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Mobilized Peripheral Blood: An Updated Perspective, Darja Karpova, Michael P Rettig, John F Dipersio

Open Access Publications

Enforced egress of hematopoietic stem cells (HSCs) out of the bone marrow (BM) into the peripheral circulation, termed mobilization, has come a long way since its discovery over four decades ago. Mobilization research continues to be driven by the need to optimize the regimen currently available in the clinic with regard to pharmacokinetic and pharmacodynamic profile, costs, and donor convenience. In this review, we describe the most recent findings in the field and how we anticipate them to affect the development of mobilization strategies in the future. Furthermore, the significance of mobilization beyond HSC collection, i.e. for chemosensitization, conditioning, and …

Efficacy And Safety Of Eluxadoline In Patients With Irritable Bowel Syndrome With Diarrhea Who Report Inadequate Symptom Control With Loperamide: Relief Phase 4 Study, Darren M. Brenner, Gregory S. Sayuk, Catherine R. Gutman, Esther Jo, Steven J. R. Elmes, Louis W. C. Liu, Brooks D. Cash

Open Access Publications

No abstract provided.

Clinical Performance Of A Novel Fully Synthetic Dura Substitute, Umang Khandpur, Wilson Ray, Matthew Macewan

Open Access Publications

No abstract provided.

Somatosensory Predictors Of Response To Pregabalin In Painful Chemotherapy-Induced Peripheral Neuropathy: A Randomized, Placebo-Controlled, Crossover Study, Alexander Hincker, Karen Frey, Lesley Rao, Nina Wagner-Johnston, Arbi Ben Abdallah, Benjamin Tan, Manik Amin, Tanya Wildes, Rajiv Shah, Pall Karlsson, Kristopher Bakos, Katarzyna Kosicka, Leonid Kagan, Simon Haroutounian

Open Access Publications

No abstract provided.

A Herpesvirus Encoded Qa-1 Mimic Inhibits Natural Killer Cell Cytotoxicity Through Cd94/Nkg2a Receptor Engagement, Xiaoli Wang, Sytse J. Piersma, Christopher A. Nelson, Ya-Nan Dai, Ted Christensen, Eric Lazear, Liping Yang, Marjolein Sluijter, Thorbald Van Hall, Ted H. Hansen, Wayne M. Yokoyama, Daved H. Fremont

Open Access Publications

A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of 'missing-self' recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here, we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, …

Cd4+ T Cells Induce Rejection Of Urothelial Tumors After Immune Checkpoint Blockade, Yuji Sato, Jennifer K Bolzenius, Abdallah M Eteleeb, Xinming Su, Christopher A Maher, Jennifer K Sehn, Vivek K Arora

Open Access Publications

Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role of CD4+ T cells in ICB-induced antitumor activity is not well defined; however, CD4+ T cells are speculated to play a supportive role in the development of CD8+ T cells that kill tumor cells after recognition of tumor antigens presented by MHC class I. To investigate the mechanisms of ICB-induced activity against UC, we developed mouse organoid-based transplantable models that have histologic and genetic similarity to human bladder cancer. We found that ICB can induce tumor rejection and protective immunity with these …

Lrrk1 Regulation Of Actin Assembly In Osteoclasts Involves Serine 5 Phosphorylation Of L-Plastin, Mingjue Si, Helen Goodluck, Canjun Zeng, Songqin Pan, Elizabeth M Todd, Sharon Celeste Morley, Xuezhong Qin, Subburaman Mohan, Weirong Xing

Open Access Publications

Mice with disruption of Lrrk1 and patients with nonfunctional mutant Lrrk1 exhibit severe osteopetrosis phenotypes because of osteoclast cytoskeletal dysfunction. To understand how Lrrk1 regulates osteoclast function by modulating cytoskeleton rearrangement, we examined the proteins that are differentially phosphorylated in wild-type mice and Lrrk1-deficient osteoclasts by metal affinity purification coupled liquid chromatography/mass spectrometry (LC/MS) analyses. One of the candidates that we identified by LC/MS is L-plastin, an actin bundling protein. We found that phosphorylation of L-plastin at serine (Ser) residues 5 was present in wild-type osteoclasts but not in Lrrk1-deficient cells. Western blot analyses with antibodies specific for Ser5 phosphorylated …

In Vivo Characterization Of Connective Tissue Remodeling Using Infrared Photoacoustic Spectra, Yuan Qu, Peng Hu, Junhui Shi, Konstantin Maslov, Peinan Zhao, Chiye Li, Jun Ma, Alejandro Garcia-Uribe, Karen Meyers, Emily Diveley, Stephanie Pizzella, Lisa Muench, Nina Punyamurthy, Naomi Goldstein, Oji Onwumere, Mariana Alisio, Kaytelyn Meyenburg, Jennifer Maynard, Kristi Helm, Emma Altieri, Janessia Slaughter, Sabrina Barber, Tracy Burger, Christine Kramer, Jessica Chubiz, Monica Anderson, Ronald Mccarthy, Sarah K England, George A Macones, Molly J Stout, Methodius Tuuli, Lihong V Wang

Open Access Publications

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this …

Unilateral, 3d Arm Movement Kinematics Are Encoded In Ipsilateral Human Cortex, David T. Bundy, Nicholas Szrama, Mrinal Pahwa, Eric C. Leuthardt

Open Access Publications

There is increasing evidence that the hemisphere ipsilateral to a moving limb plays a role in planning and executing movements. However, the exact relationship between cortical activity and ipsilateral limb movements is uncertain. We sought to determine whether 3D arm movement kinematics (speed, velocity, and position) could be decoded from cortical signals recorded from the hemisphere ipsilateral to the moving limb. By having invasively monitored patients perform unilateral reaches with each arm, we also compared the encoding of contralateral and ipsilateral limb kinematics from a single cortical hemisphere. In four motor-intact human patients (three male, one female) implanted with electrocorticography …

Changes In The Us Burden Of Chronic Kidney Disease From 2002 To 2016: An Analysis Of The Global Burden Of Disease Study, Benjamin Bowe, Yan Xie, Tingting Li, Ali H. Mokdad, Hong Xian, Yan Yan, Geetha Maddukuri, Ziyad Al-Aly

Open Access Publications

Introduction: Over the past 15 years, changes in demographic, social, and epidemiologic trends occurred in the United States. These changes likely contributed to changes in chronic kidney disease (CKD) epidemiology.

Objective: To describe the change in burden of CKD at the US state level from 2002 to 2016.

Design, Setting, and Participants: This systematic analysis used data and methodologies from the 2016 Global Burden of Disease study in the United States. Data on CKD from 2002 to 2016 were examined at the state level.

Main Outcomes and Measures: Disability-adjusted life years (DALYs) and death due to CKD.

Results: In this …

Dietary Protein Restriction Reduces Circulating Vldl Triglyceride Levels Via Crebh-Apoa5-Dependent And -Independent Mechanisms, J Humberto Treviño-Villarreal, Valeria Tosti, Nicola Veronese, Beatrice Bertozzi, Arnold D Bullock, Robert S Figenshau, Gerald L Andriole, Luigi Fontana, Et Al

Open Access Publications

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase …

Trex1 Is Expressed By Microglia In Normal Human Brain And Increases In Regions Affected By Ischemia, Parul H Kothari, Grant R Kolar, Joanna C Jen, Rula Hajj-Ali, Paula Bertram, Robert E Schmidt, John P Atkinson

Open Access Publications

BACKGROUND: Mutations in the three-prime repair exonuclease 1 (TREX1) gene have been associated with neurological diseases, including Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). However, the endogenous expression of TREX1 in human brain has not been studied.

METHODS: We produced a rabbit polyclonal antibody (pAb) to TREX1 to characterize TREX1 by Western blotting (WB) of cell lysates from normal controls and subjects carrying an RVCL frame-shift mutation. Dual staining was performed to determine cell types expressing TREX1 in human brain tissue. TREX1 distribution in human brain was further evaluated by immunohistochemical analyses of formalin-fixed, paraffin-embedded samples from normal controls and patients …

Glasdegib In Combination With Cytarabine And Daunorubicin In Patients With Aml Or High-Risk Mds: Phase 2 Study Results, Jorge E Cortes, Mark A Schroeder, Et Al

Open Access Publications

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m

Mouse Models Of Preterm Birth: Suggested Assessment And Reporting Guidelines, Ronald Mccarthy, Carmel Martin-Fairey, Dorothy K. Sojka, Erik D. Herzog, Emily S. Jungheim, Molly J. Stout, Justin C. Fay, Mala Mahendroo, Jeff Reese, Jennifer L. Herington, Erin J. Plosa, Elaine L. Shelton, Sarah K. England

Open Access Publications

Preterm birth affects approximately 1 out of every 10 births in the United States, leading to high rates of mortality and long-term negative health consequences. To investigate the mechanisms leading to preterm birth so as to develop prevention strategies, researchers have developed numerous mouse models of preterm birth. However, the lack of standard definitions for preterm birth in mice limits our field's ability to compare models and make inferences about preterm birth in humans. In this review, we discuss numerous mouse preterm birth models, propose guidelines for experiments and reporting, and suggest markers that can be used to assess whether …

A Novel Mode Of Capping Protein-Regulation By Twinfilin, Adam B. Johnston, Denise M. Hilton, Patrick Mcconnell, Britney Johnson, Meghan T. Harris, Avital Simone, Gaya K. Amarasinghe, John A. Cooper, Bruce L. Goode

Open Access Publications

Cellular actin assembly is controlled at the barbed ends of actin filaments, where capping protein (CP) limits polymerization. Twinfilin is a conserved in vivo binding partner of CP, yet the significance of this interaction has remained a mystery. Here, we discover that the C-terminal tail of Twinfilin harbors a CP-interacting (CPI) motif, identifying it as a novel CPI-motif protein. Twinfilin and the CPI-motif protein CARMIL have overlapping binding sites on CP. Further, Twinfilin binds competitively with CARMIL to CP, protecting CP from barbed-end displacement by CARMIL. Twinfilin also accelerates dissociation of the CP inhibitor V-1, restoring CP to an active …

Simulation Of Spontaneous G Protein Activation Reveals A New Intermediate Driving Gdp Unbinding, Xianqiang Sun, Sukrit Singh, Kendall J. Blumer, Gregory R. Bowman

Open Access Publications

Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structural and biochemical data. Surprisingly, the rate-limiting step for GDP release correlates with tilting rather than translation of the GPCR-binding helix 5. β-Strands 1 - 3 and …

Uncovering The Complex Genetics Of Human Temperament, Igor Zwir, Javier Arnedo, Dragan M Svrakic, Sandor Rozsa, Maribel Martinez, C Robert Cloninger, Et Al

Open Access Publications

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified …

Timing And Mechanism Of Conceptus Demise In A Complement Regulatory Membrane Protein Deficient Mouse, Michael P Triebwasser, Xiaobo Wu, Paula Bertram, Dennis E Hourcade, Donald Michael Nelson, John P Atkinson

Open Access Publications

PROBLEM: Crry is a widely expressed type 1 transmembrane complement regulatory protein in rodents which protects self-tissue by downregulating C3 activation. Crry

METHOD OF STUDY: We investigated the basis of Crry

RESULTS: We narrowed the critical period of the complement effect from 6.5 to 8.5 days post-coitus (dpc), which is immediately after the conceptus is exposed to maternal blood. Deposition by 5.5 dpc of maternal C3b on the placental vasculature lacking Crry

CONCLUSION: Our data are most consistent with the deposition of C3b being responsible for the failure of the allantois to fuse to the chorion leading to subsequent conceptus …

Haptoglobin Improves Shock, Lung Injury, And Survival In Canine Pneumonia, Kenneth E. Remy, Irene Cortés-Puch, Steven B. Solomon, Junfeng Sun, Benjamin M. Pockros, Jing Feng, Juan J. Lertora, Roy R. Hantgan, Xiaohua Liu, Andreas Perlegas, H. Shaw Warren, Mark T. Gladwin, Daniel B. Kim-Shapiro, Harvey G. Klein, Charles Natanson

Open Access Publications

During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S. aureus pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, …

Impaired Monocyte Cholesterol Clearance Initiates Age-Related Retinal Degeneration And Vision Loss, Norimitsu Ban, Tae Jun Lee, Abdoulaye Sene, Mayur Choudhary, Michael Lekwuwa, Zhenyu Dong, Andrea Santeford, Jonathan B. Lin, Goldis Malek, Daniel S. Ory, Rajendra S. Apte

Open Access Publications

Advanced age-related macular degeneration (AMD), the leading cause of blindness among people over 50 years of age, is characterized by atrophic neurodegeneration or pathologic angiogenesis. Early AMD is characterized by extracellular cholesterol-rich deposits underneath the retinal pigment epithelium (RPE) called drusen or in the subretinal space called subretinal drusenoid deposits (SDD) that drive disease progression. However, mechanisms of drusen and SDD biogenesis remain poorly understood. Although human AMD is characterized by abnormalities in cholesterol homeostasis and shares phenotypic features with atherosclerosis, it is unclear whether systemic immunity or local tissue metabolism regulates this homeostasis. Here, we demonstrate that targeted deletion …

Emerging Evidence For Cannabis' Role In Opioid Use Disorder, Beth Wiese, Adrianne R Wilson-Poe

Open Access Publications

No abstract provided.

Cardiovascular Consequences Of Katp Overactivity In Cantu Syndrome, Yan Huang, Conor Mcclenaghan, Theresa M Harter, Kristina Hinman, Carmen M Halabi, Scot J Matkovich, Haixia Zhang, G Schuyler Brown, Robert P Mecham, Sarah K England, Attila Kovacs, Maria S Remedi, Colin G Nichols

Open Access Publications

Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in …

Plasticity Of Differentiated Cells In Wound Repair And Tumorigenesis, Part I: Stomach And Pancreas, Joseph Burclaff, Jason C Mills

Open Access Publications

For the last century or so, the mature, differentiated cells throughout the body have been regarded as largely inert with respect to their regenerative potential, yet recent research shows that they can become progenitor-like and re-enter the cell cycle. Indeed, we recently proposed that mature cells can become regenerative via a conserved set of molecular mechanisms ('paligenosis'), suggesting that a program for regeneration exists alongside programs for death (apoptosis) and division (mitosis). In two Reviews describing how emerging concepts of cellular plasticity are changing how the field views regeneration and tumorigenesis, we present the commonalities in the molecular and cellular …

Dysregulation Of Nad+ Metabolism Induces A Schwann Cell Dedifferentiation Program, Yo Sasaki, Amber R. Hackett, Sungsu Kim, Amy Strickland, Jeffrey Milbrandt

Open Access Publications

The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD

Hepatic Tristetraprolin Promotes Insulin Resistance Through Rna Destabilization Of Fgf21, Konrad T. Sawicki, Hsiang-Chun Chang, Jason S. Shapiro, Marina Bayeva, Adam De Jesus, Brian N. Finck, Jason A. Wertheim, Perry J. Blackshear, Hossein Ardehali

Open Access Publications

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat …

Maternal Diet And Morbidity Factors Associated With Low Birth Weight In Haiti: A Case-Control Study, Abdirahim Rashid, Thomas Park, Kenneth Macneal, Lora Iannotti, Will Ross

Open Access Publications

No abstract provided.

Hepatic Ketogenic Insufficiency Reprograms Hepatic Glycogen Metabolism And The Lipidome, D. André D'Avignon, Patrycja Puchalska, Baris Ercal, Yingju Chang, Shannon E. Martin, Mark J. Graham, Gary J. Patti, Xianlin Han, Peter A. Crawford

Open Access Publications

While several molecular targets are under consideration, mechanistic underpinnings of the transition from uncomplicated nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) remain unresolved. Here we apply multiscale chemical profiling technologies to mouse models of deranged hepatic ketogenesis to uncover potential NAFLD driver signatures. Use of stable-isotope tracers, quantitatively tracked by nuclear magnetic resonance (NMR) spectroscopy, supported previous observations that livers of wild-type mice maintained long term on a high-fat diet (HFD) exhibit a marked increase in hepatic energy charge. Fed-state ketogenesis rates increased nearly 3-fold in livers of HFD-fed mice, a greater proportionate increase than that observed for …

Identification Of A Rhythmic Firing Pattern In The Enteric Nervous System That Generates Rhythmic Electrical Activity In Smooth Muscle, Nick J. Spencer, Timothy J. Hibberd, Lee Travis, Lukasz Wiklendt, Marcello Costa, Hongzhen Hu, Simon J. Brookes, David A. Wattchow, Phil G. Dinning, Damien J. Keating, Julian Sorensen

Open Access Publications

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of …

Modulation Of Subsets Of Cardiac B Lymphocytes Improves Cardiac Function After Acute Injury, Luigi Adamo, Lora J Staloch, Cibele Rocha-Resende, Scot J Matkovich, Wenlong Jiang, Geetika Bajpai, Carla J Weinheimer, Attila Kovacs, Joel D Schilling, Philip M Barger, Deepta Bhattacharya, Douglas L Mann

Open Access Publications

Despite the long-standing recognition that the immune response to acute myocardial injury contributes to adverse left ventricular (LV) remodeling, it has not been possible to effectively target this clinically. Using 2 different in vivo models of acute myocardial injury, we show that pirfenidone confers beneficial effects in the murine heart through an unexpected mechanism that depends on cardiac B lymphocytes. Naive hearts contained a large population of CD19+CD11b-CD23-CD21-IgD+IgMlo lymphocytes, and 2 smaller populations of CD19+CD11b+ B1a and B1b cells. In response to tissue injury, there was an increase in neutrophils, monocytes, macrophages, as well as an increase in CD19+ CD11b- …

Novel Drug Targets For Ductus Arteriosus Manipulation: Looking Beyond Prostaglandins, Elaine L Shelton, Gautam K Singh, Colin G Nichols

Open Access Publications

Forty years ago, non-steroidal anti-inflammatory drugs were first reported to decrease systemic prostaglandin levels and promote ductus arteriosus (DA) closure. And yet, prolonged patency of the DA (PDA) remains a significant clinical problem, complicated by imperfect therapies and wide variations in treatment strategy. There are few pharmacology-based tools available for treating PDA (indomethacin, ibuprofen, and acetaminophen), or for maintaining DA patency (PGE