bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mechanisms of mRNA degradation
Authors: Conti Elena , Bono Fulvia , Glavan Filip , Lorentzen Esben 
Published: June 2021

Eukaryotes have evolved quality‐control mechanisms that allow cells to remove defective messenger RNAs (mRNAs). Aberrant mRNA with premature stop codons (PTCs) are recognized and degraded by a process known as nonsense‐mediated mRNA decay (NMD). The NMD pathway is conserved from lower to higher eukaryotes. In humans, the recognition of a PTC‐containing mRNA depends on both splicing and translation.In the nucleus, a complex of proteins known as the exon junction complex (EJC) is deposited on mRNA upon splicing and stays stably bound until the nucleic acid is exported to the cytoplasm. Here, the crosstalk between a ribosome stalled at a PTC and a downstream EJC elicits a cascade of interactions that ultimately lead to the recruitment of ribonucleases and mRNA degradation. The talk will focus on our current understanding of the molecular mechanisms of NMD as elucidated by structural biology.
Body composition and Bone Health of Obese Adolescents with vitamin D deficiency
Authors: Lenders Carine , Feldman Henry A , Merewood Anne , Sweeney Carol , Wilson Darrell M , Lee Phillip DK , Abrams Stephanie H , Gitelman Stephen E , Wertz Marcia S , Chen Tai C , Holick Michael F 
Published: June 2021

Objectives:To evaluate body composition and bone health of obese adolescents with and without vitamin D deficiencyMethods:Data from 58 out of 92 obese adolescents aged 13–17.9 years evaluated for the Glaser Metformin Trial were obtained. Bone mineral content (BMC), lean body mass, and total body fat from DXA‐scan and visceral fat from CT‐scan were measured. Vitamin D status was determined using plasma 25(OH)D and iPTH. Vitamin D deficiency was defined as 25(OH)D<20 ng/mL. Osteocalcin was used as a biomarker for bone formation and CTX for bone resorption. Mean±SD and Student t test were used for analysis.Results:Adolescents were 15±1.4 y. old, had a BMI of 36±5 kg/m2, 55 were Tanner Stage>2, 38 were female, and 8 were black. Their level of 25(OH)D was 25±10 ng/ml, iPTH 16±10 pg/ml, osteocalcin 45±22 ng/ml, CTX 1.5±0.9 ng/ml, and BMC 2273±402 g. A total of 17/58 were vitamin D deficient but none had high iPTH (max 48 pg/ml). The group with vs. without vitamin D deficiency had similar lean body mass (57±3 vs. 56±1 kg, p=0.77), differed in total body fat (43±1 vs. 39±1%, p=0.002), but not visceral fat (11±1 vs. 13±1%, p=0.17). They had lower osteocalcin (35±3 vs. 49±4 ng/ml, p=0.04) but similar CTX (1.2±0.2 vs.1.6±0.1 ng/ml, p=0.10) and BMC (2345±93 vs. 2243±65 g, p=0.39).Conclusion:Vitamin D deficiency was associated with fat mass and lower osteocalcin, but was not a predictor of BMC in obese adolescents.
Plasminogen activator inhibitor‐1 is negatively associated with fasting plasma monounsaturated fatty acids but not influenced by postprandial polyunsaturated fatty acid composition in men with high fasting triacylglycerol
Authors: Dekker Mark J , Mazurak Vera C , Wright Amanda J , Graham Terry E , Robinson Lindsay E 
Published: June 2021

Increased consumption of dietary monounsaturated fatty acids (MUFA) is associated with a favorable risk factor profile associated with the metabolic syndrome (MetS), including lowered plasminogen activator inhibitor (PAI)‐1. In addition, the postprandial response to dietary fat has emerged as a dynamic metabolic period associated with MetS. Plasma fatty acid composition was measured in men with high fasting triacylglycerol (n=8, HTAG>1.69 mmol/L) and low fasting TAG (n=8, LTAG<1.7 mmol/L). Each subject underwent three postprandial oral fat tolerance tests (OFTT) of 1g/kg body weight emulsified lipids consisting of varied PUFA/saturated fatty acid (P/S) ratios of 0.2, 1.0 and 2.0, with blood collected through 8h. Fasting MUFA was negatively correlated with total PAI‐1 antigen (P<0.001, r=−0.98) and PAI‐1 activity (P<0.02, r=−0.8) in HTAG, but not LTAG. Fasting total PUFA concentration was positively correlated with total PAI‐1 antigen (P=0.03, r=0.75) in HTAG, but not LTAG. There was no difference in postprandial PAI‐1 total or activity in response to three OFTTs with similar MUFA but varied PUFA TAG composition. These data suggest that elevated MUFA concentrations may have beneficial effects on PAI‐1 in HTAG subjects and that postprandial PUFA concentrations do not influence postprandial PAI‐1 in this population.Supported by the Ontario Ministry of Agriculture, Food and Rural Affairs (OMAFRA) and NSERC
Dietary DHA and ARA alter the expression of 1700 hepatic genes including the tumor suppressor TOB1 in baboon neonates
Authors: Brenna J. Thomas , Anthony Joshua C. , Pan Bruce S. , Hsieh Andrea T. , Nathanielsz Peter W. , Kothapalli Kumar S.D. 
Published: June 2021

Background. We have recently shown that 1100 cerebral genes are differentially expressed in 12 week old baboon neonates consuming medium and high levels of DHA, with ARA. Here we report on differential hepatic gene expression induced by these diets.Methods. Baboon neonates were randomized at birth to three formulas: C, 0/0 DHA/ARA; L, 0.33/0.67%w/w; L3, 1.0/0.67. At 12 weeks, liver was collected and Affymetrix Gene chips assessed gene expression. Significance was determined by t‐tests, and Ingenuity® pathway analysis detected gene relationships.Results. More than 1700 of 54,000 probe sets (ps) were differentially expressed. Most significantly upregulated was TOB1, hepatic tumor suppressor associated with ERBB2. SCD (9‐desaturase) and FADS1 (5‐desaturase) were downregulated. ELOVL6, a PUFA elongase and BHMT (one carbon metabolism) were upregulated with increasing DHA. Ingenuity pathway analysis identified network TOB1 and SCD with many genes interacting with CTNNB1 and ERBB2. A number of (n = 52) transcripts with predicted peroxisome proliferator response elements were differentially expressed, including TOB1.Conclusions. Dietary DHA/ARA within the normal range found in breastmilk had widespread influence on gene expression, including TOB1 and many genes associated with PUFA metabolism. Funding: Mead Johnson Nutritionals, Evansville, IN.
Retinyl ester formation by lecithin:retinol acyltransferase (LRAT) is a key regulator of retinoid homeostasis in mouse embryogenesis
Authors: Wassef Lesley , Kim Youn‐Kyung , Hamberger Leora , Palczewski Krzysztof , Blaner William S , Quadro Loredana 
Published: June 2021

The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids (vitamin A and its derivatives). The mechanisms through which mammalian developing tissues maintain adequate retinoid levels in the face of perturbations in maternal vitamin A dietary intake have not been established. We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis. Pregnant mice, lacking both LRAT and retinol‐binding protein (RBP), the serum specific carrier for retinol, were maintained on diets containing different amounts of vitamin A. Maternal dietary vitamin A deprivation during pregnancy generated a severe retinoid‐deficient phenotype of the embryo due to the retinoid deficient status of the double mutant dams rather than to the lack of embryonic LRAT. Moreover, LRAT acts together with Cyp26A1, one of the enzymes that catalyze the degradation of retinoic acid, and possibly with Stra6, the recently identified cell surface receptor for retinol‐RBP, in maintaining adequate levels of retinoids in embryonic and extraembryonic tissues.Work supported by the National Research Initiative Grant no. 2006‐35200‐16580 from the USDA‐CSREES, Program 31.0.
Herpes oncolytic vectors effectively treat prostate carcinomas with neural invasion while preserving nerve function
Authors: Kelly Kaitlyn Jane , Brader Peter , Rein Avigail , Shah Jatin , Wong Richard , Fong Yuman , Gil Ziv 
Published: June 2021

Prostate carcinoma has a high propensity for neural invasion (NI) and resection of these tumors often leads to erectile dysfunction. We hypothesized that oncolytic therapy using attenuated herpes simplex virus (HSV) will selectively target cancer cells invading nerves while preserving neural function.Prostate cancer cell lines PC3, DU145, and LNCap were infected with HSVs (NV1023 and NV1066) in vitro and cytotoxicity was assessed over 7 days. HSV had significant oncolytic effect on all prostate cancer cell lines. An in vivo model of NI was established by implanting prostate carcinoma cells in the sciatic nerves of nude mice. Mice were treated with NV1023 or saline 7 days after establishment of tumors. Treatment with attenuated viruses had no toxic effect on nerves (n=30). Significant reduction in tumor size and inhibition of NI was found 6–8 weeks after treatment (P <0.005, n=30). The control animals developed complete paralysis <5 weeks post‐treatment, whereas most NV1023‐treated animals had preserved nerve function >12 weeks after treatment (P <0.0001, n=7–10).Attenuated HSVs effectively treat prostate carcinomas with NI, while preserving nerve function. These findings may hold significant clinical implications for prostate cancer patients and for other neurotrophic tumors.Research support was provided by FAMRI.
Disruption of androgen receptor activity by synthetic and dietary aryl hydrocarbon receptor ligands
Authors: Ralph Jody Love , Guns Emma T , Nelson Colleen C 
Published: June 2021

There is a growing concern that many of the environmental and dietary chemicals that are ingested by humans but have not been thoroughly tested for endocrine activity may pose a significant health threat. These chemicals may have the potential to mimic or antagonize hormone action, possibly through binding to steroid receptors and interfering with transcriptional activity. The prostate is highly sensitive to androgens and requires precise hormonal control to regulate its growth and function.Prostate cells express both androgen receptor and aryl hydrocarbon receptor (AhR) and cross‐talk between the two pathways may affect the function of the prostate cell. A number of methods were used to characterize the impact of dietary and environmental AhR ligands on androgen action in a prostate cancer‐derived cell line. Our in vitro cell culture‐based assay utilizes androgen‐responsive promoter constructs in conjunction with a luciferase reporter gene. These results combined with those from a binding assay indicate that several of the AhR ligands, including resveratrol, indole 3 carbinol, curcumin and hexachlorobenzene antagonize androgen‐initiated transcriptional activity without binding to the androgen receptor. Environmental and dietary compounds have been implicated in the rising incidence of prostate cancer and insight into the mechanisms of endocrine disruption will help to clarify their role.
Role of Epac1, an exchange factor for Rap GTPase, in endothelial microtubule dynamics and barrier function
Authors: Sehrawat Seema , Cullere Xavier , Patel Sunita , Italiano Joseph , Mayadas Tanya 
Published: June 2021

Vascular leakage leading to excessive tissue fluid accumulation often has severe pathological consequences and contributes to morbidity and mortality in disease. Rap1 GTPase activation by its cAMP responsive nucleotide exchange factor Epac present in endothelial cells increases endothelial cell barrier function with an associated increase in cortical actin. Here, Epac1 was shown to be responsible for these actin changes and to co‐localize with microtubules in human umbilical vein endothelial cells. Importantly, Epac activation with a cAMP analogue, 8‐pCPT‐2′O‐Me‐cAMP (O‐Me‐cAMP) resulted in a net increase in the length of microtubules. This did not require cell‐cell interactions or Rap GTPase activation and was attributed to microtubule growth as assessed by time‐lapse microscopy of HUVEC expressing flourophore‐linked microtubule plus‐end marker end‐binding protein 3. An intact microtubule network was required for Epac mediated changes in cortical actin and barrier enhancement but was not required for Rap activation. Finally, Epac activation reversed microtubule dependent reductions in vascular permeability induced by TNFα and TGFβ. Thus Epac can directly promote microtubule growth in endothelial cells. This, together with Epac mediated Rap activation leads to an increase in cortical actin, which has functional significance for vascular permeability. Elucidation of the mechanism of Epac regulation of MT and actin may lead to potential therapies for edema in acute vascular syndromes.Funding was provided by NIH HL (PPG), NIH HL036028 (TNM), HL68130 (JI). XC was supported by KO1AR054984, and SP by training grant HL066978 (L. Silberstein) and a Ruth L. Kirschstein fellowship HL082133‐01.
Visualization of neuron‐astroglia interaction
Authors: Okabe Shigeo 
Published: June 2021

Formation and maintenance of synapses are important in proper functions of the nervous system. Visualization of synapse structure and molecules localized in this micro‐compartment requires fluorescence imaging with high resolution and sensitivity. Two‐photon microscopy is a unique optical system suitable for the detection of submicron‐scale fluorescent structures deep inside the nervous tissue. By using selective labeling methods of neurons and glial cells in hippocampal slices in combination with two‐photon microscopy, dynamic interactions between postsynaptic spines and astrocytes were visualize. We labeled a small subset of astrocytes with GFP and introduced rhodamine‐dextran into pyramidal neurons in the close vicinity of GFP‐positive astrocytes. Two‐photon time‐lapse imaging of both dendritic spines filled with rhodamine‐dextran and GFP‐positive astrocytic processes revealed frequent physical interactions between two structural components. Dendritic spines with previous episodes of astrocytic contacts showed longer lifetime. Direct contacts with astrocytes also promoted maturation of dendritic protrusions into stable spines with prominent head structure. Stabilization of spines by astrocytic contacts requires intercellular signaling pathway dependent on ephrin/Eph interaction. These observations indicate importance of direct astrocytic contacts in stabilization and maturation of dendritic spines, where most excitatory synapses onto pyramidal neurons are formed.Highly correlated structural changes of synapses and glial cell processes illustrate importance of two‐photon time‐lapse imaging of living nervous tissue in understanding molecular mechanisms of neural circuit development and its maintenance in the brain.
Regenerative medicine: enabling technologies for clinical translation
Authors: Yoo James J. 
Published: June 2021

Tissue engineering and regenerative medicine has emerged as an innovative scientific field that focuses on development of new approaches to repairing cells, tissues and organs for clinical applications. Recent advances in this field have offered new therapeutic opportunities that facilitate the restoration and maintenance of normal tissue function. Consistent with the goals of tissue engineering and regenerative medicine, we have followed a strategy that has shown to be effective clinically. This approach involves the use of biocompatible matrices either with or without cells. The matrices are either used as cell delivery vehicles or as scaffolds to promote and enhance tissue regeneration. When cells are used, donor tissue is dissociated into individual cells, which are expanded in culture, attached to a support matrix, and reimplanted into recipient for recovery of tissue function.Over the past years, research investigations have been actively pursued in various tissue systems using tissue engineering and regenerative medicine concepts and technologies. Although these tissues have shown their potential applicability experimentally, only a limited number of tissues have been successfully engineered for clinical use to date. This is due to various obstacles encountered in the tissue building process. The progress toward clinical translation, current challenges hampering organ development and potential solutions to overcome technical hurdles will be discussed.
An Investigation into the Cellular and Molecular Basis for Newt Spinal Cord Regeneration
Authors: Odelberg Shannon J , Kent David , Zukor Katherine , Atkinson Donald L , Stevenson Tamara J , Hoang William 
Published: June 2021

An adult newt has the remarkable ability to regenerate its spinal cord and regain function after suffering a paralysis‐inducing injury. Function is usually regained in about 6–9 weeks following a complete transection of the thoracic spinal cord. Following tail amputation, the spinal cord regenerates in synchrony with the regrowth of the tail. Spinal cord regeneration is dependent upon several factors: 1) a robust and organized ependymal cell response; 2) the ability of the newt axons to regenerate; and 3) the absence of an axon growth‐inhibiting scar at the lesion site. We have characterized the timing of the ependymal cell response following both thoracic spinal cord transections and tail amputations and have determined that DNA synthesis is initiated by the seventh day in both types of injuries. Using differential display, microarray analysis, and real‐time RT‐PCR, we have identified several members of the matrix metalloproteinase (MMP) gene family as well as a few novel cytokines that are excellent candidates for regulating newt spinal cord regeneration. We are currently assessing the role of these genes in the regenerative process.Supported by The Craig H. Neilsen Foundation
Of extracellular matrix, the genome and the microenvironment in breast cancer: No cell is an island
Authors: Bissell Mina J 
Published: June 2021

Development of robust and versatile 3‐D culture models for studying functional differentiation of normal mammary gland and steps in breast cancer has allowed us to conclude that tissue structure and epithelial polarity are overarching suppressor mechanisms that play crucial roles in maintenance of the differentiated state and how the loss of these has significant ramifications in cancer and in response to therapeutic agents. These assays and the concepts derived from the experiments are now pursued by many other laboratories. To move these concepts to the next stage, we have embarked on developing complementary assays:1) Can we apply the knowledge gained so far to finding more effective therapeutics? 2) how to make other versatile models to understand the process of branching morphogenesis of the mammary gland, in particular, how the epithelial cells invade the fat pad in organized branching patterns without breaching the basement membrane. This knowledge is crucial for understanding where the regulation goes awry in breast cancer cells when they invade and metastasize; and 3) how to improve the monocellular 3D models to reflect the complexity of the mammary gland. I will discuss the progress the laboratory has made in these and other areas.
Automated, continuous analysis of embryonic gene expression with cellular resolution in C. elegans
Authors: Waterston Robert H. , Murphy John Isaac , Bao Zhirong , Blick Daniel , Boeck Max E. , Boyle Thomas J. , Mericle Barbara , Preston Elicia , Sandel Matt J. , Zhao Zhongying 
Published: June 2021

We have developed methods that automatically analyze the kinetics of gene expression in the C. elegans with cellular resolution continuously during embryogenesis. From 3D movies of developing embryos expressing histone‐GFP fusion proteins in all nuclei, we use computational methods to detect cell divisions and determine the lineage. We simultaneously image a histone‐RFP reporter driven by a promoter of interest. By interrogating the nuclear positions determined in the lineage tracing we obtain quantitative measurements of expression for each cell at each time point. Because the cell lineage is invariant, we can directly map each independent expression pattern onto the reference lineage to obtain composite pictures of gene activity. We are applying the method systematically to reveal the expression of each transcription factor in embryonic development, and have already generated expression patterns for key developmental regulators, including pha‐4 (forkhead), cnd‐1 (NeuroD), hlh‐1 (MyoD) and the GATA factors end‐3, elt‐2 and elt‐7. Comparing the expression of multiple genes expressed within a single cell and its ancestors reveals the subtleties of expression and regulatory pathways. We have begun testing some of these predictions by examining the impact of RNAi knockdown of the regulator on expression levels of predicted targets.The automated lineage methods also allow new phenotypic analyses.
The Mre11/Rad50 complex and its roles in processing of DNA double‐strand breaks
Authors: Paull Tanya T. , Nicolette Matthew , Lengsefld Bettina 
Published: June 2021

The repair of DNA double‐strand breaks by homologous recombination pathways requires that the ends of the DNA be processed into 3′ single‐strands. In E. coli this processing is catalyzed by the RecBCD enzyme, but functional orthologs of this complex do not appear to be present in eukaryotes. The Mre11/Rad50/Xrs2 (MRX) complex has been implicated in DNA processing during meiosis in budding yeast. In addition, the MRX complex has been shown to affect DNA processing events in vegetative cells, and recent evidence suggests that the human Mre11/Rad50/Nbs1 (MRN) complex also contributes to end processing in human cells as well.It is clear from the work of many laboratories that Mre11/Rad50 does not act alone in processing DNA in vivo, but functions in concert with other conserved factors. The Sae2 protein in S. cerevisiae has been identified as a factor required for efficient DNA end processing in both mitotic and meiotic yeast cells. We have investigated the biochemical properties of the Sae2 protein in vitro and found unexpectedly that Sae2 possesses endonuclease activity on single‐stranded DNA and at single‐strand/double‐strand junctions. This is consistent with the proposed role of Sae2 in processing 5′ ends of DNA at double‐strand breaks in vivo. These and other experiments investigating the roles of both Sae2 and Mre11/Rad50/Xrs2 in DNA end processing will be discussed.
Aged Garlic Extract Improves Vascular Function in Asymptomatic Individuals with Subclinical Atherosclerosis
Authors: Budoff Matthew Jay , Ahmadi Naser , Gul Khawar , Hajsadeghi Fereshteh , Usman Nudrat , Nuguri Vivek , Flores Ferdinand , Nasir Khurram , Naghavi Morteza 
Published: June 2021

This study evaluates changes associated with Aged Garlic Extract (AGE) use in vascular reactivity during cuff‐occlusive reactive hyperemia by Digital Thermal monitoring (DTM) and progression of coronary artery calcium scores (CACS).Methods: A placebo‐controlled, double‐blind, randomized trial, 65 (mean age: 60±9 years, 78% males) intermediate risk patients were enrolled and 60 completed the study protocol in which they either received four capsules of AGE (250 mg), Vitamin B12 (100mcg), Folic Acid (300 mcg), Vitamin B6 (12.5mg) and L‐Arginine (100mg) or placebo daily 1 year. Changes in vascular endothelial function, TMP AUC (Post‐cuff deflation Area Under the temperature Curve), index of thermal vascular reactivity, and CAC were assessed over 1 year follow up in both groups.Results: At baseline there was no difference between both groups in their CAC scores (AGE: 291±50 vs. Placebo: 347±67, p=0.3) as well in TMP AUC (AGE: 291±50 vs. Placebo: 95±11, p=0.7). As shown in figure, Over 1 year follow‐up there was significantly higher improvement in TMP AUC and less progression of CACS with AGE compared to placebo independent of age, gender and risk factors. (TMP AUC: 2.9, 95%CI 1.5–4.7, p0.02) and (CAC: 0.71, 95% CI 0.53=0.9, p0.02).Conclusion: This study suggests that AGE can improve thermal vascular function and reduce CAC progression in asymptomatic adults with intermediate risk.