Medicine and Health Sciences Commons^™

Kstar: An Algorithm To Predict Patient-Specific Kinase Activities From Phosphoproteomic Data, Sam Crowl, Ben T Jordan, Hamza Ahmed, Cynthia X Ma, Kristen M Naegle

2020-Current year OA Pubs

Kinase inhibitors as targeted therapies have played an important role in improving cancer outcomes. However, there are still considerable challenges, such as resistance, non-response, patient stratification, polypharmacology, and identifying combination therapy where understanding a tumor kinase activity profile could be transformative. Here, we develop a graph- and statistics-based algorithm, called KSTAR, to convert phosphoproteomic measurements of cells and tissues into a kinase activity score that is generalizable and useful for clinical pipelines, requiring no quantification of the phosphorylation sites. In this work, we demonstrate that KSTAR reliably captures expected kinase activity differences across different tissues and stimulation contexts, allows for …

Hippocampal Threat Reactivity Interacts With Physiological Arousal To Predict Ptsd Symptoms, Büşra Tanriverdi, Stacey L House, Deanna M. Barch, Et Al.

2020-Current year OA Pubs

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected …

Hima2: High-Dimensional Mediation Analysis And Its Application In Epigenome-Wide Dna Methylation Data, Chamila Perera, Haixiang Zhang, Yinan Zheng, Lifang Hou, Annie Qu, Cheng Zheng, Ke Xie, Lei Liu

2020-Current year OA Pubs

Mediation analysis plays a major role in identifying significant mediators in the pathway between environmental exposures and health outcomes. With advanced data collection technology for large-scale studies, there has been growing research interest in developing methodology for high-dimensional mediation analysis. In this paper we present HIMA2, an extension of the HIMA method (Zhang in Bioinformatics 32:3150-3154, 2016). First, the proposed HIMA2 reduces the dimension of mediators to a manageable level based on the sure independence screening (SIS) method (Fan in J R Stat Soc Ser B 70:849-911, 2008). Second, a de-biased Lasso procedure is implemented for estimating regression parameters. Third, …

Oilcloth Sessions As An Implementation Strategy: A Qualitative Study In Denmark, Jeanette Wassar Kirk, Nina Þórný Stefánsdóttir, Byron J Powell, Mette Bendtz Lindstroem, Ove Andersen, Tine Tjørnhøj-Thomsen, Per Nilsen

2020-Current year OA Pubs

BACKGROUND: The aim of this study was to explore healthcare professionals, managers, and other key employees' experiences of oilcloth sessions as a strategy when implementing new emergency departments in Denmark, based on their participations in these sessions. The study addresses the importance of securing alignment in implementation strategies. Too often, this does not get enough attention in the literature and in practice. In this study, alignment among components was achieved in an educational implementation strategy called oilcloth sessions.

METHODS: The study is based on participants' observations of 13 oilcloth sessions and follow-up via 53 semi-structured interviews with the board of …

Comparing Statistical Methods In Assessing The Prognostic Effect Of Biomarker Variability On Time-To-Event Clinical Outcomes, Feng Gao, Jingqin Luo, Jingxia Liu, Fei Wan, Guoqiao Wang, Mae Gordon, Chengjie Xiong

2020-Current year OA Pubs

BACKGROUND: In recent years there is increasing interest in modeling the effect of early longitudinal biomarker data on future time-to-event or other outcomes. Sometimes investigators are also interested in knowing whether the variability of biomarkers is independently predictive of clinical outcomes. This question in most applications is addressed via a two-stage approach where summary statistics such as variance are calculated in the first stage and then used in models as covariates to predict clinical outcome in the second stage. The objective of this study is to compare the relative performance of various methods in estimating the effect of biomarker variability. …

Post-Covid-19 Conditions Among Children 90 Days After Sars-Cov-2 Infection, Anna L. Funk, Fahd D. Ahmad, Et Al.

2020-Current year OA Pubs

No abstract provided.

Myt1l In The Making: Emerging Insights On Functions Of A Neurodevelopmental Disorder Gene, Jiayang Chen, Allen Yen, Colin P Florian, Joseph D Dougherty

2020-Current year OA Pubs

Large scale human genetic studies have shown that loss of function (LoF) mutations in MYT1L are implicated in neurodevelopmental disorders (NDDs). Here, we provide an overview of the growing number of published MYT1L patient cases, and summarize prior studies in cells, zebrafish, and mice, both to understand MYT1L's molecular and cellular role during brain development and consider how its dysfunction can lead to NDDs. We integrate the conclusions from these studies and highlight conflicting findings to reassess the current model of the role of MYT1L as a transcriptional activator and/or repressor based on the biological context. Finally, we highlight additional …

Electro-Mechanical Coupling Of Kcnq Channels Is A Target Of Epilepsy-Associated Mutations And Retigabine, Nien-Du Yang, Richard Kanyo, Lu Zhao, Jingru Li, Po Wei Kang, Alex Kelly Dou, Kelli Mcfarland White, Jingyi Shi, Jeanne M Nerbonne, Harley T Kurata, Jianmin Cui

2020-Current year OA Pubs

KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore …

Longitudinal Analysis Of Risk Factors Associated With Severe Acute Respiratory Coronavirus Virus 2 (Sars-Cov-2) Infection Among Hemodialysis Patients And Healthcare Personnel In Outpatient Hemodialysis Centers, Sumanth Gandra, Tingting Li, Kimberly A. Reske, Kate Peacock, Karl G. Hock, Silvana Bommarito, Candace Miller, Henry Stewart, Na Le Dang, Christopher W. Farnsworth, Margaret A. Olsen, Jennie H. Kwon, David K. Warren, Victoria J. Fraser

2020-Current year OA Pubs

No abstract provided.

Draft Genome Sequence Of A Mycobacterium Strain Isolated From A Clinical Wound Sample, Eric M Ransom, Sanjam S Sawhney, Gautam Dantas, Carey-Ann D Burnham, Skye R S Fishbein

2020-Current year OA Pubs

We report the draft genome sequence of an unusual Mycobacterium isolate recovered from a patient's arm tissue. The 4,025,753-bp draft genome exhibits a GC content of 71.02%, and a 16S rRNA gene analysis found that the closest relative was Mycobacterium grossiae.

Tumor Microenvironment In Pancreatic Ductal Adenocarcinoma: Implications In Immunotherapy, Caitlyn Smith, Wei Zheng, Jixin Dong, Yaohong Wang, Jinping Lai, Xiuli Liu, Feng Yin

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug …

Acrylamide Inhibits Long-Term Potentiation And Learning Involving Microglia And Pro-Inflammatory Signaling, Yukitoshi Izumi, Chika Fujii, Kazuko A O'Dell, Charles F Zorumski

2020-Current year OA Pubs

Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary exposure to acrylamide could impair cognitive function because of its neurotoxicity. Using rat hippocampal slices, we tested whether acrylamide alters induction of long-term potentiation (LTP), a cellular model of learning and memory. We hypothesized that acrylamide impairs cognitive function via activation of pro-inflammatory cytokines because robust upregulation of NLRP3 inflammasome has been reported. Although acrylamide up to 3 mM did not alter basal synaptic transmission, incubation with 10 μM or acute administration of 100 μM acrylamide inhibited induction of …

Proteomic Biomarkers Of The Apnea Hypopnea Index And Obstructive Sleep Apnea: Insights Into The Pathophysiology Of Presence, Severity, And Treatment Response, Katie L J Cederberg, Yo-El S Ju, Et Al

2020-Current year OA Pubs

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (

A Virtual Community Of Practice: An International Educational Series In Pediatric Neurocritical Care, Jennifer C Erklauer, Jennifer L Griffith, Kristin P Guilliams, Et Al

2020-Current year OA Pubs

Pediatric neurocritical care (PNCC) is a rapidly growing field. Challenges posed by the COVID-19 pandemic on trainee exposure to educational opportunities involving direct patient care led to the creative solutions for virtual education supported by guiding organizations such as the Pediatric Neurocritical Care Research Group (PNCRG). Our objective is to describe the creation of an international, peer-reviewed, online PNCC educational series targeting medical trainees and faculty. More than 1600 members of departments such as pediatrics, pediatric critical care, and child neurology hailing from 75 countries across six continents have participated in this series over a 10-month period. We created an …

Kathryn V. Holmes: A Career Of Contributions To The Coronavirus Field, Aurelio Bonavia, Samuel R Dominguez, Gabriela Dveksler, Sara Gagneten, Megan Howard, Scott Jeffers, Zhaohui Qian, Mary Kathryn Smith, Larissa B Thackray, Dina B Tresnan, David E Wentworth, David R Wessner, Richard K Williams, Tanya A Miura

2020-Current year OA Pubs

Over the past two years, scientific research has moved at an unprecedented rate in response to the COVID-19 pandemic. The rapid development of effective vaccines and therapeutics would not have been possible without extensive background knowledge on coronaviruses developed over decades by researchers, including Kathryn (Kay) Holmes. Kay's research team discovered the first coronavirus receptors for mouse hepatitis virus and human coronavirus 229E and contributed a wealth of information on coronaviral spike glycoproteins and receptor interactions that are critical determinants of host and tissue specificity. She collaborated with several research laboratories to contribute knowledge in additional areas, including coronaviral pathogenesis, …

Changes In Health Care Access During The Covid-19 Pandemic: Estimates Of National Japanese Data, June 2020-October 2021, Yuta Tanoue, Cyrus Ghaznavi, Takayuki Kawashima, Akifumi Eguchi, Daisuke Yoneoka, Shuhei Nomura

2020-Current year OA Pubs

The COVID-19 pandemic has disrupted health care access around the world, both for inpatients and outpatients. We applied a quasi-Poisson regression to national, monthly data on the number of outpatients, number of inpatients, length of average hospital stay, and the number of new hospitalizations from March 2015 to October 2021 to assess how these outcomes changed between June 2020 to October 2021. The number of outpatient visits were lower-than-predicted during the early phases of the pandemic but normalized by the fall of 2021. The number of inpatients and new hospitalizations were lower-than-predicted throughout the pandemic, and deficits in reporting continued …

Graded Variation In T1w/T2w Ratio During Adolescence: Measurement, Caveats, And Implications For Development Of Cortical Myelin, Graham L Baum, John C Flournoy, Matthew F Glasser, Michael P Harms, Patrick Mair, Ashley F P Sanders, Deanna M Barch, Randy L Buckner, Susan Bookheimer, Mirella Dapretto, Stephen Smith, Kathleen M Thomas, Essa Yacoub, David C Van Essen, Leah H Somerville

2020-Current year OA Pubs

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D;

Heart Sparing Radiotherapy Techniques In Breast Cancer: A Focus On Deep Inspiration Breath Hold, Hayley B Stowe, Neal D Andruska, Francisco Reynoso, Maria Thomas, Carmen Bergom

2020-Current year OA Pubs

Adjuvant radiation therapy is a critical component of breast cancer management. However, when breast cancer patients receive incidental radiation to the heart, there is an increased risk of cardiac disease and mortality. This is most common for patients with left-sided breast cancers and those receiving nodal irradiation as part of treatment. The overall risk of cardiac toxicity increases 4-16% with each Gray increase in mean heart radiation dose, with data suggesting that no lower limit exists which would eliminate cardiac risk entirely. Radiation techniques have improved over time, leading to lower cardiac radiation exposure than in the past. This decline …

The Hippo Pathway Regulates Axis Formation And Morphogenesis In Hydra, Maria Brooun, Willi Salvenmoser, Catherine Dana, Marius Sudol, Robert Steele, Bert Hobmayer, Helen Mcneill

2020-Current year OA Pubs

How did cells of early metazoan organisms first organize themselves to form a body axis? The canonical Wnt pathway has been shown to be sufficient for induction of axis in Cnidaria, a sister group to Bilateria, and is important in bilaterian axis formation. Here, we provide experimental evidence that in cnidarian

Examination Of The Interaction Between Parental Military-Status And Race Among Non-Hispanic Black And Non-Hispanic White Adolescents With Overweight/Obesity, M K Higgins Neyland, Denise E Wilfley, Et Al.

2020-Current year OA Pubs

OBJECTIVES: Adolescent military-dependents experience distinct risk and protective factors, which may necessitate additional clinical considerations. In civilian youth, overweight/obesity is associated with eating, internalizing, and externalizing difficulties, with some studies reporting more difficulties among non-Hispanic White (vs. non-Hispanic Black) youth. It is unknown if these disparities exist among adolescent military-dependents, or between civilian and military-dependent youth.

METHODS: Non-Hispanic Black (187 civilian, 38 military-dependent) and non-Hispanic White (205 civilian, 84 military-dependent) adolescents with overweight/obesity (14.7 ± 1.6 years; 73.9% girls; body mass index adjusted for age and sex 1.9 ± 0.5) completed a disordered-eating interview; parents completed a measure assessing their …

Effect Of Race On Prediction Of Brain Amyloidosis By Plasma Aβ42/Aβ40, Phosphorylated Tau, And Neurofilament Light, Suzanne E Schindler, Rachel L Henson, Yan Li, Benjamin Saef, Krista L Moulder, David Bradford, Anne M Fagan, Brian A Gordon, Tammie L S Benzinger, Joyce Balls-Berry, Randall J Bateman, Chengjie Xiong, John C Morris, Et Al

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.

METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,

RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were

DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and …

Activation Domains Can Decouple The Mean And Noise Of Gene Expression, Kaiser Loell, Yawei Wu, Max V Staller, Barak Cohen

2020-Current year OA Pubs

Regulatory mechanisms set a gene's average level of expression, but a gene's expression constantly fluctuates around that average. These stochastic fluctuations, or expression noise, play a role in cell-fate transitions, bet hedging in microbes, and the development of chemotherapeutic resistance in cancer. An outstanding question is what regulatory mechanisms contribute to noise. Here, we demonstrate that, for a fixed mean level of expression, strong activation domains (ADs) at low abundance produce high expression noise, while weak ADs at high abundance generate lower expression noise. We conclude that differences in noise can be explained by the interplay between a TF's nuclear …

Snmmi/Acr/Asnc/Scmr Joint Credentialing Statement For Cardiac Pet/Mri, Terrence D Ruddy, Mouaz Al-Mallah, James A Arrighi, John P Bois, David A Bluemke, Marcelo F Di Carli, Vasken Dilsizian, Robert J Gropler, Hossein Jadvar, Saurabh Malhotra, Matthieu Pelletier-Galarneau, Thomas H Schindler, Pamela K Woodard, Panithaya Chareonthaitawee

2020-Current year OA Pubs

No abstract provided.

Brd9 Degraders As Chemosensitizers In Acute Leukemia And Multiple Myeloma, Ellen Weisberg, Abdel Kareem Azab, Jennifer Sun, Barbara Muz, Et Al

2020-Current year OA Pubs

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique …

Ddr2 Expression In Cancer-Associated Fibroblasts Promotes Ovarian Cancer Tumor Invasion And Metastasis Through Periostin-Itgb1, Favour A Akinjiyan, Ritu M Dave, Emily Alpert, Gregory D Longmore, Katherine C Fuh

2020-Current year OA Pubs

Ovarian cancer has the highest mortality of all gynecologic malignancies. As such, there is a need to identify molecular mechanisms that underlie tumor metastasis in ovarian cancer. Increased expression of receptor tyrosine kinase, DDR2, has been associated with worse patient survival. Identifying downstream targets of DDR2 may allow specific modulation of ovarian cancer metastatic pathways. Additionally, stromal cells play a critical role in metastasis. The crosstalk between tumor and stromal cells can lead to tumor progression. We first identified that tumor cells co-cultured with DDR2-expressing fibroblasts had lower periostin expression when compared to tumor cells co-cultured with DDR2-depleted fibroblasts. We …

Clinical And Occupational Risk Factors For Coronavirus Disease 2019 (Covid-19) In Healthcare Personnel, Jennie H. Kwon, Philip J. Budge, Caroline A. O'Neil, Kate Peacock, Eva M. Aagaard, Victoria J. Fraser, Margaret A. Olsen, Hilary Babcock

2020-Current year OA Pubs

No abstract provided.

Α-Synuclein Conformational Plasticity: Physiologic States, Pathologic Strains, And Biotechnological Applications, Amanda Li, Cyrus Rastegar, Xiaobo Mao

2020-Current year OA Pubs

α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is implicated in a class of neurodegenerative disorders collectively termed α-synucleinopathies. Notably, αS does not adopt a single "amyloid fold", but rather exists as structurally distinct amyloid-like conformations referred to as "strains". The inoculation of animal models with different strains induces distinct pathologies, and emerging evidence suggests that the propagation of disease-specific strains underlies the differential pathologies observed …

Metrics To Evaluate Implementation Scientists In The Usa: What Matters Most?, Brenna B Maddox, Mary L Phan, Y Vivian Byeon, Courtney Benjamin Wolk, Rebecca E Stewart, Byron J Powell, Kelsie H Okamura, Melanie Pellecchia, Emily M Becker-Haimes, David A Asch, Rinad S Beidas

2020-Current year OA Pubs

BACKGROUND: Implementation science has grown rapidly as a discipline over the past two decades. An examination of how publication patterns and other scholarly activities of implementation scientists are weighted in the tenure and promotion process is needed given the unique and applied focus of the field.

METHODS: We surveyed implementation scientists (mostly from the USA) to understand their perspectives on the following matters: (1) factors weighted in tenure and promotion for implementation scientists, (2) how important these factors are for success as an implementation scientist, (3) how impact is defined for implementation scientists, (4) top journals in implementation science, and …

Slitrk2 Variants Associated With Neurodevelopmental Disorders Impair Excitatory Synaptic Function And Cognition In Mice, Salima El Chehadeh, Dorothy K Grange, Et Al

2020-Current year OA Pubs

SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of …

Single-Cell Transcriptional Regulation And Genetic Evolution Of Neuroendocrine Prostate Cancer, Ziwei Wang, Daofeng Li, Hyung Joo Lee, Et Al.

2020-Current year OA Pubs

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer, with a 10% five-year survival rate. However, little is known about its origin and the mechanisms governing its emergence. Our study characterized ADPC and NEPC in prostate tumors from 7 patients using scRNA-seq. First, we identified two NEPC gene expression signatures representing different phases of