The effect of misophonia on cognitive and social judgments.

Misophonia, a heightened aversion to certain sounds, turns common cognitive and social exercises (e.g., paying attention during a lecture near a pen-clicking classmate, coexisting at the dinner table with a food-chomping relative) into challenging endeavors. How does exposure to triggering sounds impact cognitive and social judgments? We investigated this question in a sample of 65 participants (26 misophonia, 39 control) from the general population. In Phase 1, participants saw faces paired with auditory stimuli while completing a gender judgment task, then reported sound discomfort and identification. In Phase 2, participants saw these same faces with novel ones and reported face likeability and memory. For both oral and non-oral triggers, misophonic participants gave higher discomfort ratings than controls did-especially when identification was correct-and performed slower on the gender judgment. Misophonic participants rated lower likeability than controls did for faces they remembered with high discomfort sounds, and face memory was worse overall for faces originally paired with high discomfort sounds. Altogether, these results suggest that misophonic individuals show impairments on social and cognitive judgments if they must endure discomforting sounds. This experiment helps us better understand the day-to-day impact of misophonia and encourages usage of individualized triggers in future studies.

Joint contributions of preview and task instructions on visual search strategy selection.

People tend to employ suboptimal attention control strategies during visual search. Here we question why people are suboptimal, specifically investigating how knowledge of the optimal strategies and the time available to apply such strategies affect strategy use. We used the Adaptive Choice Visual Search (ACVS), a task designed to assess attentional control optimality. We used explicit strategy instructions to manipulate explicit strategy knowledge, and we used display previews to manipulate time to apply the strategies. In the first two experiments, the strategy instructions increased optimality. However, the preview manipulation did not significantly boost optimality for participants who did not receive strategy instruction. Finally, in Experiments 3A and 3B, we jointly manipulated preview and instruction with a larger sample size. Preview and instruction both produced significant main effects; furthermore, they interacted significantly, such that the beneficial effect of instructions emerged with greater preview time. Taken together, these results have important implications for understanding the strategic use of attentional control. Individuals with explicit knowledge of the optimal strategy are more likely to exploit relevant information in their visual environment, but only to the extent that they have the time to do so.

Terms of debate: Consensus definitions to guide the scientific discourse on visual distraction.

Hypothesis-driven research rests on clearly articulated scientific theories. The building blocks for communicating these theories are scientific terms. Obviously, communication - and thus, scientific progress - is hampered if the meaning of these terms varies idiosyncratically across (sub)fields and even across individual researchers within the same subfield. We have formed an international group of experts representing various theoretical stances with the goal to homogenize the use of the terms that are most relevant to fundamental research on visual distraction in visual search. Our discussions revealed striking heterogeneity and we had to invest much time and effort to increase our mutual understanding of each other's use of central terms, which turned out to be strongly related to our respective theoretical positions. We present the outcomes of these discussions in a glossary and provide some context in several essays. Specifically, we explicate how central terms are used in the distraction literature and consensually sharpen their definitions in order to enable communication across theoretical standpoints. Where applicable, we also explain how the respective constructs can be measured. We believe that this novel type of adversarial collaboration can serve as a model for other fields of psychological research that strive to build a solid groundwork for theorizing and communicating by establishing a common language. For the field of visual distraction, the present paper should facilitate communication across theoretical standpoints and may serve as an introduction and reference text for newcomers.

Suppression of a salient distractor protects the processing of target features.

We are often bombarded with salient stimuli that capture our attention and distract us from our current goals. Decades of research have shown the robust detrimental impacts of salient distractors on search performance and, of late, in leading to altered feature perception. These feature errors can be quite extreme, and thus, undesirable. In search tasks, salient distractors can be suppressed if they appear more frequently in one location, and this learned spatial suppression can lead to reductions in the cost of distraction as measured by reaction time slowing. Can learned spatial suppression also protect against visual feature errors? To investigate this question, participants were cued to report one of four briefly presented colored squares on a color wheel. On two-thirds of trials, a salient distractor appeared around one of the nontarget squares, appearing more frequently in one location over the course of the experiment. Participants' responses were fit to a model estimating performance parameters and compared across conditions. Our results showed that general performance (guessing and precision) improved when the salient distractor appeared in a likely location relative to elsewhere. Critically, feature swap errors (probability of misreporting the color at the salient distractor's location) were also significantly reduced when the distractor appeared in a likely location, suggesting that learned spatial suppression of a salient distractor helps protect the processing of target features. This study provides evidence that, in addition to helping us avoid salient distractors, suppression likely plays a larger role in helping to prevent distracting information from being encoded.

Oral Omilancor Treatment Ameliorates Clostridioides difficile Infection During IBD Through Novel Immunoregulatory Mechanisms Mediated by LANCL2 Activation.

BACKGROUND: Clostridioides difficile infection (CDI) is an opportunistic infection of the gastrointestinal tract, commonly associated with antibiotic administration, that afflicts almost 500 000 people yearly only in the United States. CDI incidence and recurrence is increased in inflammatory bowel disease (IBD) patients. Omilancor is an oral, once daily, first-in-class, gut-restricted, immunoregulatory therapeutic in clinical development for the treatment of IBD. METHODS: Acute and recurrent murine models of CDI and the dextran sulfate sodium-induced concomitant model of IBD and CDI were utilized to determine the therapeutic efficacy of oral omilancor. To evaluate the protective effects against C. difficile toxins, in vitro studies with T84 cells were also conducted. 16S sequencing was employed to characterize microbiome composition. RESULTS: Activation of the LANCL2 pathway by oral omilancor and its downstream host immunoregulatory changes decreased disease severity and inflammation in the acute and recurrence models of CDI and the concomitant model of IBD/CDI. Immunologically, omilancor treatment increased mucosal regulatory T cell and decreased pathogenic T helper 17 cell responses. These immunological changes resulted in increased abundance and diversity of tolerogenic gut commensal bacterial strains in omilancor-treated mice. Oral omilancor also resulted in accelerated C. difficile clearance in an antimicrobial-free manner. Furthermore, omilancor provided protection from toxin damage, while preventing the metabolic burst observed in intoxicated epithelial cells. CONCLUSIONS: These data support the development of omilancor as a novel host-targeted, antimicrobial-free immunoregulatory therapeutic for the treatment of IBD patients with C. difficile-associated disease and pathology with the potential to address the unmet clinical needs of ulcerative colitis and Crohn's disease patients with concomitant CDI.

Omilancor is an oral, gut-restricted first-in-class immunoregulatory therapeutic for the treatment of inflammatory bowel disease (IBD). This study demonstrates for the first time that omilancor provides therapeutic efficacy in models of acute and recurrent Clostridioides difficile infection (CDI), and concomitant CDI and IBD, by increasing regulatory T cell function while suppressing effector responses, plus modulating gut microbiome composition and preserving epithelial barrier function.

Treating Autoimmune Diseases With LANCL2 Therapeutics: A Novel Immunoregulatory Mechanism for Patients With Ulcerative Colitis and Crohn's Disease.

Lanthionine synthetase C-like 2 (LANCL2) therapeutics have gained increasing recognition as a novel treatment modality for a wide range of autoimmune diseases. Genetic ablation of LANCL2 in mice results in severe inflammatory phenotypes in inflammatory bowel disease (IBD) and lupus. Pharmacological activation of LANCL2 provides therapeutic efficacy in mouse models of intestinal inflammation, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. Mechanistically, LANCL2 activation enhances regulatory CD4 + T cell (Treg) responses and downregulates effector responses in the gut. The stability and suppressive capacities of Treg cells are enhanced by LANCL2 activation through engagement of immunoregulatory mechanisms that favor mitochondrial metabolism and amplify IL-2/CD25 signaling. Omilancor, the most advanced LANCL2 immunoregulatory therapeutic in late-stage clinical development, is a phase 3 ready, first-in-class, gut-restricted, oral, once-daily, small-molecule therapeutic in clinical development for the treatment of UC and CD. In this review, we discuss this novel mechanism of mucosal immunoregulation and how LANCL2-targeting therapeutics could help address the unmet clinical needs of patients with autoimmune diseases, starting with IBD.

Oral LANCL2 therapeutics are a safe and effective treatment modality for the long-term management of autoimmune diseases, including UC and CD, without causing systemic immunosuppression. This review discusses in detail the immunoregulatory mechanisms of action of LANCL2 therapeutics. More specifically, the article describes how omilancor, a first-in-class, oral, once daily, gut-restricted LANCL2 therapeutic could help address the unmet clinical needs of patients with IBD and other immune-mediated diseases.

Modulation of colonic immunometabolic responses during Clostridioides difficile infection ameliorates disease severity and inflammation.

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea, and its clinical symptoms can span from asymptomatic colonization to pseudomembranous colitis and even death. The current standard of care for CDI is antibiotic treatment to achieve bacterial clearance; however, 15 to 35% of patients experience recurrence after initial response to antibiotics. We have conducted a comprehensive, global colonic transcriptomics analysis of a 10-day study in mice to provide new insights on the local host response during CDI and identify novel host metabolic mechanisms with therapeutic potential. The analysis indicates major alterations of colonic gene expression kinetics at the acute infection stage, that are restored during the recovery phase. At the metabolic level, we observe a biphasic response pattern characterized by upregulated glycolytic metabolism during the peak of inflammation, while mitochondrial metabolism predominates during the recovery/healing stage. Inhibition of glycolysis via 2-Deoxy-D-glucose (2-DG) administration during CDI decreases disease severity, protects from mortality, and ameliorates colitis in vivo. Additionally, 2-DG also protects intestinal epithelial cells from C. difficile toxin damage, preventing loss of barrier integrity and secretion of proinflammatory mediators. These data postulate the pharmacological targeting of host immunometabolic pathways as novel treatment modalities for CDI.

Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.

Learned spatial suppression is not always proactive.

Learning to ignore distractors is critical for navigating the visual world. Research has suggested that a location frequently containing a salient distractor can be suppressed. How does such suppression work? Previous studies provided evidence for proactive suppression, but methodological limitations preclude firm conclusions. We sought to overcome these limitations with a new search-probe paradigm. On search trials, participants searched for a shape oddball target while a salient color singleton distractor frequently appeared in a high-probability location. On randomly interleaved probe trials, participants discriminated the orientation of a tilted bar presented briefly at one of the search locations, allowing us to index the spatial distribution of attention at the moment the search would have begun. Results on search trials replicated previous findings: reduced attentional capture when a salient distractor appeared in the high-probability location. However, critically, probe discrimination was no different at the high-probability and low-probability locations. We increased the incentive to ignore the high-probability location in Experiment 2 and found, strikingly, that probe discrimination accuracy was greater at the high-probability location. These results suggest that the high-probability location was initially selected before being suppressed, consistent with a reactive mechanism. Overall, the accuracy probe procedure demonstrates that learned spatial suppression is not always proactive, even when response time metrics seem consistent with such an inference. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions.

We built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.

Neural evidence for non-orofacial triggers in mild misophonia.

Misophonia, an extreme aversion to certain environmental sounds, is a highly prevalent yet understudied condition plaguing roughly 20% of the general population. Although neuroimaging research on misophonia is scant, recent work showing higher resting-state functional connectivity (rs-fMRI) between auditory cortex and orofacial motor cortex in misophonia vs. controls has led researchers to speculate that misophonia is caused by orofacial mirror neurons. Since orofacial motor cortex was defined using rs-fMRI, we attempted to theoretically replicate these findings using orofacial cortex defined by task-based fMRI instead. Further, given our recent work showing that a wide variety of sounds can be triggering (i.e., not just oral/nasal sounds), we investigated whether there is any neural evidence for misophonic aversion to non-orofacial stimuli. Sampling 19 adults with varying misophonia from the community, we collected resting state data and an fMRI task involving phoneme articulation and finger-tapping. We first defined "orofacial" cortex in each participant using rs-fMRI as done previously, producing what we call resting-state regions of interest (rsROIs). Additionally, we functionally defined regions (fROIs) representing "orofacial" or "finger" cortex using phoneme or finger-tapping activation from the fMRI task, respectively. To investigate the motor specificity of connectivity differences, we subdivided the rsROIs and fROIs into separate sensorimotor areas based on their overlap with two common atlases. We then calculated rs-fMRI between each rsROI/fROI and a priori non-sensorimotor ROIs. We found increased connectivity in mild misophonia between rsROIs and both auditory cortex and insula, theoretically replicating previous results, with differences extending across multiple sensorimotor regions. However, the orofacial task-based fROIs did not show this pattern, suggesting the "orofacial" cortex described previously was not capturing true orofacial cortex; in fact, using task-based fMRI evidence, we find no selectivity to orofacial action in these previously described "orofacial" regions. Instead, we observed higher connectivity between finger fROIs and insula in mild misophonia, demonstrating neural evidence for non-orofacial triggers. These results provide support for a neural representation of misophonia beyond merely an orofacial/motor origin, leading to important implications for the conceptualization and treatment of misophonia.

Assessing the generality of strategy optimization across distinct attentional tasks.

Individuals vary substantially in the degree to which they optimize their performance in attentional tasks. How do such individual markers of attentional strategy relate across different tasks? Previous research has failed to observe significant correlations in strategy optimization between distinct visual search tasks (Clarke et al., 2022); suggesting that strategy optimization is not unitary, or determined by a single trait variable. Here we test whether strategy optimization shows some degree of generality, specifically across tasks with similar attentional components. We employed the Adaptive Choice Visual Search (ACVS; Irons & Leber, 2018a), a visual search paradigm designed to directly measure attentional control strategy. In 2 studies, we had participants complete the ACVS and a modified, but similar, task with 1 altered attentional component (specifically, the requirement to use feature-based attention and enumeration, respectively). We found positive correlations in strategy optimization between tasks that do versus do not involve feature-based attention (r = .38, p = .0068) and across tasks that do versus do not require enumeration (r = .33, p = .018). These results provide novel evidence for generality of strategy optimization, although the strength of the correlations was weaker than the within-task test-retest reliability of strategy measurements. Thus, while some generality exists, strategy optimization appears to be quite heterogeneous. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

WITHDRAWN: EFFICACY, SAFETY, AND TOLERABILITY OF OMILANCOR IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF PATIENTS WITH ULCERATIVE COLITIS.

BACKGROUND: Omilancor is an oral, once-daily, gut-restricted, small molecule, first-in-class therapeutic for Crohn's disease (CD) and ulcerative colitis (UC) that targets the novel LANCL2 pathway. Through LANCL2 activation, omilancor increases the suppressive capacity of regulatory immune cells, including regulatory CD4+ T cells (Tregs), locally within the intestinal mucosa. In a Phase I study in normal healthy volunteers no changes in AEs or trends in safety laboratory trends were observed up to daily oral doses of 7500 mg/day. METHODS: In a Phase 2, proof of concept, double blind, parallel-group study, adult patients with Mayo Clinic scores (MCS) of 4 - 10 and endoscopic subscores of 2 or more were randomly assigned to groups given omilancor 440 mg QD (n=66), omilancor 880 mg QD (n=66) or placebo (n=66) for 12 weeks. The primary endpoint was clinical remission after 12 weeks as defined by rectal bleeding (RB) equal to 0, stool frequency (SF) equal to 0 or 1 and endoscopic appearance (MES) equal to 0 or 1. A modified intent to treat (mITT) population was defined by patients with RB > 0, histological activity and elevated fecal calprotectin (FCP) at baseline. Secondary endpoints included histological remission as defined by a Geboes score < 3.1 with absence of neutrophils in the lamina propria, endoscopic remission as defined by a MES < 2, normalization of FCP and pharmacokinetics (PK) of omilancor in stool, tissue and plasma. RESULTS: Oral omilancor was well tolerated with no trends in AE profile observed and most AEs of mild severity and no dose-limiting toxicities. In the mITT population, clinical remission was induced in 30.4% of omilancor treated patients relative to 3.7% of patients given placebo (Δ = 26.7, p = 0.01), thereby meeting the primary endpoint. Endoscopic remission was induced in 41.7% of patients treated with omilancor relative to 18.6% of patients given placebo (Δ = 23.1, p = 0.07). Histological remission was induced in 41.7% of patients treated with omilancor relative to 22.2% of patients given placebo (Δ = 19.5, p = 0.14). In patients with elevated baseline FCP, normalization occurred in 43.8% of the omilancor 880 mg group and 40.6% of the omilancor 440 mg group relative to 21.4% of the placebo group after 2 weeks (p = 0.048). PK analysis validated a gut-restricted profile with stable drug levels in stool over the 12-week treatment period and penetration into colonic biopsy tissue with limited systemic exposure. Reduction of patient reported outcomes occurred during the OLE with nearly 90% of patients reaching SF ≤ 1 and RB = 0 after 36 weeks of open-label treatment. CONCLUSIONS: Once a day oral dosing with omilancor was well-tolerated and induced clinical remission in a Phase II mild to moderate UC population. A Phase II study in CD and a Phase III program in UC (PACIFY) were initiated in 2021 and are currently recruiting.

Exploratory studies with NX-13: oral toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1.

Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is an emerging therapeutic target for a spectrum of human diseases. NX-13 is a small molecule therapeutic designed to target and activate NLRX1 to induce immunometabolic changes resulting in lower inflammation and therapeutic responses in inflammatory bowel disease (IBD). This study investigates the safety of NX-13 in a seven-day, repeat-dose general toxicity study in male and female Sprague Dawley rats at oral doses of 500 and 1000 mg/kg. Weights, clinical signs, functional observational battery, clinical pathology and histopathology were used for evaluation. Daily oral dosing of NX-13 up to 1000 mg/kg did not result in any changes in weight, abnormal clinical signs or behavior. No significant differences were observed between treated and control rats in hematology or blood biochemistry. Histopathological evaluation of 12 tissues demonstrated no differences between controls and treated rats. There were no changes in weights of brain, heart, kidney, liver or spleen. Pharmacokinetic analysis of a single oral dose of NX-13 at 10 mg/kg in Sprague Dawley rats provided a maximum plasma concentration of 57 ng/mL at 0.5 h post-dose. Analysis of colon tissue after oral dosing with 1 and 10 mg/kg indicated high peak concentrations (10 and 100 µg/g, respectively) that scale in a dose-proportional manner. These experiments suggest that NX-13 is safe and well-tolerated in rats given oral doses as high as 1000 mg/kg with a favorable gastrointestinal localized pharmacokinetic profile, confirming NX-13 as a promising therapeutic for Crohn's disease and ulcerative colitis.

Stable individual differences in strategies within, but not between, visual search tasks.

A striking range of individual differences has recently been reported in three different visual search tasks. These differences in performance can be attributed to strategy, that is, the efficiency with which participants control their search to complete the task quickly and accurately. Here, we ask whether an individual's strategy and performance in one search task is correlated with how they perform in the other two. We tested 64 observers and found that even though the test-retest reliability of the tasks was high, an observer's performance and strategy in one task was not predictive of their behaviour in the other two. These results suggest search strategies are stable over time, but context-specific. To understand visual search, we therefore need to account not only for differences between individuals but also how individuals interact with the search task and context.

Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific.

The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process A. fumigatus conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.

First-in-class topical therapeutic omilancor ameliorates disease severity and inflammation through activation of LANCL2 pathway in psoriasis.

Psoriasis (PsO) is a complex immune-mediated disease that afflicts 100 million people. Omilancor is a locally-acting, small molecule that selectively activates the Lanthionine Synthetase C-like 2 (LANCL2) pathway, resulting in immunoregulatory effects at the intersection of immunity and metabolism. Topical omilancor treatment in an imiquimod-induced mouse model of PsO ameliorates disease severity, epidermal hyperplasia and acanthosis. Further, pharmacological activation of LANCL2 results in significant downregulation of proinflammatory markers including local reduction of IL17, and infiltration of proinflammatory cell subsets. These therapeutic effects were further validated in an IL-23 PsO model. This model reported increased preservation of homeostatic skin structure, accompanied by a decreased infiltration of proinflammatory T cell subsets. In CD4+ T cells and Th17 cells, the LANCL2 pathway regulates proinflammatory cytokine production, proliferation and glucose metabolism. Metabolically, the loss of Lancl2 resulted in increased glycolytic rates, lactate production and upregulated enzymatic activity of hexokinase and lactate dehydrogenase (LDH). Inhibition of LDH activity abrogated the increased proliferation rate in Lancl2-/- CD4+ T cells. Additionally, topical omilancor treatment decreased the metabolic upregulation in keratinocytes, keratinocyte hyperproliferation and expression of inflammatory markers. Omilancor is a promising topical, LANCL2-targeting therapeutic candidate for the treatment of PsO and other dermatology indications.

Enemy of My Enemy: A Novel Insect-Specific Flavivirus Offers a Promising Platform for a Zika Virus Vaccine.

Vaccination remains critical for viral disease outbreak prevention and control, but conventional vaccine development typically involves trade-offs between safety and immunogenicity. We used a recently discovered insect-specific flavivirus as a vector in order to develop an exceptionally safe, flavivirus vaccine candidate with single-dose efficacy. To evaluate the safety and efficacy of this platform, we created a chimeric Zika virus (ZIKV) vaccine candidate, designated Aripo/Zika virus (ARPV/ZIKV). ZIKV has caused immense economic and public health impacts throughout the Americas and remains a significant public health threat. ARPV/ZIKV vaccination showed exceptional safety due to ARPV/ZIKV's inherent vertebrate host-restriction. ARPV/ZIKV showed no evidence of replication or translation in vitro and showed no hematological, histological or pathogenic effects in vivo. A single-dose immunization with ARPV/ZIKV induced rapid and robust neutralizing antibody and cellular responses, which offered complete protection against ZIKV-induced morbidity, mortality and in utero transmission in immune-competent and -compromised murine models. Splenocytes derived from vaccinated mice demonstrated significant CD4+ and CD8+ responses and significant cytokine production post-antigen exposure. Altogether, our results further support that chimeric insect-specific flaviviruses are a promising strategy to restrict flavivirus emergence via vaccine development.

What sound sources trigger misophonia? Not just chewing and breathing.

OBJECTIVES: Misophonia is a highly prevalent yet understudied condition characterized by aversion toward particular environmental sounds. Oral/nasal sounds (e.g., chewing, breathing) have been the focus of research, but variable experiences warrant an objective investigation. Experiment 1 asked whether human-produced oral/nasal sounds were more aversive than human-produced nonoral/nasal sounds and non-human/nature sounds. Experiment 2 additionally asked whether machine-learning algorithms could predict the presence and severity of misophonia. METHOD: Sounds were presented to individuals with misophonia (Exp.1: N = 48, Exp.2: N = 45) and members of the general population (Exp.1: N = 39, Exp.2: N = 61). Aversiveness ratings to each sound were self-reported. RESULTS: Sounds from all three source categories-not just oral/nasal sounds-were rated as significantly more aversive to individuals with misophonia than controls. Further, modeling all sources classified misophonia with 89% accuracy and significantly predicted misophonia severity (r = 0.75). CONCLUSIONS: Misophonia should be conceptualized as more than an aversion to oral/nasal sounds, which has implications for future diagnostics and experimental consistency moving forward.