bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Chaperon‐Like Protein HYPK Binds Arl4 Small GTPases to Modulate Cell Migration
Authors: Lee Fang-Jen Scott , Lin Ming-Chieh 
Published: April 2020

ADP‐ribosylation factor (Arf)‐like 4 proteins are a group of small GTPases that control actin remodeling and promote cell migration. Their expression is finely tuned during development and only detectable in specific tissues. Dysregulation of Arl4s is linked with several cancers but little investigation reveals how they are regulated. Here we identified huntingtin yeast two‐hybrid protein K (HYPK) as a novel interacting partner of Arl4A and Arl4D, but not Arl4C. HYPK, primarily known as huntingtin (Htt) interacting protein, is reported to reduce aggregates and apoptosis induced by Htt and exhibited chaperone‐like activity. We show that HYPK interacts with Arl4A/D and modulates Arl4A/D‐dependent cellular phenotypes and cell migration ability. Arl4A/D does not appear to involve in HYPK‐mediated reduction of Htt aggregation. Residues 115–129 within C‐terminal conserved domain, possessing chaperon‐like activity of HYPK, is required and sufficient to interact with Arl4A/D. Losing of HYPK nullifies Arl4A‐induced cell migration, and only WT, but not Arl4A‐binding‐defective HYPK mutant, can rescue this phenotype. In addition, Arl4A exhibits reduced plasma membrane signals and its ability to maintain trans‐Golgi integrity in HYPK knockdown cells. Taken together, we infer that HYPK may serve as an upstream modulator of Arl4A/D to confer function of Arl4 small GTPases.Support or Funding InformationThis work was supported by grants from the National Health Research Institutes (NHRI) in Taiwan (NHRI‐EX106‐10601B1)
The Novel Roles of Dusp6 in Gut Barrier Modulation and Microbiome Shaping
Authors: KAO CHENG-YUAN , Chang Cherng-Shyang , Liao Yi-Chu , Huang Chih-Ting , Lin Chiao-Mei , Ruan Jhen-Wei , Liao Yu-Chieh 
Published: April 2020

Gut microbiome has been associated with many human disorders and conditions such as allergy, obesity, inflammatory bowel disease and various types of cancers. Many of these diseases have become important health issues worldwide and effective strategies for their treatment and/or prevention are highly desired. We previously have found that dual‐specificity phosphatase 6 (Dusp6)‐deficient mice had reduced body weight gain and alleviated metabolic disorders. Notably, 16S rRNA gene sequencing revealed that the gut/fecal microbiota in Dusp6‐deficient mice was more resistant to high‐fat‐diet‐ induced dysbiosis compared with wild‐type mice. The RNA‐seq gut transcriptome analysis has shown several potential mechanisms driving the microbiota alteration in Dusp6‐deficient mice. We also found that Dusp6 knockout mice compared with wild‐type littermate mice were more resistant to dextran sulfate sodium (DSS)‐induced colitis and the mechanisms of the Dusp6 deficiency in shaping gut microbiome and barrier integrity were investigated. In summary, these findings indicate that Dusp6‐deficiency is a novel host genetic factor that could modulate gut barrier and inhibiting DUSP6 might be a novel strategy to maintain gut microbiome eubiosis.Support or Funding InformationThis work was supported by the following grants: IM‐108‐PP‐04 from NHRI and 106‐2628‐B‐ 400‐001‐MY3, 106‐2923‐B‐400‐001‐MY3, 108‐2321‐B‐400‐011‐ from MOST.
Investigation of HMGB1 binding interactions with cell clearance molecules
Authors: Wade Elizabeth , Troisi Maria , Broome Payson , Halsell Jonah , Alverado Alice , Desani Alexis , O’Murphy Fiona , Fairweather Samantha , Bell Anthony Jerome 
Published: April 2020

High Mobility Group Box 1 (HMGB1) is a highly abundant DNA‐binding protein. HMGB1 was initially classified as an architectural nuclear protein that facilitates transcription factor binding, chromatin remodeling as well as genetic recombination and repair. It is now clear that HMGB1 also functions in the extracellular matrix (ECM) as a proinflammatory cytokine. More specifically, HMGB1 acts as a damage‐associated molecular pattern molecule. In this capacity, HMGB1 binds immune receptors (i.e. CXR4,RAGE and TLRs) to promote leukocyte migration and amplify proinflammatory gene expression. Ideally, HMGB1 would operate in the ECM to expunge infectious pathogens. However, this does not seem to always be the case. Studies show that the presence of HMGB1 in the ECM is also linked with diseases associated with defective cell clearance, such as lupus (SLE) and cystic fibrosis (CF). The investigation of HMGB1 in cell clearance is an understudied area of research. We hypothesize that HMGB1 exacerbates SLE and CF by binding to cell clearance molecules in the ECM to prevent the proper removal of apoptotic cells. In SLE, failed cell clearance can lead to breaking immune tolerance. In CF, chronic tissue damage is mediated by neutrophils that are not effectively engulfed by macrophages. We will evaluate HMGB1 binding interactions with four categories of cell clearance molecules: i)“eat‐me” signals, ii)“find‐me” signals, iii) phagocyte receptors and iv)adaptor molecules and opsonins. We will use circular dichroism (CD), far‐western blots and surface plasmon resonance to investigate HMGB1 binding interactions with each class of cell clearance biomolecule.Support or Funding InformationUniversity of San Diego
Group A Streptococci Shift the Balance of Muscular Mitochondrial Dynamics
Authors: Tsai Pei-Jane , Hsu Chih-Yu , Lai Wei-Ting , Wang Yi-Cian , Tsai Yau-Sheng 
Published: April 2020

The most severe form of invasive group A Streptococcus (GAS) disease is necrotizing fasciitis described as rapidly muscle destruction. Muscles are responsible for energetic functions which are mostly provided by proper mitochondrial function. Mitochondria are the highly dynamic organelles, constantly undergoing fusion and fission. Pathogen aim at preserving the bacterial replication niche by targeting to mitochondria and inducing cell death. This prompted us to specifically analyze the effect on muscular mitochondria upon GAS infection. By using electron microscopic analysis of GAS‐infected muscle tissue, the muscle is strongly damaged and the mitochondria are fragmented and structurally abnormal. Further, we found GAS alters the morphology of cell mitochondria, inducing fragmentation of the mitochondria network which accompanied by decreasing the levels of fusion protein in mouse muscle cell, C2C12. Furthermore, our data demonstrate that mitochondrial function is not strictly dependent on morphology. Our results reveal that disruption of fusion induces more profound defects on lacking of fission during GAS infection, and imply that while fusion is required throughout life, fission is more important later in life likely to combat bacterial infection. Overall, our study provides important new insights into the central role of mitochondrial dynamics in innate immunity.Support or Funding InformationMOST 108‐2320‐B‐006‐013
Exercise Training Combined with Hydrochlorothiazide is More Efficient than Antihypertensive Treatment Alone to Promote Cardiofunctional Benefits in a Model of Hypertension and Menopause
Authors: Ferreira Maycon , Silva Michel , Silva Gabriel , Dias Danielle , Bernardes Nathalia , Irigoyen Maria-Cláudia , De Angelis Kátia 
Published: April 2020

The largest proportion of hypertensive women are in postmenopause and this hypertension is poor controlled. Experimental model has shown that exercise training (ET) is effective to reduce arterial pressure (AP) and to mitigate of autonomic dysfunction. Following current guidelines for hypertension treatment, the association of antihypertensives therapy (AT) with ET is strongly recommended. Here, we investigate the effects of the ET plus AT on functional and hemodynamic parameters in an experimental model of hypertension and menopause. Female spontaneously hypertensive rats (150–180g, 3 months old) were ovariectomized and randomly assigned into 3 groups (4–6 animals/group): ovariectomized (OVX) sedentary (OS), OVX sedentary treated with hydrochlorothiazide (OSH) and OVX trained treated with hydrochlorothiazide (OTH). Ovarian hormone deprivation was performed through bilateral ovariectomy. Rats underwent the maximal running test and 1‐repetition maximum (RM) test in the first, fourth and eighth weeks. Hydrochlorothiazide (30 mg/kg) was dissolved in the drinking water. Noninvasive arterial pressure (AP) was assessment by the tail cuff plethysmography. Concurrent ET (40–60% maximal capacity) was performed on a motor treadmill (aerobic training) and on a ladder adapted to rats (resistance training), 3 days/wk for 8 weeks. Carotid artery and jugular vein catheterization were performed and the systolic (SAP), diastolic (DAP) and mean AP (MAP), as well as heart rate (HR) were recorded. OTH presented a higher aerobic capacity compared to OS group (group effect, p<0.05). In addition, trained and treated with antihypertensive therapy showed a higher load resistance capacity in relation to OS and OSH groups (group effect, p<0.05). There was an interaction effect between time and group in both aerobic capacity (p<0.05) and load resistance capacity (p<0.05). Similarly, interaction effect was observed for noninvasive SAP (p<0.05), and OTH presented a lower value compared to OS group (group effect, p<0.05). In addition, DAP and MAP were lower in the OSH compared to OS group, as well as the OTH group showed lower HR in relation to OS group. No differences were observed for DAP and MAP between OSH and OTH groups. To date, our results suggest that exercise training associated with hydrochlorothiazide treatment induce additional cardiofunctional benefits than antihypertensive treatment alone.Support or Funding InformationCAPES‐DS and FAPESP.
Expression of AIF, PARP and microRNAs miR‐145, miR‐210, miR‐486 associated with apoptosis in the corpus cavernosum of rats subjected to chronic alcoholism model
Authors: Fazan Valéria Paula Sassoli , Assis Cirino Mucio L. , Schiavoni Vagner S. , Lizarte Neto Fermino S. , Melo de Carvalho Camila A. , Novais Paulo Cezar , da Cunha Tirapelli Daniela Pretti , Molina Carlos Alberto F. , Júnior Silvio Tucci , Tirapelli Luis Feranado 
Published: April 2020

IntroductionSince penile erection is dependent on competent vascularization, substances that are known to damage vessels and their functions can affect it. An example is excessive alcohol consumption. Chronic and excessive alcohol consumption has a cytotoxic effect that harms health in general, but especially in events that are dependent on the integrity of vascularization such as penile erection. Previous studies from our group described some consequences of using ethanol on penile erection. Nevertheless, the molecular mechanisms surrounding microRNAs, apoptosis process and their relationship with erectile dysfunction associated with alcohol consumption are still poorly understood.ObjectivesTo evaluate the mechanism of apoptosis by the expression of AIF and PARP, as well as their regulatory microRNAs: miR‐145, miR‐210 and miR‐486, in the corpus cavernosum of rats submitted to a semivoluntary alcoholism model.Material and methods24 Wistar rats were divided into two groups: control (C) and treated with 20% ethanol (A) for seven weeks. The corpus cavernosum samples were prepared for immunohistochemical analysis of AIF and PARP protein expression, and gene expression for miR‐145, miR‐210, miR‐486 microRNAs in cavernous tissue was quantified by real time PCR.ResultsThe immunohistochemical analysis showed little nuclear positive labeling for the protein PARP and AIF in the corpus cavernosum of both control and ethanol treated animals. The analysis of miR‐145, ‐210 and ‐486 microRNA expression in the 12 animals studied showed no significant difference between the control and alcoholized groups.ConclusionsThe expression of AIF and PARP and their regulatory microRNAs involved in apoptotic process (miR‐145, miR‐210 and miR‐486) were not altered in the corpus cavernosum of rats submitted to the semivoluntary alcoholism.Support or Funding InformationFAPESP, CNPq, CAPES and FAEPA
Vitamin D mitigates intestinal inflammation through modulation of oxidative stress, autophagy and intestinal permeability in Cftr‐null mice
Authors: Mailhot Genevieve , Morin Genevieve , Laffont Alisson 
Published: April 2020

BackgroundThe gut is the earliest organ affected by cystic fibrosis (CF), often in utero. Besides maldigestion and malabsorption, the other common intestinal manifestation is chronic inflammation, which exerts a negative impact on the nutrition, lung health and quality of life of these individuals. To date, few treatments exist to alleviate CF intestinal inflammation. Vitamin D plays anti‐inflammatory roles in the intestine through autocrine and/or paracrine actions, but its potential has been poorly investigated in the context of CF disease. Due to its anatomic location, the gut is the tissue exposed to the largest amount of vitamin D from external sources, making this vitamin an attractive therapeutic option. We previously showed that intestinal mucosa from CF mice exhibited increased eosinophilic infiltration compared to non‐CF mice, an effect that was reversed by the administration of a high‐vitamin D3 diet. We thus postulate that vitamin D mitigates CF intestinal inflammation through regulation of critical processes involved in inflammatory responses, such as permeability, oxidative stress and autophagy.MethodsTwelve‐week old BALB/c CF (Cftr−/−) and non‐CF (Cftr+/+) mice were fed ad libitum a normal vitamin D3 diet (1,500 IU/kg diet) or a high‐vitamin D3 diet (5,000 IU/kg diet) for 8 weeks. Intestinal sections were harvested and assessed for the expression of markers of oxidative stress (e.g. deoxyguanidine), intestinal permeability (e.g. zonulin‐1) and autophagy (e.g.LC3, p62) by means of quantitative PCR, immunofluorescence and Western blotting.ResultsDeoxyguanidine (a marker of oxidative DNA damage) and zonulin‐1 duodenal immunostaining was increased in Cftr−/− mice fed with the normal vitamin D3 diet compared to diet‐matched Cftr+/+ mice. Protein ratio of LC3‐II to LC3‐I was higher whereas p62 expression was lower in the duodena of Cftr−/− mice, suggesting enhanced baseline autophagy. Cftr−/− mice fed the high vitamin D3 diet showed a decreased expression of deoxyguanidine, zonulin‐1 and LC3‐II to LC3‐I ratio and an increased p62 expression to levels of Cftr+/+ mice. Of note, the high‐vitamin D3 diet did not have any measurable impact on the intestinal mucosa of Cftr+/+ mice, which was comparable to that of Cftr+/+ mice fed the normal vitamin D3 diet.ConclusionsTogether, our findings show that the Cftr−/− duodenal mucosa exhibits increased permeability, autophagy and oxidative damage that may all contribute to the chronic inflammatory state. A high vitamin D3 diet given for 8 weeks reverses those alterations, making this vitamin a potential therapeutic option for CF intestinal inflammation.Support or Funding InformationThis work was supported by a grant from Cystic Fibrosis Canada
Sex‐Specific Alterations on Muscle Plasticity and Myogenesis in Offspring Rats from Vitamin D Deficient Mothers
Authors: Navegantes Luiz , Reis Natany , Turatti João , Gonçalves Dawit , Silveira Willian , Lautherbach Natália , Almeida Lucas , de Assis Ana Paula , Zanon Neusa , Heck Lilian , Kettelhut Isis 
Published: April 2020

ObjectiveTo analyze the impact of maternal Vitamin D deficiency (VDD) on offspring muscle development in adulthood of male and female rats.MethodsTwelve 5‐week‐old female Wistar Hannover rats were fed either a Vit. D3+ diet (AIN93G with 1000 IU vitamin D3/kg diet) or Vit. D3− diet (AIN93G without vitamin D3) for six weeks and then bred to male rats. Mothers were maintained on the diets throughout gestation and lactation. At weaning, male and female offsprings were separated in four groups: male and female offspring control (M‐CTRL and F‐CTRL, respectively) pups of dams with Vit. D3+ diet; male and female offspring VDD (M‐VDD and F‐VDD, respectively) pups of dams with Vit. D3− diet. Offspring received a standard diet (Nuvilab) until 180 days of age, at which point tissues were harvested for analysis. *P≤0,05 (CEUA 052/2018).ResultsBoth male and female VDD groups showed a reduction in the calcidiol serum concentration (23±1 vs 40±2 ng/ml in M‐CTRL and 23±2.2 ng/ml vs 36.6±0.9 ng/ml in F‐CTRL) without affecting Ca+2 serum. At weaning, M‐VDD weighed less than M‐CTRL rats but recovered weight in the 60 days post weaning and acquired a greater body weight accompanied by a higher mass of white and brown adipose tissue at 180 days. Extensor digitorum longus (EDL) muscles from the M‐VDD showed a decrease (20 %; p<0.05) in the number of total fibers and an increase in the cross sectional area of IIB (17 %), IIA (19 %) and IIAX (21%; p<0.05) fibers. VDD also deregulated myogenesis as indicated by the higher levels of MyoD (43%; p<0.05) and Myogenin (160%; p<0.05) and in the number of satellite cells (128.8±14 vs 91±7.6 nuclei Pax7+ in the MO‐CTRL). To further investigate the signaling pathways involved in the muscle hypertrophy effect in the M‐VDD group, p‐IGF‐1/insulin receptor levels, and different insulin downstream targets related to protein synthesis including Ser 473p‐Akt, Ser 21/9 p‐GSK‐3β and Ser 209p‐eIF4e were measured. VDD increased all these parameters and in parallel increased plasma insulin and muscle IGF‐1 mRNA levels, but did not affect mTOR signaling. These changes were not found in Soleus from the M‐VDD group and in both EDL and Soleus from the female offspring.ConclusionMaternal VDD selectively affect the development of glycolytic muscle in male offspring characterized by hypoplasia, hypertrophy and deregulated myogenesis. The muscle hypertrophy is a compensatory mechanism probably due to the greater insulin sensitivity and activation of the Akt pathway. Muscles from female offspring seem to be protected from this metabolic disturbance showing a clear sex‐specific effect induced by maternal VDD.Support or Funding InformationFAPESP (19/06517‐1; 18/10089‐2)
Amniotic fluid mesenchymal stem cells ameliorate lung alveolar epithelium regeneration and reverse lung fibrosis of chronic obstructive pulmonary disease
Authors: Chen Chuan-Mu , Yang Jing-Chan , Yen Chih-Ching , Chen Hsiao-Ling 
Published: April 2020

Pulmonary emphysema progression is attributed not only to alveolar structure loss and pulmonary regeneration impairment but also to excessive inflammatory response, proteolytic and anti‐proteolytic activity imbalance, lung epithelial cell apoptosis and abnormal lung remodeling. To ameliorate lung damage with higher efficiency through lung tissue engineering and cell therapy, predifferentiating graft cells into more restricted cell types before transplantation could enhance their ability to anatomically and functionally integrate into damaged lung. An optimal lung epithelial progenitor‐like cells (LEPLCs) predifferentiation condition has been established in eGFP‐expressing amniotic fluid mesenchymal stem cells (AFMSCs). Transplantation of LEPLCs significantly improved regeneration of lung tissue as they integrated into the lung alveolar structure, relieved airway inflammation, alleviated amount of DNA damage in alveolar cells, increased expression of growth factors such as vascular endothelial growth factor, and reduced expression of matrix metalloproteinases and lung remodeling factors when compared with the elastase‐induced pulmonary emphysema mice injected with AFMSCs. In conclusion, transplantation of predifferentiated AFMSCs through intratracheal injection showed better alveolar regeneration and reverse lung fibrosis in PPE‐induced pulmonary emphysema mice.Support or Funding InformationThis research was supported by grant MOE‐108‐S‐0023‐A from the Ministry of Education of Taiwan.
Investigation of Wnt Pathway Genes in a Highly Regenerative Marine Invertebrate
Authors: Hughes Jun-Wei Brendan , Ward Vivienne , Jamison Cameron Ann , Johnson Christine , Sumner Jack Thomas , Keeling Elena 
Published: April 2020

Colonial ascidians are the closest known relatives to vertebrates that retain whole body regeneration. Understanding molecular pathways involved in regeneration in a diverse range of organisms will provide insights into evolutionary changes in regeneration. Specifically, our research explores Wnt signaling in the colonial ascidian Botrylloides violaceus; this highly conserved pathway is universally involved in studied animals with any regenerative ability. A recent rough draft genome for B. violaceus reveals multiple putative ligands, receptors, and downstream effectors from the Wnt pathway. Primers designed from the draft genome are being used in PCR to validate these predicted genes. Future studies will use qPCR to track gene expression of different Wnt pathway members through regeneration.Support or Funding InformationThe Frost Fund, College of Science and Mathematics at California Polytechnic State University, San Luis Obispo
Effects of Elevated CO2 on Yellowfin tuna (Thunnus albacares) Early Life Stage Respiration and Ammonia Excretion
Authors: Heuer Rachael M. , Wang Yadong M. , Pasparakis Christina , Scholey Vernon , Margulies Daniel , Grosell Martin 
Published: April 2020

Although the impacts of near‐future projected CO2 levels on coastal fishes are well‐documented, few studies have addressed impacts to broad‐ranging pelagic fish species which generally live in a more stable environment and therefore may be more impacted by change. The early life stages of pelagic fish may be especially sensitive to CO2, since acid‐base regulatory mechanisms are not fully developed. Furthermore, few studies have examined how CO2 exposure could impact nitrogenous waste excretion in early life stage fish. In the present study, we examined the impacts of near‐future CO2 on early life stages of the Yellowfin tuna (Thunnus albacares). Tuna embryos were obtained from a captive spawning broodstock population of Yellowfin tuna at the IATTC Achotines Laboratory. Tuna were exposed to either control or 1900 matm CO2 (prediction for year 2300) directly after spawn and through the first 3 days of development as embryos hatched into yolk sac larvae. Metabolic rate, ammonia tissue accumulation, and ammonia excretion were quantified at various timepoints throughout development. Since Rh proteins putatively transport CO2 in addition to ammonia, samples to assess mRNA expression of Rh proteins were also taken at each developmental timepoint. Exposure to elevated CO2 did not significantly impact the metabolic rate of developing tuna, however, at the final larval stage, a 22% decrease in metabolic rate was noted. This decline was immediately preceded by a significant increase in ammonia excretion in CO2‐exposed larvae, despite no difference in ammonia tissue accumulation when comparing control and CO2‐exposed larvae. Interestingly, CO2‐exposed larvae exhibited a significant increase in urea accumulation at this timepoint. These data suggest that larvae are producing more nitrogenous waste, but are able to avoid the build‐up of toxic ammonia by maintaining higher levels of ammonia excretion and/or by converting ammonia to urea. Analysis of mRNA expression of Rh proteins is ongoing and may provide a mechanism for this increased nitrogenous waste excretion. These results suggest egg and yolk sac larvae life stages of yellowfin tuna may be equipped with mechanisms to counteract increases in CO2. This research was made possible by a grant from The Gulf of Mexico Research Initiative. Grant No: SA‐1520.Support or Funding InformationThis research was made possible by a grant from The Gulf of Mexico Research Initiative. Grant No: SA‐1520.