Hedgehog Signaling Regulates Apical Actin Morphology

poster abstractStereocilia are highly patterned actin based cell protrusions found on the apical surface of auditory hair cells. They are formed mainly from bundled filamentous actin and its associated actin cross-linking proteins. Interestingly, stereocilia develop around another cell appendage, the microtubule based kinocilium, which is the primary cilium for a hair cell. Primary cilia are found on most somatic cells and play a significant role in the regulation and proper transduction of the Hedgehog (Hh) pathway. In the current study, we are testing the hypothesis that Hh pathway activity can alter actin bundling and elongation. In support of this idea, ectopic activation or repression of Hh signaling changed the morphology of stereocilia in vivo. To further test our hypothesis, we used a CL4 porcine kidney epithelial cell culture system stably expressing the actin crosslinking protein ESPN fused to green fluorescent protein. These cells serve as an in vitro model of apical actin protrusions similar to mature stereocilia in vivo. We manipulated Hh signaling in these cells using both a genetic and a pharmacological approach. In the pharmacological approach, CL4 cells were treated with the hedgehog agonist (Purmophamine) and antagonist (Cyclopamine), at varying concentrations for 48 hours. Genetically, the Hh pathway was ectopically activated by overexpressing the transcription factor Gli1, Gli2, Gli3, and SmoA1 repressed by expressing Gli3R. Immunofluorescent (IF) and scanning electron microscopy (SEM) revealed that CL4 cells dramatically altered the apical actin structures under these conditions. In particular, activating Gli transcription decreased apical actin-based structures while antagonizing activity resulted in more actinbased protrusions. This data strongly supports the hypothesis that the Hh signaling pathway can regulate the actin cytoskeleton

Language Contributions to Early Word Reading Success

Title:Identifying kindergarten children at risk for developmental language disorder and dyslexia using a whole-classroom screen. Purpose: The aim of this study was to determineif two whole-classroom screeners of language and literacy skills administered to local kindergarten classrooms can reliably identify children at risk for developmental language disorder (DLD) and dyslexia. Method: Two cohorts of kindergarten children in asingle public-school district (n = 1127) completed two separate 25-minute, whole-classroom screens in the Fall of 2018 and 2019; one targeting grammatical skills (language) and the other targeting phonological and orthographic awareness skills (literacy).A subsample of these children completed an assessment battery of standardized and norm-referenced assessments of nonverbal intelligence, word reading, language, as well as hearing and articulation screenings.Results: The language classroom screen showed acceptable classification accuracy for identifying children at risk forDLD overall(sensitivity = 88% and specificity = 52%). The literacy classroom screen showed acceptable classification accuracy for identifying children at risk for dyslexiaoverall(sensitivity = 81% and specificity = 63%). Conclusion: Whole-classroom screens for language and literacy show potential for efficient identification of children who may benefit from comprehensive assessments for DLD and dyslexia without relying on their parents or teachers to raise concerns.Further, using a whole-classroom screener that can be administered to a large group of children simultaneously under 25 minutes versus current educational practice of a 10-15 minute, individually-administered assessment for each student in a classroom would reduce time and financial burdens on school systems which has important implications for recent U.S. legislation around early identification of dyslexia in all children. Field/subject: Physical/Occupational Therapy & Speech Language Patholog

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians

College student sleep quality and mental and physical health are associated with food insecurity in a multi-campus study

Objective: To assess the relationship between food insecurity, sleep quality, and days with mental and physical health issues among college students. Design: An online survey was administered. Food insecurity was assessed using the ten-item Adult Food Security Survey Module. Sleep was measured using the nineteen-item Pittsburgh Sleep Quality Index (PSQI). Mental health and physical health were measured using three items from the Healthy Days Core Module. Multivariate logistic regression was conducted to assess the relationship between food insecurity, sleep quality, and days with poor mental and physical health. Setting: Twenty-two higher education institutions. Participants: College students (n 17 686) enrolled at one of twenty-two participating universities. Results: Compared with food-secure students, those classified as food insecure (43·4 %) had higher PSQI scores indicating poorer sleep quality (P \u3c 0·0001) and reported more days with poor mental (P \u3c 0·0001) and physical (P \u3c 0·0001) health as well as days when mental and physical health prevented them from completing daily activities (P \u3c 0·0001). Food-insecure students had higher adjusted odds of having poor sleep quality (adjusted OR (AOR): 1·13; 95 % CI 1·12, 1·14), days with poor physical health (AOR: 1·01; 95 % CI 1·01, 1·02), days with poor mental health (AOR: 1·03; 95 % CI 1·02, 1·03) and days when poor mental or physical health prevented them from completing daily activities (AOR: 1·03; 95 % CI 1·02, 1·04). Conclusions: College students report high food insecurity which is associated with poor mental and physical health, and sleep quality. Multi-level policy changes and campus wellness programmes are needed to prevent food insecurity and improve student health-related outcomes

Second-line treatments in children with immune thrombocytopenia: Effect on platelet count and patient-centered outcomes

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding or improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (p=0.04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, p=0.01 and 81% to 43%, p=0.004) and non-skin-related bleeding symptoms (58% to 14%, p=0.0001 and 54% to 17%, p=0.0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.Peer reviewe

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Status for miljøet i norske havområder - Rapport fra Overvåkingsgruppen 2023

I denne rapporten gir Overvåkingsgruppen, for første gang, en felles vurdering av miljøtilstanden i Barentshavet og havområdene utenfor Lofoten, Norskehavet og Nordsjøen med Skagerrak. Det er også første rapport som bruker resultater fra det nylig utviklede fagsystemet for vurdering av økologisk tilstand. I denne rapporten dekkes to hovedtemaer: (1) Dominerende trekk i status og utvikling i økosystemet i alle tre havområdene, basert på vurderingene av økologisk tilstand, Overvåkingsgruppens rapport om forurensning fra 2022, indikatorer fra Overvåkingsgruppen som ikke er dekket under vurdering av økologisk tilstand, samt rapporter og annen relevant informasjon fra forskning, og (2) en vurdering av karbonbinding i marint plankton, marine vegetasjonstyper og marine sedimenter. I tillegg er det gitt en oppsummering for endringer i ytre påvirkning, vurdering av kunnskapsbehov samt en vurdering av indikatorverdier i forhold til referanseverdier og tiltaksgrenser. Vurderingen av dominerende trekk i utvikling og tilstand av miljøet som er gitt i kapittel 2, utgjør Overvåkingsgruppens bidrag til Faglig forums samlerapport om det faglige grunnlaget for revisjon og oppdatering av de helhetlige forvaltningsplanene for norske havområder.Status for miljøet i norske havområder - Rapport fra Overvåkingsgruppen 2023publishedVersio

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Abstract: In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859–1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482–1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene

Distinct attentional function profiles in older adults receiving cancer chemotherapy

PurposeWhile attentional function is an extremely important patient outcome for older adults, research on changes in function in this group is extremely limited. The purposes of this study were to: identify subgroups of older patients (i.e., latent growth classes) based on changes in their level of self-reported attentional function; determine which demographic and clinical characteristics were associated with subgroup membership; and determine if these subgroups differed on quality of life (QOL) outcomes.MethodsOlder oncology outpatients (n = 365) who were assessed for changes in attention and working memory using the Attentional Function Index a total of six times over two cycles of chemotherapy (CTX). QOL was assessed using the Medical Outcomes Study-Short Form 12 and the QOL-Patient Version Scale. Latent profile analysis (LPA) was used to identify subgroups of older adults with distinct attentional function profiles.ResultsThree distinct attentional functional profiles were identified (i.e., low, moderate, and high attentional function). Compared to the high class, older adults in the low and moderate attentional function classes had lower functional status scores, a worse comorbidity profile and were more likely to be diagnosed with depression. In addition, QOL scores followed an expected pattern (low class &lt; moderate class &lt; high attentional function class).ConclusionsThree distinct attentional function profiles were identified among a relatively large sample of older adults undergoing CTX. The phenotypic characteristics associated with membership in the low and moderate latent classes can be used by clinicians to identify high risk patients