellular systems to pharmacologically induce a shift toward terminal commitment. While this approach has been a paradigm in treating certain hematological malignancies, efforts to translate this success to solid tumors have met with limited success. Mammary-specific activation of PKA in mouse models leads to aberrant differentiation and diminished self-renewing potential of the basal compartment, which harbors mammary repopulating cells. PKA activation results in tumors that are more benign, exhibiting reduced metastatic propensity, loss of tumor-initiating potential, and increased sensitivity to chemotherapy. Analysis of tumor histopathology revealed features of overt differentiation with papillary characteristics. Longitudinal single-cell profiling at the hyperplasia and tumor stages uncovered an altered path of tumor evolution whereby PKA curtails the emergence of aggressive subpopulations. Acting through the repression of SOX4, PKA activation promotes tumor differentiation and represents a possible adjuvant to chemotherapy for certain breast cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.devcel.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726035PMC
December 2020

Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities.

Nat Commun 2020 05 20;11(1):2517. Epub 2020 May 20.

Departments of Cancer Biology, Boston, MA, USA.

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16399-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239950PMC
May 2020

Targeting Cancer Gene Dependencies with Anthrax-Mediated Delivery of Peptide Nucleic Acids.

ACS Chem Biol 2020 06 11;15(6):1358-1369. Epub 2020 May 11.

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Antisense oligonucleotide therapies are important cancer treatments, which can suppress genes in cancer cells that are critical for cell survival. has recently emerged as a promising gene target that encodes a key splicing factor in the SF3B protein complex. Over 10% of cancers have lost one or more copies of the gene, rendering these cancers vulnerable after further suppression. is just one example of a CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) gene, but over 120 additional candidate CYCLOPS genes are known. Antisense oligonucleotide therapies for cancer offer the promise of effective suppression for CYCLOPS genes, but developing these treatments is difficult due to their limited permeability into cells and poor cytosolic stability. Here, we develop an effective approach to suppress CYCLOPS genes by delivering antisense peptide nucleic acids (PNAs) into the cytosol of cancer cells. We achieve efficient cytosolic PNA delivery with the two main nontoxic components of the anthrax toxin: protective antigen (PA) and the 263-residue -terminal domain of lethal factor (LF). Sortase-mediated ligation readily enables the conjugation of PNAs to the C terminus of the LF protein. LF and PA work together in concert to translocate PNAs into the cytosol of mammalian cells. Antisense PNAs delivered with the LF/PA system suppress the gene and decrease cell viability, particularly of cancer cells with partial copy-number loss of . Moreover, antisense PNAs delivered with a HER2-binding PA variant selectively target cancer cells that overexpress the HER2 cell receptor, demonstrating receptor-specific targeting of cancer cells. Taken together, our efforts illustrate how PA-mediated delivery of PNAs provides an effective and general approach for delivering antisense PNA therapeutics and for targeting gene dependencies in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.9b01027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521945PMC
June 2020

Brief Report: Problem Gambling in International and Domestic University Students.

Am J Addict 2020 01 3;29(1):77-81. Epub 2019 Dec 3.

School of Psychology, Deakin University, Geelong, Victoria, Australia.

Background And Objectives: International students comprise an ethnic minority subpopulation who may be at increased risk for the development of gambling problems. This study aimed to explore the psychosocial factors associated with gambling problems in international and domestic university students in Australia.

Methods: One hundred seventy-three (n = 173) university students (127 domestic, 45 international) completed measures of gambling participation, problem gambling, psychosocial factors (depression, anxiety, perceived social support, loneliness, gambling-related cognitive distortions) and English language difficulties.

Results: Gambling participation, but not problem gambling status, was lower in international than domestic students. Only anxiety and cognitive distortions were associated with problem gambling in domestic students; and only cognitive distortions were associated with problem gambling in international students. International student status failed to moderate the relationships between any psychosocial factor and problem gambling status.

Conclusions And Scientific Significance: Future research is required to elucidate problem gambling risk and protective factors in this ethnic minority subgroup, with a view to guide culturally sensitive initiatives. (Am J Addict 2019;00:00-00).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajad.12981DOI Listing
January 2020

Prevalence and Characteristics of Twitter Posts About Court-Ordered, Tobacco-Related Corrective Statements: Descriptive Content Analysis.

JMIR Public Health Surveill 2019 Oct 8;5(4):e12878. Epub 2019 Oct 8.

Health Communication and Informatics Research Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD, United States.

Background: Three major US tobacco companies were recently ordered to publish corrective statements intended to prevent and restrain further fraud about the health effects of smoking. The court-ordered statements began appearing in newspapers and on television (TV) in late 2017.

Objective: The objective of this study was to examine the social media dissemination of the tobacco corrective statements during the first 6 months of the implementation of the statements.

Methods: We conducted a descriptive content analysis of Twitter posts using an iterative search strategy through Crimson Hexagon and randomly selected 19.74% (456/2309) of original posts occurring between November 1, 2017, and March 27, 2018, for coding and analysis. We assessed post volume over time, source or author, valence, linked content, and reference to the industry (eg, big tobacco, tobacco industry, and Philip Morris) and media outlet (TV or newspaper). Retweeted content was coded for source/author and prevalence.

Results: Most posts were published in November 2017, surrounding the initial release of the corrective statements. Content was generally neutral (58.7%, 268/456) or positive (33.3%, 152/456) in valence, included links to additional information about the statements (94.9%, 433/456), referred to the industry (87.7%, 400/456), and did not mention a specific media channel on which the statements were aired or published (15%). The majority of original posts were created by individual users (55.2%, 252/456), whereas the majority of retweeted posts were posted by public health organizations (51%). Differences by source are reported, for example, organization posts are more likely to include a link to additional information compared with individual users (P=.03).

Conclusions: Conversations about the court-ordered corrective statements are taking place on Twitter and are generally neutral or positive in nature. Public health organizations may be increasing the prevalence of these conversations through social media engagement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/12878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806118PMC
October 2019

Integrated assessment of visual perception abnormalities in psychotic disorders and relationship with clinical characteristics.

Psychol Med 2019 07 4;49(10):1740-1748. Epub 2018 Sep 4.

McLean Hospital, Belmont, and Harvard Medical School,Boston, MA,USA.

Background: The visual system is recognized as an important site of pathology and dysfunction in schizophrenia. In this study, we evaluated different visual perceptual functions in patients with psychotic disorders using a potentially clinically applicable task battery and assessed their relationship with symptom severity in patients, and with schizotypal features in healthy participants.

Methods: Five different areas of visual functioning were evaluated in patients with schizophrenia and schizoaffective disorder (n = 28) and healthy control subjects (n = 31) using a battery that included visuospatial working memory (VSWM), velocity discrimination (VD), contour integration, visual context processing, and backward masking tasks.

Results: The patient group demonstrated significantly lower performance in VD, contour integration, and VSWM tasks. Performance did not differ between the two groups on the visual context processing task and did not differ across levels of interstimulus intervals in the backward masking task. Performances on VSWM, VD, and contour integration tasks were correlated with negative symptom severity but not with other symptom dimensions in the patient group. VSWM and VD performances were also correlated with negative sychizotypal features in healthy controls.

Conclusion: Taken together, these results demonstrate significant abnormalities in multiple visual processing tasks in patients with psychotic disorders, adding to the literature implicating visual abnormalities in these conditions. Furthermore, our results show that visual processing impairments are associated with the negative symptom dimension in patients as well as healthy individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0033291718002477DOI Listing
July 2019

Effects of distributional information on categorization of prosodic contours.

Psychon Bull Rev 2018 06;25(3):1153-1160

Department of Brain and Cognitive Sciences, University of Rochester, 304 Meliora Hall, Rochester, NY, 14627, USA.

Although prosody clearly affects the interpretation of utterances, the mapping between prosodic representations and acoustic features is highly variable. Listeners may in part cope with this variability by adapting to distributions of acoustic features in the input. We examined whether listeners adapt to distributional changes using the construction It looks like an X. When pronounced with an H* pitch accent on the final noun and a low boundary tone, the construction supports an affirmative interpretation (e.g., It looks like a ZEBRA [and I think it is one]). Conversely, when pronounced with a L+H* pitch accent and a rising boundary tone, it suggests a negative interpretation (e.g., It LOOKS like a zebra.... [but it is not]). Experiment 1 elicited pragmatic interpretations of resynthesized 12-step continua with these two contours as the end points. In Experiment 2, one group of listeners heard items sampled from the most ambiguous region along the continua followed by affirmative continuations (e.g., It looks like a zebra because it has stripes all over its body) and items near the contrastive endpoint followed by negative continuations (e.g., It looks like a zebra but it is actually something else). Another group heard the reverse (i.e., ambiguous items with negative continuations and non-contrastive items with affirmative continuations). The two groups of participants subsequently derived diverging interpretations for novel ambiguous items, suggesting that prosodic processing involves flexible mappings between acoustic features and prosodic representations that are meaningful in interpretation of speech.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3758/s13423-017-1332-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720936PMC
June 2018

Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.

Elife 2017 02 8;6. Epub 2017 Feb 8.

Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor , is also frequently mutated in cancer. We validated as a CYCLOPS gene and found that human cancer cells harboring partial copy-loss lack a reservoir of SF3b complex that protects cells with normal copy number from cell death upon partial suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type as a novel, non-driver cancer gene dependency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.23268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357138PMC
February 2017

A Hierarchical Generative Framework of Language Processing: Linking Language Perception, Interpretation, and Production Abnormalities in Schizophrenia.

Front Hum Neurosci 2015 27;9:643. Epub 2015 Nov 27.

Department of Psychiatry-Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown MA, USA ; Department of Psychology, Tufts University, Medford MA, USA.

Language and thought dysfunction are central to the schizophrenia syndrome. They are evident in the major symptoms of psychosis itself, particularly as disorganized language output (positive thought disorder) and auditory verbal hallucinations (AVHs), and they also manifest as abnormalities in both high-level semantic and contextual processing and low-level perception. However, the literatures characterizing these abnormalities have largely been separate and have sometimes provided mutually exclusive accounts of aberrant language in schizophrenia. In this review, we propose that recent generative probabilistic frameworks of language processing can provide crucial insights that link these four lines of research. We first outline neural and cognitive evidence that real-time language comprehension and production normally involve internal generative circuits that propagate probabilistic predictions to perceptual cortices - predictions that are incrementally updated based on prediction error signals as new inputs are encountered. We then explain how disruptions to these circuits may compromise communicative abilities in schizophrenia by reducing the efficiency and robustness of both high-level language processing and low-level speech perception. We also argue that such disruptions may contribute to the phenomenology of thought-disordered speech and false perceptual inferences in the language system (i.e., AVHs). This perspective suggests a number of productive avenues for future research that may elucidate not only the mechanisms of language abnormalities in schizophrenia, but also promising directions for cognitive rehabilitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnhum.2015.00643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661240PMC
December 2015

Anticipatory Deaccenting in Language Comprehension.

Lang Cogn Neurosci 2015 Feb;30(1-2):197-211

Brain & Cognitive Sciences, University of Rochester ; Linguistics, University of Rochester.

We evaluated the hypothesis that listeners can generate expectations about upcoming input using anticipatory deaccenting, in which the absence of a nuclear pitch accent on an utterance-new noun is licensed by the subsequent repetition of that noun (e.g. ). The phonemic restoration paradigm was modified to obscure word-initial segmental information uniquely identifying the final word in a spoken instruction, resulting in a stimulus compatible with two lexical alternatives (e.g. /). In Experiment 1, we measured participants' final interpretations and response times. Experiment 2 used the same materials in a crowd-sourced gating study. Sentence interpretations at gated intervals, final interpretations, and response times provided converging evidence that the anticipatory deaccenting pattern contributed to listeners' referential expectations. The results illustrate the availability and importance of sentence-level accent patterns in spoken language comprehension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23273798.2014.885534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309389PMC
February 2015

Metrical expectations from preceding prosody influence perception of lexical stress.

J Exp Psychol Hum Percept Perform 2015 Apr 26;41(2):306-23. Epub 2015 Jan 26.

Department of Brain & Cognitive Sciences, University of Rochester.

Two visual-world experiments tested the hypothesis that expectations based on preceding prosody influence the perception of suprasegmental cues to lexical stress. The results demonstrate that listeners' consideration of competing alternatives with different stress patterns (e.g., 'jury/gi'raffe) can be influenced by the fundamental frequency and syllable timing patterns across material preceding a target word. When preceding stressed syllables distal to the target word shared pitch and timing characteristics with the first syllable of the target word, pictures of alternatives with primary lexical stress on the first syllable (e.g., jury) initially attracted more looks than alternatives with unstressed initial syllables (e.g., giraffe). This effect was modulated when preceding unstressed syllables had pitch and timing characteristics similar to the initial syllable of the target word, with more looks to alternatives with unstressed initial syllables (e.g., giraffe) than to those with stressed initial syllables (e.g., jury). These findings suggest that expectations about the acoustic realization of upcoming speech include information about metrical organization and lexical stress and that these expectations constrain the initial interpretation of suprasegmental stress cues. These distal prosody effects implicate online probabilistic inferences about the sources of acoustic-phonetic variation during spoken-word recognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/a0038689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380594PMC
April 2015

Interpreting prosodic cues in discourse context.

Lang Cogn Neurosci 2015 Jan;30(1-2):149-166

Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY, US ; Department of Linguistics, University of Rochester, Rochester, NY, US.

Two visual-world experiments investigated whether and how quickly discourse-based expectations about the prosodic realization of spoken words modulate interpretation of acoustic-prosodic cues. Experiment 1 replicated effects of segmental lengthening on activation of onset-embedded words (e.g. ) using resynthetic manipulation of duration and fundamental frequency (F0). In Experiment 2, the same materials were preceded by instructions establishing information-structural differences between competing lexical alternatives (i.e. repeated vs. newly-assigned thematic roles) in critical instructions. Eye-movements generated upon hearing the critical target word revealed a significant interaction between information structure and target-word realization: Segmental lengthening and pitch excursion elicited more fixations to the onset-embedded competitor when the target word remained in the same thematic role, but not when its thematic role changed. These results suggest that information structure modulates the interpretation of acoustic-prosodic cues by influencing expectations about fine-grained acoustic-phonetic properties of the unfolding utterance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01690965.2013.862285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294268PMC
January 2015

The Application of an Etiological Model of Personality Disorders to Problem Gambling.

J Gambl Stud 2015 Dec;31(4):1179-99

School of Psychological Sciences, Monash University, Melbourne, VIC, Australia.

Problem gambling is a significant mental health problem that creates a multitude of intrapersonal, interpersonal, and social difficulties. Recent empirical evidence suggests that personality disorders, and in particular borderline personality disorder (BPD), are commonly co-morbid with problem gambling. Despite this finding there has been very little research examining overlapping factors between these two disorders. The aim of this review is to summarise the literature exploring the relationship between problem gambling and personality disorders. The co-morbidity of personality disorders, particularly BPD, is reviewed and the characteristics of problem gamblers with co-morbid personality disorders are explored. An etiological model from the more advanced BPD literature-the biosocial developmental model of BPD-is used to review the similarities between problem gambling and BPD across four domains: early parent-child interactions, emotion regulation, co-morbid psychopathology and negative outcomes. It was concluded that personality disorders, in particular BPD are commonly co-morbid among problem gamblers and the presence of a personality disorder complicates the clinical picture. Furthermore BPD and problem gambling share similarities across the biosocial developmental model of BPD. Therefore clinicians working with problem gamblers should incorporate routine screening for personality disorders and pay careful attention to the therapeutic alliance, client motivations and therapeutic boundaries. Furthermore adjustments to therapy structure, goals and outcomes may be required. Directions for future research include further research into the applicability of the biosocial developmental model of BPD to problem gambling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10899-014-9504-zDOI Listing
December 2015

Exhaled breath condensate pH does not discriminate asymptomatic gastroesophageal reflux or the response to lansoprazole treatment in children with poorly controlled asthma.

J Allergy Clin Immunol Pract 2014 Sep-Oct;2(5):579-86.e7. Epub 2014 May 21.

Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Va.

Background: Although exhaled breath condensate (EBC) pH has been identified as an "emerging" biomarker of interest for asthma clinical trials, the clinical determinants of EBC pH remain poorly understood. Other studies have associated acid reflux-induced respiratory symptoms, for example, cough, with transient acidification of EBC.

Objective: We sought to determine the clinical and physiologic correlates of EBC acidification in a highly characterized sample of children with poorly controlled asthma. We hypothesized that (1) children with asymptomatic gastroesophageal reflux determined by 24-hour esophageal pH monitoring would have a lower EBC pH than children without gastroesophageal reflux, (2) treatment with lansoprazole would alter EBC pH in those children, and (3) EBC acidification would be associated with increased asthma symptoms, poorer asthma control and quality of life, and increased formation of breath nitrogen oxides (NOx).

Methods: A total of 110 children, age range 6 to 17 years, with poor asthma control and esophageal pH data enrolled in the Study of Acid Reflux in Children with Asthma (NCT00442013) were included. Children submitted EBC samples for pH and NOx measurement at randomization and at study weeks 8, 16, and 24.

Results: Serial EBC pH measurements failed to distinguish asymptomatic gastroesophageal reflux and was not associated with breath NOx formation. EBC pH also did not discriminate asthma characteristics such as medication and health care utilization, pulmonary function, and asthma control and quality of life both at baseline and across the study period.

Conclusion: Despite the relative ease of EBC collection, EBC pH as a biomarker does not provide useful information of children with asthma who were enrolled in asthma clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2014.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163012PMC
May 2015

Is it or isn't it: listeners make rapid use of prosody to infer speaker meanings.

Cognition 2014 Nov 14;133(2):335-42. Epub 2014 Aug 14.

Department of Brain and Cognitive Sciences, University of Rochester, United States.

A visual world experiment examined the time course for pragmatic inferences derived from visual context and contrastive intonation contours. We used the construction It looks like an X pronounced with either (a) a H(*) pitch accent on the final noun and a low boundary tone, or (b) a contrastive L+H(*) pitch accent and a rising boundary tone, a contour that can support contrastive inference (e.g., It LOOKSL+H*like a zebraL-H%… (but it is not)). When the visual display contained a single related set of contrasting pictures (e.g. a zebra vs. a zebra-like animal), effects of LOOKSL+H* emerged prior to the processing of phonemic information from the target noun. The results indicate that the prosodic processing is incremental and guided by contextually-supported expectations. Additional analyses ruled out explanations based on context-independent heuristics that might substitute for online computation of contrast.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cognition.2014.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163505PMC
November 2014

Infection dynamics of sylvatic dengue virus in a natural primate host, the African Green Monkey.

Am J Trop Med Hyg 2014 Oct 4;91(4):672-6. Epub 2014 Aug 4.

Department of Biology, New Mexico State University, Las Cruces, New Mexico; Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland; Center for Tropical Diseases, Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas; Institute for Human Infections and Immunity and Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas; Tulane National Primate Research Center, Tulane University, Covington, Louisiana.

The four serotypes of mosquito-borne dengue virus (DENV-1, -2, -3, and -4) that circulate in humans each emerged from an enzootic, sylvatic cycle in non-human primates. Herein, we present the first study of sylvatic DENV infection dynamics in a primate. Three African green monkeys were inoculated with 10(5) plaque-forming units (pfu) DENV-2 strain PM33974 from the sylvatic cycle, and one African green monkey was inoculated with 10(5) pfu DENV-2 strain New Guinea C from the human cycle. All four monkeys seroconverted (more than fourfold rise in 80% plaque reduction neutralization titer [PRNT80]) against the strain of DENV with which they were inoculated; only one (33%) of three monkeys infected with sylvatic DENV showed a neutralizing antibody response against human-endemic DENV. Virus was detected in two of three monkeys inoculated with sylvatic DENV at low titer (≤ 1.3 log10pfu/mL) and brief duration (≤ 2 days). Clinical signs included rash and elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.13-0492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183386PMC
October 2014

Plasma metabolomic biomarker panel to distinguish patients with amyotrophic lateral sclerosis from disease mimics.

Amyotroph Lateral Scler Frontotemporal Degener 2014 Sep 1;15(5-6):362-70. Epub 2014 Jul 1.

Metabolon, Inc , Durham , North Carolina.

Our objective was to identify plasma biomarkers of ALS that can aid in distinguishing patients with ALS from those with disease mimics. In this multi-center study, plasma samples were collected from 172 patients recently diagnosed with ALS, 50 healthy controls, and 73 neurological disease mimics. Samples were analyzed using metabolomics. Using all identified biochemicals detected in > 50% of all samples in the metabolomics analysis, samples were classified as ALS or mimic with 65% sensitivity and 81% specificity by LASSO analysis (AUC of 0.76). A subset panel of 32 candidate biomarkers classified these diagnosis groups with a specificity of 90%/sensitivity 58% (AUC of 0.81). Creatinine was lower in subjects with lower revised ALS Functional Rating Scale (ALSFRS-R) scores. In conclusion, ALS can be distinguished from neurological disease mimics by global biochemical profiling of plasma samples. Our analysis identified ALS versus mimics with relatively high sensitivity. We identified a subset of 32 metabolites that identify patients with ALS with a high specificity. Interestingly, lower creatinine correlates significantly with a lower ALSFRS-R score. Finally, molecules previously reported to be important in disease pathophysiology, such as urate, are included in our metabolite panel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/21678421.2014.908311DOI Listing
September 2014

SLAP deficiency decreases dsDNA autoantibody production.

Clin Immunol 2014 Feb 31;150(2):201-9. Epub 2013 Dec 31.

Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA; Department of Pediatrics, University of Colorado Denver, 13001 E. 17th Place, Aurora, CO 80045, USA; Department of Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA; Division of Rheumatology, Colorado Children's Hospital, 13123 E. 16th Ave., Aurora, CO 80045, USA. Electronic address:

Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP(-/-) mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP(-/-) 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2013.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053206PMC
February 2014

Prediction, explanation, and the role of generative models in language processing.

Behav Brain Sci 2013 Jun 10;36(3):211-2. Epub 2013 May 10.

Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY 14627-0268, USA.

We propose, following Clark, that generative models also play a central role in the perception and interpretation of linguistic signals. The data explanation approach provides a rationale for the role of prediction in language processing and unifies a number of phenomena, including multiple-cue integration, adaptation effects, and cortical responses to violations of linguistic expectations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0140525X12002312DOI Listing
June 2013

Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression.

Obesity (Silver Spring) 2013 Dec 13;21(12):E561-70. Epub 2013 Jun 13.

Metabolon, Inc., Durham, North Carolina, USA.

Objectives: A spectrum of disorders including simple steatosis, nonalcoholic steatohepatitis, fibrosis, and cirrhosis is described by nonalcoholic fatty liver disease (NAFLD). With the increased prevalence of obesity, and consequently NAFLD, there is a need for novel therapeutics in this area. To facilitate this effort, a cellular model of hepatic steatosis was developed using HepaRG cells and the resulting biochemical alterations were determined.

Design And Methods: Using global metabolomic profiling, by means of a novel metabolite extraction procedure, the metabolic profiles in response to the saturated fatty acid palmitate, and a mixture of saturated and unsaturated fatty acids, palmitate and oleate (1:2) were examined.

Results: We observed elevated levels of the branched chain amino acids, tricarboxylic acid cycle intermediates, sphingosine and acylcarnitines, and reduced levels of carnitine in the steatotic HepaRG model with both palmitate and palmitate:oleate treatments. In addition, elevated levels of diacylglycerols and monoacylglycerols as well as altered bile acid metabolism were selectively displayed by palmitate-induced steatotic cells.

Conclusions: Biochemical changes in pathways important in the transition to hepatic steatosis including insulin resistance, altered mitochondrial metabolism, and oxidative stress are revealed by this global metabolomic approach. Moreover, the utility of this in vitro model for investigating the mechanisms of steatotic progression, insulin resistance, and lipotoxicity in NAFLD was demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.20440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689848PMC
December 2013

Residential proximity to a major roadway is associated with features of asthma control in children.

PLoS One 2012 17;7(5):e37044. Epub 2012 May 17.

Department of Pediatrics, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America.

Background: While several studies suggest that traffic-related air pollutants are detrimental for respiratory health, few studies have examined relationships between residential proximity to a major roadway and asthma control in children. Furthermore, a major limitation of existing research is reliance on self-reported outcomes. We therefore determined the spatial relationship between the distance from a major roadway and clinical, physiologic and inflammatory features of asthma in a highly characterized sample of asthmatic children 6-17 years of age across a wide range of severities. We hypothesized that a closer residential proximity to a major roadway would be associated with increased respiratory symptoms, altered pulmonary function and a greater magnitude of airway and systemic inflammation.

Methodology/principal Findings: 224 children 6-17 years with confirmed asthma completed questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, exhaled breath condensate collection and venipuncture. Residential distance from a major roadway was determined by mapping the geographic coordinates of the residential address in Geographic Information System software. The distance between the home address and the nearest major roadway was calculated according to the shortest distance between the two points (i.e., "as the crow flies"). Asthmatic children living in closer proximity to a major roadway had an increased frequency of wheezing associated with increased medication requirements and more hospitalizations even after controlling for potential confounders. These children also had increased airway resistance, increased airway inflammation reflected by a lower breath condensate pH, and higher plasma EGF concentrations.

Conclusions/significance: These findings suggest that closer residential proximity to a major roadway is associated with poorer asthma control in school-age children. Assessment of residential proximity to major roadways may be useful in the clinical evaluation of asthma in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037044PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355164PMC
January 2013

Cancer detection and biopsy classification using concurrent histopathological and metabolomic analysis of core biopsies.

Genome Med 2012 Apr 30;4(4):33. Epub 2012 Apr 30.

Metabolon, Inc,, 617 Davis Drive, Suite 400, Durham, NC 27713, USA.

Background: Metabolomics, the non-targeted interrogation of small molecules in a biological sample, is an ideal technology for identifying diagnostic biomarkers. Current tissue extraction protocols involve sample destruction, precluding additional uses of the tissue. This is particularly problematic for high value samples with limited availability, such as clinical tumor biopsies that require structural preservation to histologically diagnose and gauge cancer aggressiveness. To overcome this limitation and increase the amount of information obtained from patient biopsies, we developed and characterized a workflow to perform metabolomic analysis and histological evaluation on the same biopsy sample.

Methods: Biopsies of ten human tissues (muscle, adrenal gland, colon, lung, pancreas, small intestine, spleen, stomach, prostate, kidney) were placed directly in a methanol solution to recover metabolites, precipitate proteins, and fix tissue. Following incubation, biopsies were removed from the solution and processed for histology. Kidney and prostate cancer tumor and benign biopsies were stained with hemotoxylin and eosin and prostate biopsies were subjected to PIN-4 immunohistochemistry. The methanolic extracts were analyzed for metabolites on GC/MS and LC/MS platforms. Raw mass spectrometry data files were automatically extracted using an informatics system that includes peak identification and metabolite identification software.

Results: Metabolites across all major biochemical classes (amino acids, peptides, carbohydrates, lipids, nucleotides, cofactors, xenobiotics) were measured. The number (ranging from 260 in prostate to 340 in colon) and identity of metabolites were comparable to results obtained with the current method requiring 30 mg ground tissue. Comparing relative levels of metabolites, cancer tumor from benign kidney and prostate biopsies could be distinguished. Successful histopathological analysis of biopsies by chemical staining (hematoxylin, eosin) and antibody binding (PIN-4, in prostate) showed cellular architecture and immunoreactivity were retained.

Conclusions: Concurrent metabolite extraction and histological analysis of intact biopsies is amenable to the clinical workflow. Methanol fixation effectively preserves a wide range of tissues and is compatible with chemical staining and immunohistochemistry. The method offers an opportunity to augment histopathological diagnosis and tumor classification with quantitative measures of biochemicals in the same tissue sample. Since certain biochemicals have been shown to correlate with disease aggressiveness, this method should prove valuable as an adjunct to differentiate cancer aggressiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/gm332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446261PMC
April 2012

Emerging viruses in the Felidae: shifting paradigms.

Viruses 2012 02 7;4(2):236-57. Epub 2012 Feb 7.

Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, MD 21702, USA.

The domestic cat is afflicted with multiple viruses that serve as powerful models for human disease including cancers, SARS and HIV/AIDS. Cat viruses that cause these diseases have been studied for decades revealing detailed insight concerning transmission, virulence, origins and pathogenesis. Here we review recent genetic advances that have questioned traditional wisdom regarding the origins of virulent Feline infectious peritonitis (FIP) diseases, the pathogenic potential of Feline Immunodeficiency Virus (FIV) in wild non-domestic Felidae species, and the restriction of Feline Leukemia Virus (FeLV) mediated immune impairment to domestic cats rather than other Felidae species. The most recent interpretations indicate important new evolutionary conclusions implicating these deadly infectious agents in domestic and non-domestic felids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v4020236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315214PMC
February 2012

Biochemical alterations associated with ALS.

Amyotroph Lateral Scler 2012 Jan 25;13(1):110-8. Epub 2011 Nov 25.

Metabolon Inc., North Carolina, USA.

Our objective was to identify metabolic pathways affected by ALS using non-targeted metabolomics in plasma, comparing samples from healthy volunteers to those from ALS patients. This discovery could become the basis for the identification of therapeutic targets and diagnostic biomarkers of ALS. Two distinct cross-sectional studies were conducted. Plasma was collected from 62 (Study 1) and 99 (Study 2) participants meeting El Escorial criteria for possible, probable, or definite ALS; 69 (Study 1) and 48 (Study 2) healthy controls samples were collected. Global metabolic profiling was used to detect and evaluate biochemical signatures of ALS. Twenty-three metabolites were significantly altered in plasma from ALS patients in both studies. These metabolites include biochemicals in pathways associated with neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction, all of which are proposed disease mechanisms in ALS. The data also suggest possible hepatic dysfunction associated with ALS. In conclusion, the data presented here provide insight into the pathophysiology of ALS while suggesting promising areas of focus for future studies. The metabolomics approach can generate novel hypotheses regarding ALS disease mechanisms with the potential to identify therapeutic targets and novel diagnostic biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/17482968.2011.619197DOI Listing
January 2012

Association of Rho-associated protein kinase 1 with E-cadherin complexes is mediated by p120-catenin.

Mol Biol Cell 2012 Jan 26;23(1):99-110. Epub 2011 Oct 26.

Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.

The dynamic functional linkage of cadherins with the underlying actin cytoskeleton is tightly regulated to achieve proper cell-cell adhesion. p120-catenin (p120) regulates both cadherin stability and actin dynamics, but the relationship between these two functions remains unclear. Using a novel proteomic approach called reversible cross-link immunoprecipitation, or ReCLIP, we previously identified a physical interaction between p120 and Rho-associated protein kinase 1 (ROCK1), a major effector of RhoA. In this paper, we show that a discrete fraction of cellular ROCK1 coimmunoprecipitates with p120 and precisely colocalizes to adherens junctions (AJs). Manipulation of AJs using a calcium-switch assay and cadherin-blocking antibodies indicates direct recruitment of ROCK1 to newly forming junctions. Importantly, we find that p120 links ROCK1 to the cadherin complex, as ROCK1 coimmunoprecipitates with wild-type but not p120-uncoupled E-cadherin. Moreover, depletion of ROCK1 using short-hairpin RNA results in dramatic mislocalization of the cadherin complex and junctional actin. These data are consistent with a model in which p120 dynamically regulates Rho-GTPase activity at the cadherin complex through transient interaction with several of its up- and downstream effectors, including ROCK1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.E11-06-0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248908PMC
January 2012
-->