bluuebunny/crossref_metadata_2025_split huggingface dataset:
The RGD PhenoMiner Database and Query Tool: A Resource for Quantitative Phenotypes in the Rat
Authors: Smith Jennifer R , De Pons Jeffrey L , Laulederkind Stanley J , Hayman G Thomas , Wang Shur‐Jen , Hoffman Matthew J , Zhao Yiqing , Tutaj Marek , Ghiasvand Omid , Dwinell Melinda R , Shimoyama Mary E 
Published: November 2023

Phenotype is defined as any one trait, or any group of traits, which contribute to the physical, biochemical, and physiological makeup of an individual as determined by both genetic composition and environmental influences. As such, the information needed to fully describe a measurement of a phenotype or trait should include both an indication of the genetics of the organism being assessed and information about environmental influences that might affect the measurement. The Rat Genome Database (http://rgd.mcw.edu) has developed a system to standardize and fully describe quantitative phenotype measurements using a suite of controlled vocabularies. These quantitative phenotype records, available through the PhenoMiner tool (http://rgd.mcw.edu/phenotypes/), include information on the trait being assessed (Vertebrate Trait Ontology), the exact measurement that was made (Clinical Measurement Ontology), the method used to make that measurement (Measurement Method Ontology), the condition(s) under which the measurement was made (Experimental Condition Ontology), and the sample measured—and by extension, its associated genetics—including information on rat strain (Rat Strain Ontology), number of individuals, sex and age. This structure has provided the framework to integrate more than 60,000 phenotype records, including over 17,000 cardiovascular measurements from approximately 140 different studies. PhenoMiner's flexible query wizard allows researchers to retrieve, view and download data from multiple studies, and to compare experimental values across multiple strains, methods and/or conditions, allowing investigators to choose appropriate disease models and controls among the vast number of rat strains available. Work is currently underway to utilize these data to statistically determine expected ranges for standard measurements in commonly used rat strains and to provide methods by which users can compare their own data to the expected ranges.Support or Funding InformationThe National Heart, Lung, and Blood Institute of the National Institutes of Health, Grant #R01HL064541
Loss of Arhgef11 on the Genetic Background of the Dahl Salt‐Sensitive (SS) Rat Significantly Attenuates Blood Pressure and Renal Injury
Authors: Johnson Ashley C. , Garrett Michael R 
Published: November 2023

We have previously implicated genetic variants in Arhgef11, a Rho guanine nucleotide exchange factor, in kidney injury exhibited in the Dahl salt‐sensitive (SS) rat, a widely studied model of hypertension and chronic kidney disease. ARHGEF11, through the exchange of GDP for GTP, plays a central role in the activation of RhoA signaling cascades via a number of cell stimuli that can impact cytoskeletal structure and influence cell‐cell contacts and promote cell transformation. The SS form of Arhgef11 is associated with increased expression (before onset of detectable injury) as well as several SNPs are predicted to have impact on protein function (compared to kidney injury resistant SHR). The study of an SS‐Arhgef11‐minimal congenic model, which substituted the SS allele with that of the SHR, demonstrated significantly decreased proteinuria, tubulointerstitial injury/fibrosis, and improved renal hemodynamics compared to the SS. Primary proximal tubule cells cultured from the SS exhibited increased expression of Arhgef11, activation of Rho‐ROCK, and were more prone (vs. control) to epithelial‐mesenchymal transition (EMT), a driver of fibrosis. In the current study, we sought to investigate the loss of Arhgef11 on renal injury and renal function. A study comparing the SS‐WT and SS‐Arhgef11−/− animals for measures of renal injury (proteinuria) and blood pressure on low‐salt (0.3% NaCl) found that knockout animals exhibited a significant reduction in proteinuria, but no significant difference in blood pressure. On an elevated‐salt diet (2% NaCl), SS‐Arhgef11−/− animals demonstrated a significant (p<0.001) attenuation of proteinuria/renal injury (41±7.9 mg/24 hrs) and reduction in blood pressure (124±2.6 mm Hg) compared to SS‐WT (149±15.3 mg/24 hrs and 151±5.9 mm Hg). A more extensive characterization of renal injury (e.g. histological, transcriptome, etc.) and renal hemodynamics (RBF, GFR, and RVR) is being currently planned. In summary, genetic studies using several animal models, genetically modified cells, and primary cells identified a gene/pathway involved in kidney injury, which could ultimately lead to new insight into the pathophysiology CKD.Support or Funding InformationSupported by NIH/NHLBI HL094446 and funds from University of Mississippi Medical Center
Effects of DHA on Orchidectomy‐Associated Alterations in Vascular Responses
Authors: Villalpando Diva M. , del Campo Lara , Navarro Rocío , Largó Carlota , Muñoz David , Tabernero María , Otero Cristina , García Hugo S. , Ferrer Mercedes 
Published: November 2023

The loss of gonadal function induces vascular dysfunction by altering the release and action of NO, prostanoids and reactive oxygen species. Although, the cardioprotective effect of n‐3 polyunsaturated fatty acids has been documented, the specific effect of docosahexaenoic acid (DHA) in vascular function of orchidectomized rats has been scantly investigated. Therefore, the objective of this study was to analyze whether a DHA‐supplemented diet prevents vasodilator and vasoconstrictor alterations induced by impaired gonadal function. For this purpose, mesenteric arteries from control (C) and orchidectomized (CX) 6 months‐old Sprague‐Dawley rats were used. Control rats were fed with a control diet (V‐C), while CX rats were fed with a control diet (V‐CX) or one containing 2% (w/w) DHA (DHA‐CX). Hydrogen peroxide and antioxidant activity were analyzed in serum samples. Mesenteric artery segments were used to analyze: (i) the levels of NO and thromboxane A2 (TXA2); (ii) the vasodilator response induced by acetylcholine (Ach) in the absence and presence of L‐NAME and indomethacin, the respective inhibitors of NO synthase and cyclooxygenases; (iii) the vasodilator response to the NO donor, sodium nitroprusside (SNP); and (iv) the effect of L‐NAME on the contractile response induced by noradrenaline (NA). The results showed that orchidectomy increased the production of hydrogen peroxide while decreased the antioxidant activity and the DHA‐diet prevented these alterations. The release of NO was decreased in arteries from CX rats and it was restored by the DHA‐diet. The Ach‐induced response was decreased by L‐NAME plus indometacin in arteries from all groups, being the smallest decrease that of arteries from the V‐CX group. In KCl‐precontracted arteries, the SNP‐induced relaxation was greater in arteries from V‐CX group than those of C or CX‐DHA groups. Regarding NA‐induced response, L‐NAME failed to modify that response in V‐CX group, while in arteries from C and CX‐DHA L‐NAME increased the NA‐induced response. These results show that orchidectomy promotes oxidative stress that accounts for a decreased NO and an increased TXA2 release. The DHA‐supplemented diet in CX rats restored the redox status by decreasing hydrogen peroxide production and by increasing the antioxidant activity; in turn, the production of NO was recovered. Dietary DHA supplementation in CX rats increased the participation of NO in the Ach‐induced vasodilation and in the NA‐induced vasoconstriction.Support or Funding InformationSupported by grants (to M. F.) from the Fondo de Investigaciones Sanitarias (PI1100416), Comunidad de Madrid (S2013/ABI‐2783, “INSPIRA1‐CM”) and Fondo Europeo de Desarrollo Regional.
Effects of Androgens on the Function of Mesenteric Arteries from Normotensive and Hypertensive Rats
Authors: Isidoro Lucía , Villalpando Diva M. , Perusquía Mercedes , Ferrer Mercedes 
Published: November 2023

It has been suggested that androgens may exert cardiovascular protective actions by regulating the release and function of different vascular factors. In addition, increasing attention is paying to testosterone (TES) and its 5‐reduced metabolites, 5α‐ and 5β‐dihydrotestosterone (5α‐ and 5β‐DHT) to induce vasorelaxation in several vascular beds and hypotensive effects in normotensive conscious rats. Interestingly, 5β‐DHT is the most potent vasorelaxant androgen which is genomically inactive. In view of these data, and the lack of studies analyzing the effects of TES, 5α‐ and 5β‐DHT on the function of mesenteric artery from hypertensive rats, the objective of this study was to investigate whether hypertension alters the androgens‐mediated vasorelaxation, as well as their effects on the contractile response induced by electrical field stimulation (EFS); the vasomotor responses induced by the three major released neurotransmitters: noradrenaline (NA), calcitonine gene‐related peptide (CGRP) and nitric oxide were also analyzed. For this purpose, mesenteric artery segments from male Spontaneously Hypertensive rats (SHR) and its normotensive counterparts, Wistar‐Kyoto (WKY) rats, were used to analyze: (i) the concentration‐vasodilator response curve (0.1 μM – 0.1 mM) to TES, 5α‐ and 5β‐DHT; (ii) the effect of androgens (10 nM, incubated for 30 min) on the contractile response induced by EFS (200 mA; 0.3 ms; 1, 2, 4, 8, 16 Hz), and (iii) the vasoconstrictor‐response curve to NA (1 nM–10 μM), and the vasodilator‐response curve to CGRP (1 pM – 0.1 μM) and to the nitric oxide donor, sodium nitroprusside (SNP, 1 pM – 10 μM). The results showed that TES induced a similar relaxation in arteries from SHR or WKY rats, while 5β‐DHT‐induced a greater relaxation in arteries from SHR than those of WKY rats. In arteries from WKY rats, androgens did not modify the EFS‐ or NA‐induced contraction nor the CGRP‐induced relaxation, and only 5β‐DHT increased the SNP‐induced relaxation. In arteries from SHR, androgens unaltered the NA‐induced response, while TES and 5β‐DHT increased the SNP‐induced vasodilation in similar extent. The fact that 5β‐DHT increased the CGRP‐induced vasodilation in a greater extent than TES did, might account for the increased EFS‐induced contraction observed in the presence of TES. These results suggest that 5β‐DHT could be a drug with potential therapeutic benefits for the treatment of hypertension.Support or Funding InformationSupported by grants (to M.F.) from the Fondo de Investigaciones Sanitarias (PI1100406), Comunidad de Madrid (S2013/ABI‐2783, “INSPIRA1‐CM”) and Fondo Europeo de Desarrollo Regional.
Cold‐Induced Metabolic Adjustments in Brown Adipose Tissue and Skeletal Muscle Gene Expression are Influenced by Time‐of‐Day
Authors: Machado Frederico Sander Mansur , Zhang Zhi , Su Yan , Jansen Remi , Foppen Ewout , Coimbra Cândido Celso , Kalsbeek Andries 
Published: November 2023

BackgroundCyclic daily changes in environmental conditions are key signals for anticipatory and adaptive adjustments of most living species, including mammals. Exposure to a lower ambient temperature increases thermogenic activity of brown adipose tissue and skeletal muscle. Given that the components of the molecular clock interact with the thermal and metabolic mechanisms directly involved with the defense of body temperature, the present study evaluated the interdependence of homeostatic and circadian‐related mechanisms in response to a cold stimulus at distinctive moments of the day.MethodsMale Wistar rats were subjected to a single 3‐h episode of cold ambient temperature (4°C) at one of 6 time‐points along the light/dark cycle starting at: ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22 (ZT0 being the time of light onset and ZT12 time of dark onset). Metabolic rate, body temperature, locomotor activity, feeding and drinking behavior were recorded during both control (room temperature) and cold conditions at each time‐point. Immediately after the 3‐h cold stimulus, rats were euthanized and both the soleus and brown adipose tissue were collected for rtPCR analysis of genes of interest.ResultsExposure to a lower environmental temperature during the light (i.e., sleep) phase resulted in a slight hyperthermia associated with an increased metabolic rate. This association occurred regardless of time‐of‐day differences in increased locomotor activity. Additionally, the well‐known shift in substrate oxidation towards fat metabolism was attenuated during the inactive phase. These metabolic changes were accompanied by tissue‐specific adjustments to both cold and time‐of‐day in core‐clock genes expression, such as DBP and Rev‐erbα in the brown adipose tissue and CLOCK, PER1, CRY1, CRY2 and also Rev‐erbα in the soleus skeletal muscle. Simultaneously, different pathways in substrate oxidation and thermogenesis were also tissue‐specifically affected by time‐of‐day and cold.ConclusionIn summary, the present results show a strong interdependence between homeostatic adjustments to environmental challenges, the daily rhythms in thermal balance and behavior and the core components of the molecular clock.Support or Funding InformationCAPES and ZonMw
Cross talk between Skeletal muscle and Brown adipose tissue during cold and diet induced thermogeneis
Authors: Periasamy Muthu 
Published: November 2023

The importance of brown adipose tissue as a site of nonshivering thermogenesis has been well documented. Emerging studies suggest that skeletal muscle is also an important site of thermogenesis especially when brown adipose tissue function is lacking. We recently showed that sarcolipin (SLN), an uncoupler of the sarco(endo) plasmic reticulum Ca2+ ATPase (SERCA) pump, could contribute to heat production in skeletal muscle. In this study, we sought to understand how loss of UCP1 or SLN is compensated during cold exposure and whether they are both necessary for thermogenesis. Toward this goal, we generated a UCP1; SLN double knock‐out (DKO) mouse model and challenged the single and DKO mice to acute and long‐term cold exposures. Results from this study show that there is up‐regulation of SLN expression in UCP1‐KO mice, and loss of SLN is compensated by increased expression of UCP1 and browning of white adipose tissue. We found that the DKO mice were viable when reared at thermoneutrality. When challenged to acute cold, the DKO were extremely cold‐sensitive and became hypothermic Paradoxically, the DKO mice were able to survive gradual cold challenge, but these mice lost significant weight and depleted their fat stores, despite having higher caloric intake. Interestingly loss of either SLN or UCP1 alone was sufficient to cause high fat diet‐induced obesity. No compensatory upregulation of UCP1 in SLN−/− mice or vice versa was found. However loss of both mechanisms failed to exacerbate the obesity phenotype. These studies imply that brown adipose tissue and skeletal muscle are recruited differently during cold vs diet induced thermogenesis.Support or Funding InformationNIH R01‐HL‐088555 and R01‐DK098240‐01American Diabetes Association Basic Science Research Award (7‐13‐BS‐131) (to MP) and by the NIDDK‐NIH Award (K01‐DK102772) (to NCB).
Effect of Gut Microbiota Eradication on Adaptive Thermogenesis in Mice
Authors: Beserra Bruna Teles Soares , da Costa Silva Janice , Oliveira Fernanda Cerqueira Barroso , Ribeiro Carolina Martins , Perreira Sidney Alcântara , de Assis Rocha Neves Francisco , Coelho Michella Soares , Amato Angélica Amorim 
Published: November 2023

The gut microbiota is identified as an important regulator of metabolism and plays a relevant role in the development and progression of obesity. Among the mechanisms proposed to explain the regulation of energy metabolism by the gut microbiota, is its influence on host's energy expenditure. One of the components of energy expenditure is the adaptive thermogenesis, resulting from the activity of thermogenic adipose tissue, consisting of the beige or brown adipocyte. This type of thermogenesis seems to be important for the metabolic health of rodents and humans.ObjectiveTo investigate the effect of gut microbiota eradication on the thermongenic phenotype of adipose tissue in lean and obese mice.MethodsFive week old C57BL/6 male mice fed a control or high‐fat diet (HFD) for 10 weeks were randomly assigned to receive vehicle, antibiotics (ciprofloxacin 0.2g l−1 and vancomycin 0.5 g l−1 from the 10th to the 15th week, in drinking water), the b3‐adrenergic agonist CL 316,243 (1mg/kg/d for 5 days, intraperitoneally) or the combination of antibiotics and CL 316,243. Weight gain, energy intake and water intake were measured. Visceral adipose tissue white (vWAT), subcutaneous adipose tissue white (sWAT) and interescapular adipose brown (iBAT) were excised for determination of adiposity and expression of thermogenesis‐related gene.Results(p<0.05 compared with vehicle, 5 mice/group): There was no difference in weight gain, energy intake and water intake among the study groups, both in control and HFD‐fed mice. Control diet‐fed mice treated with the combination of antibiotics and CL 316,243 exhibited decreased vWAT and sWAT mass, whereas mice fed a HFD had a slight but nonsignificant trend towards decreased vWAT and sWAT mass. There was no difference in iBAT mass in mice fed a control and HFD and treated with antibiotics and/or CL 316,243 for both diets. There was a trend towards increased expression of the thermogenesis‐related gene Ucp‐1 in vWAT and sWAT of mice fed control or HFD and treated with antibiotics. In mice treated with both antibiotics and CL 316,243 there was a significant increase in Ucp1 expression in these WAT depots. Ucp1 expression in iBAT was unchanged by either treatment.ConclusionOur findings indicate that gut microbiota eradication by antibiotics increases the thermogenic phenotype in WAT and therefore suggest that some components of microbiota may have a negative impact in adaptive thermogenesis.Support or Funding InformationCNPq/CAPES/FAPDF
Fish‐oils Increase BAMBI Expression to Protect Against Fibrotic Activity in LPS Stimulated Hepatic Tissue
Authors: Schaller Megan L. , Harris Matthew P. , Kamm Dakota , Witt Kenneth A. , Sandoval Karin E. , Wooten Joshua S. 
Published: November 2023

Non‐alcoholic steatohepatitis (NASH), defined as excess hepatic lipid and chronic inflammation, provides an environment prone for the development of hepatic fibrosis. Recent evidence suggests that the antifibrotic protein BAMBI (BMP‐Activin membrane bound inhibitor) is downregulated in the presence of inflammation, and may be central to the development of fibrosis. Diets rich in omega‐3 (ω‐3) fatty acids are known to provide anti‐inflammatory effects; however, the effects of ω‐3 fatty acids on hepatic fibrosis are not well‐established.PURPOSETo determine the effects of fish‐oils on the hepatic fibrosis signaling cascade, following 32‐weeks of high‐fat feeding in a LPS‐induced model of NASH.METHODSMale C57BL/6 mice were randomly assigned to one of four diets for 32 weeks (n=9/group): low‐fat lard based (LFL, 10% kcal fat), low‐fat fish‐oil based (LFFO, 10% kcal fat), high‐fat lard based (HFL, 41% kcal fat), or high‐fat fish‐oil based (HFFO, 41% kcal fat). Following in situ LPS stimulation, liver mRNA expression of CD14, TLR4, MyD88, BAMBI, and TGF‐β1 was quantified using quantitative RT‐PCR. Differences between diets were identified using a one‐way ANOVA with statistical significance set at p<0.05.RESULTSFollowing LPS stimulation, CD14 was increased 2.5 fold (p=0.020) in HFFO when compared to HFL. Despite the increase in CD14, TLR4 showed no difference between groups. In contrast, MyD88 was 2.8 fold greater (p<0.001) in HFL compared to HFFO. In comparison to untreated tissue, BAMBI was 1.7 fold (p=0.017) higher in the HFFO LPS‐stimulated tissue, which best explained the 1‐fold (p=0.004) lower expression of TGF‐β1 in HFFO when compared to HFL post‐LPS stimulation.CONCLUSIONDespite the increase in extracellular LPS signaling receptor CD14, the consumption of fish‐oils produced a protective intracellular response as observed by an increase in BAMBI and decrease in TGF‐β1. These results suggest that a diet high in ω‐3 fatty acids may protect against the development of hepatic fibrosis.Support or Funding InformationSupported by NIH R21NS090282‐01
Use of Low‐Density Lipoprotein receptor and Very Low‐Density Lipoprotein Receptor as potential genetic markers to investigate the development of obesity in a non‐model fish species, Ictalurus punctarus
Authors: Ordonez‐Castillo Norelia , Abernathy Oaklee , Spainhour Rebekah , Kobayashi Yass 
Published: November 2023

Dyslipidemia is a metabolic disorder that often develops in association with obesity. Most research regarding human metabolic disorders, including dyslipidemia, has been conducted using rodents. However, channel catfish selected for increased growth often develop obese‐like phenotype with increased fat accumulation in the abdomen, suggesting channel catfish can be useful in investigating the mechanism(s) associated with development of obesity in humans. Objectives of this experiment were to identify the genes encoding mRNA for two low density lipoprotein receptors (LDLrA and LDLrB) and examine their tissue distributions in channel catfish (Ictalurus punctarus). In addition, mRNA encoding very low density lipoprotein receptor (VLDLr) was identified and characterized. Channel catfish LDLrA, LDLrB, and VLDLr mRNA sequences were identified by screening the channel catfish genome database and their expression was examined in the brain, spleen, trunk kidney, liver, Bockmann body, and muscle. The PCR amplicon for respective mRNA was highly similar (>70%) with other species of fish. The sequences of LDLrA and LDLrB mRNA also shared a high degree of similarities (>65%) with rodents and humans. Expression of LDLrA and VLDLr mRNA sequences were detected at various levels in all tissues examined. LDLrB mRNA sequences were also detected at various levels in all tissues except in the brain. Currently, the changes in expression of the three mRNA expressions in relation to changes in food intake and development of obese‐like phenotype are being investigated.Support or Funding InformationThis research is supported by the Kansas Idea Network of Biomedical Research Excellence (P20GM103418).