bluuebunny/crossref_metadata_2025_split huggingface dataset:
SPARC: Development of Human and Rodent Neuro‐Functionalized Computational Anatomical Models with Detailed Mapping of Peripheral Nervous System
Authors: Lloyd Bryn , Farcito Silvia , Cassarà Antonino , Zhuang Katie , Neufeld Esra , Kuster Niels 
Published: April 2020

There is a growing trend within the neuroscience community and the medical and health industries towards bioelectronics medicine: applying electrical signals to the nervous system to control and modulate functions of the body. These so‐called “electroceuticals” include numerous types of neurostimulation devices. To this end, we have developed reference animal and human anatomical models with unprecedented details in the peripheral nervous system, and connectivity to organs and muscles, which were functionalized with compartmental neuronal dynamics models to investigate device interactions with neuronal electrophysiology. The whole body rat model is being segmented from co‐registered high‐resolution (80 × 80 × 80 μm) magnetic resonance imaging (MRI) and computed tomography (CT) images of a female rat. The Visible Korean Human
(1) male and female cryosection data was used as the basis for the new human phantoms, due to the unique resolution (0.1 × 0.1 × 0.2 mm) and quality of these images. To model important peripheral nerves trajectories, the nerves were segmented and anatomically correct trajectories were extracted automatically using a set of anatomical rules specifying, which dorsal or ventral roots are connected to a given nerve. Functionalization is achieved by assigning electrophysiological models of myelinated and unmyelinated axons to axon trajectories within nerve models based on histological investigations documented in the literature
(2).The new human female and male human models called Yoon‐sun and Jeduk respectively, have been released as part of the Virtual Population
(3) V4.0 model library. The neuro‐functionalized rat will be completed soon. These models will become integration centers for NIH SPARC neuroanatomy and electrophysiology models
(4) and are expected to significantly influence the field of computational neuro‐electrophysiology research enabling studies of multi‐scale models with realistic anatomies and electrophysiology. Simulations will enhance our understanding of mechanisms of neurostimulation, e.g., by MRI gradient fields, provide experimental test‐beds for new therapeutic approaches and devices, and enable study of safety aspects, thus providing a tool to facilitate regulatory submissions and standardization activities.Support or Funding InformationThis work has been done with funding from NIH SPARC (1OT3OD025348‐01S1). The work on human anatomical models also received funding from Innosuisse (25290.1 PFLS‐LS) and KIAT.Computational rat model is shown with muscle tissue and limbs clipped to show interior tissue structures.Figure 1Side‐by‐side visualization of different tissue structures in the female computational human anatomical model ‘Yoon‐sun’. The model contains approximately 1100 separate tissues, with detailed bones, organs, muscles, blood vessels and peripheral nervous system (right).Figure 2
Exploring the Anti‐Cancer Properties of Efavirenz, in Comparison to Thalidomide
Authors: McNeil Rosie Thecla , Penny Clement Brian 
Published: April 2020

IntroductionIt has been suggested that “highly active antiretroviral therapy” (HAART) caused resolution of secondary pulmonary cancers. The question then is: ‘Do antiretroviral drugs (ARD) possess anti‐cancer properties, and if so, then how? Efavirenz, a Non‐Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and a first line drug used to manage HIV‐1 infection in both adults and children, is hereby investigated, in comparison with the known anti‐angiogenic and anti‐cancer drug, thalidomide.MethodologyEmbryonic CAMs of 30 fertile eggs of the domestic fowl (Gallus gallus variant Domesticus) were used as in vivo vascular test environment as follows: they were randomly allocated (n=6) to Human recombinant VEGF (R&D Systems), Thalidomide (Sigma‐Aldrich), Control 1 group treated with 70% ethanol (diluent), Control 2 group of embryos that were not manipulated and Efavirenz, (Sequoia Research Products).ResultsEfavirenz suppressed angiogenesis in Chick CAM in 100% of the subjects, showing more anti‐angiogenic properties than thalidomide. Embryonic viability (as a product of CAM angiogenesis) in all the experimental groups (n=6) was as follows: Control 6 (100%); VEGF 5 (83.3%); Thalidomide 1 (17%) and Efavirenz 0 (0.0%). Thalidomide failed to suppress angiogenesis in 17% of the subjects. Moreover, unlike thalidomide, Efavirenz also suppressed erythropoiesis.Discussion and ConclusionThe role of vascular endothelial growth factor (VEGF) in both developmental and pathological angiogenesis has been studied (e.g. Ferrara, 2000; Hagedorn et al. 2004; Losordo et al., 2004; Maharaj, 2006; Makanya et al., 2007). VEGF is a specific and potent mitogen for endothelial cells that is expressed in a distinct temporo‐spatial pattern during mammalian lung development. Since cancer cell growth and viability depends on neo‐vascularization, this property of Efavirenz, which is antagonistic to VEGF activities, may cause spontaneous resolution of HIV‐associated cancers in patients placed on HAART. In a future work, the mechanism of action of this notable ARD will be further investigated.Support or Funding InformationSupported by Sefako Makgatho Health Sciences University (SMU), Ga‐Rankuwa, Gauteng province of South Africa CAM Images CAM IMAGESCAM ImagesFigure 1
Results

Group

Mean Angiogenic effect

Standard Deviation

F

P‐value

VEGF

0.83

0.41

Thalidomide

0.17

0.41

9.306

*0.0005

Efavirenz

0

0

Control 1

0.67

0.52

Control 2

1

0

*indicates the p value is significant, p < 0.005. Possessing 17% angiogenicity implies the thalidomide failed as an anti‐angiogenic drug in the one embryo. Moreover, one of the embryos the thalidomide group reached the end of the experiment but died within seconds of exposure. CAM had one short thriving blood vessel on the CAM surface. In Efavirenz‐treated CAMS, no blood vessels were seen and neither was there any sign of erythropoiesis.
Experimental Diabetic Nephropathy is Associated with Increased Expression of Inflammatory Proteins in the Kidney
Authors: Deshmukh Hemalata , Prabhakar Sharma 
Published: April 2020

AimsDiabetic Nephropathy (DN) is the leading cause of end stage renal disease (ESRD) but pathogenesis of DN is far from clear and hence the treatment remains sub‐optimal. Many studies alluded to the role of chronic inflammation in DN. A recent study in human DN identified 17 different inflammatory proteins collectively called Kidney Risk Inflammatory Signature (KRIS) molecules. (Niewczas et al Nat Med 2019) . These proteins, mostly belonging to tumor necrosis factor (TNF) family predicted risk of progression to ESRD. We tested the hypothesis that the expression of some of such KRIS proteins in experimental models including renal cells cultured in high ambient glucose concentration and kidneys from diabetic animal models is increased. 2.MethodsTo test our hypothesis, we used rat mesangial cells (RMC) in culture and ZSF rats —an established animal model for DN. RMC were grown in DMEM media with either low glucose (5.5 mM) or high glucose (25 mM) for 48 hours and expression of these molecules was determined by Western Blot technique and ELISA. Specifically, we examined TNFα R1 and IL15α proteins. In addition RMC grown in low glucose media for a week were incubated in high glucose media for 48 hours and examined for KRIS proteins. ZSF rats (both male and female) were grown on Purina 50008 diet to render them hyperglycemic and euthanized at 40 weeks of age. Male CD rats (non‐diabetic) were used as controls. Blood and urine samples were obtained at the start and end of the study. Kidneys were harvested, tissue was homogenized and homogenates examined for protein expression by WB. 3.ResultsZSF rats developed obesity, diabetes, hyperlipidemia and proteinuria. Male ZSF rats were heavier (650 gm vs 510 gm) and more hyperglycemic (295 mg/dl vs.210 mg/dl) than females. CD rats were normoglycemic with normal kidney function. Kidney homogenates from ZSF rats demonstrated increased expression of both TNFαR1 and IL15α proteins. These changes were more significant in male than female ZSF rats. RMC exposed to high glucose for 48 hours either directly or after chronic exposure to low glucose demonstrated similar increase in expression of TNFαR1 and IL15α proteins compared to low glucose. 4.ConclusionsIn renal cells exposed to high glucose and in ZSF (diabetic) rats with nephropathy, the expression of TNFαR1 and IL15α proteins, which are inflammatory mediators are increased. Male ZSF rats expressed more significant disease and increase in KRIS proteins indicating the need for further investigations into the role of gender in disease progression in murine models of DN. These results suggest that inflammatory proteins from TNF family are overexpressed in diabetic nephropathy models and that renal injury from chronic hyperglycemia may be mediated by at least in part by chronic inflammation. 5.Support or Funding InformationThis research was funded by Larry and Jane Woirhaye Memorial Research FoundationInflammatory Protein Expression in RMCFigure 1
Reteplase Encapsulated in Minocycline‐Containing Nanoparticles Retains Thrombolytic Activity
Authors: Nong Jia , Marcos-Contreras Oscar A. , Glassman Patrick M. , Muzykantov Vladimir M. 
Published: April 2020

Thrombolytic therapy is a critical potion of the treatment regimen for a number of life‐threatening conditions, including cardiovascular disease and stroke. Although thrombolytic drugs have shown profound effect on dissolving clots, short half‐life (t1/2 of minutes) and hemorrhagic complications are significant challenges associated with their use. Nanotechnology has shown to prolong the blood circulation time of drugs and to improve their efficacy and safety. However, leakage of thrombolytic drug‐loaded nanocarriers (NC) from intravascular compartment into brain parenchyma due to compromised blood‐brain barrier integrity following ischemia can still lead to adverse effects. Therefore, it is necessary to combine neuroprotection with thrombolysis therapy in ischemic stroke treatment. Here we have developed NC that contains reteplase, an engineered tissue‐type plasminogen activator, and minocycline, a neuroprotective agent. The formation of the NC is based on metal ion‐assisted self‐assembly of complexes using negatively charged heparin and minocycline. The reteplase is incorporated into the NC through a protein binding site on minocycline. The entrapment efficiency of reteplase and minocycline were 91.8% and 78.3%, respectively. By tracing radiolabeled reteplase, our results showed that the NC significantly increased the blood circulation time of reteplase compared to free reteplase (Panel A). In the in vitro clot lysis assay, the free reteplase or reteplase‐loaded NC (NC(ret)) were incubated with pre‐formed plasma clots and the results indicated that the NC formation did not compromise the thrombolytic function of reteplase (Panel B). In the pulmonary embolism model, free reteplase or NC(ret) was injected 10 min after 125I‐labeled microemboli. Blood and organs were collected 1 hr‐post injection of microemboli to study the retention of clot in the lung after the treatment. Our results showed that the reteplase‐loaded NC significantly reduced the clot retention in the lung (Panel C). All together, we have developed NC containing neuroprotective agent that maintain the function of thrombolytic drug. Future studies will be focused on evaluating the neuroprotective properties of the NC, relative to free drug.Support or Funding InformationNIH (RO1 HL128398‐02 and RO1 HL 143806‐01), Cardiovascular Institute of Philadelphia (400‐4119‐2)Characteristics of Reteplase‐Containing Nanocarriers. A: Blood pharmacokinetics of free reteplase (ret) and NC‐encapsulated reteplase (NC(ret)). Comparisons by students t‐test. B: In vitro fibrinolytic activity of ret and NC(ret). C: Lysis of pulmonary emboli following injection of ret and NC(ret). Comparisons by 1‐way ANOVA with Dunnett's test. * denotes p<0.05, ** p<0.01, *** p<0.001.Figure 1
Mechanism of Activation of the Ubiquitin E3 Ligase, Parkin
Authors: Gehring Kalle , Sauvé Véronique , Sung George , Kozlov Guennadi 
Published: April 2020

The Parkinson disease associated proteins, Parkin and PINK1, together comprise a mitochondrial quality control system that promotes neuronal survival through autophagy of damaged mitochondria. In the pathway, PINK1 acts as a sensor of depolarized mitochondria and phosphorylates ubiquitin to recruit and activate Parkin on the mitochondrial outer membrane. Parkin ubiquitinates mitochondrial proteins, which leads to the removal of the damaged mitochondria through mitophagy. We have carried out structural and functional studies of Parkin to understand its regulation and mechanism of activation
1–
3. Parkin exhibits low basal activity as a ubiquitin ligase and requires activation both in vitro and in cells. Multiple features inhibit Parkin activity: the E2‐binding site on RING1 is blocked, the catalytic site is partially occluded, and the incoming E2~Ub linkage is far from the parkin catalytic site (Fig.
1). In response to mitochondrial damage, Parkin is activated by PINK1 via a two‐step mechanism involving binding of Parkin to phosphorylated ubiquitin and a large‐scale conformational change induced by Parkin phosphorylation (Fig.
2). Positive feedback in the Parkin/PINK1 pathway generates a binary, all‐or‐nothing switch for the induction of mitophagy. These structural studies are critical for understanding how Parkin and PINK1 protect neurons and provide a framework for the design of small molecules for treating Parkinson disease.Support or Funding InformationSupported by the Michael J Fox Foundation, the Canadian Institutes of Health Research, and the Canada Research Chair program.Autoinhibited conformation of Parkin.The crystal structure of Parkin revealed that the catalytic and E2‐binding sites are occluded by interdomain contacts mediated by the ubiquitin‐like domain, Repressor Element of Parkin (REP) and RING0 domain
1. Disruption of the inhibitory contacts derepresses ligase activity.Figure 1Active complex of Parkin with ubiquitin‐charged E2 enzyme and phospho‐ubiquitin (Ub).The crystal structure of activated Parkin showed that phosphorylation of the Parkin Ubl domain induces a large conformational change allowing the catalytic RING2 domain to interact with the bound E2~Ub
3. Hydrogen‐deuterium exchange experiments confirm that the RING2 domain is released and accessible upon Ubl binding to RING0.Figure 2
A Rodent Model of Reperfused Hemorrhagic Myocardial Infarction
Authors: Nair Anand R. , Cokic Ivan , Johnson Eric , Yang Hsin-Jung , Francis Joseph , Dharmakumar Rohan 
Published: April 2020

BackgroundIntramyocardial hemorrhage following reperfusion is strongly associated with major adverse cardiovascular events (MACE) in myocardial infarction (MI) patients. Previous work from by us and others have shown that prolonged ischemic periods prior to reperfusion drives the development of intramyocardial hemorrhage in large animal models, characterized by the presence of iron composites within the infarct zones in the acute and chronic periods following MI. Yet the mechanisms contributing to the adverse outcomes associated with hemorrhagic myocardial infarction (hMI) is not well understood, partly due to the lack of small animal models of hMI. Here, we demonstrate a novel rodent model that mimics reperfused hMI.Methods & ResultsSprague‐Dawley rats underwent either a 90‐min ischemia and then reperfusion (I/R) (n=22), a 60‐min I/R (n=20) or 30‐min I/R (n=18) of the left anterior descending coronary artery. Sham rats were used as controls. 90‐min I/R always yielded hMI, while 30‐min I/R consistently yielded non‐hMI with no reflow. But, 60‐min I/R resulted in both hMIs (60%) and non‐hMI (40%), with both groups showing evidence for zones of no reflow within MI. Ex‐vivo late‐gadolinium‐enhancement (LGE) and T2* cardiac MRI performed on excised hearts from 90‐min I/R rats revealed colocalization of iron deposits with the scarred tissue. Histological studies verified tissue damage (H&E) detected on LGE and the presence of iron (Perl’s stain) observed on T2*‐CMR. Protein expression of proinflammatory markers (TNF‐α, IL‐1β and MMP‐9) were increased in the 90‐min I/R group when compared to sham‐controls and 30‐min I/R groups. Further, transmission electron microscopy performed on 90‐min I/R myocardium showed accumulation of granular iron particles within the phagosomes.ConclusionShort (30‐min) and long (90‐min) ischemic periods before reperfusion consistently resulted in non‐hMI and hMI respectively in rats. This novel rodent model can be a useful tool to elucidate the molecular mechanisms of cardiovascular pathology associated with reperfused hemorrhagic myocardial infarctions.Late Reperfusion Leads to Development of hMIRepresentative LGE and T2*‐w images from ex‐vivo cardiac MRI showing myocardial infarction and hemorrhage respectively from late‐reperfusion (90‐min I/R) and early‐reperfusion (30‐min I/R) groups. Histological images of H&E staining from regions negative for MI (green box) and H&E and Perl’s stained images from regions positive for MI (blue box) are shown.Figure 1
Leishmania major degrades murine CXCL1
Authors: Yorek Matthew S. , Mazgaeen Lalita , Gurung Prajwal 
Published: April 2020

Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year. Innate immune system plays a central role in controlling L. major infection by initiating a signaling cascade that results in the production of pro‐inflammatory cytokines and recruitment of both innate and adaptive immune cells. Upon infection with L. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils and macrophages to the site of infection. Herein, we report that L. major specifically targets murine CXCL1 for degradation and this allows L. major to establish infection in the host. The degradation of CXCL1 is not dependent on host factors because L. major can directly degrade recombinant CXCL1 in a cell‐free system. This degradation is specific to murine CXCL1 as murine CXCL2 as well as human CXCL1 and CXCL2 are not degraded. Using mass spectrometry, we have determined that the unknown L. major protease cleaves at the C‐terminal end of murine CXCL1. Using protease inhibitors our data suggest that the L. major unknown protease is a metalloprotease involved in the direct degradation of CXCL1. Finally, we have tested a peptide spanning the cleavage site which can be used to inhibit L. major protease activity and pathogenesis.Support or Funding InformationThis work was supported by NIH K22, NIEHS P30 and University of Iowa Start‐up funds to P.G.Upon infection with L. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils and macrophages to the site of infection. We have identified that a secreted L. major protease cleaves at the C‐terminal end of murine CXCL1. This protease is likely a metalloproteases as Zn2+ chelators inhibit degradation of CXCL1. The degradation of CXCL1 dampens the hosts ability to resolve infection.Figure 1
Endogenous hydrogen sulfide improves vascular remodeling through PPARδ/SOCS3 signaling
Authors: Tian Danyang , Wu Yuming , Teng Xu , Jin sheng , Chen Yuhong 
Published: April 2020

Mounting evidences demonstrated the deficiency of hydrogen sulfide (H2S) implicated the progression of cardiovascular diseases. This study aimed to investigate the beneficial role of endogenous H2S on vascular remodeling in CSE inhibitor, DL‐propargylglycine (PPG), treated mice. The deficiency of endogenous H2S exhibited aggravated active and passive contraction, coupled with thicken aortic walls, vascular remodeling with collagen deposition, increased phosphorylation of STAT3 and decreased PPARδ, SOCS3, which were reversed by sodium hydrosulfide chronic treatment for 4 weeks. Aggravated active and passive contraction, upregulated p‐STAT3, downregulated SOCS3 in PPG mice aortas could be corrected by PPARδ agonist GW501516. On the contrary, PPARδ antagonist GSK0660 exhibited opposite effects on vascular contraction, expressions of p‐STAT3, SOCS3 in aortas. PPG inhibited expression of PPARδ and SOCS3, stimulated the phosphorylation of STAT3, inflammatory molecules production in vascular smooth muscle cells (VSMCs). PPARδ agonist normalized the phenotype transformation from contractile to synthetic in both PPG mice aortas and PPG treated VSMCs. NaHS offered similar functions with PPARδ agonist. In a word, endogenous H2S benefits against vascular remodeling through preserving PPARδ/SOCS3 inflammatory signaling pathway. Deficiency of endogenous H2S should be considered as a risk factor for VSMCs dysfunction.Support or Funding InformationThis study was supported by the National Natural Science Foundation of China (Grant 31671185, 31871154, 91849120), the Natural Science Foundation of Hebei Province of China (H2017206269), the Hebei Province for Innovation Talents Support Plan (Grant LJRC017), and the Research Foundation for Higher Education of Hebei Province (GCC2014032, ZD2019027).The loss of endogenous H2S aggravated LPS‐induced myocardial dysfunction.Figure 1
p65‐mediated Mettl3/Mettl14 transactivation and m6A‐dependent TGF‐β1 translation aggravates fibrosis progression in nonalcoholic steatohepatitis
Authors: Feng Yue , Dong Haibo , Sun Bo , Hu Yun , Guo Shihui , Yang Yang , Jia Yimin , Zhao Ruqian 
Published: April 2020

N6‐methyladenosine (m6A) RNA modification has been reported to play an important role in hepatic carcinoma (HCC). Non‐alcoholic steatohepatitis (NASH) predisposes the progressive development of liver fibrosis, cirrhosis and HCC, yet whether and how m6A is involved in the critical transition of NASH to fibrosis remains elusive. Here we demonstrate an up‐regulation of Mettl3/Mettl14 and global m6A hypermethylation in the liver of high‐fat diet‐induced NASH and fibrosis rat model, with increased serum lipopolysaccharide (LPS). LPS‐induced profibrotic TGF‐β1 translation in Kupffer cells (KC), which is prevented by Mettl3/Mettl14 knockdown, coincides with higher m6A level on 5’UTR of TGF‐β1 mRNA. NF‐κB p65 transactivates Mettl3/Mettl14, which leads to
m
6
A‐dependent translation of TGF‐β1 mRNA in a cap‐independent manner. Our findings identify m6A modification as a new player in p65‐mediated inflammatory signaling and TGF‐β1‐activated fibrosis progression in NASH.Support or Funding InformationThis work was supported by the National Key Research and Development Program of China (2016YFD0500502), the National Natural Science Foundation of China (31672512) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).m6A modification is essential in the process of NASH to liver fibrosis by connecting gene transcription with Mettl3/Mettl14. The regulatory role of the classic transcriptional factors NF‐κB p65, that keeps high m6A modification of the TGF‐β1 mRNA 5’UTR provides fundamental insight into the post‐transcriptional gene regulation network in KC activation, revealing potential novel ways to regulate the process of NASH to liver fibrosis.Figure 1