Expanding the Model of Macrophage Chemotaxis: Exploring the Connection Between the Leading Edge Chemosensory Pathway and Cytoskeletal Restructuring

Macrophages are essential first responders in the innate immune system. They protect the host organism by seeking out, identifying, engulfing, and breaking down pathogens or damaged tissue. These actions are reliant on the cell&rsquo;s ability to migrate up a chemoattractant gradient via the process of chemotaxis. Previous studies in the Falke lab at the University of Colorado, Boulder, as well as other labs in the field, elucidated the mechanisms of early events in chemosensing at the macrophage leading edge membrane. Such chemosensing often involves both the binding of chemoattractant to a leading edge receptor tyrosine kinase (RTK) yielding phosphotyrosine production, and the presence of a leading edge Ca2+ signal that recruits protein kinase C-alpha (PKC).&nbsp; In turn the phosphotyrosine signal and the PKC activity together stimulate the lipid kinase phosphoinositide 3-kinase (PI3K) to produce the signaling lipid phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). Less is known about how the chemosensory pathway and the PIP3 lipid signal control the leading edge cytoskeletal restructuring necessary for migration. My thesis research has analyzed the current literature, enabling me to develop a circuit diagram linking the leading edge chemosensory pathway to the actin dynamics involved in chemotactic cell movement. This review summarizes evidence that the actin nucleation promoting factors, Wiskott-Aldrich syndrome protein (WASP) and WASP-family Verprolin-homologous protein 2 (WAVE2) are directly regulated by the chemosensory pathway, and in turn, control branched actin formation via actin-binding protein ⅔ (Arp ⅔). The WASP and WAVE2 proteins are each recruited to the leading edge membrane and activated by their homologous but distinct activating signals: phosphoinositides, Rho family GTPases, and BAR proteins. Additionally, the kinase mammalian target of rapamycin (mTOR) promotes actin filament stabilization and initiates a positive feedback loop to maintain chemotactic signaling. Membrane remodeling processes accompany these pathways to decrease the membrane strain created by the expanding actin network. The relief of strain is driven by the relaxation of membrane wrinkles and the trafficking of membrane vesicles from unstimulated regions of the cell to the leading edge. Overall, my literature research has generated a circuit diagram summarizing the connections between the components of the leading edge chemosensory and cytoskeletal systems that together control macrophage-directed migration up attractant gradients. The resulting circuit diagram reveals key areas for further research directions that the Falke lab can pursue to generate a deeper mechanistic understanding of macrophage chemotaxis.</p

A Regime-Based Evaluation of Southern and Northern Great Plains Warm-Season Precipitation Events in WRF

A competitive neural network known as the self-organizing map (SOM) is used to objectively identify synoptic patterns in the North American Regional Reanalysis (NARR) for warm-season (April-September) precipitation events over the Southern and Northern Great Plains (SGP/NGP) from 2007 to 2014. Classifications for both regions demonstrate contrast in dominant synoptic patterns ranging from extratropical cyclones to subtropical ridges, all of which have preferred months of occurrence. Precipitation from deterministic Weather Research and Forecasting (WRF) Model simulations run by the National Severe Storms Laboratory (NSSL) are evaluated against National Centers for Environmental Prediction (NCEP) Stage IV observations. The SGP features larger observed precipitation amount, intensity, and coverage, as well as better model performance than the NGP. Both regions' simulated convective rain intensity and coverage have good agreement with observations, whereas the stratiform rain (SR) is more problematic with weaker intensity and larger coverage. Further evaluation based on SOM regimes shows that WRF bias varies with the type of meteorological forcing, which can be traced to differences in the diurnal cycle and properties of stratiform and convective rain. The higher performance scores are generally associated with the extratropical cyclone condition than the subtropical ridge. Of the six SOM classes over both regions, the largest precipitation oversimulation is found for SR dominated classes, whereas a nocturnal negative precipitation bias exists for classes featuring upscale growth of convection.Climate Model Development and Validation (CMDV) program - Office of Biological and Environmental Research in the U.S. Department of Energy Office of Science under University of Arizona [DE-SC0017015]; NOAA R2O project at the University of North Dakota [NA15NWS468004]; Climate Model Development and Validation program; Water Cycle and Climate Extreme Modeling science focus area - Office of Biological and Environmental Research in the U.S. Department of Energy Office of Science; U.S. Department of Energy (DOE) [DE-AC05-76RL01830]6 month embargo; published online: 2 July 2019This 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]

Client Centered Care through a Collaborative Lens to treat symptoms of Long Haul Covid

Research poster reflecting on the benefits and challenges of interprofessional collaboration in caring for a patient dealing with long term COVID-19 via simulated Telehealth appointments. Multiple discoveries were made as different professions worked together to overcome technological and educational barriers to care for a patient diagnosed with a poorly understood and novel medical condition. Health professions Involved included: Allopathic Medicine, Osteopathic Medicine, Physician Assistant, Occupational Therapy, Pharmacy, Dental Hygiene, Social Work, Physical Therapy, and Nursing.https://dune.une.edu/cecespring2022/1004/thumbnail.jp

Abetalipoproteinemia Due to a Novel Splicing Variant in MTTP in 3 Siblings

Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the MTTP gene encoding the microsomal triglyceride transfer protein large subunit. ABL is characterized by absence of apolipoprotein B–containing lipoproteins and deficiencies in fat-soluble vitamins leading to multisystem involvement of which neurological complications are the most serious. We present 3 siblings with ABL who were born to non-consanguineous parents of Filipino and Chinese background. Identical twin boys with long-standing failure to thrive and malabsorption were diagnosed at age 2 years. ABL therapy with vitamins and a specialized diet was initiated, replacing total parenteral nutrition at age 3 years. Their younger sister was diagnosed from a blood sample taken at birth; treatment was instituted shortly thereafter. We observed in the twins reversal and in their sister prevention of ABL systemic features following early implementation of fat restriction and high doses of oral fat-soluble vitamins. A targeted sequencing panel found that each affected sibling is homozygous for a novel MTTP intron 13 -2A\u3eG splice acceptor site mutation, predicted to abolish splicing of intron 13. This variant brings to more than 60 the number of reported pathogenic mutations, which are summarized in this article. The twin boys and their sister are now doing well at 11 and 4 years of age, respectively. This experience underscores the importance of early initiation of targeted specialized dietary and fat-soluble vitamin replacements in ABL

Measuring & Mapping Mortality in the Elm City: Identifying and Addressing Health Inequities in New Haven with Years of Potential Life Lost (YPLL) and Other Health Determinants

Population health in the City of New Haven, including health care access, health outcomes, and mortality, is influenced by socioeconomic disparities. These disparities exist on both the individual and neighborhood scale, and across demographics such as age, sex, race, and ethnicity. Continued analyses to understand these disparities is imperative to elucidate public health concerns and to design and to implement appropriate initiatives and interventions. The objectives of this study were as follows: To measure the leading causes of death, average life expectancy, and premature death in New Haven using mortality data and stratifying by key variables including age, sex, race, and ethnicity, and to characterize the relationships between mortality, geographic location, and other demographic variables.https://elischolar.library.yale.edu/ysph_pbchrr/1019/thumbnail.jp

Associations between changes in ferritin levels and susceptibility-weighted imaging filtered phase in patients with relapsing–remitting multiple sclerosis over 24weeks of therapy with subcutaneous interferon beta-1a three times weekly

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A Pilot Phase II Study of Digoxin in Patients with Recurrent Prostate Cancer as Evident by Rising PSA

Background: Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 – 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.Results: Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease 25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients. Conclusions: Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer

Relaxation and related therapies for people with multiple sclerosis (MS): A systematic review

Objective: To establish the effectiveness of relaxation and related therapies in treating Multiple Sclerosis related symptoms and sequelae. Data Sources: PsycINFO, PubMed, Embase, CINAHL, ProQuest Dissertations and Theses Global databases were searched. Methods: We included studies from database inception until 31 December 2021 involving adult participants diagnosed with multiple sclerosis or disseminated sclerosis, which featured quantitative data regarding the impact of relaxation interventions on multiple sclerosis-related symptoms and sequelae. Studies which examined multi-modal therapies - relaxation delivered in combination with non-relaxation interventions - were excluded. Risk of bias was assessed using the Revised Risk of Bias tool for randomised trials – ROB2, Risk of Bias in Non-Randomised Studies of Interventions ROBINS-I), and within and between-group effects were calculated (Hedges’ g). Results: Twenty-eight studies met inclusion criteria. Twenty-three of these were randomised controlled trials, with 1246 total participants. This review reports on this data, with non-randomised study data reported in supplemental material. Post –intervention relaxation was associated with medium to large effect-size improvement for depression, anxiety, stress and fatigue. The effects of relaxation were superior to wait-list or no treatment control conditions; however, comparisons with established psychological or physical therapies were mixed. Individual studies reported sustained effects (≤ 6 months) with relaxation for stress, pain and quality of life. Most studies were rated as having a high/serious risk of bias. Conclusion: There is emerging evidence that relaxation therapies can improve outcomes for persons with multiple sclerosis. Given the high risk of bias found for included studies, stronger conclusions cannot be drawn

The Vehicle, Fall 1983

Vol. 25, No. 1 Table of Contents Amish BoyDevon Flesorpage 3 SyllogismJ. Maura Davispage 3 Ten SecondsD.L. Lewispage 4 The Cedar ChestBridget M. Howepage 4 A Christmas With CarolSteve Longpage 5 TeethMichelle Mitchellpage 7 An I-Love-You PoemD.L. Lewispage 8 The Dragon SlayerSusan Gradypage 8 A DefinitionAmy J. Eadespage 9 FingernailsSuzanne Hornpage 10 The Liar\u27s TableBrook Wilsonpage 10 Fifi\u27s Last PartySteve Longpage 12 Absence/PresenceSuzanne Hornpage 13 From the Rantings of a Mad Astronomy StudentAmy J. Eadespage 13 In the Name of the Father, the Son, and MachiavelliF. Link Rapierpage 15 Errant LoverBecky Lawsonpage 16 DaddyKevin Lylespage 16 GhostsGary Ervinpage 17 TangoF. Link Rapierpage 17 Grandma\u27s SlippersBecky Lawsonpage 18 EdgesAmy J. Eadespage 19 Having ChildrenDevon Flesorpage 20 Young Black GirlKevin Lylespage 21 CatSuzanne Hornpage 22 Breakfast for OneMichelle Mitchellpage 22 A Modest ProposalBrooke Sanfordpage 23 Post MortemF. Link Rapierpage 26 Who Said I Forgot?Lynne Krausepage 27 The Corner Booth at StuckeysMaggie Kennedypage 28 The First DayDavis Brydenpage 29 DownLynne Krausepage 30 Fairie RingDevon Flesorpage 31 The LaundrymatKathy Fordpage 32 Sunday in OctoberBridget M. Howepage 32 The Kitchen WindowMaggie Kennedypage 33 UntitledChristina Maire Vitekpage 34 8th Grade Field Trip to SpringfieldMichelle Mitchellpage 34 Children of the FortiesF. Link Rapierpage 35 one winter and i was eightGary Ervinpage 35 Don\u27t we all know?Thomas B. Waltrippage 36 The TravelerMaggie Kennedypage 36 The VisitKathy Fordpage 40 CubismMaggie Kennedypage 40https://thekeep.eiu.edu/vehicle/1042/thumbnail.jp

The Vehicle, Fall 1983

Vol. 25, No. 1 Table of Contents Amish BoyDevon Flesorpage 3 SyllogismJ. Maura Davispage 3 Ten SecondsD.L. Lewispage 4 The Cedar ChestBridget M. Howepage 4 A Christmas With CarolSteve Longpage 5 TeethMichelle Mitchellpage 7 An I-Love-You PoemD.L. Lewispage 8 The Dragon SlayerSusan Gradypage 8 A DefinitionAmy J. Eadespage 9 FingernailsSuzanne Hornpage 10 The Liar\u27s TableBrook Wilsonpage 10 Fifi\u27s Last PartySteve Longpage 12 Absence/PresenceSuzanne Hornpage 13 From the Rantings of a Mad Astronomy StudentAmy J. Eadespage 13 In the Name of the Father, the Son, and MachiavelliF. Link Rapierpage 15 Errant LoverBecky Lawsonpage 16 DaddyKevin Lylespage 16 GhostsGary Ervinpage 17 TangoF. Link Rapierpage 17 Grandma\u27s SlippersBecky Lawsonpage 18 EdgesAmy J. Eadespage 19 Having ChildrenDevon Flesorpage 20 Young Black GirlKevin Lylespage 21 CatSuzanne Hornpage 22 Breakfast for OneMichelle Mitchellpage 22 A Modest ProposalBrooke Sanfordpage 23 Post MortemF. Link Rapierpage 26 Who Said I Forgot?Lynne Krausepage 27 The Corner Booth at StuckeysMaggie Kennedypage 28 The First DayDavis Brydenpage 29 DownLynne Krausepage 30 Fairie RingDevon Flesorpage 31 The LaundrymatKathy Fordpage 32 Sunday in OctoberBridget M. Howepage 32 The Kitchen WindowMaggie Kennedypage 33 UntitledChristina Maire Vitekpage 34 8th Grade Field Trip to SpringfieldMichelle Mitchellpage 34 Children of the FortiesF. Link Rapierpage 35 one winter and i was eightGary Ervinpage 35 Don\u27t we all know?Thomas B. Waltrippage 36 The TravelerMaggie Kennedypage 36 The VisitKathy Fordpage 40 CubismMaggie Kennedypage 40https://thekeep.eiu.edu/vehicle/1042/thumbnail.jp