Open Access. Powered by Scholars. Published by Universities.®

Medicine and Health Sciences Commons

Open Access. Powered by Scholars. Published by Universities.®

Articles 1 - 30 of 3551

Full-Text Articles in Medicine and Health Sciences

Saponin Tql1055 Adjuvant-Containing Vaccine Confers Protection Upon Mycobacterium Tuberculosis Challenge In Mice, Mushtaq Ahmed, Eric Farris, Rosemary V Swanson, Shibali Das, Yan Yang, Tyler Martin, Shabaana A Khader Dec 2024

Saponin Tql1055 Adjuvant-Containing Vaccine Confers Protection Upon Mycobacterium Tuberculosis Challenge In Mice, Mushtaq Ahmed, Eric Farris, Rosemary V Swanson, Shibali Das, Yan Yang, Tyler Martin, Shabaana A Khader

2020-Current year OA Pubs

Tuberculosis (TB), caused by the intracellular pathogen


The Association Of Caregiver Attitudes, Information Sources, And Trust With Hpv Vaccine Initiation Among Adolescents, Akila Anandarajah, Thembekile Shato, Sarah Humble, Alan R Barnette, Heather M Brandt, Lisa M Klesges, Vetta L Sanders Thompson, Michelle I Silver Dec 2024

The Association Of Caregiver Attitudes, Information Sources, And Trust With Hpv Vaccine Initiation Among Adolescents, Akila Anandarajah, Thembekile Shato, Sarah Humble, Alan R Barnette, Heather M Brandt, Lisa M Klesges, Vetta L Sanders Thompson, Michelle I Silver

2020-Current year OA Pubs

This study described caregiver attitudes and the information sources they access about HPV vaccination for adolescents and determined their influence on human papillomavirus (HPV) vaccination initiation. An online survey was administered to 1,016 adults in July 2021. Participants were eligible if they were the caregiver of a child aged 9-17 residing in Mississippi, Arkansas, Tennessee, Missouri, and select counties in Southern Illinois. Multivariate logistic regression was used to estimate the association of caregiver attitudes and information sources with HPV vaccination. Information from doctors or healthcare providers (87.4%) and internet sources other than social media (31.0%) were the most used sources …


Emergent Microenvironments Of Nucleoli, Matthew R King, Kiersten M Ruff, Rohit V Pappu Dec 2024

Emergent Microenvironments Of Nucleoli, Matthew R King, Kiersten M Ruff, Rohit V Pappu

2020-Current year OA Pubs

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features including the substrate binding domains, the sequence features of intrinsically disordered regions, and the multivalence of these distinct types …


Cognitive Flexibility Training For Chronic Pain: A Randomized Clinical Study, Katherine J. Holzer, Marko S. Todorovic, Elizabeth A. Wilson, Aaron Steinberg, Michael S. Avidan, Simon Haroutounian Apr 2024

Cognitive Flexibility Training For Chronic Pain: A Randomized Clinical Study, Katherine J. Holzer, Marko S. Todorovic, Elizabeth A. Wilson, Aaron Steinberg, Michael S. Avidan, Simon Haroutounian

2020-Current year OA Pubs

INTRODUCTION: Previous studies suggest an association between cognitive flexibility and development of chronic pain after surgery. It is not known whether cognitive flexibility can be improved in patients with chronic pain.

OBJECTIVES: This study tested whether a neurocognitive training program results in improved cognitive flexibility and pain in patients with chronic pain.

METHODS: We conducted a single-center, prospective, randomized study investigating 5-week daily neurocognitive training in patients with chronic pain. Participants (n = 145) were randomized into neurocognitive training or care as usual, and they completed assessments at baseline, posttreatment, and 3 months. The treatment group was asked to spend …


Prevotella Copri And Microbiota Members Mediate The Beneficial Effects Of A Therapeutic Food For Malnutrition, Hao-Wei Chang, Evan M Lee, Yi Wang, Cyrus Zhou, Kali M Pruss, Suzanne Henrissat, Robert Y Chen, Clara Kao, Matthew C Hibberd, Hannah M Lynn, Daniel M Webber, Marie Crane, Jiye Cheng, Ye Chen, Jeffrey I Gordon, Et Al. Apr 2024

Prevotella Copri And Microbiota Members Mediate The Beneficial Effects Of A Therapeutic Food For Malnutrition, Hao-Wei Chang, Evan M Lee, Yi Wang, Cyrus Zhou, Kali M Pruss, Suzanne Henrissat, Robert Y Chen, Clara Kao, Matthew C Hibberd, Hannah M Lynn, Daniel M Webber, Marie Crane, Jiye Cheng, Ye Chen, Jeffrey I Gordon, Et Al.

2020-Current year OA Pubs

Microbiota-directed complementary food (MDCF) formulations have been designed to repair the gut communities of malnourished children. A randomized controlled trial demonstrated that one formulation, MDCF-2, improved weight gain in malnourished Bangladeshi children compared to a more calorically dense standard nutritional intervention. Metagenome-assembled genomes from study participants revealed a correlation between ponderal growth and expression of MDCF-2 glycan utilization pathways by Prevotella copri strains. To test this correlation, here we use gnotobiotic mice colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains, with or without P. copri isolates closely matching the metagenome-assembled genomes. Combining gut metagenomics and metatranscriptomics …


Dna Combing Versus Dna Spreading And The Separation Of Sister Chromatids, Alice Meroni, Sophie E Wells, Carmen Fonseca, Arnab Ray Chaudhuri, Keith W Caldecott, Alessandro Vindigni Apr 2024

Dna Combing Versus Dna Spreading And The Separation Of Sister Chromatids, Alice Meroni, Sophie E Wells, Carmen Fonseca, Arnab Ray Chaudhuri, Keith W Caldecott, Alessandro Vindigni

2020-Current year OA Pubs

DNA combing and DNA spreading are two central approaches for studying DNA replication fork dynamics genome-wide at single-molecule resolution by distributing labeled genomic DNA on coverslips or slides for immunodetection. Perturbations in DNA replication fork dynamics can differentially affect either leading or lagging strand synthesis, for example, in instances where replication is blocked by a lesion or obstacle on only one of the two strands. Thus, we sought to investigate whether the DNA combing and/or spreading approaches are suitable for resolving adjacent sister chromatids during DNA replication, thereby enabling the detection of DNA replication dynamics within individual nascent strands. To …


Structure Of Alpha-Synuclein Fibrils Derived From Human Lewy Body Dementia Tissue, Dhruva D Dhavale, Katherine Basore, Isabelle R Gordon, Jialu Liu, Jennifer Y O'Shea, Michael J Rau, Zachary Smith, Brock Summers, Richard J Perrin, Joel S Perlmutter, James A J Fitzpatrick, Paul T Kotzbauer, Et Al. Mar 2024

Structure Of Alpha-Synuclein Fibrils Derived From Human Lewy Body Dementia Tissue, Dhruva D Dhavale, Katherine Basore, Isabelle R Gordon, Jialu Liu, Jennifer Y O'Shea, Michael J Rau, Zachary Smith, Brock Summers, Richard J Perrin, Joel S Perlmutter, James A J Fitzpatrick, Paul T Kotzbauer, Et Al.

2020-Current year OA Pubs

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted …


Impact Of Imaging Frequency On Progression-Free Survival In Alliance Trials Enrolling Patients With Follicular Lymphoma, Sarah C Rutherford, Jun Yin, Levi D Pederson, Kristie A Blum, Peter Martin, Sin-Ho Jung, Barbara Grant, Cara Rosenbaum, Bruce D Cheson, Nancy L Bartlett, Sumithra J Mandrekar, John P Leonard Mar 2024

Impact Of Imaging Frequency On Progression-Free Survival In Alliance Trials Enrolling Patients With Follicular Lymphoma, Sarah C Rutherford, Jun Yin, Levi D Pederson, Kristie A Blum, Peter Martin, Sin-Ho Jung, Barbara Grant, Cara Rosenbaum, Bruce D Cheson, Nancy L Bartlett, Sumithra J Mandrekar, John P Leonard

2020-Current year OA Pubs

No abstract provided.


Next Generation Microfluidics: Fulfilling The Promise Of Lab-On-A-Chip Technologies, Umut A Gurkan, Jorge Di Paola, Et Al. Mar 2024

Next Generation Microfluidics: Fulfilling The Promise Of Lab-On-A-Chip Technologies, Umut A Gurkan, Jorge Di Paola, Et Al.

2020-Current year OA Pubs

Microfluidic lab-on-a-chip technologies enable the analysis and manipulation of small fluid volumes and particles at small scales and the control of fluid flow and transport processes at the microscale, leading to the development of new methods to address a broad range of scientific and medical challenges. Microfluidic and lab-on-a-chip technologies have made a noteworthy impact in basic, preclinical, and clinical research, especially in hematology and vascular biology due to the inherent ability of microfluidics to mimic physiologic flow conditions in blood vessels and capillaries. With the potential to significantly impact translational research and clinical diagnostics, technical issues and incentive mismatches …


Intergenerational Protective Anti-Gut Commensal Immunoglobulin G Originates In Early Life, Brigida Rusconi, Adina K Bard, Ryan Mcdonough, Angel M Kindsvogel, Jacqueline D Wang, Sreeram Udayan, Keely G Mcdonald, Rodney D Newberry, Phillip I Tarr Mar 2024

Intergenerational Protective Anti-Gut Commensal Immunoglobulin G Originates In Early Life, Brigida Rusconi, Adina K Bard, Ryan Mcdonough, Angel M Kindsvogel, Jacqueline D Wang, Sreeram Udayan, Keely G Mcdonald, Rodney D Newberry, Phillip I Tarr

2020-Current year OA Pubs

Maternal immunoglobulins of the class G (IgGs) protect offspring from enteric infection, but when, where, and how these antibodies are physiologically generated and confer protection remains enigmatic. We found that circulating IgGs in adult mice preferentially bind early-life gut commensal bacteria over their own adult gut commensal bacteria. IgG-secreting plasma cells specific for early-life gut bacteria appear in the intestine soon after weaning, where they remain into adulthood. Manipulating exposure to gut bacteria or plasma cell development before, but not after, weaning reduced IgG-secreting plasma cells targeting early-life gut bacteria throughout life. Further, the development of this anti-gut commensal IgG …


Targeting Cxcr4, Vla-4, And Cxcr2 For Hematopoietic Stem Cell Mobilization, Daniel Cancilla, Michael P Rettig, Darja Karpova, Haresh Thakellapalli, Megh Singh, Marvin J Meyers, Peter G Ruminski, Stephanie Christ, Ezhilarasi Chendamarai, Feng Gao, Leah Gehrs, Julie K Ritchey, Michael Prinsen, John F Dipersio Mar 2024

Targeting Cxcr4, Vla-4, And Cxcr2 For Hematopoietic Stem Cell Mobilization, Daniel Cancilla, Michael P Rettig, Darja Karpova, Haresh Thakellapalli, Megh Singh, Marvin J Meyers, Peter G Ruminski, Stephanie Christ, Ezhilarasi Chendamarai, Feng Gao, Leah Gehrs, Julie K Ritchey, Michael Prinsen, John F Dipersio

2020-Current year OA Pubs

No abstract provided.


Phase 2 Study Of Add-On Parsaclisib For Patients With Myelofibrosis And Suboptimal Response To Ruxolitinib: Final Results, Abdulraheem Yacoub, Stephen T Oh, Et Al. Mar 2024

Phase 2 Study Of Add-On Parsaclisib For Patients With Myelofibrosis And Suboptimal Response To Ruxolitinib: Final Results, Abdulraheem Yacoub, Stephen T Oh, Et Al.

2020-Current year OA Pubs

Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, …


The Disordered N-Terminal Tail Of Sars-Cov-2 Nucleocapsid Protein Forms A Dynamic Complex With Rna, Jasmine Cubuk, Jhullian J Alston, J Jeremías Incicco, Alex S Holehouse, Kathleen B Hall, Melissa D Stuchell-Brereton, Andrea Soranno Mar 2024

The Disordered N-Terminal Tail Of Sars-Cov-2 Nucleocapsid Protein Forms A Dynamic Complex With Rna, Jasmine Cubuk, Jhullian J Alston, J Jeremías Incicco, Alex S Holehouse, Kathleen B Hall, Melissa D Stuchell-Brereton, Andrea Soranno

2020-Current year OA Pubs

The SARS-CoV-2 Nucleocapsid (N) protein is responsible for condensation of the viral genome. Characterizing the mechanisms controlling nucleic acid binding is a key step in understanding how condensation is realized. Here, we focus on the role of the RNA binding domain (RBD) and its flanking disordered N-terminal domain (NTD) tail, using single-molecule Förster Resonance Energy Transfer and coarse-grained simulations. We quantified contact site size and binding affinity for nucleic acids and concomitant conformational changes occurring in the disordered region. We found that the disordered NTD increases the affinity of the RBD for RNA by about 50-fold. Binding of both nonspecific …


Pathogenic Variants In Crx Have Distinct Cis-Regulatory Effects On Enhancers And Silencers In Photoreceptors, James L Shepherdson, Ryan Z Friedman, Yiqiao Zheng, Chi Sun, Inez Y Oh, David M Granas, Barak A Cohen, Shiming Chen, Michael A White Mar 2024

Pathogenic Variants In Crx Have Distinct Cis-Regulatory Effects On Enhancers And Silencers In Photoreceptors, James L Shepherdson, Ryan Z Friedman, Yiqiao Zheng, Chi Sun, Inez Y Oh, David M Granas, Barak A Cohen, Shiming Chen, Michael A White

2020-Current year OA Pubs

Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox (


Mapping Human Tissues With Highly Multiplexed Rna In Situ Hybridization, Kian Kalhor, Amanda Knoten, Joseph P Gaut, Sanjay Jain, Et Al. Mar 2024

Mapping Human Tissues With Highly Multiplexed Rna In Situ Hybridization, Kian Kalhor, Amanda Knoten, Joseph P Gaut, Sanjay Jain, Et Al.

2020-Current year OA Pubs

In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human …


Combined Kras-Mapk Pathway Inhibitors And Her2-Directed Drug Conjugate Is Efficacious In Pancreatic Cancer, Ashenafi Bulle, Peng Liu, Kuljeet Seehra, Sapana Bansod, Yali Chen, Kiran Zahra, Vikas Somani, Iftikhar Ali Khawar, Hung-Po Chen, Paarth B Dodhiawala, Lin Li, Yutong Geng, Chia-Kuei Mo, Jay Mahsl, Li Ding, Ramaswamy Govindan, Sherri Davies, Jacqueline Mudd, William G Hawkins, Ryan C Fields, David G Denardo, Jason M Held, Patrick M Grierson, Andrea Wang-Gillam, Marianna B Ruzinova, Kian-Huat Lim, Et Al. Mar 2024

Combined Kras-Mapk Pathway Inhibitors And Her2-Directed Drug Conjugate Is Efficacious In Pancreatic Cancer, Ashenafi Bulle, Peng Liu, Kuljeet Seehra, Sapana Bansod, Yali Chen, Kiran Zahra, Vikas Somani, Iftikhar Ali Khawar, Hung-Po Chen, Paarth B Dodhiawala, Lin Li, Yutong Geng, Chia-Kuei Mo, Jay Mahsl, Li Ding, Ramaswamy Govindan, Sherri Davies, Jacqueline Mudd, William G Hawkins, Ryan C Fields, David G Denardo, Jason M Held, Patrick M Grierson, Andrea Wang-Gillam, Marianna B Ruzinova, Kian-Huat Lim, Et Al.

2020-Current year OA Pubs

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 …


Epitope Mapping Of Japanese Encephalitis Virus Neutralizing Antibodies By Native Mass Spectrometry And Hydrogen/Deuterium Exchange, Jagat Adhikari, James Heffernan, Melissa Edeling, Estefania Fernandez, Prashant N Jethva, Michael S Diamond, Daved H Fremont, Michael L Gross Mar 2024

Epitope Mapping Of Japanese Encephalitis Virus Neutralizing Antibodies By Native Mass Spectrometry And Hydrogen/Deuterium Exchange, Jagat Adhikari, James Heffernan, Melissa Edeling, Estefania Fernandez, Prashant N Jethva, Michael S Diamond, Daved H Fremont, Michael L Gross

2020-Current year OA Pubs

Japanese encephalitis virus (JEV) remains a global public health concern due to its epidemiological distribution and the existence of multiple strains. Neutralizing antibodies against this infection have shown efficacy in in vivo studies. Thus, elucidation of the epitopes of neutralizing antibodies can aid in the design and development of effective vaccines against different strains of JEV. Here, we describe a combination of native mass spectrometry (native-MS) and hydrogen/deuterium exchange mass spectrometry (HDX-MS) to complete screening of eight mouse monoclonal antibodies (MAbs) against JEV E-DIII to identify epitope regions. Native-MS was used as a first pass to identify the antibodies that …


Two Dot1 Enzymes Cooperatively Mediate Efficient Ubiquitin-Independent Histone H3 Lysine 76 Tri-Methylation In Kinetoplastids, Victoria S Frisbie, Hideharu Hashimoto, Yixuan Xie, Francisca N De Luna Vitorino, Josue Baeza, Tam Nguyen, Zhangerjiao Yuan, Janna Kiselar, Benjamin A Garcia, Erik W Debler Mar 2024

Two Dot1 Enzymes Cooperatively Mediate Efficient Ubiquitin-Independent Histone H3 Lysine 76 Tri-Methylation In Kinetoplastids, Victoria S Frisbie, Hideharu Hashimoto, Yixuan Xie, Francisca N De Luna Vitorino, Josue Baeza, Tam Nguyen, Zhangerjiao Yuan, Janna Kiselar, Benjamin A Garcia, Erik W Debler

2020-Current year OA Pubs

In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 through histone H2B mono-ubiquitin interaction, while the kinetoplastid Trypanosoma brucei di-methyltransferase DOT1A and tri-methyltransferase DOT1B efficiently methylate the homologous H3K76 without H2B mono-ubiquitination. Based on structural and biochemical analyses of DOT1A, we identify key residues in the methyltransferase motifs VI and X for efficient ubiquitin-independent H3K76 methylation in kinetoplastids. Substitution of a basic to an acidic residue within motif VI (Gx


Prediction Of 3-Dimensional Coverage Surface Area Of The Femoral Head In Hip Dysplasia Through Conventional Computed Tomography, Tomoyuki Kamenaga, Lucas Ritacco, Pablo A Slullitel, Chadi Nahal, Jeffrey J Nepple, John C Clohisy, Cecilia Pascual-Garrido Mar 2024

Prediction Of 3-Dimensional Coverage Surface Area Of The Femoral Head In Hip Dysplasia Through Conventional Computed Tomography, Tomoyuki Kamenaga, Lucas Ritacco, Pablo A Slullitel, Chadi Nahal, Jeffrey J Nepple, John C Clohisy, Cecilia Pascual-Garrido

2020-Current year OA Pubs

BACKGROUND: Assessment of 3-dimensional (3D) femoral head coverage is critical in evaluating, preoperative planning, and treating hip dysplasia.

PURPOSE: To (1) propose a mathematical model to establish 3D femoral head coverage using conventional computed tomography (CT), (2) determine the correlation of 2D parameters with 3D coverage, and (3) characterize the patterns of dysplasia based on 3D morphology.

STUDY DESIGN: Cross-sectional study; Level of evidence, 3.

METHODS: We identified 30 patients (n = hips) with symptomatic dysplasia and 30 patients (n = hips) without dysplasia. Patients with dysplastic hips were matched with regard to sex, age, and body mass index to …


Predation Without Direction Selectivity, Jenna Krizan, Xiayingfang Song, Michael J Fitzpatrick, Ning Shen, Florentina Soto, Daniel Kerschensteiner Mar 2024

Predation Without Direction Selectivity, Jenna Krizan, Xiayingfang Song, Michael J Fitzpatrick, Ning Shen, Florentina Soto, Daniel Kerschensteiner

2020-Current year OA Pubs

Across the animal kingdom, visual predation relies on motion-sensing neurons in the superior colliculus (SC) and its orthologs. These neurons exhibit complex stimulus preferences, including direction selectivity, which is thought to be critical for tracking the unpredictable escape routes of prey. The source of direction selectivity in the SC is contested, and its contributions to predation have not been tested experimentally. Here, we use type-specific cell removal to show that narrow-field (NF) neurons in the mouse SC guide predation. In vivo recordings demonstrate that direction-selective responses of NF cells are independent of recently reported stimulus-edge effects. Monosynaptic retrograde tracing reveals …


Htra1 Disaggregates Α-Synuclein Amyloid Fibrils And Converts Them Into Non-Toxic And Seeding Incompetent Species, Sheng Chen, Anuradhika Puri, Braxton Bell, Joseph Fritsche, Hector H Palacios, Maurie Balch, Macy L Sprunger, Matthew K Howard, Jeremy J Ryan, Jessica N Haines, Gary J Patti, Albert A Davis, Meredith E Jackrel Mar 2024

Htra1 Disaggregates Α-Synuclein Amyloid Fibrils And Converts Them Into Non-Toxic And Seeding Incompetent Species, Sheng Chen, Anuradhika Puri, Braxton Bell, Joseph Fritsche, Hector H Palacios, Maurie Balch, Macy L Sprunger, Matthew K Howard, Jeremy J Ryan, Jessica N Haines, Gary J Patti, Albert A Davis, Meredith E Jackrel

2020-Current year OA Pubs

Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 …


Sequence-Structure-Function Characterization Of The Emerging Tetracycline Destructase Family Of Antibiotic Resistance Enzymes, Kevin S Blake, Hirdesh Kumar, Anisha Loganathan, Emily E Williford, Luke Diorio-Toth, Yao-Peng Xue, Wai Kwan Tang, Tayte P Campbell, David D Chong, Steven Angtuaco, Timothy A Wencewicz, Niraj H Tolia, Gautam Dantas Mar 2024

Sequence-Structure-Function Characterization Of The Emerging Tetracycline Destructase Family Of Antibiotic Resistance Enzymes, Kevin S Blake, Hirdesh Kumar, Anisha Loganathan, Emily E Williford, Luke Diorio-Toth, Yao-Peng Xue, Wai Kwan Tang, Tayte P Campbell, David D Chong, Steven Angtuaco, Timothy A Wencewicz, Niraj H Tolia, Gautam Dantas

2020-Current year OA Pubs

Tetracycline destructases (TDases) are flavin monooxygenases which can confer resistance to all generations of tetracycline antibiotics. The recent increase in the number and diversity of reported TDase sequences enables a deep investigation of the TDase sequence-structure-function landscape. Here, we evaluate the sequence determinants of TDase function through two complementary approaches: (1) constructing profile hidden Markov models to predict new TDases, and (2) using multiple sequence alignments to identify conserved positions important to protein function. Using the HMM-based approach we screened 50 high-scoring candidate sequences in Escherichia coli, leading to the discovery of 13 new TDases. The X-ray crystal structures of …


The Novel Drug Candidate S2/Iapinh Improves Survival In Models Of Pancreatic And Ovarian Cancer, Takaomi Hagi, Suwanna Vangveravong, Rony Takchi, Qingqing Gong, S Peter Goedegebuure, Herve Tiriac, Brian A Van Tine, Matthew A Powell, William G Hawkins, Dirk Spitzer Mar 2024

The Novel Drug Candidate S2/Iapinh Improves Survival In Models Of Pancreatic And Ovarian Cancer, Takaomi Hagi, Suwanna Vangveravong, Rony Takchi, Qingqing Gong, S Peter Goedegebuure, Herve Tiriac, Brian A Van Tine, Matthew A Powell, William G Hawkins, Dirk Spitzer

2020-Current year OA Pubs

Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in …


Simulation-Based Analysis Of Trial Design In Regional Anesthesia, Melisa Pasli, Dmitry Tumin, Ryan Guffey Mar 2024

Simulation-Based Analysis Of Trial Design In Regional Anesthesia, Melisa Pasli, Dmitry Tumin, Ryan Guffey

2020-Current year OA Pubs

BACKGROUND: In regional anesthesia, the efficacy of novel blocks is typically evaluated using randomized controlled trials (RCTs), the findings of which are aggregated in systematic reviews and meta-analyses. Systematic review authors frequently point out the small sample size of RCTs as limiting conclusions from this literature. We sought to determine via statistical simulation if small sample size could be an expected property of RCTs focusing on novel blocks with typical effect sizes.

METHODS: We simulated the conduct of a series of RCTs comparing a novel block versus placebo on a single continuous outcome measure. Simulation analysis inputs were obtained from …


Gestational Testosterone Excess Early To Mid-Pregnancy Disrupts Maternal Lipid Homeostasis And Activates Biosynthesis Of Phosphoinositides And Phosphatidylethanolamines In Sheep, Nadia Saadat, Brooke Pallas, Joseph Ciarelli, Arpita Kalla Vyas, Vasantha Padmanabhan Mar 2024

Gestational Testosterone Excess Early To Mid-Pregnancy Disrupts Maternal Lipid Homeostasis And Activates Biosynthesis Of Phosphoinositides And Phosphatidylethanolamines In Sheep, Nadia Saadat, Brooke Pallas, Joseph Ciarelli, Arpita Kalla Vyas, Vasantha Padmanabhan

2020-Current year OA Pubs

Gestational hyperandrogenism is a risk factor for adverse maternal and offspring outcomes with effects likely mediated in part via disruptions in maternal lipid homeostasis. Using a translationally relevant sheep model of gestational testosterone (T) excess that manifests maternal hyperinsulinemia, intrauterine growth restriction (IUGR), and adverse offspring cardiometabolic outcomes, we tested if gestational T excess disrupts maternal lipidome. Dimensionality reduction models following shotgun lipidomics of gestational day 127.1 ± 5.3 (term 147 days) plasma revealed clear differences between control and T-treated sheep. Lipid signatures of gestational T-treated sheep included higher phosphoinositides (PI 36:2, 39:4) and lower acylcarnitines (CAR 16:0, 18:0, 18:1), …


A Phase I Trial Of Pevonedistat In Combination With Ruxolitinib For The Treatment Of Myelofibrosis, Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J Cox, Amy W Zhou, Stephen T Oh Mar 2024

A Phase I Trial Of Pevonedistat In Combination With Ruxolitinib For The Treatment Of Myelofibrosis, Tim Kong, Nicole Gaudin, Karyn Gordon, Maggie J Cox, Amy W Zhou, Stephen T Oh

2020-Current year OA Pubs

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most …


The Identification Of Small Molecule Inhibitors With Anthelmintic Activities That Target Conserved Proteins Among Ruminant Gastrointestinal Nematodes, Hyeim Jung, Dante Zarlenga, John C Martin, Peter Geldhof, Kymberlie Hallsworth-Pepin, Makedonka Mitreva Mar 2024

The Identification Of Small Molecule Inhibitors With Anthelmintic Activities That Target Conserved Proteins Among Ruminant Gastrointestinal Nematodes, Hyeim Jung, Dante Zarlenga, John C Martin, Peter Geldhof, Kymberlie Hallsworth-Pepin, Makedonka Mitreva

2020-Current year OA Pubs

Gastrointestinal nematode (GIN) infections are a major concern for the ruminant industry worldwide and result in significant production losses. Naturally occurring polyparasitism and increasing drug resistance that potentiate disease outcomes are observed among the most prevalent GINs of veterinary importance. Within the five major taxonomic clades, clade Va represents a group of GINs that predominantly affect the abomasum or small intestine of ruminants. However, the development of effective broad-spectrum anthelmintics against ruminant clade Va GINs has been challenged by a lack of comprehensive druggable genome resources. Here, we first assembled draft genomes for three clade Va species (


Durable Immunity To Ebv After Rituximab And Third-Party Lmp-Specific T Cells: A Children's Oncology Group Study, Birte Wistinghausen, Robert J Hayashi, Et Al. Mar 2024

Durable Immunity To Ebv After Rituximab And Third-Party Lmp-Specific T Cells: A Children's Oncology Group Study, Birte Wistinghausen, Robert J Hayashi, Et Al.

2020-Current year OA Pubs

Posttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus-infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein-specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally …


Germline Knockout Of Nr2e3 Protects Photoreceptors In Three Distinct Mouse Models Of Retinal Degeneration, Alexander V Kolesnikov, Daniel P Murphy, Joseph C Corbo, Vladimir J Kefalov Mar 2024

Germline Knockout Of Nr2e3 Protects Photoreceptors In Three Distinct Mouse Models Of Retinal Degeneration, Alexander V Kolesnikov, Daniel P Murphy, Joseph C Corbo, Vladimir J Kefalov

2020-Current year OA Pubs

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting


Guiding Principles For Adolescent Web-Based Portal Access Policies: Interviews With Informatics Administrators, Bryan Sisk, Alison L Antes, Christine Bereitschaft, Madi Enloe, Fabienne Bourgeois, James Dubois Mar 2024

Guiding Principles For Adolescent Web-Based Portal Access Policies: Interviews With Informatics Administrators, Bryan Sisk, Alison L Antes, Christine Bereitschaft, Madi Enloe, Fabienne Bourgeois, James Dubois

2020-Current year OA Pubs

BACKGROUND: Web-based patient portals are tools that could support adolescents in managing their health and developing autonomy. However, informatics administrators must navigate competing interests when developing portal access policies for adolescents and their parents.

OBJECTIVE: We aimed to assess the perspectives of informatics administrators on guiding principles for the development of web-based health care portal access policies in adolescent health care.

METHODS: We interviewed informatics administrators from US hospitals with ≥50 dedicated pediatric beds. We performed a thematic analysis of guiding principles for developing and implementing adolescent portal access policies.

RESULTS: We interviewed 65 informatics leaders who represented 63 pediatric …