bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small HDL, diabetes, and proinflammatory effects in macrophages
Authors: Kothari Vishal , He Yi , Kramer Farah , Barnhart Shelley , Kanter Jenny E , Tang Jingjing , Frey Jeremy M , Vaisar Tomas , Heinecke Jay W , Bornfeldt Karin E 
Published: June 2021

Atherosclerosis, an inflammatory disease of the arterial wall, is the commonest cause of cardiovascular disease (CVD) events. Elevated levels of high‐density lipoprotein (HDL) cholesterol are generally believed to protect against CVD and to reduce inflammatory activation of macrophages, a key cell type in lesions of atherosclerosis. However, HDL can also exert proinflammatory effects in macrophages by inducing cholesterol depletion. Because small HDL (7–8.5 nm diameter) is most effective in removing cholesterol from cells by the ABCA1 pathway, we hypothesized that small HDL is the most proinflammatory HDL population. Small‐, medium‐ and large HDL populations were isolated from a human apolipoprotein A‐I transgenic LDL receptor‐deficient mouse model (APOA1Tg;Ldlr−/−). Depletion of cholesterol by HDL increased the ability of toll‐like receptor (TLR) ligands to induce proinflammatory mediators in macrophages. This effect was prevented by cholesterol loading of the macrophages. Small HDL had a significantly stronger effect on Tnfa (3‐fold over LPS alone) and Il1b (2.5‐fold over LPS alone) gene expression than medium or large HDL particles. Inhibition or deletion of the sheddase ADAM17 in macrophages prevented the proinflammatory effects of HDL. Patients with type 1 diabetes mellitus (T1DM) exhibit an increased risk of CVD despite having normal or high HDL‐cholesterol. To investigate the effect of diabetes on HDL subpopulations, we crossed a virally‐induced mouse model of T1DM (Ldlr−/−;GpTg) with the human APOA1Tg;Ldlr−/− mouse. The mice (APOA1Tg;Ldlr−/−;GpTg, n=8–10) were injected with a liver‐specific adeno‐associated virus driving expression of human cholesteryl ester transfer protein (hCETP) to mimic human physiology. Diabetic mice had an increased HDL particle concentration (~2‐fold) associated with a significant increase in serum HDL cholesterol efflux capacity through both ABCA1 and ABCG1, compared with non‐diabetic mice. The largest increase was in the small HDL particle concentration (15 μM vs 6 μM in non‐diabetic mice). Moreover, resident peritoneal macrophages from diabetic mice exhibited increased cytokine gene expression, as compared with non‐diabetic littermates. Our findings demonstrate that higher levels of small HDL, as observed in a mouse model of diabetes, can exacerbate inflammatory activation in non‐lipid loaded macrophages in an ADAM17‐dependent manner. We have found similar changes in HDL concentration and function in humans with T1DM, suggesting that our mouse model might provide novel insights into CVD risk in T1DM patients.Support or Funding Informationfunded in part by the National Institutes of Health, grants DP3DK108209, P01HL092969, P30 DK017047, and P01HL128203This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biomarkers of Hemostatic Dysregulation and Inflammation in Lymphoma: Potential Relevance to Thrombogenesis
Authors: Bontekoe Emily , Antic Darko , Jocik Vera , Hoppensteadt Debra , Siddiqui Fakiha , Baig Nausheen , Fareed Jawed 
Published: June 2021

ObjectiveCancer‐associated thrombosis and venous thromboembolism (VTE) continue to be a major complication of malignancy. There is increased incidence of clinically overt deep thrombosis (DVT) in cancer patients. Profiling biomarkers involved in hemostatic dysregulation and inflammatory processes in the lymphoma patient population may provide additional insight into the pathogenesis of thrombotic complications in lymphoma. This study aimed to profile hemostatic dysregulation and inflammatory biomarkers in patients with Hodgkin lymphoma, non‐Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. The primary hypothesis of this study is that hemostatic activation and inflammatory biomarkers may be increased in lymphoma patients.MethodsCitrated blood samples were collected from the Hematology Clinic, University of Belgrade, Serbia. Plasma levels of plasmin activator (PAI‐1), D‐dimer (DD), Factor XIIIa (XIIIa), C‐reactive protein (CRP), microparticle (MP), Von Willebrand Factor (vWF), Protein S (PS), urokinase like plasminogen activator (uPA), tumor necrosis factor alpha (TNF‐α), Beta 2 glycoprotein (β2GPI), and Fibronectin (FN) were measured in 96 lymphoma patients, along with a control/pooled plasma prepared from 50 healthy normal individuals. Commercially available ELISA kits were used for profiling these markers. All results were compiled and calculated as mean + SD and % change.ResultsThe results from this study demonstrated elevated levels of DD, CRP, vWF, TNF‐α, uPA, and PS in comparison to normal human plasma. Plasma levels were decreased for PAI‐1 (3%), XIIIa (5%), MP (46%), β2GPI (8%) and FC (15%). Of the lymphoma patient samples with elevated levels of biomarkers, 34% of individual patients had elevated DD, 66% had elevated CRP levels, 50% had elevated vWF levels, 80% had elevated levels of TNFα, and 90% had elevated levels of uPA. However, when comparing each specific type of lymphoma in relation to the ratio of each biomarkers (DD, CRP, vWF, TNF‐α, and uPA), there was no significant difference between individual lymphoma subgroups (p>.05).ConclusionThe elevated levels of hemostatic dysregulation and inflammatory biomarkers in lymphoma patient samples are suggestive of an increased VTE risk in these patients. The elevated DD, CRP, vWF, TNFα, and uPA clearly suggest a trend towards increased thrombogenesis. Individual patients showing increased amounts of each elevated biomarker proves the significance and use of D‐dimer, CRP, vWF, TNFα and uPA in identifying the level of thrombosis risk.Support or Funding InformationNone.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
How comparative anatomy provides insight into human anatomy
Authors: Throckmorton Zachary 
Published: June 2021

Human anatomy instructors in the United States have remarkably varied backgrounds for an academic discipline; we work alongside those trained at every scale of biological organization, from molecular genetics to ecology, and these different training regimens provide anatomy departments with a variety of strengths. In this talk, I outline and detail how comparative whole organism anatomy can be useful in teaching human anatomy, primarily in the context of traditional lectures (at both the undergraduate and graduate levels) through three broad categories. First, understanding how relatively anatomically more complex animals like humans develop embryologically is facilitated by appreciating the anatomy of relatively simpler animals like platyhelminth and annelid worms; furthermore, some developmental defects are better understood through the lens of evo‐devo (i.e., normal conditions in other animals are sometimes abnormal conditions in humans, like syndactyly in bats). Second, comparative functional biomechanics yields insight into normal and abnormal musculoskeletal function. The trade‐offs between joint stability or flexibility, or power arm ratios for power or speed, are well‐illustrated by extreme morphology of homologous structures in other animals, such as the incredibly speedy ankles of cheetahs compared to the relatively powerful ankles of humans. Third, much of any scientific professional's development relies upon mastery of Greek‐ and Latin‐derived vocabulary; genus and species names of animals can help anatomy students better remember structural terms. For example, Pterodactylus was a remarkable genus of flying reptiles, and understanding the etymology of the Greek words “pteron” (wing) and “dactyl” (finger) helps students appreciate how the sphenoid bone's pterygoid process and the pterygoid muscles are wing‐shaped, and the clinical conditions syndactyly and polydactyly refer to webbed or conjoined fingers and extra fingers, respectively.Application of human anatomy knowledge by physicians to animals gave rise to the field of comparative anatomy in the 1600s; Edward Tyson, a human physician, recognized chimpanzees were more like humans than monkeys, and porpoises were more like land mammals than fish from detailed comparative gross dissections. These observations of patterns in the anatomy of humans and animals contributed to Darwin and Wallace independently developing the theory of evolution, which underpins the national One Health initiative. Recognizing humanity's shared ancestry with animals ensures a measure of shared descendance in the instruction of human and animal anatomical education.Support or Funding InformationThis work was supported by the American Association of Anatomists and the Arkansas College of Osteopathic Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dopaminergic Circuits in Reward and Aversion
Authors: Lammel Stephan 
Published: June 2021

The mesocorticolimbic dopamine (DA) system, which is composed of DA neurons in the ventral tegmental area (VTA) projecting to nucleus accumbens and medial prefrontal cortex, has been intensively studied because of its importance in reward processing, drug addiction and other neuropsychiatric diseases. Importantly, while VTA DA neurons were thought to form a homogeneous cell population, recent research has demonstrated a much greater diversity of VTA DA cell type and function. Accordingly, VTA DA neurons encode much more than reward and also contribute to negative affect such as aversion and social defeat stress. How VTA DA neurons could mediate both reward and aversion is currently unknown and an important goal of my research. In my presentation, I will discuss work from the lab that has elucidated the circuit architecture and function of the reciprocal connectivity in the mesolimbic DA system (Yang et al., 2018; Neuron). Moreover, I will discuss recent data that demonstrate the identification of a subcircuit within the mesolimbic DA system that contributes to the encoding of conditioned and unconditioned aversive stimuli (de Jong et al., Neuron, in press). Collectively, our work suggest that we need to develop a new perspective on the DA circuitry that will guide future treatment strategies for addiction and other neuropsychiatric disorders where dysfunction of the neural systems underlying motivated behaviors have been strongly implicated.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
SK2/3 modulation of neural development
Authors: Ogundele Olalekan M 
Published: June 2021

Regulation of ionotropic NMDA Receptor (NMDAR) potentiation at hippocampal synapses is dependent ‐ partly ‐ on ion channel gating by Ca++ activated K channels (SK2/3). Given that NMDAR is involved in the regulation of neuronal migration and synaptic development, the objective of this study is to determine whether an increased activity of SK2/3 during a critical period of brain development can alter neural circuit formation.A single dose of intrahippocampal injection of CyPPA (SK2/3 potentiator) was stereotactically injected into the hippocampus and cortex of post‐natal day (PND) 2 mice [SK2/3(+)]. At PND55, the brain of the treated animals and sham were microdissected and processed for immunofluorescence (Saggital) and immunoblot analysis.Here, we showed that pharmacological hyperactivation of SK2/3 in the neonatal brain significantly ablated the expression of synaptic kinases that are associated with NMDAR signaling in development, and adult synaptic function. Notably, CaMKIIα, PI3K, and PKB expressions were significantly downregulated in the hippocampus of SK2(+) mice when assessed at PND55. These changes were associated with altered neuronal distribution and path of migrating neural projections in the hippocampus and cortex of mice. Aberrant migration of lower layer cortical neurons (Tbr1+) neurons was evident in the layers of the cortex and the CA1 of the hippocampus. The distribution of synaptic structural proteins ‐ Homer1 and F‐actin – further underscores the re‐distribution of neural projections and synapses in SK2/3(+) brain.Support or Funding InformationLSU SVM Faculty Start up, LSU SVM Corp GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Circadian Control of Animal Physiology
Authors: Sehgal Amita , Zhang Shirley , Artiushin Greg 
Published: June 2021

We are interested in the mechanisms that generate circadian (~24 hour) cycles of physiology and behavior. Our studies use primarily a Drosophila model, which was invaluable for dissecting molecular mechanisms of the clock, but they also include mammalian models where appropriate. We are interested in the control of behavior by brain clocks and in the control of physiology by brain and peripheral clocks. We recently identified a clock in the Drosophila blood brain barrier (BBB) that confers a 24 hour rhythm on to permeability of the BBB. Specifically, the BBB clock regulates the activity of efflux transporters, such that these transporters pump xenobiotics out of the brain during the day, but are less active at night, thereby increasing BBB permeability at night. The underlying mechanism involves rhythmic expression of gap junctions that serve to maintain 24 hour cycles of magnesium, a positive regulator of efflux transporters, in BBB cells. As many drugs are targets of efflux transporters, we asked if permeability of such drugs is different at different times of day. Indeed, we found that phenytoin/Dilantin has time‐of‐day specific effects in a drosophila seizure model. In recent work, we have characterized rhythms of the BBB in mammalian cells and are addressing the relevant mechanisms.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
How Replication Stress Drives Genome Instability
Authors: Forsburg Susan 
Published: June 2021

DNA replication stress can result from intrinsic challenges (such as defective replication proteins, collisions with transcription machinery, or synthesis through repetitive sequences), or extrinsic agents (such as agents that damage DNA (UV, MMS, CPT) or starve for nucleotides (HU)). The cell deploys a variety of checkpoint and repair proteins to manage accumulation of single stranded DNA, replication fork stalling, fork regression and recombination intermediates to repair. Increasingly, it is clear that the response to stress is not just important for completion of S phase, but impacts mitosis and faithful chromosome segregation. Thus, response to replication stress is an initial barrier to malignant transformation.Our study employs a model genetic system, the fission yeast S. pombe. We are using mutations that attenuate core components of the replication machinery or epigenetic components, to investigate different kinds of stress and how they engage, or evade, the normal cellular response. Our approach is grounded in analysis of the intact cell and determining the consequences of replication stress including mutation, chromosome mis‐segregation, or gross chromosome rearrangements and translocation. A key component is monitoring stress responders in real time using dynamic live cell imaging. Recent studies have focused on how checkpoint evasion leads to ongoing mitosis and chromosome rearrangement, and on how the response of cells in the meiotic pathway differs from the vegetative cell cycle. Current investigations will be discussed.Support or Funding InformationNIH R35 GM118109This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
PMNs promote Non‐Homologous End‐Joining (NHEJ)‐mediated survival of colorectal cancer cells in inflammatory setting
Authors: Bui Triet M , Wiesolek Hannah , Butin‐Israeli Veronika , Sumagin Ronen 
Published: June 2021

Exacerbated Inflammation that can be driven by neutrophil (PMN) infiltration is one of the major risk factors for development and progression of colorectal cancer (CRC). Using a biopsy‐based acute‐injury model, we previously showed that miRNAs derived from PMN‐microparticles (MPs) inhibit Homologous Recombination (HR), leading to accumulation of Double‐Strand Breaks (DSBs). These observations led us to investigate the effects of long‐term exposure of intestinal epithelial cancer cells HCT116 to PMNs and PMN‐MPs. Consistent with the acute‐injury model, long‐term PMN‐MP treatment led to HR suppression with concomitant accumulation of DSBs, increased aneuploidy and apoptosis within 7 population doublings (PD7). With continued HR inhibition by PMN‐MPs, by PD12 we observed an upregulation of Non‐Homologous End‐Joining (NHEJ) activity. Importantly, DSBs and cell apoptosis were also significantly decreased at PD12, despite elevated aneuploidy, suggesting that PMN‐induced NHEJ activation promotes tumor cell survival and aneuploidy.To test this in vivo, we employed a tumor xenograft model in conjunction with an antibody‐based PMN depletion strategy. Consistent with in vitro observations, HR inhibition, NHEJ upregulation, decreased apoptosis, and increased aneuploidy were confirmed in PMN‐infiltrated (PMN+) tumors as compared to PMN‐depleted (PMN−) tumors. To examine whether PMNs indeed provide survival advantage to tumor cells and help them overcome DSB accumulation, we performed ex vivo clonogenicity assay, where cells were challenged with DSB‐inducing agents Camptothecin (CMPT). PMN+ tumor cells were resistant to CMPT treatment and were able to more efficiently re‐propagate compared to parental HCT116 cells and PMN‐ tumor cells, which underwent apoptosis in response to CMPT‐induced genotoxic stress. Consistently, in PMN‐ tumor cells, upregulation of H2AX and cell cycle regulatory genes (p16INK4a, p27Kip1, TP53, p21Cip1) was observed, indicating inefficient DNA Damage repair. As such, our findings define a new regulatory role of PMNs in promoting CRC survival during carcinogenesis.Support or Funding InformationThis work was supported by grants from the National Institutes of Health (NIH) DK101675, Digestive Health Foundation, Chicago and by the Robert H. Lurie Comprehensive Cancer Center (Eisenberg Scholar grant) and by American Cancer Society to Ronen Sumagin.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Roles for Notch‐Sox9 in biliary epithelial cells‐to‐hepatocytes differentiation during liver regeneration
Authors: Ko Sungjin , Russell Jacquelyn O. , Shin Donghun Pal , Monga Satdarshan Pal 
Published: June 2021

Liver regeneration after most forms of injury is mediated through proliferation of hepatocytes. However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair. Promotion of LPC‐to‐hepatocyte differentiation in patients with chronic liver disease could serve as a potential new therapeutic option, but first requires the identification of the molecular mechanisms driving this process. Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development, and has also been implicated in regulating LPC differentiation during regeneration. SRY‐related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development. We have recently shown that inhibition of Hdac1 activity during liver regeneration in both zebrafish and mouse models enhances sox9 expression in LPCs and impairs LPC‐to‐hepatocyte differentiation. Therefore, we hypothesized that inhibition of Notch signaling would promote LPC‐to‐hepatocyte differentiation by repressing sox9 expression. To this end, we blocked Notch activation during liver regeneration through treatment with γ‐secretase inhibitor LY411575 in a zebrafish LPC‐driven regeneration model and demonstrated enhanced induction of Hnf4a in LPCs. Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction. Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC‐specific Sox9b overexpression impaired LPC‐to‐hepatocyte differentiation. Moreover, LY411575 treatment promoted the differentiation of murine LPCs into hepatocytes in vitro. Lastly, we administrated LY411575 to mice with hepatocyte‐specific deletion of β‐catenin, which induces differentiation of LPCs into hepatocytes following a choline‐deficient, ethionine‐supplemented (CDE) diet. We also examined the effect of liver‐specific Sox9 ablation upon CDE diet liver injury. Our results will elucidate the detailed roles for Notch‐Sox9 signaling in liver regeneration and LPC‐to‐hepatocyte differentiation.Support or Funding InformationThe work was supported by NIH grants to D.S. (DK101426), S.P.M. (DK62277, DK100287, CA204586), and J.O.R. (T32EB0010216, 1F31DK115017). S.P.M. is an Endowed Chair for Experimental Pathology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.