248 research outputs found
The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.
No full textCiliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions
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JAGGER localization and function are dependent on GPI anchor addition
No full textKey message: GPI anchor addition is important for JAGGER localization and in vivo function. Loss of correct GPI anchor addition in JAGGER, negatively affects its localization and function. Abstract: In flowering plants, successful double fertilization requires the correct delivery of two sperm cells to the female gametophyte inside the ovule. The delivery of a single pair of sperm cells is achieved by the entrance of a single pollen tube into one female gametophyte. To prevent polyspermy, Arabidopsis ovules avoid the attraction of multiple pollen tubes to one ovule–polytubey block. In Arabidopsis jagger mutants, a significant number of ovules attract more than one pollen tube to an ovule due to an impairment in synergid degeneration. JAGGER encodes a putative arabinogalactan protein which is predicted to be anchored to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Here, we show that JAGGER fused to citrine yellow fluorescent protein (JAGGER-cYFP) is functional and localizes mostly to the periphery of ovule integuments and transmitting tract cells. We further investigated the importance of GPI-anchor addition domains for JAGGER localization and function. Different JAGGER proteins with deletions in predicted ω-site regions and GPI attachment signal domain, expected to compromise the addition of the GPI anchor, led to disruption of JAGGER localization in the cell periphery. All JAGGER proteins with disrupted localization were also not able to rescue the polytubey phenotype, pointing to the importance of GPI-anchor addition to in vivo function of the JAGGER protein. © 2024, The Author(s).Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway.
No full textAlström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS
Serum 25-hydroxyvitamin D and cognitive decline in the very old: The Newcastle 85+ study
No full textBackground and purpose:
Studies investigating the association between 25-hydroxyvitamin D [25(OH)D] and cognition in the very old (85+) are lacking.
Methods:
Cross-sectional (baseline) and prospective data (up to 3 years follow-up) from 775 participants in the Newcastle 85+ Study were analysed for global (measured by the Standardized Mini-Mental State Examination) and attention-specific (measured by the attention battery of the Cognitive Drug Research test) cognitive performance in relation to season-specific 25(OH)D quartiles.
Results:
Those in the lowest and highest season-specific 25(OH)D quartiles had an increased risk of impaired prevalent (1.66, 95% confidence interval 1.06–2.60, P = 0.03; 1.62, 95% confidence interval 1.02–2.59, P = 0.04, respectively) but not incident global cognitive functioning or decline in functioning compared with those in the middle quartiles adjusted for sociodemographic, health and lifestyle confounders. Random effects models showed that participants belonging to the lowest and highest 25(OH)D quartiles, compared with those in the middle quartiles, had overall slower (log-transformed) attention reaction times for Choice Reaction Time (lowest, b = 0.023, P = 0.01; highest, b = 0.021, P = 0.02), Digit Vigilance Task (lowest, b = 0.009, P = 0.05; highest,b = 0.01, P = 0.02) and Power of Attention (lowest, b = 0.017, P = 0.02;highest, b = 0.022, P = 0.002) and greater Reaction Time Variability (lowest,b = 0.021, P = 0.02; highest, b = 0.02, P = 0.03). The increased risk of worse global cognition and attention amongst those in the highest quartile was not observed in non-users of vitamin D supplements/medication.
Conclusion:
Low and high season-specific 25(OH)D quartiles were associated with prevalent cognitive impairment and poorer overall performance in attention-specific tasks over 3 years in the very old, but not with global cognitive decline or incident impairment
Correction: Reproducibility of fluorescent expression from engineered biological constructs in E. coli
No full textThe Acknowledgments contain several errors in the “2014 iGEM Interlab Study Contributors” section. In the “ETH_Zurich” subsection, the correct spelling of “Verena Jagger” is “Verena Jäggin”. In the “HUST-China” subsection, the correct spelling of “Yunjun Yang” is “Yunjun Yan”. In the “Leicester” subsection, the name “Ross Campbell” should be listed after “Richard Badge”. In the “Marburg” subsection, the name “Daniel F. Hurtgen” should be listed after “Matthias Franz”
Correction: Reproducibility of fluorescent expression from engineered biological constructs in E. coli
No full textThe Acknowledgments contain several errors in the “2014 iGEM Interlab Study Contributors” section. In the “ETH_Zurich” subsection, the correct spelling of “Verena Jagger” is “Verena Jäggin”. In the “HUST-China” subsection, the correct spelling of “Yunjun Yang” is “Yunjun Yan”. In the “Leicester” subsection, the name “Ross Campbell” should be listed after “Richard Badge”. In the “Marburg” subsection, the name “Daniel F. Hurtgen” should be listed after “Matthias Franz”
Burnout among public health workers during the COVID-19 response: Results from a follow-up survey
No full textCopyright: © 2024 Scales et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data, codebook, and the survey have been uploaded into the DesignSafe data repository (PRJ-4545). The project is currently being published, and the following citation is being processed by DesignSafe to go live: Scales, S., K. Kintziger, K. Stone, M. Jagger, J. Horney. (2024) "Public Health Workforce COVID-19 Burnout." DesignSafe-CI. https://doi.org/10.17603/ds2-y5jp-ff88 We will update if there are any changes to the project file DOI.The public health workforce began the response to the COVID-19 pandemic with a critical workforce deficit, losing 20% of staff between 2018 and 2019. This study assesses changes in burnout among a cohort of 80 public health workers in the U.S. who completed multiple assessments during the ongoing COVID-19 response via Qualtrics. Self-reported burnout was assessed using a 5-point, validated, non-proprietary single-item measure. A binary burnout variable (1,2 = No; 3,4,5 = Yes) was created based on responses. Burnout direction (e.g., decreased, same, increased) was derived from changes in five-level work-related burnout scores. Factors indicating work-related exhaustion was higher among individuals reporting burnout in the follow-up survey compared to those without burnout. Baseline burnout, hours worked per week, and sleep quality were significant predictors of burnout at follow-up. A higher proportion of respondents reported burnout at follow-up than at the baseline survey. The ubiquitous nature of burnout among public health workers is a threat to the wellbeing of individuals in the workforce and the population’s health at large. Investments in expanding and supporting the public health workforce are needed.Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist
Opportunities and challenges for personal heat exposure research
No full textabstract: Background:
Environmental heat exposure is a public health concern. The impacts of environmental heat on mortality and morbidity at the population scale are well documented, but little is known about specific exposures that individuals experience.
Objectives:
The first objective of this work was to catalyze discussion of the role of personal heat exposure information in research and risk assessment. The second objective was to provide guidance regarding the operationalization of personal heat exposure research methods.
Discussion:
We define personal heat exposure as realized contact between a person and an indoor or outdoor environment that poses a risk of increases in body core temperature and/or perceived discomfort. Personal heat exposure can be measured directly with wearable monitors or estimated indirectly through the combination of time–activity and meteorological data sets. Complementary information to understand individual-scale drivers of behavior, susceptibility, and health and comfort outcomes can be collected from additional monitors, surveys, interviews, ethnographic approaches, and additional social and health data sets. Personal exposure research can help reveal the extent of exposure misclassification that occurs when individual exposure to heat is estimated using ambient temperature measured at fixed sites and can provide insights for epidemiological risk assessment concerning extreme heat.
Conclusions:
Personal heat exposure research provides more valid and precise insights into how often people encounter heat conditions and when, where, to whom, and why these encounters occur. Published literature on personal heat exposure is limited to date, but existing studies point to opportunities to inform public health practice regarding extreme heat, particularly where fine-scale precision is needed to reduce health consequences of heat exposure.Corresponding Author:
David Hondula
Arizona State University
[email protected]
Inflammatory markers and incident frailty in men and women:the English Longitudinal Study of Ageing
No full textCross-sectional studies show that higher blood concentrations of inflammatory markers tend to be more common in frail older people, but longitudinal evidence that these inflammatory markers are risk factors for frailty is sparse and inconsistent. We investigated the prospective relation between baseline concentrations of the inflammatory markers C-reactive protein (CRP) and fibrinogen and risk of incident frailty in 2,146 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. The relationship between CRP and fibrinogen and risk of incident frailty differed significantly by sex (p for interaction term
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