Contents: Volume 46

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EACMFS Prizes & Awards

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Announcements

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Author Index: Volume 46

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Keyword index: Volume 46

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Parent-Implemented Communication Treatment for Infants and Toddlers With Hearing Loss: A Randomized Pilot Trial

Purpose

Despite advances in cochlear implant and hearing aid technology, many children with hearing loss continue to exhibit poorer language skills than their hearing peers. This randomized pilot trial tested the effects of a parent-implemented communication treatment targeting prelinguistic communication skills in infants and toddlers with hearing loss.

Method

Participants included 19 children between 6 and 24 months of age with moderate to profound, bilateral hearing loss. Children were randomly assigned to the parent-implemented communication treatment group or a "usual care" control group. Parents and children participated in 26, hour-long home sessions in which parents were taught to use communication support strategies. The primary outcome measures were the Communication and Symbolic Behavior Scales (Wetherby & Prizant, 2003), a measure of child prelinguistic skills, and parental use of communication support strategies during a naturalistic play session.

Results

Parents in the treatment group increased their use of communication support strategies by 17%. Children in the treatment group made statistically significant more gains in speech prelinguistic skills (d = 1.09, p = .03) as compared with the control group. There were no statistically significant differences in social and symbolic prelinguistic skills; however, the effect sizes were large (d = 0.78, p = .08; d = 0.91, p = .10).

Conclusions

This study provides modest preliminary support for the short-term effects of a parent-implemented communication treatment for children with hearing loss. Parents learned communication support strategies that subsequently impacted child prelinguistic skills. Although these results appear promising, the sample size is very small. Future research should include a larger clinical trial and child-level predictors of response to treatment.

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Age Effects on Concurrent Speech Segregation by Onset Asynchrony

Purpose

For elderly listeners, it is more challenging to listen to 1 voice surrounded by other voices than for young listeners. This could be caused by a reduced ability to use acoustic cues—such as slight differences in onset time—for the segregation of concurrent speech signals. Here, we study whether the ability to benefit from onset asynchrony differs between young (18–33 years) and elderly (55–74 years) listeners.

Method

We investigated young (normal hearing, N = 20) and elderly (mildly hearing impaired, N = 26) listeners' ability to segregate 2 vowels with onset asynchronies ranging from 20 to 100 ms. Behavioral measures were complemented by a specific event-related brain potential component, the object-related negativity, indicating the perception of 2 distinct auditory objects.

Results

Elderly listeners' behavioral performance (identification accuracy of the 2 vowels) was considerably poorer than young listeners'. However, both age groups showed the same amount of improvement with increasing onset asynchrony. Object-related negativity amplitude also increased similarly in both age groups.

Conclusion

Both age groups benefit to a similar extent from onset asynchrony as a cue for concurrent speech segregation during active (behavioral measurement) and during passive (electroencephalographic measurement) listening.

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The Development of a Self-Efficacy Measurement Tool For Counseling in Speech-Language Pathology

Purpose

This study aimed to develop and administer an adapted survey tool to measure counseling skills in graduate students and early-career speech-language pathologists, focusing on the concept of counselor self-efficacy.

Method

An online survey, adapted from the Counselor Activity Self-Efficacy Scales (Lent, Hill, & Hoffman, 2003), was administered. Two hundred ninety-four surveys were completed. An exploratory factor analysis was conducted, along with measures of reliability and validity, in order to determine the psychometric properties of the tool.

Results

Factor analysis supported a 5-factor solution, with subscales reflecting Emotional Support Skills, Session Management Skills, and Helping Skills in 3 domains: Exploration, Insight, and Action. Strong internal consistency was found for each subscale and for the total scale scores. Significant intercorrelations between subscale scores were expected and confirmed. Construct validity was examined with reference to American Speech-Language-Hearing Association and Council for Academic Accreditation in Audiology and Speech-Language Pathology practice guidelines and clinical competencies. Preliminary comparative data were analyzed to demonstrate utility of the tool in measuring effects of experience on self-efficacy ratings.

Conclusion

The adapted Counselor Activity Self-Efficacy Scales for speech-language pathologists is psychometrically sound; factor analysis, reliability, and validity were in line with reported values for the original survey tool. Potential uses for the survey tool within the field of speech-language pathology are discussed, along with implications for graduate education and clinical supervision related to counseling skills.

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Resident Education in Laryngeal Stroboscopy and Perceptual Voice Evaluation: An Assessment

To evaluate otolaryngology residents' level of confidence and understanding in interpreting laryngeal stroboscopy.

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High Fc{gamma}R Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy [TUMOR IMMUNOLOGY]

Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL-2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8⁺ T cells all mitigated the therapeutic response, showing a coordinated immune rejection by innate and adaptive immune cells. FcRs were essential for the therapeutic effect, with a dominant role for FcRI and a minor role for FcRIII and FcRIV. FcR expression on NK cells and granulocytes was dispensable, indicating that other tumoricidal functions of NK cells were involved and implicating that FcRI, -III, and -IV exerted their activity on macrophages. Indeed, F4/80⁺Ly-6C⁺ inflammatory macrophages in the tumor microenvironment displayed high levels of these receptors. Whereas administration of the anti-TRP1 Ab alone reduced the frequency of these macrophages, the combination with a TLR agonist retained these cells in the tumor microenvironment. Thus, the addition of innate stimulatory compounds, such as TLR ligands, to tumor-specific Ab therapy could greatly enhance its efficacy in solid cancers via optimal exploitation of FcRs.

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In This Issue [IN THIS ISSUE]

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Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential [NOVEL IMMUNOLOGICAL METHODS]

In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor–recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.

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Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus-Specific CD8+ T Cells [CUTTING EDGE]

Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8⁺ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8⁺ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8⁺ T cells are characterized by a polyfunctional IFN- signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8⁺ T cells responding to ZIKV infection.

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TLR-7 Stress Signaling in Differentiating and Mature Eosinophils Is Mediated by the Prolyl Isomerase Pin1 [ALLERGY AND OTHER HYPERSENSITIVITIES]

The response of eosinophils (Eos) to respiratory virus has emerged as an important link between pulmonary infection and allergic asthmatic exacerbations. Eos activate innate immune responses through TLR signaling. In this study, using mouse and human Eos and mice lacking the prolyl isomerase Pin1 selectively in Eos, we show that Pin1 is indispensable for eosinophilopoiesis in the bone marrow (BM) and mature cell function in the presence of TLR7 activation. Unbiased in vivo analysis of mouse models of allergic airway inflammation revealed that TLR7 activation in knockout mice resulted in systemic loss of Eos, reduced IFN production, and an inability to clear respiratory viruses. Consistent with this finding, BM mouse Eos progenitors lacking Pin1 showed markedly reduced cell proliferation and survival after TLR7 activation. Mechanistically, unlike wild-type cells, Pin1 null mouse Eos were defective in the activation of the endoplasmic reticulum stress-induced unfolded protein response. We observed significant reductions in the expression of unfolded protein response components and target genes, aberrant TLR7 cleavage and trafficking, and reduced granule protein production in knockout Eos. Our data strongly suggest that Pin1 is required for BM Eos generation and function during concurrent allergen challenge and viral infection.

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Filtering Next-Generation Sequencing of the Ig Gene Repertoire Data Using Antibody Structural Information [SYSTEMS IMMUNOLOGY]

Next-generation sequencing of the Ig gene repertoire (Ig-seq) produces large volumes of information at the nucleotide sequence level. Such data have improved our understanding of immune systems across numerous species and have already been successfully applied in vaccine development and drug discovery. However, the high-throughput nature of Ig-seq means that it is afflicted by high error rates. This has led to the development of error-correction approaches. Computational error-correction methods use sequence information alone, primarily designating sequences as likely to be correct if they are observed frequently. In this work, we describe an orthogonal method for filtering Ig-seq data, which considers the structural viability of each sequence. A typical natural Ab structure requires the presence of a disulfide bridge within each of its variable chains to maintain the fold. Our Ab Sequence Selector (ABOSS) uses the presence/absence of this bridge as a way of both identifying structurally viable sequences and estimating the sequencing error rate. On simulated Ig-seq datasets, ABOSS is able to identify more than 99% of structurally viable sequences. Applying our method to six independent Ig-seq datasets (one mouse and five human), we show that our error calculations are in line with previous experimental and computational error estimates. We also show how ABOSS is able to identify structurally impossible sequences missed by other error-correction methods.

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The Goldilocks Zone of Type I IFNs: Lessons from Human Genetics [BRIEF REVIEWS]

Type I IFNs (IFN-Is) are powerful cytokines. They provide remarkable protection against viral infections, but their indiscriminate production causes severe self-inflicted damage that can be lethal, particularly in early development. In humans, inappropriately high IFN-I levels caused by defects in the regulatory mechanisms that control IFN-I production and response result in clinical conditions known as type I interferonopathies. In essence, type I interferonopathies define the upper limit of safe, IFN-related inflammation in vivo. Conversely, the loss of IFN-I responsiveness increases susceptibility to viral infections, but, surprisingly, most affected individuals survive despite these inborn errors of immunity. These findings suggest that too much IFN-I early in life is toxic, but that insensitivity to IFN-I is perhaps not the death sentence it was initially thought to be. Human genetic analyses have suggested that seemingly insignificant levels of IFN-regulated gene activity may be sufficient for most of the antiviral defenses used by humans in natura.

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Blocking Matrix Metalloproteinase-9 Abrogates Collagen-Induced Arthritis via Inhibiting Dendritic Cell Migration [AUTOIMMUNITY]

Trafficking of dendritic cells (DCs) to lymph nodes (LNs) to present Ags is a crucial step in the pathogenesis of rheumatoid arthritis (RA). Matrix metalloproteinase-9 (MMP-9) is the key molecule for DC migration. Thus, blocking MMP-9 to inhibit DC migration may be a novel strategy to treat RA. In this study, we used anti–MMP-9 Ab to treat collagen-induced arthritis (CIA) in DBA/1J mice and demonstrated that anti–MMP-9 Ab treatment significantly suppressed the development of CIA via the modulation of DC trafficking. In anti–MMP-9 Ab–treated CIA mice, the number of DCs in draining LNs was obviously decreased. In vitro, anti–MMP-9 Ab and MMP-9 inhibitor restrained the migration of mature bone marrow–derived DCs in Matrigel in response to CCR7 ligand CCL21. In addition, blocking MMP-9 decreased T and B cell numbers in LNs of CIA mice but had no direct influence on the T cell response to collagen II by CD4⁺ T cells purified from LNs or spleen. Besides, anti–MMP-9 Ab did not impact on the expression of MHC class II, CD40, CD80, CD86, and chemokine receptors (CCR5 and CCR7) of DCs both in vivo and in vitro. Furthermore, we discovered the number of MMP-9^–/– DCs trafficking from footpads to popliteal LNs was dramatically reduced as compared with wild type DCs in both MMP-9^–/– mice and wild type mice. Taken together, these results indicated that DC-derived MMP-9 is the crucial factor for DC migration, and blocking MMP-9 to inhibit DC migration may constitute a novel strategy of future therapy for RA and other similar autoimmune diseases.

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Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida [INNATE IMMUNITY AND INFLAMMATION]

The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to Francisella tularensis subspecies novicida infection, leading to maturation of IL-1β and IL-18 and pyroptosis. AIM2 is critical for host protection against F. novicida infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase-1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to F. novicida infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in F. novicida–infected bone marrow–derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow–derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome.

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Cutting Edge: B Cells Expressing Cyclic Citrullinated Peptide-Specific Antigen Receptor Are Tolerized in Normal Conditions [CUTTING EDGE]

Generation of neoantigens by citrullination is implicated in the production of anti–citrullinated protein Abs in rheumatoid arthritis, but citrullination is also a physiological process. To verify whether citrullin-specific B cells are immunologically ignorant or tolerant in normal conditions, transgenic (Tg) mice expressing IgM with the V region of an anti–cyclic citrullinated peptide (CCP) mAb cloned from a rheumatoid arthritis patient were generated. CCP-specific B cells developed in the anti-CCP IgM Tg mice with an alteration of bone marrow B cell fractions, and the number of mature B cells decreased compared with wild-type or the control anti–influenza nucleoprotein–specific IgM Tg mice. In addition, B cells in anti-CCP IgM Tg mice are functionally anergic. Thus, tolerance is induced in CCP-specific B cells in vivo, suggesting that the immune systems are naturally exposed to citrullinated Ags, and anti-CCP Ab production requires additional steps beyond the generation of neoantigens by citrullination.

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Cutting Edge: FHR-1 Binding Impairs Factor H-Mediated Complement Evasion by the Malaria Parasite Plasmodium falciparum [CUTTING EDGE]

Human complement is the first line of defense against invading pathogens, including the malaria parasite Plasmodium falciparum. We previously demonstrated that human complement represents a particular threat for the clinically relevant blood stages of the parasite. To evade complement-mediated destruction, the parasites acquire factor H (FH) via specific receptors. We now report that the FH-related protein FHR-1 competes with FH for binding to the parasites. FHR-1, which is composed of five complement control protein domains with variable homology to FH but lacks C3b regulatory activity, accumulates on the surfaces of intraerythrocytic schizonts and free merozoites. Although binding of FH to schizont-infected RBCs and merozoites is increased in FHR-1–deficient human serum, the addition of recombinant FHR-1 decreases FH binding. The presence of FHR-1 consequently impairs C3b inactivation and parasite viability. We conclude that FHR-1 acts as a protective factor in human immunity by counteracting FH-mediated microbial complement evasion.

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The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell-Specific Expression of RALDH2 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

RALDH2 expressed in dendritic cells (DCs) plays a critical role in the development of regulatory T cells in mesenteric lymph nodes. Despite the importance of RALDH2 in intestinal immunity, little is known about the mechanism of DC-specific expression of RALDH2. In the current study, we focused on the hematopoietic cell–specific transcription factors PU.1 and IRF4 as the determinants of Aldh1a2 gene expression. The mRNA level of Aldh1a2, and subsequently the enzyme activity, were decreased by knockdown of PU.1 and IRF4 in bone marrow–derived DCs (BMDCs) of BALB/c mice. Chromatin immunoprecipitation assays showed that PU.1 and IRF4 bound to the Aldh1a2 gene ~2 kb upstream from the transcription start site in BMDCs. A reporter assay and an EMSA revealed that the Aldh1a2 promoter was synergistically transactivated by a heterodimer composed with PU.1 and IRF4 via the EICE motif at –1961/–1952 of the gene. The effect of small interfering RNAs for Spi1 and Irf4 and specific binding of PU.1 and IRF4 on the Aldh1a2 gene were also observed in DCs freshly isolated from spleen and mesenteric lymph nodes, respectively. GM-CSF stimulation upregulated the Aldh1a2 transcription in Flt3 ligand–generated BMDCs, in which the IRF4 expression and the PU.1 recruitment to the Aldh1a2 promoter were enhanced. We conclude that PU.1 and IRF4 are transactivators of the Aldh1a2 gene in vitro and ex vivo.

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Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling [TRANSPLANTATION]

Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB-, C3-, C4-, C5-, C5aR1-, C5aR2-, and C6-deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1β, IL-9, and IL-12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI.

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Talin1 Methylation Is Required for Neutrophil Infiltration and Lipopolysaccharide-Induced Lethality [INNATE IMMUNITY AND INFLAMMATION]

Talin1, a well-established integrin coactivator, is critical for the transmigration of neutrophils across the vascular endothelium into various organs and the peritoneal cavity during inflammation. Several posttranslational modifications of talin1 have been proposed to play a role in this process. In this study, we show that trimethylation of talin1 at Lys2454 by cytosolic Ezh2 is substantially increased in murine peritoneal neutrophils upon induction of peritonitis. By reconstituting talin1-deficient mouse myeloid cells with wild-type, methyl-mimicking, or unmethylatable talin1 variants, we demonstrate that methylation of talin1 at Lys2454 is important for integrin-dependent neutrophil infiltration into the peritoneal cavity. Furthermore, we show that treatment with an Ezh2 inhibitor or reconstitution of talin1-deficient myeloid cells with unmethylatable talin1 significantly reduces the number of organ-infiltrating neutrophils and protects mice from LPS-induced mortality.

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CD8{alpha}+ Dendritic Cells Dictate Leukemia-Specific CD8+ T Cell Fates [TUMOR IMMUNOLOGY]

APCs are essential for the orchestration of antitumor T cell responses. Batf3-lineage CD8α⁺ and CD103⁺ dendritic cells (DCs), in particular, are required for the spontaneous initiation of CD8⁺ T cell priming against solid tumors. In contrast, little is known about the APCs that regulate CD8⁺ T cell responses against hematological malignancies. Using an unbiased approach, we aimed to characterize the APCs responsible for regulating CD8⁺ T cell responses in a syngeneic murine leukemia model. We show with single-cell resolution that CD8α⁺ DCs alone acquire and cross-present leukemia Ags in vivo, culminating in the induction of leukemia-specific CD8⁺ T cell tolerance. Furthermore, we demonstrate that the mere acquisition of leukemia cell cargo is associated with a unique transcriptional program that may be important in regulating tolerogenic CD8α⁺ DC functions in mice with leukemia. Finally, we show that systemic CD8α⁺ DC activation with a TLR3 agonist completely prevents their ability to generate leukemia-specific CD8⁺ T cell tolerance in vivo, resulting instead in the induction of potent antileukemia T cell immunity and prolonged survival of leukemia-bearing mice. Together, our data reveal that Batf3-lineage DCs imprint disparate CD8⁺ T cell fates in hosts with solid tumors versus systemic leukemia.

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Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3+ Regulatory T Cells [IMMUNE REGULATION]

Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3⁺ regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell–mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation.

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Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool [CLINICAL AND HUMAN IMMUNOLOGY]

Autonomous migration is a central characteristic of immune cells, and changes in this function have been correlated to the progression and severity of diseases. Hence, the identification of pathologically altered leukocyte migration patterns might be a promising approach for disease surveillance and prognostic scoring. However, because of the lack of standardized and robust assays, migration patterns have not been clinically exploited so far. In this study, we introduce an easy-to-use and cross-laboratory, standardized two-dimensional migration assay for neutrophil granulocytes from peripheral blood. By combining time-lapse video microscopy and automated cell tracking, we calculated the average migration of neutrophils from 111 individual participants of the German Heinz Nixdorf Recall MultiGeneration study under steady-state, formyl-methionyl-leucyl-phenylalanine–, CXCL1-, and CXCL8-stimulated conditions. Comparable values were obtained in an independent laboratory from a cohort in Belgium, demonstrating the robustness and transferability of the assay. In a double-blinded retrospective clinical analysis, we found that neutrophil migration strongly correlated with the Revised International Prognostic Scoring System scoring and risk category of myelodysplastic syndrome (MDS) patients. In fact, patients suffering from high-risk subtypes MDS with excess blasts I or II displayed highly significantly reduced neutrophil migration. Hence, the determination of neutrophil migration patterns might represent a useful tool in the surveillance of MDS. Taken together, we suggest that standardized migration assays of neutrophils and other leukocyte subtypes might be broadly applicable as prognostic and surveillance tools for MDS and potentially for other diseases.

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DRB4*01:01 Has a Distinct Motif and Presents a Proinsulin Epitope That Is Recognized in Subjects with Type 1 Diabetes [AUTOIMMUNITY]

DRB4*01:01 (DRB4) is a secondary HLA-DR product that is part of the high-risk DR4/DQ8 haplotype that is associated with type 1 diabetes (T1D). DRB4 shares considerable homology with HLA-DR4 alleles that predispose to autoimmunity, including DRB1*04:01 and DRB1*04:04. However, the DRB4 protein sequence includes distinct residues that would be expected to alter the characteristics of its binding pockets. To identify high-affinity peptides that are recognized in the context of DRB4, we used an HLA class II tetramer-based approach to identify epitopes within multiple viral Ags. We applied a similar approach to identify antigenic sequences within glutamic acid decarboxylase 65 and pre-proinsulin that are recognized in the context of DRB4. Seven sequences were immunogenic, eliciting high-affinity T cell responses in DRB4⁺ subjects. DRB1*04:01-restricted responses toward many of these peptides have been previously described, but responses to a novel pre-proinsulin 9–28 peptide were commonly observed in subjects with T1D. Furthermore, T cells that recognized this peptide in the context of DRB4 were present at significantly higher frequencies in patients with T1D than in healthy controls, implicating this as a disease-relevant specificity that may contribute to the breakdown of β cell tolerance in genetically susceptible individuals. We then deduced a DRB4 motif and confirmed its key features through structural modeling. This modeling suggested that the core epitope within the pre-proinsulin 9–28 peptide has a somewhat unusual binding motif, with tryptophan in the fourth binding pocket of DRB4, perhaps influencing the availability of this complex for T cell selection.

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Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease [CLINICAL AND HUMAN IMMUNOLOGY]

Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1β and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1β and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1β and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1β and IL-18 and seemed to suppress the production of IL-1β and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD.

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Multiplexed FluoroSpot for the Analysis of Dengue Virus- and Zika Virus-Specific and Cross-Reactive Memory B Cells [NOVEL IMMUNOLOGICAL METHODS]

Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne pathogens that have a significant impact on human health. Immune sera, mAbs, and memory B cells (MBCs) isolated from patients infected with one DENV type can be cross-reactive with the other three DENV serotypes and even more distantly related flaviviruses such as ZIKV. Conventional ELISPOTs effectively measure Ab-secreting B cells but because they are limited to the assessment of a single Ag at a time, it is challenging to distinguish serotype-specific and cross-reactive MBCs in the same well. We developed a novel multifunction FluoroSpot assay using fluorescently labeled DENV and ZIKV (FLVs) that measures the cross-reactivity of Abs secreted by single B cells. Conjugation efficiency and recognition of FLVs by virus-specific Abs were confirmed by flow cytometry. Using a panel of DENV immune, ZIKV immune, and naive PBMC, FLVs were able to simultaneously detect DENV serotype-specific, ZIKV-specific, DENV serotype cross-reactive, and DENV/ZIKV cross-reactive Abs secreted by individual MBCs. Our findings indicate that the FLVs are sensitive and specific tools to detect specific and cross-reactive MBCs. These reagents will allow the assessment of the breadth as well as the durability of DENV/ZIKV B cell responses following vaccination or natural infection. This novel approach using FLVs in a FluoroSpot assay can be applied to other diseases such as influenza in which prior immunity with homosubtype- or heterosubtype-specific MBCs may influence subsequent infections.

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Data-Driven Classification of Dysarthria Profiles in Children With Cerebral Palsy

Purpose

The objectives of this study were to examine different speech profiles among children with dysarthria secondary to cerebral palsy (CP) and to characterize the effect of different speech profiles on intelligibility.

Method

Twenty 5-year-old children with dysarthria secondary to CP and 20 typically developing children were included in this study. Six acoustic and perceptual speech measures were selected to quantify a range of segmental and suprasegmental speech characteristics and were measured from children's sentence productions. Hierarchical cluster analysis was used to identify naturally occurring subgroups of children who had similar profiles of speech features.

Results

Results revealed 4 naturally occurring speech clusters among children: 1 cluster of children with typical development and 3 clusters of children with dysarthria secondary to CP. Two of the 3 dysarthria clusters had statistically equivalent intelligibility levels but significantly differed in articulation rate and degree of hypernasality.

Conclusion

This study provides initial evidence that different speech profiles exist among 5-year-old children with dysarthria secondary to CP, even among children with similar intelligibility levels, suggesting the potential for developing a pediatric dysarthria classification system that could be used to stratify children with dysarthria into meaningful subgroups for studying speech motor development and efficacy of interventions.

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School-Aged Children's Phonological Accuracy in Multisyllabic Words on a Whole-Word Metric

Purpose

The purpose of this study is to examine differences in phonological accuracy in multisyllabic words (MSWs) on a whole-word metric, longitudinally and cross-sectionally, for elementary school–aged children with typical development (TD) and with history of protracted phonological development (PPD).

Method

Three mismatch subtotals, Lexical influence, Word Structure, and segmental Features (forming a Whole Word total), were evaluated in 3 multivariate analyses: (a) a longitudinal comparison (n = 22), at age 5 and 8 years; (b) a cross-sectional comparison of 8- to 10-year-olds (n = 12 per group) with TD and with history of PPD; and (c) a comparison of the group with history of PPD (n = 12) with a larger 5-year-old group (n = 62).

Results

Significant effect sizes (η_p ²) found for mismatch totals were as follows: (a) moderate (Lexical, Structure) and large (Features) between ages 5 and 8 to 10 years, mismatch frequency decreasing developmentally, and (b) large between 8- to 10-year-olds with TD and with history of PPD (Structure, Features; minimal lexical influences), in favor of participants with TD. Mismatch frequencies were equivalent for 8- to 10-year-olds with history of PPD and 5-year-olds with TD. Classification accuracy in original subgroupings was 100% and 91% for 8- to 10-year-olds with TD and with history of PPD, respectively, and 86% for 5-year-olds with TD.

Conclusion

Phonological accuracy in MSW production was differentiated for elementary school–aged children with TD and PPD, using a whole-word metric. To assist with the identification of children with ongoing PPD, the metric has the ability to detect weaknesses and track progress in global MSW phonological production.

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Structural Relationship Between Cognitive Processing and Syntactic Sentence Comprehension in Children With and Without Developmental Language Disorder

Purpose

We assessed the potential direct and indirect (mediated) influences of 4 cognitive mechanisms we believe are theoretically relevant to canonical and noncanonical sentence comprehension of school-age children with and without developmental language disorder (DLD).

Method

One hundred seventeen children with DLD and 117 propensity-matched typically developing (TD) children participated. Comprehension was indexed by children identifying the agent in implausible sentences. Children completed cognitive tasks indexing the latent predictors of fluid reasoning (FLD-R), controlled attention (CATT), complex working memory (cWM), and long-term memory language knowledge (LTM-LK).

Results

Structural equation modeling revealed that the best model fit was an indirect model in which cWM mediated the relationship among FLD-R, CATT, LTM-LK, and sentence comprehension. For TD children, comprehension of both sentence types was indirectly influenced by FLD-R (pattern recognition) and LTM-LK (linguistic chunking). For children with DLD, canonical sentence comprehension was indirectly influenced by LTM-LK and CATT, and noncanonical comprehension was indirectly influenced just by CATT.

Conclusions

cWM mediates sentence comprehension in children with DLD and TD children. For TD children, comprehension occurs automatically through pattern recognition and linguistic chunking. For children with DLD, comprehension is cognitively effortful. Whereas canonical comprehension occurs through chunking, noncanonical comprehension develops on a word-by-word basis.

Supplemental Material

https://doi.org/10.23641/asha.7178939

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The Coexistence of Disabling Conditions in Children Who Stutter: Evidence From the National Health Interview Survey

Purpose

Stuttering is a disorder that has been associated with coexisting developmental disorders. To date, detailed descriptions of the coexistence of such conditions have not consistently emerged in the literature. Identifying and understanding these conditions can be important to the overall management of children who stutter (CWS). The objective of this study was to generate a profile of the existence of disabling developmental conditions among CWS using national data.

Method

Six years of data from the National Health Interview Survey (2010–2015) were analyzed for this project. The sample consisted of children whose respondents clearly indicated the presence or absence of stuttering. Chi-square tests of independence were used for comparing categorical variables; and independent-samples t tests, for comparing continuous variables. Multiple logistic regression analyses were used for determining the odds of having a coexisting disabling developmental condition.

Results

This study sample included 62,450 children, of which 1,231 were CWS. Overall, the presence of at least 1 disabling developmental condition was 5.5 times higher in CWS when compared with children who do not stutter. The presence of stuttering was also associated with higher odds of each of the following coexisting developmental conditions: intellectual disability (odds ratio [OR] = 6.67, p < .001), learning disability (OR = 5.45, p < .001), attention-deficit hyperactivity disorder/attention-deficit disorder (OR = 3.09, p < .001), seizures (OR = 7.52, p < .001), autism/Asperger's/pervasive developmental disorder (OR = 5.48, p < .001), and any other developmental delay (OR = 7.10, p < .001).

Conclusion

Evidence from the National Health Interview Survey suggests a higher prevalence of coexisting developmental disabilities in CWS. The existence of coexisting disabling developmental conditions should be considered as part of an overall management plan for CWS.

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Relations Between Teacher Talk Characteristics and Child Language in Spoken-Language Deaf and Hard-of-Hearing Classrooms

Purpose

The aim of this study was to examine relations between teachers' conversational techniques and language gains made by their deaf and hard-of-hearing students. Specifically, we considered teachers' reformulations of child utterances, language elicitations, explicit vocabulary and syntax instruction, and wait time.

Method

This was an observational, longitudinal study that examined the characteristics of teacher talk in 25 kindergarten through second-grade classrooms of 68 deaf and hard-of-hearing children who used spoken English. Standardized assessments provided measures of child vocabulary and morphosyntax in the fall and spring of a school year. Characteristics of teacher talk were coded from classroom video recordings during the winter of that year.

Results

Hierarchical linear modeling indicated that reformulating child statements and explicitly teaching vocabulary were significant predictors of child vocabulary gains across a school year. Explicitly teaching vocabulary also significantly predicted gains in morphosyntax abilities. There were wide individual differences in the teachers' use of these conversational techniques.

Conclusion

Reformulation and explicit vocabulary instruction may be areas where training can help teachers improve, and improvements in the teachers' talk may benefit their students.

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Masthead

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A Multimethod Analysis of Pragmatic Skills in Children and Adolescents With Fragile X Syndrome, Autism Spectrum Disorder, and Down Syndrome

Purpose

Pragmatic language skills are often impaired above and beyond general language delays in individuals with neurodevelopmental disabilities. This study used a multimethod approach to language sample analysis to characterize syndrome- and sex-specific profiles across different neurodevelopmental disabilities and to examine the congruency of 2 analysis techniques.

Method

Pragmatic skills of young males and females with fragile X syndrome with autism spectrum disorder (FXS-ASD, n = 61) and without autism spectrum disorder (FXS-O, n = 40), Down syndrome (DS, n = 42), and typical development (TD, n = 37) and males with idiopathic autism spectrum disorder only (ASD-O, n = 29) were compared using variables obtained from a detailed hand-coding system contrasted with similar variables obtained automatically from the language analysis program Systematic Analysis of Language Transcripts (SALT).

Results

Noncontingent language and perseveration were characteristic of the pragmatic profiles of boys and girls with FXS-ASD and boys with ASD-O. Boys with ASD-O also initiated turns less often and were more nonresponsive than other groups, and girls with FXS-ASD were more nonresponsive than their male counterparts. Hand-coding and SALT methods were largely convergent with some exceptions.

Conclusion

Results suggest both similarities and differences in the pragmatic profiles observed across different neurodevelopmental disabilities, including idiopathic and FXS-associated cases of ASD, as well as an important sex difference in FXS-ASD. These findings and congruency between the 2 language sample analysis techniques together have important implications for assessment and intervention efforts.

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Prevalence of Publication Bias Tests in Speech, Language, and Hearing Research

Purpose

The purpose of this research note is to systematically document the extent that researchers who publish in American Speech-Language-Hearing Association (ASHA) journals search for and include unpublished literature in their meta-analyses and test for publication bias.

Method

This research note searched all ASHA peer-reviewed journals for published meta-analyses and reviewed all qualifying articles for characteristics related to the acknowledgment and assessment of publication bias.

Results

Of meta-analyses published in ASHA journals, 75% discuss publication in some form; however, less than 50% test for publication bias. Further, only 38% (n = 11) interpreted the findings of these tests.

Conclusion

Findings reveal that more attention is needed to the presence and impact of publication bias. This research note concludes with 5 recommendations for addressing publication bias.

Supplemental Material

https://doi.org/10.23641/asha.7268648

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Verb Variability and Morphosyntactic Priming With Typically Developing 2- and 3-Year-Olds

Purpose

This study was specifically designed to examine how verb variability and verb overlap in a morphosyntactic priming task affect typically developing children's use and generalization of auxiliary IS.

Method

Forty typically developing 2- to 3-year-old native English-speaking children with inconsistent auxiliary IS production were primed with 24 present progressive auxiliary IS sentences. Half of the children heard auxiliary IS primes with 24 unique verbs (high variability). The other half heard auxiliary IS primes with only 6 verbs, repeated 4 times each (low variability). In addition, half of the children heard prime–target pairs with overlapping verbs (lexical boost), whereas the other half heard prime–target pairs with nonoverlapping verbs (no lexical boost). To assess use and generalization of the targeted structure to untrained verbs, all children described probe items at baseline and 5 min and 24 hr after the priming task.

Results

Children in the high variability group demonstrated strong priming effects during the task and increased auxiliary IS production compared with baseline performance 5 min and 24 hr after the priming task, suggesting learning and generalization of the primed structure. Children in the low variability group showed no significant increases in auxiliary IS production and fell significantly below the high variability group in the 24-hr posttest. Verb overlap did not boost priming effects during the priming task or in posttest probes.

Conclusions

Typically developing children do indeed make use of lexical variability in their linguistic input to help them extract and generalize abstract grammatical rules. They can do this quite quickly, with relatively stable, robust learning occurring after a single optimally variable input session. With reduced variability, learning does not occur.

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Identification of Affective State Change in Adults With Aphasia Using Speech Acoustics

Purpose

The current study aimed to identify objective acoustic measures related to affective state change in the speech of adults with post-stroke aphasia.

Method

The speech of 20 post-stroke adults with aphasia was recorded during picture description and administration of the Western Aphasia Battery–Revised (Kertesz, 2006). In addition, participants completed the Self-Assessment Manikin (Bradley & Lang, 1994) and the Stress Scale (Tobii Dynavox, 1981–2016) before and after the language tasks. Speech from each participant was used to detect a change in affective state test scores between the beginning and ending speech.

Results

Machine learning revealed moderate success in classifying depression, minimal success in predicting depression and stress numeric scores, and minimal success in classifying changes in affective state class between the beginning and ending speech.

Conclusions

The results suggest the existence of objectively measurable aspects of speech that may be used to identify changes in acute affect from adults with aphasia. This work is exploratory and hypothesis-generating; more work will be needed to make conclusive claims. Further work in this area could lead to automated tools to assist clinicians with their diagnoses of stress, depression, and other forms of affect in adults with aphasia.

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Sensitivity to Morphosyntactic Information in Preschool Children With and Without Developmental Language Disorder: A Follow-Up Study

Purpose

This study tested children's sensitivity to tense/agreement information in fronted auxiliaries during online comprehension of questions (e.g., Are the nice little dogs running?). Data from children with developmental language disorder (DLD) were compared to previously published data from typically developing (TD) children matched according to sentence comprehension test scores.

Method

Fifteen 5-year-old children with DLD and fifteen 3-year-old TD children participated in a looking-while-listening task. Children viewed pairs of pictures, 1 with a single agent and 1 with multiple agents, accompanied by a sentence with a fronted auxiliary (is + single agent or are + two agents) or a control sentence. Proportion looking to the target was measured.

Results

Children with DLD did not show anticipatory looking based on the number information contained in the auxiliary (is or are) as the younger TD children had. Both groups showed significant increases in looking to the target upon hearing the subject noun (e.g., dogs).

Conclusions

Despite the groups' similar sentence comprehension abilities and ability to accurately respond to the information provided by the subject noun, children with DLD did not show sensitivity to number information on the fronted auxiliary. This insensitivity is considered in light of these children's weaker command of tense/agreement forms in their speech. Specifically, we consider the possibility that failure to grasp the relation between the subject–verb sequence (e.g., dogs running) and preceding information (e.g., are) in questions in the input contributes to the protracted inconsistency in producing auxiliary forms in obligatory contexts by children with DLD.

Supplemental Material

https://doi.org/10.23641/asha.7283459

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Comparison of intraoral biofilm reduction on silver-coated and silver ion-implanted stainless steel bracket material

Abstract

Purpose

The objective of this in situ study was to quantify the intraoral biofilm reduction on bracket material as a result of different surface modifications using silver ions. In addition to galvanic silver coating and physical vapor deposition (PVD), the plasma immersion ion implantation and deposition (PIIID) procedure was investigated for the first time within an orthodontic application.

Materials and methods

An occlusal splint equipped with differently silver-modified test specimens based on stainless steel bracket material was prepared for a total of 12 periodontally healthy patients and was worn in the mouth for 48 h. The initially formed biofilm was fluorescently stained and a quantitative comparative analysis of biofilm volume, biofilm surface coverage and live/dead distribution of bacteria was performed by confocal laser scanning microscopy (CLSM).

Results

Compared to untreated stainless steel bracket material, the antibacterial effect of the PIIID silver-modified surface was just as significant with regard to reducing the biofilm volume and the surface coverage as the galvanically applied silver layer and the PVD silver coating. Regarding the live/dead distribution, however, the PIIID modification was the only surface that showed a significant increase in the proportion of dead cells compared to untreated bracket material and the galvanic coating.

Conclusions

Orthodontic stainless steel with a silver-modified surface by PIIID procedure showed an effective reduction in the intraoral biofilm formation compared to untreated bracket material, in a similar manner to PVD and galvanic silver coatings applied to the surface. Additionally, the PIIID silver-modified surface has an increased bactericidal effect.

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Dual exposure to smoking and household air pollution is associated with an increased risk of severe asthma in adults in Brazil

The relationship between smoking, household pollution, dual exposure and severity of asthma in adults has not been sufficiently studied. We examined and compared the effects of cigarette smoking, domestic wood...

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Automatic Classification of Speech Overlaps: Feature Representation and Algorithms

Publication date: Available online 10 December 2018

Source: Computer Speech & Language

Author(s): Shammur Absar Chowdhury, Evgeny A. Stepanov, Morena Danieli, Giuseppe Riccardi

Abstract

Overlapping speech is a natural and frequently occurring phenomenon in human–human conversations with an underlying purpose. Speech overlap events may be categorized as competitive and non-competitive. While the former is an attempt to grab the floor, the latter is an attempt to assist the speaker to continue the turn. The presence and distribution of these categories are indicative of the speakers' states during the conversation. Therefore, understanding these manifestations is crucial for conversational analysis and for modeling human–machine dialogs. The goal of this study is to design computational models to classify overlapping speech segments of dyadic conversations into competitive vs non-competitive acts using lexical and acoustic cues, as well as their surrounding context. The designed overlap representations are evaluated in both linear – Support Vector Machines (SVM) – and non-linear – feed-forward (FFNN), convolutional (CNN) and long short-term memory (LSTM) neural network – models. We experiment with lexical and acoustic representations and their combinations from both speaker channels in feature and hidden space. We observe that lexical word-embedding features significantly increase the overall F₁-measure compared to both acoustic and bag-of-ngrams lexical representations, suggesting that lexical information can be utilized as a powerful cue for overlap classification. Our comparative study shows that the best computational architecture is an FFNN along with a combination of word embeddings and acoustic features.

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Etiology of subjective taste loss

Background

Taste complaints are commonly encountered in clinical practice. Although changes in taste function may arise from varied etiologies, numerous other factors may impact patients' taste perceptions, the most common of which is olfactory dysfunction. Thus, patients with taste complaints may or may not have measurable deficits in taste function. This poses a challenge to providers faced with evaluation of patients with taste disorders, and may delay diagnosis and management.

Methods

We retrospectively examined records of 1108 patients evaluated at the Virginia Commonwealth University Health System Smell and Taste Clinic and compared patients' subjective taste complaints with results of objective testing of the senses of taste and smell.

Results

A total of 358 patients had a subjective taste complaint and results from both gustatory and olfactory function tests. Patients were grouped by subjective complaint as "taste only" (n = 63) or "taste and smell" (n = 295). Of patients reporting a "taste‐only" complaint, 25.4% had abnormal gustatory function, whereas 44.4% had abnormal olfactory function. For those reporting taste‐and‐smell complaints, only 9.5% had abnormal gustatory function, whereas 86.8% had abnormal olfactory function.

Conclusion

This study supports the hypothesis that patients who present with a taste complaint are more likely to have an underlying olfactory than gustatory impairment. However, those with a taste‐only complaint are more likely to have objective gustatory deficits than those with a taste‐and‐smell complaint. These findings may prove useful to healthcare providers who evaluate patients presenting with complaints of taste loss.

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Dynamics of aesthetic experience are reflected in the default-mode network

Publication date: Available online 10 December 2018

Source: NeuroImage

Author(s): Amy M. Belfi, Edward A. Vessel, Aenne Brielmann, Ayse Ilkay Isik, Anjan Chatterjee, Helmut Leder, Denis G. Pelli, G. Gabrielle Starr

Abstract

Neuroaesthetics is a rapidly developing interdisciplinary field of research that aims to understand the neural substrates of aesthetic experience: While understanding aesthetic experience has been an objective of philosophers for centuries, it has only more recently been embraced by neuroscientists. Recent work in neuroaesthetics has revealed that aesthetic experience with static visual art engages visual, reward and default-mode networks. Very little is known about the temporal dynamics of these networks during aesthetic appreciation. Previous behavioral and brain imaging research suggests that critical aspects of aesthetic experience have slow dynamics, taking more than a few seconds, making them amenable to study with fMRI. Here, we identified key aspects of the dynamics of aesthetic experience while viewing art for various durations. In the first few seconds following image onset, activity in the DMN (and high-level visual and reward regions) was greater for very pleasing images; in the DMN this activity counteracted a suppressive effect that grew longer and deeper with increasing image duration. In addition, for very pleasing art, the DMN response returned to baseline in a manner time-locked to image offset. Conversely, for non-pleasing art, the timing of this return to baseline was inconsistent. This differential response in the DMN may therefore reflect the internal dynamics of the participant's state: The participant disengages from art-related processing and returns to stimulus-independent thought. These dynamics suggest that the DMN tracks the internal state of a participant during aesthetic experience.

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Metabolism Plays a Key Role during Macrophage Activation

Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key roles in controlling tissue homeostasis, infections, and excessive inflammation. Macrophages remove dead cells in a process named efferocytosis, contributing to the healthy tissue maintenance. Recently, it became clear that the main macrophage functions are under metabolic control. Modulation of glucose, fatty acid, and amino acid metabolism is associated with various macrophage activations in response to external stimuli. Deciphering these metabolic pathways provided critical information about macrophage functions.

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Activation of GABAB Receptor Suppresses Diabetic Neuropathic Pain through Toll-Like Receptor 4 Signaling Pathway in the Spinal Dorsal Horn

Diabetic neuropathic pain (DNP) is a prevalent complication in diabetes patients. Neuronal inflammation and activation of Toll-like receptor 4 (TLR4) are involved in the occurrence of DNP. However, the underlying mechanisms remain unclear. Downregulation of gamma-aminobutyric acid B (GABAB) receptor contributes to the DNP. GABAB receptor interacts with NF-κB, a downstream signaling factor of TLR4, in a neuropathic pain induced by chemotherapy. In this study, we determined the role of TLR4/Myd88/NF-κB signaling pathways coupled to GABAB receptors in the generation of DNP. Intrathecal injection of baclofen (GABAB receptor agonist), LPS-RS ultrapure (TLR4 antagonist), MIP (MyD88 antagonist), or SN50 (NF-κB inhibitor) significantly increased paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) in DNP rats, while intrathecal injection of saclofen (GABAB receptor blocker) decreased PWT and PWTL in DNP rats. The expression of TLR4, Myd88, NF-κBp65, and their downstream components IL-1 and TNF-α was significantly higher in the spinal cord tissue in DNP rats compared to control rats. Following inhibition of TLR4, Myd88, and NF-κB, the expression of IL-1 and TNF-α decreased. Activation of GABAB receptors downregulated the expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. Blockade of GABAB receptors significantly upregulated expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. These data suggest that activation of the TLR4/Myd88/NF-κB signaling pathway is involved in the occurrence of DNP in rats. Activation of GABAB receptor in the spinal cord may suppress the TLR4/Myd88/NF-κB signaling pathway and alleviate the DNP.

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