bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of Prokineticin 2 and Prokineticin Receptor 1 in low shear stress‐induced vascular remodeling in mice
Authors: Jiang Zhilong , Huang Qi , Jiang Yue , Liao Qingchuan , Zhang Youzhi 
Published: April 2020

Low shear stress induced vascular remodeling emerging atherosclerosis. Prokineticin 2 (PK2) via prokineticin receptor 1(PKR1), is an angiogenic factor. However, little is known about the effect of the low shear stress on PK2/PKR1 signaling in vascular remodeling. The present study aimed that the PK2/PKR1 signaling was involved in low shear stress‐induced vascular remodeling in vivo. Higher protein expression of PK2 and PKR1 was examined in the aortic arch exerting low shear stress in physiological conditions. Further, in pathological conditions, murine model of partial carotid ligation exerted low shear stress, which induced neointima formation with media and adventitia growth, emerging vascular remodeling. It was worth noting that positive staining of PK2 distributed more in neointima area in ligated mice. Lastly, ligated carotid arteries also exerted higher protein expression of PK2 and PKR1. Thus, PK2/PKR1 signaling was involved in the low shear stress‐ induced vascular remodeling in physiological curvature of aortic arch and pathological ligation, which attempted to analyze a potential role of PK2/PKR1 signaling in vascular remodeling associated with atherosclerosis.Support or Funding InformationThe National Natural Science Foundation of China (NO. 81603110).
Mitochondrial Dysfunction Contributes to Germ Cell Apoptosis via the JNK/p53/ survivin Pathway
Authors: Al-Maghrebi May , Fadel Fatemah , Al-Kandari Nora , Khashab Farah , Al-Saleh Farah 
Published: April 2020

The aim is to show whether the c‐Jun N‐terminal kinases (JNK) signaling is a regulator of oxidative DNA damage, germ cell apoptosis (GCA) and mitochondrial dysfunction during testicular ischemia reperfusion injury (tIRI) using the JNK inhibitor SP600125. Male Sprague‐Dawley rats (n=36) were equally divided into 3 groups: sham, tIRI only and tIRI + SP600125 (15 mg/Kg, i.p.). Testicular ischemia was induced for 1 hour followed by 4 hours reperfusion prior to animal sacrifice. Spermatogenesis was evaluated by light microscopy using the Johnsen’s scoring system. Expression of oxidative stress and GCA genes and proteins were evaluated by real‐time PCR and colorimetric assays, respectively. Activation of the JNK/p53/survivin signaling pathway was detected by immunofluorescence (IF) staining. Indicators of mitochondrial dysfunction were examined by Western blot and colorimetric assays. In comparison to sham group, the tIRI testes showed a significant decrease in the antioxidant activity of superoxide dismutase, which was associated with increased lipid and protein oxidation products. Oxidative DNA damage was reflected by a significant increase in the number of single and double DNA strand breaks and increased concentration of 8‐OHdG DNA adducts. Spermatogenic damage was associated with the activation of caspases 9 and 3 and an elevated Bax to Bcl2 ratio. This was also accompanied by a significantly heightened IF expression of the phosphorylated forms of JNK and p53 paralleled with the down‐regulation of survivin. Mitochondrial dysfunction was reflected by NADH depletion, overexpression of uncoupling protein 2 and increased levels of cytochrome c protein. Such tIRI‐induced modulations were all attenuated by SP600125 treatment prior to reperfusion. In conclusion, mitochondrial dysfunction could contribute to GCA during tIRI under the control of the JNK/p53/survivin signaling pathway.Support or Funding InformationThis study was supported by Kuwait University Grants YM 15/17 (College of Graduate Studies ) and SRU02/13 (Research Administration).
Exo1‐independent MMR at euchromatin is error‐prone and involves Pol ζ and Rev1
Authors: Gujar Vaibhavi V. , Dahal Basanta K. , Kadyrova Lyudmila K. , Kadyrov Farid 
Published: April 2020

Genomes are under a constant attack by exogenous and endogenous agents that cause various forms of DNA damage. If the DNA damage is left unrepaired, it leads to a mutation. The mutation might alter the cell’s phenotype and trigger a disease. DNA repair processes and the high‐fidelity DNA replication play an important role in maintaining genome integrity. DNA mismatch repair (MMR) is a key DNA repair process that corrects DNA replication errors that have escaped proofreading. MMR can occur in an error‐free and error‐prone manner. Both error‐free and error‐prone MMR mechanisms have a strong impact on human health. Previous research has established that the exonuclease Exo1 is a non‐essential MMR factor that participates in MMR by removing the DNA mismatch in a 5′→3′ hydrolytic reaction. We have found that the Exo1‐independent MMR at euchromatin is error prone and occurs in a DNA polymerase (Pol) ζ‐ and DNA polymerase Rev1‐dependent manner. Surprisingly, the Pol ζ‐ and Rev1‐dependent error‐prone MMR does not involve PCNA K164 residue and ubiquitin ligase Siz1, factors that cooperate with Pol ζ in other DNA transactions. Our results have suggested that a novel error prone MMR mechanism is activated in response to the loss of a non‐essential MMR factor.Support or Funding InformationNational Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM095758
Spontaneous CAN1 mutation rates in euchromatic CAN1 gene

Genotype

CAN1 mutation rate

Absolute rate (×10−8)

95% CI (×10−8)

Relative rate

Wild‐type

19

16–24

1

exo1Δ

120n,q

100–190

6

pol30‐K164R

24

18–31

1

msh2Δ

600p

450–800

32

pol30‐K164R msh2Δ

550p

400–650

29

pol30‐K164R exo1Δ

120q

100–190

6

siz1Δ

29

17–42

1.5

exo1Δ siz1Δ

120n

73–160

6

The mutant strains are isogenic to E134 (wild type). CI represents 95% confidence interval. The mutation rates marked n,p,q do not statistically differ from each other. p=0.5, 0.06, 0.1 respectively.
Anti‐adipogenic Effects of Anthocyanin‐enriched Riceberry Rice Extract (Oryza sativa L.) in 3T3‐L1 Preadipocytes
Authors: Kongthitilerd Phutthida , Cheng Henrique , Suantawee Tanyawan , Adisakwattana Sirichai 
Published: April 2020

Riceberry rice containing anthocyanins is a new pigmented variety of rice from Thailand with various biological activities such as antioxidant, anti‐inflammatory, anti‐hyperglycemia, and anti‐cancer. The present study aimed to investigate the effects of Riceberry rice extract (RBE) on adipogenic differentiation in mice 3T3‐L1 cells. RBE was obtained using water followed by freeze dryer lyophilization. Then, total phenolic compounds, total anthocyanin contents, and major anthocyanins in RBE were analyzed. The 3T3‐L1 preadipocytes were cultured in differentiation media and supplemented with RBE 1, 10, 20 and 50 μg/ml concentrations. After 8 days of incubation, cell viability, mature adipocyte number, triglyceride levels, and glucose uptake were determined. The mRNA expression of transcription factors and adipogenic genes including PPARγ, C/EBPα, FasN, ACC, aP2, AdipoQ, Leptin, Resistin, InsR, and Glut4 were also examined. The results revealed that RBE contained total phenolic compounds (63.33±2.4 mg gallic acid equivalent/g extract) and total anthocyanin (10.13±0.14 mg cyanidin‐3‐glucoside/g extract). The anthocyanins detected were cyanidin‐3‐glucoside and peonidin‐3‐glucoside. In 3T3‐L1 cells, RBE significantly reduced the number of mature adipocytes and triglyceride accumulation in a concentration‐dependent manner. In addition, the treatment of 3T3‐L1 cells with the various RBE concentrations did not cause cytotoxicity. Furthermore, the mRNA expression of major transcription factors, PPARγ and C/EBPα were significantly downregulated by RBE (20 and 50 μg/ml) in both early phase (day 3) and late phase (day 8) of adipogenesis. At 50 μg/ml RBE, there was a significant reduction in mRNA expression levels of all adipogenic genes. Interestingly, RBE (10, 20 and 50 μg/ml) significantly reduced glucose uptake into adipocytes via downregulated InsR and Glut4 mRNA expression. These findings suggest that RBE could potentially be used as an anti‐obesity agent by inhibiting adipogenesis and reducing glucose uptake in adipocytes.Support or Funding InformationDutsadi Phiphat Scholarship from Chulalongkorn University, LSU‐SVM CORP
Teacher Knows Best: Student‐requested YouTube‐based Pre‐matriculation Resources do not Alleviate Student Anxiety in Anatomy
Authors: Attardi Stefanie M. , Gould Douglas J. , Pratt Rebecca L. , Roach Victoria A. 
Published: April 2020

RationaleEmerging trends in the literature report student preference for and dependence on video‐based resources. These sentiments were echoed by students at Oakland University William Beaumont School of Medicine (OUWB) through focus groups and course evaluations. These data supported the creation of a series of YouTube videos, to deliver introductory information (such as the structure of the anatomy curriculum, facilities, and resources) to students prior to their matriculation. The aim of this investigation was to assess if anatomy pre‐matriculation videos would affect students’ anatomy specific state anxiety levels.MethodsTwo professionally‐produced YouTube videos covering introductory topics, were distributed to 2019 matriculants. These videos were designed according to Meyer’s 12 Principles of Multimedia Learning, and in‐line with Cognitive Load Theory. To evaluate the longitudinal impact of the videos, students completed the State‐Trait Anxiety Inventory and a demographic questionnaire in 2018 (n=120; 94% response rate) and 2019 (n=118; 95% response rate), with the 2018 cohort serving as a historical control for comparison.ResultsThese data confirmed equivalence between the two groups in terms of general trait anxiety between 2018 and 2019 (Independent Samples Mann‐Whitney U; p = 0.854). Equivalence was observed between the two cohorts in terms of anatomy specific state anxiety, even when student video exposure was controlled for (Independent Samples Kruskall‐Wallace; p = 0.495). These data did confirm a long‐held suspicion among educators, revealing that anatomy specific state anxiety is significantly lower in those students with prior anatomy exposure (Independent Samples Mann‐Whitney U; p=0.006). Further inquiry into students’ prior anatomy experience identified that individuals with post‐secondary dissection experience are significantly less anxious than their peers without anatomical experience (Independent Samples Kruskall‐Wallace, with Bonferroni correction; p=0.023).ConclusionsThese results may serve as a cautionary tale to educators who are considering curricular reform in anatomy with the intention of reducing student anxiety. While student preference for video‐based instructional materials may be prevalent, videos fail to prepare students for the psychological impact of the dissection experience.Support or Funding InformationDepartment of Foundational Medical Studies at Oakland University William Beaumont School of Medicine
A Comparison of the Effects of Several Agents Found in Common Foodstuffs on Cholecystokinin‐induced Tension in Guinea Pig Gallbladder Strips
Authors: Kline Loren 
Published: April 2020

17beta‐estradiol (E2) has an inhibitory effect on the contractility of gastrointestinal smooth muscle, including the gallbladder. The inhibition of extracellular Ca2+ entry mediated E2‐induced relaxation of either CCK‐ or KCl‐induced tension in male and female guinea pig gallbladder strips. Chrysin, an endocrine disrupter, and luteolin are flavones. Resveratrol is a non‐flavonoid phytoestrogen, quercetin a phytoestrogen, and curcumin a diarylheptanoid. All are natural constituents of common foodstuffs. All relaxed CCK‐induced tension in male guinea pig gallbladder strips. Luteolin, quercetin, curcumin, resveratrol, and chrysin relaxed the CCK‐induced tension in the gallbladder strips by blocking extracellular Ca2+ entry and intracellular Ca2+ release. The effect of luteolin was also mediated by the PKA/cAMP system while quercetin also involved NO. In addition to the Ca2+ effects, the effects of curcumin and chrysin involved the PKC system. The purpose of this study was to determine which of these agents was most potent in relaxing the CCK‐induced tension in gallbladder strips. Luteolin was the most potent (98.2±2.0%), chrysin (45.4±3.7%), resveratrol (41.1±4.0%), quercetin (42.9±3.0%), curcumin (39.4±4.0%), and E2 (64.5±2.3%) when using 50 mM of each agent. Luteolin had the largest effect at all the other concentrations used (10, 25, 50, and 100 mM) in relaxing CCK‐induced tension. Curcumin was the least potent. There was no significant difference in the amount of relaxation induced by chrysin, resveratrol, and quercetin were compared. The effect of E2 was second only to luteolin.Support or Funding InformationThis research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
Emerging role of the unfolded protein response in ER membrane homeostasis
Authors: Ernst Robert 
Published: April 2020

All cells must balance the production of proteins and lipids to maintain membrane functions. Imbalances in protein folding and lipid metabolism cause endoplasmic reticulum (ER) stress, which is associated with a wide range of complex diseases including diabetes and neurodegeneration. The central homeostatic program of the ER is the unfolded protein response (UPR), which senses accumulating unfolded proteins to control global protein synthesis, chaperone abundance, and lipid metabolism. Through these mechanisms, the UPR centrally controls decisions between cell survival, adaptation, and apoptosis. We have shown that perturbations of the cellular lipidome, referred to as lipid bilayer stress, are equally potent as unfolded proteins in activating the UPR. Using an interdisciplinary platform to study highly flexible membrane property sensors, we could show that an aberrant stiffening of the ER membrane is sufficient to activate the UPR by driving the sensor protein Ire1 into oligomers via a hydrophobic mismatch‐based mechanism. We show in vitro that the binding of soluble, unfolded proteins to Ire1 is dramatically affected by the composition of the lipid environment. Furthermore, we show that chronic ER stress is initiated and maintained by a membrane‐based mechanism: Ire1 perpetuates a vicious cycle, which leads to an accumulation of saturated lipids, massive changes of ER morphology, and dramatically increased rates of cell death. This vicious cycle can be interrupted by a single point mutation in the transmembrane domain of Ire1 thereby restoring ER morphology and cellular fitness. Together, we provide a radically new, membrane‐based perspective on the role of the UPR in acute and chronic ER stress.Support or Funding InformationOur work is supported by the DFG (SFB894) and the VW foundation (Life?, #93089).
The Role of Metabolism in Modulating Radiation Fibrosis & Lymphedema
Authors: Liu Fei-Fei 
Published: April 2020

With the improvements in cancer diagnosis and therapy, clinical outcome has increased substantially, to the extent that by 2026, there will be >20M cancer survivors in the United States alone. The majority of survivors fare well; however, there is a significant proportion of patients who continue to experience the aftermath of their treatments such as radiation fibrosis (RF) or lymphedema. Until recently, there has been little understanding of the biological basis of RF, which is defined by the aberrant accumulation of extracellular matrix (ECM), leading to reduced tissue elasticity, and potential loss of organ function. The regulation of ECM production and degradation is a complex process, mediated through the production of a myriad of cytokines such as TGFB, and environmental conditions such as hypoxia. We have recently identified that metabolic dysregulation, and in particular, downregulation of fatty acid oxidation (FAO) is a key pathway driving the production and reducing the degradation of collagen, the predominant component of the ECM. Conversely, upregulation of PPAR signaling, a major mediator of FAO, reduced transcription of key ECM genes; whilst increasing internalization and degradation of extracellular collagen. Furthermore, CD36, a membrane transporter of long chain fatty acids, was discovered to play a critical role in regulating the trafficking of collagen and lysosomal degradation. Finally, using a pharmacogenomics approach, caffeic acid was identified to be a compound which can be systemically administered, and reduced RF in pre‐clinical models.These data, along with other reports in the literature, strongly point towards the use of metabolic drugs as a therapeutic strategy by which we can mitigate the deleterious effects of RF on cancer patients. More recently, we have also uncovered that metabolic dysregulation likely plays a similar role in the development of lymphedema, a common long‐term toxicity in women after breast cancer therapy. Finally, these findings have broad application to the increasing burden of fibrosis beyond cancer, wherein end‐stage renal, liver, cardiac, and pulmonary fibrosis accounts for up to 1/3 of the deaths around the world.Support or Funding InformationThe work is funded in part by the Canadian Institutes of Health Research, Genome Canada, the Canadian Cancer Society Research Institute, the Physicians Services Incorporated Foundation, the Harry Barberian Research Scholarship, the Mariano Elia Chair in Head and Neck Cancer Research, the Peter and Shelagh Godsoe Chair in Radiation Medicine, the Princess Margaret Cancer Centre Head and Neck Translational Program, the Princess Margaret Cancer Centre Radiation Medicine Program and the Ottawa Heart Institute Research Corporation, as well by philanthropic funding from the Jesse Rasch Foundation, the Wharton family, Joe’s Team and the Ministry of Health and Long‐Term Care.
Cellular Machineries Devoted to Rubisco – the Most Abundant Enzyme
Authors: Hayer-Hartl Manajit 
Published: April 2020

Photosynthesis is a fundamental process in biology as it converts solar energy into chemical energy and thus, directly or indirectly, fuels all life on earth. The chemical energy is used to fix atmospheric CO2 and produce reduced carbon compounds in the Calvin‐Benson‐Bassham cycle. The key enzyme for this process in all photosynthetic organisms is ribulose‐1,5‐bisphosphate carboxylase/oxygenase (Rubisco), which is responsible for the conversion of an estimated amount of ~1011 tons of CO2 per annum into organic material. Rubisco is the most abundant enzyme in nature, owing in part to its low catalytic turnover rate and limited specificity for CO2 versus O2.Recent forecasts suggest that global food production will need to rise more than 25 % by 2050 to meet the ever increasing demand. Engineering a catalytically more efficient Rubisco enzyme and/or compartmentalizing Rubisco in higher plants could contribute to reaching that goal. However, the complex nature of Rubisco’s folding and assembly pathway has made these efforts exceedingly challenging. In my talk I will review recent progress in understanding the complex chaperone machineries that are necessary for the efficient biogenesis of this most abundant enzyme.
BSCL2/Seipin in Lipid Catabolism and Lipodystrophy
Authors: Chen Weiqin 
Published: April 2020

Adipose tissue is the body’s largest endocrine organ that plays a major role in systemic energy homeostasis and thermoregulation. Mutations in BSCL2 (a.k.a. Seipin) gene underlie human type 2 Berardinelli‐Seip Congenital Lipodystrophy (BSCL2) disease with near absence of adipose tissue at birth and severe metabolic diseases. Global Bscl2−/− mice largely recapitulate human BSCL2 lipodystrophy with severe insulin resistance and organomegly. Seipin is known for its critical role in controlling lipid droplet (LD) assembly at the LD‐forming subdomain of the endoplasmic reticulum (ER), but its exact functional role has been enigmatic. Our laboratory has focused on elucidating the mechanisms through which Seipin regulates adipocyte differentiation thus lipodystrophy and its associated metabolic diseases. This presentation will focus on the role of Seipin in mediating cAMP/PKA signaling to regulate lipid catabolism in mature white adipose tissue (WAT) and during perinatal brown adipose tissue (BAT) development which exert profound effect on metabolic homeostasis and thermogenesis. We will also explore the role of Seipin as a key node that links ATGL‐mediated lipolysis to govern mitochondrial dynamics and function in WAT, BAT and heart. These findings will highlight novel roles for Seipin in cellular and organismal biology and its importance in human health.Support or Funding InformationThis work was supported by NIH grant 1R01HL132182‐01.
Mechanotransduction through Integrin‐mediated Adhesions
Authors: Schwartz Martin 
Published: April 2020

Integrin‐mediated adhesions both transmit mechanical tension and sense the mechanical properties of the extracellular matrix such as stiffness and applied strains. Major human pathologies including hypertension, atherosclerosis, heart failure and fibrosis involve altered forces and tissue stiffness, or altered cell sensing of these variables. My lab investigates the basic mechanisms by which cells sense matrix stiffness, applied strains and fluid shear stress, and how these sensing mechanisms contribute to cardiovascular disorders. I will present our latest work on elucidation of these mechanotransduction pathways and their role in cardiovascular remodeling and disease.Support or Funding InformationNIH
Mechanical Force and Notch Signaling
Authors: Gordon Wendy 
Published: April 2020

The mechanical microenvironment of a cell guides cellular processes such as migration, differentiation, division, and signaling, and is thus often altered in disease. At a molecular level, mechanical stimuli alter conformations of mechanosensing proteins to communicate the stimulus to the cell interior and effect a downstream cellular response in a process called mechanotransduction. Measuring tensions sensed by cellular proteins and how tensions are altered by cellular context will lead to better understanding of the molecular mechanisms used in mechanosensing in disease‐related processes such as tumor migration. Tools to measure molecular level tensions have only emerged more recently to characterize the pN forces present across mechanosensitive proteins and have been used to measure tensions sensed by focal adhesions proteins such as vinculin, talin, and integrins, as well as cadherins. Generally, genetically encodable molecular tension sensors contain a deformable peptide linker with well‐characterized extension in response to applied force flanked by two fluorescent proteins (FP). The extent of linker stretching due to mechanical force can measured by Förster resonance energy transfer (FRET) and subsequently be correlated to a quantifiable force. We developed a genetically‐encodable molecular tension sensor based on bioluminescence resonance energy transfer (BRET) that overcomes several limitations of FRET. Using BRET as a distance reporter in molecular tension sensors allows for more sensitive readouts due to the lack of autofluorescence and phototoxicity. BRET also offers the potential for use in vivo where light excitation is not able to penetrate into tissue. We demonstrate the utility of this tension sensor in vitro and in cell based assays, using vinculin as the model system to show an enhanced dynamic range compared to field standard FRET‐based sensors. We will then present measurements of tensions sensed between cells by Notch receptors.Support or Funding InformationPew Biomedical Scholar, R35 GM119483