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Searching through memory is mediated by complex interactions between the underlying mental lexicon and the processes that operate on this lexicon. However, these interactions are difficult to study due to the effortless manner in which neurotypical individuals perform cognitive tasks. In this work, we examine these interactions within a sample of prelingually deaf individuals with cochlear implants and normal hearing individuals who were administered the verbal fluency task for the "animals" category. Specifically, we tested how different candidates for underlying mental lexicons and processes account for search behavior within the verbal fluency task across the two groups. The models learned semantic representations from different combinations of textual (word2vec) and speech-based (speech2vec) information. The representations were then combined with process models of memory search based on optimal foraging theory that incorporate different lexical sources for transitions within and between clusters of items produced in the fluency task. Our findings show that semantic, word frequency, and phonological information jointly influence search behavior and highlight the delicate balance of different lexical sources that produces successful search outcomes.

Dois eventos excepcionais e opostos marcaram os idos de janeiro de 2023 em Brasília: celebração pela posse do Presidente Lula no dia 1º e o vandalismo de uma semana depois. Eles ocorreram na Esplanada dos Ministérios e na Praça dos Três Poderes, e motivaram a feitura deste artigo. No entanto, a análise inclui outros espaços da cidade, a completarem as “quatro escalas”, como passaram a ser comumente referidos os lugares-tipo do plano de Lucio Costa: além da monumental, a residencial, a gregária e a bucólica. Metodologicamente, a inspiração vem de Evaldo Coutinho; Milton Santos; Bill Hillier e Julienne Hanson; e Pierre Bourdieu. Explora-se o conceito de “capital” do último, e caracteriza-se a sua “encenação” na empiria estudada. Sugere-se como a configuração do lugar é elemento intrinsecamente constitutivo do que ali acontece, rotineira ou excepcionalmente. O artigo tem caráter mais teórico-metodológico que empírico, embora a evidência referida ilustre o argumento.

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PLpro with IC50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of Mpro and PLpro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific Mpro and PLpro inhibitors. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

Purpose: Verbal fluency tasks assess the ability to quickly and efficiently retrieve words from the mental lexicon by requiring subjects to rapidly generate words within a phonological or semantic category. This study investigated differences between cochlear implant users and normal-hearing peers in the clustering and time course of word retrieval during phonological and semantic verbal fluency tasks. Method: Twenty-eight children and adolescents (aged 9--17 years) with cochlear implants and 33 normal-hearing peers completed measures of verbal fluency, nonverbal intelligence, speech perception, and verbal short-term/working memory. Phonological and semantic verbal fluency tests were scored for total words generated, words generated in each 10-s interval of the 1-min task, latency to first word generated, number of word clusters, average cluster size, and number of word/cluster switches. Results: Children and adolescents with cochlear implants generated fewer words than normal-hearing peers throughout the entire 60-s time interval of the phonological and semantic fluency tasks. Cochlear implant users also had slower start latency times and produced fewer clusters and switches than normal-hearing peers during the phonological fluency task. Speech perception and verbal working memory scores were more strongly associated with verbal fluency scores in children and adolescents with cochlear implants than in normal-hearing peers. Conclusions: Cochlear implant users show poorer phonological and semantic verbal fluency than normal-hearing peers, and their verbal fluency is significantly associated with speech perception and verbal working memory. These findings suggest deficits in fluent retrieval of phonological and semantic information from long-term lexical memory in cochlear implant users.

Abstract Objective Commonly used terms like “obese person” have been identified as stigmatizing by those with lived experience. Thus, this study sought to revise a commonly used measure of weight stigmatizing attitudes, the Attitudes Toward Obese Persons (ATOP) scale. Methods The original terminology in the 20‐item ATOP (e.g., “obese”) was compared to a modified version using neutral terms (e.g., “higher weight”). Participants (N = 832) were randomized to either receive the original or modified ATOP. Results There was a statistically significant difference, with a small effect size (d = −0.22), between the scores of participants who received the original ATOP (M = 69.25) and the modified ATOP (M = 72.85), t(414) = −2.27, p = 0.024. Through principal component analysis, the modified ATOP was best used as a brief, 8‐item unidimensional measure. In a second sample, confirmatory factor analysis verified the fit of the brief, 8‐item factor structure. Conclusions Findings suggest that a modified, brief version of the ATOP (ATOP‐Heigher Weight; ATOP‐HW) with neutral language is suitable for assessing negative attitudes about higher‐weight people. The ATOP‐HW may slightly underestimate weight stigma compared to the original ATOP, or the language in the ATOP may magnify negative attitudes. Further examination of the terminology used in weight stigma measures is needed to determine how to best assess weight stigma without reinforcing stigmatizing attitudes. The present study's findings suggest that the use of neutral terms in measures of anti‐fat bias is a promising solution that warrants further investigation.

Abstract Fibroblast growth factor receptor (FGFR)−2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited by a characteristic pattern of adverse events or evocation of kinase domain mutations. A comprehensive characterization of a patient cohort treated with the non-selective TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In a bed-to-bench approach, we investigate FGFR2 fusion proteins bearing critical tumor-relevant point mutations. These mutations confer growth advantage of tumor cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvatinib. In line with clinical observations, in-silico analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy, compared to FGFR-selective TKIs. Finally, the treatment of a patient with progressive disease and a newly developed kinase mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clinical data suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmountable adverse reactions of selective TKIs or acquired kinase mutations occur.

Abstract The need for widespread occurrence data to inform species conservation has prompted interest in large, national‐scale environmental DNA (eDNA) monitoring strategies. However, targeted eDNA assays are seldom validated for use across broad geographic areas. Here, we validated 46 new and previously published probe‐based qPCR assays targeting invasive species throughout the continental United States. We drew upon current taxonomies, range maps, publicly available sequences, and tissue archives to evaluate all potentially sympatric confamilial species and genetically similar extrafamilial taxa. Out of 5276 unique assay‐nontarget taxon combinations, we were able to test 4206 (80%). We characterized levels of validation and specificity for each of eight federal geographic regions and provided an online tool with state‐level information, as well as detailed assay descriptions in an appendix. Specificity testing benefited from extensive use of eDNAssay—a machine learning classifier trained to predict qPCR cross‐amplification—which we found to be 96% accurate in 649 unique tests that underwent paired in silico and in vitro testing. Predictions of assay specificity (the true negative rate) were 98–100% accurate, depending on the classification threshold used. This work provides both an immediate resource for invasive species surveillance and demonstrates an enhanced in silico, geographically subdivided validation framework to aid in future large‐scale validation efforts.

Abstract Background Norm-based scores used to assess cognitive ability have clinical value when describing functioning of patients with neuronopathic disorders compared with unaffected, same-age peers. However, they have limitations when used to assess change in cognitive ability between two timepoints, especially in children with severe cognitive decline. Calculation of Projected Retained Ability Scores (PRAS) is a novel method developed to characterize absolute change in norm-based ability test scores. In this analysis, PRAS were calculated post hoc for children with mucopolysaccharidosis II (MPS II; Hunter syndrome) and early cognitive impairment in a 52-week phase 2/3 randomized controlled trial (RCT) and its extension study of intrathecal idursulfase (idursulfase-IT). Patients completing the first year of the extension after receiving idursulfase-IT in the RCT and extension (n = 32 of 34 enrolled) or the extension only (n = 15 of 15 enrolled) were categorized according to changes in Differential Ability Scales, Second Edition, General Conceptual Ability (DAS-II GCA) scores and PRAS at 1 and 2 years. Analyses were conducted in the overall population and a subpopulation aged

Abstract We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a–d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.

A current clinical challenge in cancer is multidrug resistance (MDR) mediated by ABC transporters. Breast cancer resistance protein (BCRP) or ABCG2 transporter is one of the most important ABC transporters implicated in MDR and the use of inhibitors is a promising approach to overcome the resistance in cancer. This study aimed to characterize the molecular mechanism of ABCG2 inhibitors identified by a repurposing drug strategy using antiviral, anti-inflammatory and antiparasitic agents. Lopinavir and ivermectin can be considered as pan-inhibitors of ABC transporters, since both compounds inhibited ABCG2, P-glycoprotein and MRP1. They inhibited ABCG2 activity showing IC50 values of 25.5 and 23.4 µM, respectively. These drugs were highly cytotoxic and not transported by ABCG2. Additionally, these drugs increased the 5D3 antibody binding and did not affect the mRNA and protein expression levels. Cell-based analysis of the type of inhibition suggested a non-competitive inhibition, which was further corroborated by in silico approaches of molecular docking and molecular dynamics simulations. These results showed an overlap of the lopinavir and ivermectin binding sites on ABCG2, mainly interacting with E446 residue. However, the substrate mitoxantrone occupies a different site, binding to the F436 region, closer to the L554/L555 plug. In conclusion, these results revealed the mechanistic basis of lopinavir and ivermectin interaction with ABCG2.

A proposed treatment for malaria is a combination of fosmidomycin and clindamycin. Both compounds inhibit the methylerythritol 4-phosphate (MEP) pathway, the parasitic source of farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively). Both FPP and GGPP are crucial for the biosynthesis of several essential metabolites such as ubiquinone and dolichol, as well as for protein prenylation. Dietary prenols, such as farnesol (FOH) and geranylgeraniol (GGOH), can rescue parasites from MEP inhibitors, suggesting the existence of a missing pathway for prenol salvage via phosphorylation. In this study, we identified a gene in the genome of P. falciparum, encoding a transmembrane prenol kinase (PolK) involved in the salvage of FOH and GGOH. The enzyme was expressed in Saccharomyces cerevisiae, and its FOH/GGOH kinase activities were experimentally validated. Furthermore, conditional knockout parasites (Δ-PolK) were created to investigate the biological importance of the FOH/GGOH salvage pathway. Δ-PolK parasites were viable but displayed increased susceptibility to fosmidomycin. Their sensitivity to MEP inhibitors could not be rescued by adding prenols. Additionally, Δ-PolK parasites lost their capability to utilize prenols for protein prenylation. Experiments using culture medium supplemented with whole/delipidated human plasma in transgenic parasites revealed that human plasma has components that can diminish the effectiveness of fosmidomycin. Mass spectrometry tests indicated that both bovine supplements used in culture and human plasma contain GGOH. These findings suggest that the FOH/GGOH salvage pathway might offer an alternate source of isoprenoids for malaria parasites when de novo biosynthesis is inhibited. This study also identifies a novel kind of enzyme related to isoprenoid metabolism.

Abstract Nutria (Myocastor coypus) is a semiaquatic rodent species that is invasive across multiple regions within the United States. Here, we evaluated a qPCR assay previously described for use in Japan for application across invasive populations in the United States. We also compared two environmental DNA sampling methodologies for this assay: field filtration of large volumes of water passed through filters versus direct sampling of small volumes of water. We validated assay specificity, generality, and sensitivity, compared assay performance between two independent laboratories, and successfully tested the assay in situ on a known wild population. The filtration method required fewer samples for environmental DNA detection than direct sampling, but the choice of methods should be assessed based on specific field conditions and time and budget considerations. Our extensive assay validation and comparison across laboratories suggest that the assay is ready to be applied in environmental DNA monitoring of nutria throughout the United States.

Abstract Background Stiff left atrial syndrome (SLAS) and pulmonary vein (PV) occlusion are rare yet potentially major life-long complications after radiofrequency ablation for atrial fibrillation. While mostly controlled by medical management, SLAS can progress to refractory congestive heart failure. Treatment of PV stenosis and occlusion remains a challenging problem with ongoing risk for recurrence regardless of techniques employed. Herein we present the case of a now 51-year-old male with acquired PV occlusion and SLAS who, over the course of eleven years, despite multiple interventions, ultimately required heart transplantation. Case presentation After undergoing three radiofrequency catheter procedures for paroxysmal atrial fibrillation (AF), a hybrid ablation was planned due to reappearance of symptomatic AF. Preoperative echocardiography and chest computed tomography (CT) revealed an occlusion of both left PVs. Furthermore, left atrial dysfunction, high pulmonary artery and pulmonary wedge pressures were diagnosed as well as an important reduction of the left atrial volume. The diagnosis of stiff left atrial syndrome was made. Primary surgical repair of the left-sided PVs was performed using a pericardial patch as a tubular neo-vein, combined with cryoablation in the left and right atrium to treat the patient’s arrhythmia. Initial results were favorable, however, after two years the patient experienced progressive restenosis with hemoptysis. Therefore, stenting of the common left PV was performed. Over the years, progressive right heart failure with severe tricuspid regurgitation developed, despite maximal medical therapy, which led to the need for heart transplantation. Conclusion The impact of PV occlusion and SLAS after percutaneous radiofrequency ablation can be lifelong and devastating for the clinical course of the patient. Since the presence of a small left atrium could be an important predictor for SLAS in case of redo ablation, preprocedural imaging should guide the operator to an algorithm of a decision-making containing lesion set, energy source, and safety of re-ablation.

Abstract Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. The disease has an acute and a chronic phase in which approximately 30% of the chronic patients suffer from heart disease and/or gastrointestinal symptoms. The pathogenesis of the disease is multifactorial and involves the virulence of the strains, immunological factors and extracellular vesicles (EV) shed by the parasite which participate in cell–cell communication and evasion of the immune response. In this work, we present a transcriptomic analysis of cells stimulated with EV of the trypomastigote stage of T. cruzi. Results after EV-cell incubation revealed 322 differentially expressed genes (168 were upregulated and 154 were downregulated). In this regard, the overexpression of genes related to ubiquitin-related processes (Ube2C, SUMO1 and SUMO2) is highlighted. Moreover, the expression of Rho-GTPases (RhoA, Rac1 and Cdc42) after the interaction was analyzed, revealing a downregulation of the analyzed genes after 4 h of interaction. Finally, a protective role of EV over apoptosis is suggested, as relative values of cells in early and late apoptosis were significantly lower in EV-treated cells, which also showed increased CSNK1G1 expression. These results contribute to a better understanding of the EV-cell interaction and support the role of EV as virulence factors.

Abstract Firms use job promotions to incentivize hard work from low-level employees and to sort employees according to their skills. Since these two functions are often in conflict, a firm’s promotion strategy tries to balance them. Our model extends prior research by identifying job similarity between current and future job as a driver of a firm’s promotion strategy. When compensation costs are high or external hiring options poor, then higher job similarity leads to fewer internal promotions. Otherwise, higher job similarity can lead to more internal promotions. These results help to explain why firms with different structures or from different industries apply different promotion strategies.

Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections.

Purpose: The aim of this study was to evaluate whether families of children with sensorineural hearing loss (SNHL) are organized similarly to those of typically developing, typically hearing (TH) children and whether the dimensions of family dynamics and environment are related to spoken language development similarly in children with and without SNHL. Method: Primary caregivers of children with SNHL (n = 63) or TH (n = 65) completed the Family Environment Scale--Fourth Edition (FES-4) to assess multiple dimensions of family environment. Children's receptive vocabulary was assessed with the Peabody Picture Vocabulary Test--Fourth Edition, and their receptive language was assessed by an age-appropriate version of the Concepts and Following Directions subtest of the Clinical Evaluation of Language Fundamentals and the Sentence Comprehension subscale of the Comprehensive Assessment of Spoken Language--Second Edition. Principal component analysis was used to examine the dimensional structure of the family environment. Results: Three higher order components were derived from FES-4 subscales for both families of children with SNHL and with TH: Supportive, Controlling, and Conflicted. However, the composition of the factors themselves differed between the two groups. For the TH group, most family environment measures on the FES-4 were not associated with language outcomes. In contrast, for children with SNHL, families who were more supportive, less controlling, and less conflicted had children with better language skills. Conclusions: Three well-accepted dimensions of family dynamics and functioning apply to families of children with SNHL, but their composition differs from those of families with TH children. Family environmental dynamics were much more strongly associated with language outcomes in children with SNHL than in their TH peers. The spoken language development of children with SNHL, in particular, is better in families that provide high levels of support for each other and, in particular, low levels of control, disorganization, and conflict, reflecting the fragile nature of their spoken language development.

To date, studies assessing the safety profile of 3D printing materials for application in cardiac ablation are sparse. Our aim is to evaluate the safety and feasibility of two biocompatible 3D printing materials, investigating their potential use for intra-procedural guides to navigate surgical cardiac arrhythmia ablation. Herein, we 3D printed various prototypes in varying thicknesses (0.8 mm–3 mm) using a resin (MED625FLX) and a thermoplastic polyurethane elastomer (TPU95A). Geometrical testing was performed to assess the material properties pre- and post-sterilization. Furthermore, we investigated the thermal propagation behavior beneath the 3D printing materials during cryo-energy and radiofrequency ablation using an in vitro wet-lab setup. Moreover, electron microscopy and Raman spectroscopy were performed on biological tissue that had been exposed to the 3D printing materials to assess microparticle release. Post-sterilization assessments revealed that MED625FLX at thicknesses of 1 mm, 2.5 mm, and 3 mm, along with TPU95A at 1 mm and 2.5 mm, maintained geometrical integrity. Thermal analysis revealed that material type, energy source, and their factorial combination with distance from the energy source significantly influenced the temperatures beneath the 3D-printed material. Electron microscopy revealed traces of nitrogen and sulfur underneath the MED625FLX prints (1 mm, 2.5 mm) after cryo-ablation exposure. The other samples were uncontaminated. While Raman spectroscopy did not detect material release, further research is warranted to better understand these findings for application in clinical settings.

The neuroblastoma cell lines SH-SY5Y and Neuro2A are commonly utilized models in neurobiological research. DMEM supplemented with different nutrients and 5–10% Fetal Calf Serum (FCS) is typically used for culturing these cell lines. During special treatments, a reduced FCS content is often deployed to reduce cellular proliferation or the content of bioactive compounds. The impact of the reduction of FCS in culture media on the metabolic profile of SH-SY5Y and Neuro2A cells is currently unknown. Using an Amplex Red Assay, this study showed that the consumption of L-glutamine decreased after FCS reduction. Glucose and pyruvate consumption increased in both cell lines after the reduction of FCS. Thus, lactate production also increased with reduced FCS concentration. The reduction of FCS in the cell culture medium resulted in a reduced aerobic ATP production for SH-SY5Y cells and a complete shut down of aerobic ATP production for Neuro2A cells, measured using the Seahorse XF Real-Time ATP Rate Assay. Utilizing the Seahorse XF Glutamine Oxidation Stress Test, Neuro2A cells showed an increased utilization of L-glutamine oxidation after reduction of FCS. These results indicate that changes in FCS concentration in culture media have an impact on the different energy production strategies of SH-SY5Y and Neuro2A cells which must be considered when planning special treatments.

Purpose: Verbal working memory (VWM) delays are commonly found in prelingually deaf youth with cochlear implants (CIs), albeit with considerable interindividual variability. However, little is known about the neurocognitive information-processing mechanisms underlying these delays and how these mechanisms relate to spoken language outcomes. The goal of this study was to use error analysis of the letter-number sequencing (LNS) task to test the hypothesis that VWM delays in CI users are due, in part, to fragile, underspecified phonological representations in short-term memory. Method: Fifty-one CI users aged 7-22 years and 53 normal hearing (NH) peers completed a battery of speech, language, and neurocognitive tests. LNS raw scores and error profiles were compared between samples, and a hierarchical regression model was used to test for associations with measures of speech, language, and hearing. Results: Youth with CIs scored lower on the LNS test than NH peers and committed a significantly higher number of errors involving phonological confusions (recalling an incorrect letter/digit in place of a phonologically similar one). More phonological errors were associated with poorer performance on measures of nonword repetition and following spoken directions but not with hearing quality. Conclusions: Study findings support the hypothesis that poorer VWM in deaf children with CIs is due, in part, to fragile, underspecified phonological representations in short-term/working memory, which underlie spoken language delays. Programs aimed at strengthening phonological representations may improve VWM and spoken language outcomes in CI users.

IntroductionThis clinical trial aimed to determine the influence of attention-deficit/hyperactivity disorder (ADHD) on neuro-ophthalmologic function and brain-derived blood biomarkers following acute subconcussive head impacts.MethodsThe present trial consisted of age- and sex-matched samples with a ratio of 1:1 between two groups with a total sample size of 60 adults (age ± SD; 20.0 ± 1.8 years). Soccer players diagnosed with and medicated daily for ADHD were assigned into an ADHD group (n = 30). Soccer players without ADHD were assigned into a non-ADHD group (n = 30). Participants performed 10 soccer headers with a soccer ball projected at a velocity of 25mph. King-Devick test (KDT), near point of convergence (NPC), and serum levels of NF-L, tau, GFAP, and UCH-L1 were assessed at baseline (pre-heading) and at 2 h and 24 h post-heading.ResultsThere were no statistically significant group-by-time interactions in outcome measures. However, at baseline, the ADHD group exhibited lower neuro-ophthalmologic functions compared to the non-ADHD group (NPC: p = 0.019; KDT: p = 0.018), and persisted at 2 h-post (NPC: p = 0.007; KDT: p = 0.014) and 24 h-post heading (NPC: p = 0.001). NPC significantly worsened over time in both groups compared to baseline [ADHD: 2 h-post, 1.23 cm, 95%CI:(0.77, 1.69), p

The original article was published in Veterinary Evidence Vol 8, Issue 1 (2023): https://doi.org/10.18849/ve.v8i1.598 To aid interpretation, certain statements in the Knowledge Summary have been clarified. Refer to the full text and PDF for these amendments and corrections.

Macrophages reprogram their lipid metabolism in response to activation signals. However, a systems-level understanding of how different pro-inflammatory stimuli reshape the macrophage lipidome is lacking. Here, we use complementary "shotgun" and isotope tracer mass spectrometry approaches to define the changes in lipid biosynthesis, import, and composition of macrophages induced by various Toll-like receptors (TLRs) and inflammatory cytokines. "Shotgun" lipidomics data revealed that different TLRs and cytokines induce macrophages to acquire distinct lipidomes, indicating their specificity in reshaping lipid composition. Mechanistic studies showed that differential reprogramming of lipid composition is mediated by the opposing effects of MyD88- and TRIF-interferon-signaling pathways. Finally, we applied these insights to show that perturbing reprogramming of lipid composition can enhance inflammation and promote host defense to bacterial challenge. These studies provide a framework for understanding how inflammatory stimuli reprogram lipid composition of macrophages while providing a knowledge platform to exploit differential lipidomics to influence immunity.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Isaac A Janson,1 Ellen M Bloom,1 Kisha C Hampton,1 Emily Riehm Meier,1 Angeli G Rampersad,1 William G Kronenberger2 1Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; 2Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USACorrespondence: Isaac A Janson, Indiana Hemophilia and Thrombosis Center, 8326 Naab Road, Indianapolis, IN, 46260, USA, Tel +1-317-871-0011, Fax +1-317-871-0010, Email ijanson@ihtc.orgIntroduction: Hydroxyurea reduces the incidence of vaso-occlusive episodes, stroke, and respiratory, cardiac, and renal damage in sickle cell disease by increasing fetal hemoglobin. However, because suboptimal adherence to hydroxyurea limits its effectiveness, understanding patient-specific barriers to hydroxyurea adherence could help improve adherence and health outcomes in patients with sickle cell disease. The aim of this single-site, prospective, IRB-approved study was to validate a 24-item patient- and caregiver-reported hydroxyurea treatment adherence questionnaire, the Hydroxyurea Evaluation of Adherence for Life (HEAL) scale.Methods: A sample of 24 adults with sickle cell disease and 16 caregivers of children with sickle cell disease completed the HEAL scale, and a subset of the original sample provided a second HEAL scale for test-retest reliability. HEAL scale results were validated against global adherence ratings from participants and health-care providers, records of access to pill bottles, and laboratory values for fetal hemoglobin and absolute neutrophil count.Results and Discussion: Results demonstrated excellent internal consistency for the HEAL Total score and eight (3-item) subscale scores (Dose, Remember, Plan, Cost, Understand, Effectiveness, Laboratory, and Pharmacy), as well as strong test-retest reliability for all HEAL scores except the Cost subscale. HEAL Total scores correlated significantly with validity measures, including global adherence ratings and lab values. The HEAL scale offers significant clinical potential for understanding adherence in individual sickle cell disease patients and significant research potential for characterizing adherence in persons with sickle cell disease who are treated with hydroxyurea.Keywords: sickle cell disease, treatment adherence, hydroxyurea, reliability, validity, scale development

Understanding simple electric DC circuits often represents a great challenge to many students in lower secondary schools. As a result, students' knowledge of this subject is often dominated by alternative conceptions, even after instruction. One of the reasons for these learning difficulties is the intangibility of key physical quantities and concepts of electric circuits such as the electric potential or the electric current. A potentially effective way of making circuits more accessible to students in introductory electricity lessons represents the use of analogies or models. However, as a brief review shows, there is no single analogy or model that is ideally suited to foster an understanding of all key aspects of simple DC circuits. In order to address this issue and help learners develop a mental model of circuits, a new analogical simulation of simple electric circuits was developed. The simulation is suited for use in combination with the bike chain and the air pressure analogy and aims to support students' development of a qualitative understanding of potential difference and current in circuits as well as a treatment of circuits as a connected system. Teachers and students can access the 3D simulation free of charge using a modern browser via www.marblemodel.com.

Purpose: The aim of this study was to investigate the role of parental sensitivity in language and neurocognitive outcomes in children who are deaf and/or hard of hearing (DHH). Method: Sixty-two parent-child dyads of children with normal hearing (NH) and 64 of children who are DHH (3-8 years) completed parent and child measures of inhibitory control/executive functioning and child measures of sentence comprehension and vocabulary. The dyads also participated in a video-recorded, free-play interaction that was coded for parental sensitivity. Results: There was no evidence of associations between parental sensitivity and inhibitory control or receptive language in children with NH. In contrast, parental sensitivity was related to children's inhibitory control and all language measures in children who are DHH. Moreover, inhibitory control significantly mediated the association between parental sensitivity and child language on the Clinical Evaluation of Language Fundamentals--Fifth Edition Following Directions subscale (6-8 years)/Clinical Evaluation of Language Fundamentals Preschool--Second Edition Concepts and Following Directions subscale (3-5 years). Follow-up analyses comparing subgroups of children who used hearing aids (n = 29) or cochlear implants (CIs; n = 35) revealed similar correlational trends, with the exception that parental sensitivity showed little relation to inhibitory control in the group of CI users. Conclusions: Parental sensitivity is associated with at-risk language outcomes and disturbances in inhibitory control in young children who are DHH. Compared to children with NH, children who are DHH may be more sensitive to parental behaviors and their effects on emerging inhibitory control and spoken language. Specifically, inhibitory control, when scaffolded by positive parental behaviors, may be critically important for robust language development in children who are DHH.