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  1. Article ; Online: Emerging mechanistic understanding of cilia function in cellular signalling.

    Hilgendorf, Keren I / Myers, Benjamin R / Reiter, Jeremy F

    Nature reviews. Molecular cell biology

    2024  

    Abstract: Primary cilia are solitary, immotile sensory organelles present on most cells in the body that participate broadly in human health, physiology and disease. Cilia generate a unique environment for signal transduction with tight control of protein, lipid ... ...

    Abstract Primary cilia are solitary, immotile sensory organelles present on most cells in the body that participate broadly in human health, physiology and disease. Cilia generate a unique environment for signal transduction with tight control of protein, lipid and second messenger concentrations within a relatively small compartment, enabling reception, transmission and integration of biological information. In this Review, we discuss how cilia function as signalling hubs in cell-cell communication using three signalling pathways as examples: ciliary G-protein-coupled receptors (GPCRs), the Hedgehog (Hh) pathway and polycystin ion channels. We review how defects in these ciliary signalling pathways lead to a heterogeneous group of conditions known as 'ciliopathies', including metabolic syndromes, birth defects and polycystic kidney disease. Emerging understanding of these pathways' transduction mechanisms reveals common themes between these cilia-based signalling pathways that may apply to other pathways as well. These mechanistic insights reveal how cilia orchestrate normal and pathophysiological signalling outputs broadly throughout human biology.
    Language English
    Publishing date 2024-02-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-023-00698-5
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  2. Article ; Online: Studies of SMOOTHENED Activation in Cell-Free and Reconstituted Systems.

    Nelson, Isaac B / Myers, Benjamin R

    Methods in molecular biology (Clifton, N.J.)

    2021  Volume 2374, Page(s) 161–174

    Abstract: Much of our current understanding of Hedgehog signal transduction derives from studies involving intact cells and organisms. Here we describe the use of cell-free and reconstituted systems to study a key step in Hedgehog signal transduction: the ... ...

    Abstract Much of our current understanding of Hedgehog signal transduction derives from studies involving intact cells and organisms. Here we describe the use of cell-free and reconstituted systems to study a key step in Hedgehog signal transduction: the activation of SMOOTHENED by membrane lipids. These methods can be adapted to study other steps in Hedgehog signal transduction, particularly those that occur at the membrane.
    MeSH term(s) Cell-Free System ; Hedgehog Proteins ; Receptors, Cell Surface/metabolism ; Receptors, G-Protein-Coupled ; Signal Transduction ; Smoothened Receptor
    Chemical Substances Hedgehog Proteins ; Receptors, Cell Surface ; Receptors, G-Protein-Coupled ; Smoothened Receptor
    Language English
    Publishing date 2021-09-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1701-4_14
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  3. Article ; Online: Rapid, Direct SMOOTHENED Activity Assays in Live Cells Using cAMP-Based Conformational Sensors.

    Walker, Madison F / Myers, Benjamin R

    Methods in molecular biology (Clifton, N.J.)

    2021  Volume 2374, Page(s) 175–184

    Abstract: Communication between PATCHED1 (PTCH1) and SMOOTHENED (SMO) is fundamental to Hedgehog (Hh) signal transduction in development and disease. We describe a real-time cell-based SMO functional assay based on SMO activity-dependent changes in cellular cAMP ... ...

    Abstract Communication between PATCHED1 (PTCH1) and SMOOTHENED (SMO) is fundamental to Hedgehog (Hh) signal transduction in development and disease. We describe a real-time cell-based SMO functional assay based on SMO activity-dependent changes in cellular cAMP concentrations. This assay is capable of detecting changes in SMO conformation within minutes of PTCH1 inactivation by Hh ligands. As a result, it expands the range of experimental perturbations that can be used to dissect PTCH1-SMO communication, enabling a deeper mechanistic understanding of a longstanding mystery in Hh signal transduction.
    MeSH term(s) Cyclic AMP ; Hedgehog Proteins ; Ligands ; Receptors, G-Protein-Coupled ; Signal Transduction ; Smoothened Receptor/metabolism
    Chemical Substances Hedgehog Proteins ; Ligands ; Receptors, G-Protein-Coupled ; Smoothened Receptor ; Cyclic AMP (E0399OZS9N)
    Language English
    Publishing date 2021-09-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1701-4_15
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  4. Article: A Simple and Scalable Zebrafish Model of Sonic Hedgehog Medulloblastoma.

    Casey, Mattie J / Chan, Priya P / Li, Qing / Jette, Cicely A / Kohler, Missia / Myers, Benjamin R / Stewart, Rodney A

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ~30% of all MB cases and has significant survival disparity depending upon TP53 status. ... ...

    Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ~30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe the first zebrafish model of SHH MB using CRISPR to mutate
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.03.577834
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  5. Article ; Online: Recurrent activity in neuronal avalanches.

    Salners, Tyler / Avila, Karina E / Nicholson, Benjamin / Myers, Christopher R / Beggs, John / Dahmen, Karin A

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 4871

    Abstract: A new statistical analysis of large neuronal avalanches observed in mouse and rat brain tissues reveals a substantial degree of recurrent activity and cyclic patterns of activation not seen in smaller avalanches. To explain these observations, we adapted ...

    Abstract A new statistical analysis of large neuronal avalanches observed in mouse and rat brain tissues reveals a substantial degree of recurrent activity and cyclic patterns of activation not seen in smaller avalanches. To explain these observations, we adapted a model of structural weakening in materials. In this model, dynamical weakening of neuron firing thresholds closely replicates experimental avalanche size distributions, firing number distributions, and patterns of cyclic activity. This agreement between model and data suggests that a mechanism like dynamical weakening plays a key role in recurrent activity found in large neuronal avalanches. We expect these results to illuminate the causes and dynamics of large avalanches, like those seen in seizures.
    MeSH term(s) Rats ; Mice ; Animals ; Action Potentials/physiology ; Models, Neurological ; Nerve Net/physiology ; Neurons/physiology ; Avalanches
    Language English
    Publishing date 2023-03-24
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-31851-x
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  6. Article ; Online: The trauma pelvic X-ray: Not all pelvic fractures are created equally.

    Benjamin, Elizabeth R / Jakob, Dominik A / Myers, Lee / Liasidis, Panagiotis / Lewis, Meghan / Fu, Yong / Demetriades, Demetrios

    American journal of surgery

    2022  Volume 224, Issue 1 Pt B, Page(s) 489–493

    Abstract: Background: The primary aim of this study was to evaluate the role of the initial pelvic X-ray in identifying significant pelvic fractures, which could result in changes in the management of the patient.: Methods: Patients admitted to a level I ... ...

    Abstract Background: The primary aim of this study was to evaluate the role of the initial pelvic X-ray in identifying significant pelvic fractures, which could result in changes in the management of the patient.
    Methods: Patients admitted to a level I trauma center (2010-2019) with a severe blunt pelvic fracture (AIS ≥3) were identified. Included in the analysis were patients who underwent emergency department pelvic X-ray followed by CT scan. A control group of patients without pelvic fractures was also included in the study. All investigations were reviewed by a blinded attending trauma radiologist. Pelvic X-ray findings and CT scan reports were compared according to the specific pelvic fracture location, and severity.
    Results: Overall, pelvic X-ray was diagnosed 252 of the 285 pelvic fractures (sensitivity 88.4%) and wrongly diagnosed a facture in 3 of 97 patients without a fracture (specificity 96.9%). In 29/184 (15.8%) of patients with pelvic fracture AIS 3, the pelvic X-ray was read as normal, missing the fracture, compared with 4/101 (4.0%) in the AIS 4/5 group (p = 0.003). Pelvic X-ray had the lowest sensitivity in ischial (10.7%), iliac (28.7%), acetabular (42.4%), and sacral fractures (49.1%) and was best for detecting symphysis diastasis (89.8%).
    Conclusion: Pelvic X-ray is useful in identifying pubic symphysis diastasis. However, it misses or underestimates a significant number of fractures. CT scan evaluation should be performed in patients with a suspicious mechanism or clinical suspicion of pelvic fracture.
    MeSH term(s) Fractures, Bone/diagnostic imaging ; Humans ; Pelvic Bones/diagnostic imaging ; Pelvic Bones/injuries ; Radiography ; Retrospective Studies ; Spinal Fractures/diagnostic imaging ; X-Rays
    Language English
    Publishing date 2022-01-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2953-1
    ISSN 1879-1883 ; 0002-9610
    ISSN (online) 1879-1883
    ISSN 0002-9610
    DOI 10.1016/j.amjsurg.2022.01.009
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  7. Article ; Online: Geographic variation in the rate and route of hysterectomy for benign disease in the USA: A retrospective cross-sectional study.

    Albright, Benjamin B / Heyward, Quetrell D / Erkanli, Alaattin / Loehrer, Andrew P / Myers, Evan R / Havrilesky, Laura J / Moss, Haley A

    BJOG : an international journal of obstetrics and gynaecology

    2023  Volume 130, Issue 12, Page(s) 1502–1510

    Abstract: Objectives: To describe population rate of hysterectomy for benign disease in the USA, including geographic variation across states and Hospital Service Areas (HSAs; areas defined by common patient flows to healthcare facilities).: Design: Cross- ... ...

    Abstract Objectives: To describe population rate of hysterectomy for benign disease in the USA, including geographic variation across states and Hospital Service Areas (HSAs; areas defined by common patient flows to healthcare facilities).
    Design: Cross-sectional study.
    Setting: Four US states including 322 HSAs.
    Population: A total of 316 052 cases of hysterectomy from 2012 to 2016.
    Methods: We compiled annual hysterectomy cases, merged female populations, and adjusted for reported rates of previous hysterectomy. We assessed small-area variation and created multi-level Poisson regression models.
    Main outcome measures: Prior-hysterectomy-adjusted population rates of hysterectomy for benign disease.
    Results: The annual population rate of hysterectomy for benign disease was 49 per 10 000 hysterectomy-eligible residents, declining slightly over time, mostly among reproductive-age populations. Rates peaked among residents ages 40-49 years, and declined with increasing age, apart from an increase with universal coverage at age 65 years. We found large differences in age-standardised population rates of hysterectomy across states (range 42.2-69.0), and HSAs (range: overall 12.9-106.3; 25th-75th percentile 44.0-64.9). Among the non-elderly population, those with government-sponsored insurance had greater variation than those with private insurance (coefficient of variation 0.61 versus 0.32). Proportions of minimally invasive procedures were similar across states (71.0-74.8%) but varied greatly across HSAs (27-96%). In regression models, HSA population characteristics explained 31.8% of observed variation in annual rates. Higher local proportions of government-sponsored insurance and non-White race were associated with lower population rates.
    Conclusions: We found substantial variation in rate and route of hysterectomy for benign disease in the USA. Local population characteristics explained less than one-third of observed variation.
    MeSH term(s) Female ; Humans ; United States/epidemiology ; Middle Aged ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; Hysterectomy/methods
    Language English
    Publishing date 2023-05-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2000931-8
    ISSN 1471-0528 ; 0306-5456 ; 1470-0328
    ISSN (online) 1471-0528
    ISSN 0306-5456 ; 1470-0328
    DOI 10.1111/1471-0528.17509
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  8. Article ; Online: Demographics and Early Outcomes of Commercial Antibiotic Cement Usage for Infection Prophylaxis During Primary Total Knee Arthroplasty in Patients Older Than 65 Years: An American Joint Replacement Registry Study.

    Ricciardi, Benjamin F / Porter, Kimberly R / Myers, Thomas G / Ginnetti, John G / Kaplan, Nathan / Thirukumaran, Caroline P

    The Journal of the American Academy of Orthopaedic Surgeons

    2023  Volume 32, Issue 2, Page(s) 59–67

    Abstract: Introduction: The use of antibiotic-laden bone cement (ALBC) for infection prophylaxis in the setting of primary total knee arthroplasty (TKA) remains controversial. Using data from the American Joint Replacement Registry (AJRR), (1) we examined the ... ...

    Abstract Introduction: The use of antibiotic-laden bone cement (ALBC) for infection prophylaxis in the setting of primary total knee arthroplasty (TKA) remains controversial. Using data from the American Joint Replacement Registry (AJRR), (1) we examined the demographics of ALBC usage in the United States and (2) identified the effect of prophylactic commercially available ALBC on early revision and readmission for prosthetic joint infection (PJI) after primary TKA.
    Methods: This is a retrospective cohort study of the AJRR from 2017 to 2020. Patients older than 65 years undergoing primary cemented TKA with or without the use of commercially available antibiotic cement were eligible for inclusion (N = 251,506 patients). Data were linked to available Medicare claims to maximize revision outcomes. Demographics including age, sex, race/ethnicity, Charlson Comorbidity Index (CCI), preoperative inflammatory arthritis, region, and body mass index (BMI) class were recorded. Cox proportional hazards regression analysis was used to evaluate the association between the two outcome measures and ALBC usage.
    Results: Patients undergoing cemented TKA with ALBC were more likely to be Non-Hispanic Black ( P < 0.001), have a CCI of 2 or 3 ( P < 0.001), reside in the South ( P < 0.001), and had a higher mean BMI ( P < 0.001). In the regression models, ALBC usage was associated with increased risk of 90-day revision for PJI (hazards ratio 2.175 [95% confidence interval] 1.698 to 2.787) ( P < 0.001) and was not associated with 90-day all-cause readmissions. Male sex, higher CCI, and BMI >35 were all independently associated with 90-day revision for PJI.
    Discussion: The use of commercial ALBC in patients older than 65 years for primary TKA in the AJRR was not closely associated with underlying comorbidities suggesting that hospital-level and surgeon-level factors influence its use. In addition, ALBC use did not decrease the risk of 90-day revision for PJI and was not associated with 90-day readmission rates.
    MeSH term(s) Humans ; Male ; Aged ; United States ; Anti-Bacterial Agents/therapeutic use ; Arthroplasty, Replacement, Knee/adverse effects ; Retrospective Studies ; Bone Cements/therapeutic use ; Prosthesis-Related Infections/epidemiology ; Prosthesis-Related Infections/prevention & control ; Prosthesis-Related Infections/drug therapy ; Medicare ; Arthritis, Infectious/etiology ; Registries ; Demography ; Reoperation/adverse effects
    Chemical Substances Anti-Bacterial Agents ; Bone Cements
    Language English
    Publishing date 2023-09-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1200524-1
    ISSN 1940-5480 ; 1067-151X
    ISSN (online) 1940-5480
    ISSN 1067-151X
    DOI 10.5435/JAAOS-D-23-00434
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    Zs.MO 274: Show issues

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  9. Article ; Online: Recurrent activity in neuronal avalanches

    Tyler Salners / Karina E. Avila / Benjamin Nicholson / Christopher R. Myers / John Beggs / Karin A. Dahmen

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 10

    Abstract: Abstract A new statistical analysis of large neuronal avalanches observed in mouse and rat brain tissues reveals a substantial degree of recurrent activity and cyclic patterns of activation not seen in smaller avalanches. To explain these observations, ... ...

    Abstract Abstract A new statistical analysis of large neuronal avalanches observed in mouse and rat brain tissues reveals a substantial degree of recurrent activity and cyclic patterns of activation not seen in smaller avalanches. To explain these observations, we adapted a model of structural weakening in materials. In this model, dynamical weakening of neuron firing thresholds closely replicates experimental avalanche size distributions, firing number distributions, and patterns of cyclic activity. This agreement between model and data suggests that a mechanism like dynamical weakening plays a key role in recurrent activity found in large neuronal avalanches. We expect these results to illuminate the causes and dynamics of large avalanches, like those seen in seizures.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History, and Disease Pathophysiology.

    Gutierrez, Wade R / Luo, Yi / Dahmoush, Laila / Oleson, Jacob J / Schlaepfer, Charles H / Breyer, Benjamin N / Elliott, Sean P / Myers, Jeremy B / Vanni, Alex J / Juhr, Denise / Christel, Katherine N / Erickson, Bradley A

    The Journal of urology

    2024  , Page(s) 101097JU0000000000003962

    Abstract: Purpose: Anterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally ... ...

    Abstract Purpose: Anterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation.
    Materials and methods: Men with aUSD undergoing urethroplasty were recruited from one of 5 participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient-reported outcome measure questionnaires both pre- and postoperatively. The initial study had 3 aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire, (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue, and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation.
    Results: Of 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts (
    Conclusions: The most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, platelet-derived growth factor-BB, and CCL5, which were elevated in patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition.
    Language English
    Publishing date 2024-04-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3176-8
    ISSN 1527-3792 ; 0022-5347
    ISSN (online) 1527-3792
    ISSN 0022-5347
    DOI 10.1097/JU.0000000000003962
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