Biology Open

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ISSN / EISSN : 20466390 / 20466390
Current Publisher: The Company of Biologists (10.1242)
Total articles ≅ 1,369
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Zhanying Hu, Bo Chen, Qiong Zhao
Published: 16 April 2019
Biology Open; doi:10.1242/bio.040840

Abstract:Impaired osteoblast differentiation may result in bone metabolic disease such as osteoporosis. It was reported recently that Hedgehog (Hh) signaling and autophagy are two important regulators of bone differentiation. In order to further dissect their relationship in bone development, we used a zebrafish larvae model to investigate how disruption of one of these signaling affects the function of another and impacts osteoblast differentiation. Our results showed that activation of Hh signaling negatively regulated autophagy. However, suppression of autophagy by knocking down atg5 expression didn't alter Hh signaling, but dramatically up-regulated the expression of osteoblast related genes and increased bone mineralization especially in den region. On the contrary, inhibition of Hh signaling pathway by cyclopamine treatment suppressed the expression of osteoblast related genes and decreased bone mineralization. In agreement with these findings, blocking Hh signaling through knock down SHH and Gli2 genes led to defective osteoblast differentiation, while promoting Hh signaling by knock down Ptch1 was beneficial to osteoblast differentiation. Our results thus support that activation of Hh signaling pathway negatively regulates autophagy and consequentially promotes osteoblast differentiation. On the contrary, induction of autophagy inhibits osteoblast differentiation. Our work revealed the mechanism underlying Hh signaling pathway regulation of bone development.
Bárbara Vaccari Cardoso, Augusto Henrique Custódio, Patrícia Aline Boer, José Antonio Rocha Gontijo
Published: 15 April 2019
Biology Open, Volume 8; doi:10.1242/bio.038562

Abstract:In this study, we hypothesized that blunting of the natriuresis response to intracerebroventricularly (ICV) microinjected adrenergic agonists is involved in the development of hypertension in maternal low-protein intake (LP) offspring. A stainless steel cannula was stereotaxically implanted into the right lateral ventricle (LV), then we evaluated the ICV administration of adrenergic agonists at increasing concentrations, and of α1 and α2-adrenoceptor antagonists on blood pressure and urinary sodium handling in LP offspring relative to an age-matched normal-protein intake (NP) group. We confirmed that epinephrine (Epi) microinjected into the LV of conscious NP rats leads to enhanced natriuresis followed by a reduction in arterial pressure. This response is associated with increased proximal and post-proximal sodium excretion accompanied by an unchanged glomerular filtration rate. The current study showed, in both NP and LP offspring, that the natriuretic effect of Epi injection into the LV was abolished by prior local microinjection of an α1-adrenoceptor antagonist (prazosin). Conversely, LV α2-adrenoceptor antagonist (yohimbine) administration potentiated the action of Epi. The LV yohimbine pretreatment normalized urinary sodium excretion and reduced the blood pressure in LP compared with age-matched NP offspring. These are, as far as we are aware, the first results showing the role of central adrenergic receptors’ interaction on hypertension pathogenesis in maternal LP fetal-programming offspring. This study also provides good evidence for the existence of central nervous system adrenergic mechanisms consisting of α1 and α2-adrenoceptors, which work reciprocally on the control of renal sodium excretion and blood pressure. Although the precise mechanism of the different natriuretic response of NP and LP rats is still uncertain, these results lead us to speculate that inappropriate neural adrenergic pathways might have significant effects on tubule sodium transport, resulting in the inability of the kidneys to control hydrosaline balance and, consequently, an increase in blood pressure.
Published: 15 April 2019
Biology Open, Volume 8; doi:10.1242/bio.043349

Abstract:First Person is a series of interviews with the first authors of a selection of papers published in Biology Open, helping early-career researchers promote themselves alongside their papers. Kingsley Ugwuagbo and Sujit Maiti are co-first authors on ‘Prostaglandin E2 promotes embryonic vascular development and maturation in zebrafish’, published in BiO. Kingsley is an MSc student in the lab of Dr Mousumi Majumder at Brandon University, Canada, investigating early detection strategies in breast cancer. Sujit is a research assistant in the lab of Dr Mousumi Majumder at Brandon University, investigating the simplest approach to discovering early detection of breast cancer.
Theja Abayarathna, Brad R. Murray, Jonathan K. Webb
Published: 15 April 2019
Biology Open, Volume 8; doi:10.1242/bio.042564

Abstract:Heatwaves are a regular occurrence in Australia, and are predicted to increase in intensity and duration in the future. These changes may elevate temperatures inside lizard nests, shortening the incubation period, so that hatchlings are more likely to emerge during heatwaves. Potentially, developmental plasticity or heat hardening could buffer hatchings from future warming. For example, higher incubation temperatures could shift critical thermal maxima upwards, enabling lizards to withstand higher temperatures. To investigate whether developmental plasticity affects hatchling thermal tolerance, we incubated eggs of the velvet gecko Amalosia lesueurii under two fluctuating incubation treatments to mimic current (mean=24.3°C, range 18.4–31.1°C) and future ‘hot’ (mean=28.9°C, range 19.1–38.1°C) nest temperatures. We maintained the hatchlings under identical conditions, and measured their thermal tolerance (CTmax) aged 14 days and 42 days. We then released hatchlings at field sites, and recaptured individually marked lizards aged 6 months, to determine whether incubation induced shifts in thermal tolerance were transitory or long-lasting. We found that at age 14 days, hatchlings from hot-temperature incubation had higher CTmax [mean=39.96±0.25°C (s.d.)] than hatchlings from current-temperature incubation [mean=39.70±0.36°C (s.d.)]. Hatchlings from the current-incubation treatment also had significantly higher heat hardening capacity [mean=0.79±0.37°C (s.d.)] than hatchlings from hot-temperature incubation treatment [mean=0.47±0.17°C (s.d. )]. However, both of these incubation-induced effects did not persist into later life. By contrast, incubation treatment had significant and long-lasting effects on the cold tolerance of hatchlings. At age 14 days, current-incubated hatchlings tolerated colder temperatures [CTmin=11.24±0.41°C (s.d.)] better than hot-incubated hatchlings [CTmin=14.11±0.25°C (s.d.)]. This significant difference in cold tolerance persisted into the juvenile life stage, and was present in 6-month-old lizards that we recaptured from field sites. This finding indicates that upward shifts in cold tolerance caused by higher incubation temperatures might affect overwinter survival of lizards, but field studies linking fitness to thermal tolerance are necessary to test this idea. Overall, our results suggest that developmental plasticity for heat tolerance is unlikely to buffer lizard populations from higher temperatures.
Benjamin Souferi, Mark M. Emerson
Published: 10 April 2019
Biology Open; doi:10.1242/bio.039115

Abstract:Enhancer activity is determined by both the activity and occupancy of transcription factors as well as the specific sequences they bind. Experimental investigation of this dynamic requires the ability to manipulate components of the system, ideally in as close to an in vivo context as possible. Here we use electroporation of plasmid reporters to define critical parameters of a specific cis-regulatory element, ThrbCRM1, during retinal development. ThrbCRM1 is associated with cone photoreceptor genesis and activated in a subset of developing retinal cells that co-express the Otx2 and Onecut1 (OC1) transcription factors. Variation of reporter plasmid concentration was used to generate dose response curves and revealed an effect of binding site availability on the number and strength of cells with reporter activity. Critical sequence elements of the ThrbCRM1 element were defined using both mutagenesis and misexpression of the Otx2 and OC1 transcription factors in the developing retina. Additionally, these experiments suggest that the ThrbCRM1 element is co-regulated by Otx2 and OC1 even under conditions of sub-optimal binding of OC1.
Júlia Benini Kohler, Daniela Aparecida De Brito Cervilha, Alyne Riani Moreira, Fernanda Roncon Santana, Talita M. Farias, Maria Isabel Cardoso Alonso Vale, Milton De Arruda Martins, Carla Máximo Prado, Iolanda Calvo Tibério, Juliana Tiyaki Ito, et al.
Published: 10 April 2019
Biology Open; doi:10.1242/bio.040808

Abstract:Background: Macrophages play a pivotal role in the development of emphysema and depending on the microenvironment stimuli can be polarized into M1- or M2-like macrophage phenotypes. Aim: To compare macrophage polarizations in cigarette smoke (CS)- and porcine pancreatic elastase (PPE)-induced emphysema models. C57BL/6 mice were subdivided into four experimental groups. In the PPE group, animals received an intranasal instillation of PPE (0.677 IU); in the Saline group, animals received an intranasal instillation of Saline (0.9%). Animals from both groups were euthanized on the 28th day. In the CS group, animals were exposed to CS for 30 minutes, twice a day, 5 days per week for 12 weeks. In the Control group, animals received filtered air. Results: We observed an increase in total macrophages for both experimental models. For M1-like macrophage markers, we observed an increase in TNF-α+ and IFN-γ+ cells, Cxcl-9 and Cxcl-10 expressions in PPE and CS groups. Only for CS group, we detected an increased expression of IL-12b. For M2-like macrophages markers, we observed a down regulation for IL-10, IL-4, IL-13, Arg1 and Fizz1 and an increase of TGF-β+ cells for PPE group while for CS group there was an increase in TGF-β+ cells and IL-10 expression. All exposure groups were compared to their respective controls. Conclusions: In summary, we demonstrated that CS- and PPE-induced models resulted in different microenvironmental stimuli. CS exposure induced an environmental stimulus related to M1- and M2-like macrophage phenotypes similar to previous results described in COPD patients, whereas the elastase-induced model provided an environmental stimulus related only to the M1 phenotype.
Carrie J. Shawber, Dex-Ann Brown-Grant, Tracy Wu, Jan K. Kitajewski, Nataki C. Douglas
Published: 10 April 2019
Biology Open, Volume 8; doi:10.1242/bio.037721

Abstract:Proper development and function of the mammalian placenta requires interactions between embryo-derived trophoblasts and uterine endothelial cells to form mosaic vessels that facilitate blood flow to a developing conceptus. Notch signaling utilizes a cell-cell contact dependent mechanism to drive cell behaviors, such as differentiation and invasion. In mice, Notch2 is needed for proper placentation and embryo survival. We used transgenic mice with a dominant-negative form of Mastermind-Like1 and Cyp19-Cre and Tpbpa-Cre drivers to inhibit canonical Notch signaling in trophoblasts. Both Cre drivers resulted in robust placental expression of dominant-negative Mastermind-Like1. All pregnancies progressed beyond mid-gestation and morphological analyses of placentas revealed no differences between mutants and controls. Our data suggest that mouse placentation occurs normally despite dominant negative inhibition of trophoblast canonical Notch signaling and that Notch2 signaling via the canonical pathway is not necessary for placentation. Key Words: trophoblasts, Notch, placenta, Cyp19-Cre, Tpbpa-Cre
Xiao-Zhi Cheng, Hui-Liang Zhou, Song-Xi Tang, Tao Jiang, Qin Chen, Rui Gao, Yi-Lang Ding
Published: 9 April 2019
Biology Open; doi:10.1242/bio.041889

Abstract:Background: To investigate the biological characteristics of acquired drug-resistant cells (AqMDRs) formed by intercellular P-glycoprotein (P-gp) transfer and whether AqMDRs can form stable drug-resistant strains. Methods: Drug-sensitive BIU-87 cells were cocultured with doxorubicin(DOX)-resistant derivative BIU-87/DOX cells in Transwell chambers for up to 96 h. The presence of P-gp in recipient cell membranes (AqMDRs) was detected by confocal microscopy, CCK-8, Western blot, and RT-PCR were used to detect resistance index (RI), P-gp expression andMDR1 mRNA expression in AqMDRs after 0, 4, 8, 16, and 20passages and frozen/resuscitated 20th generation AqMDRs. Results: There was an increase in P-gp transfer with longer coculture times of drug-resistant and sensitive strains. Without DOX, although the AqMDR numbers increased with each passage, the RI and P-gp expression decreased gradually, and the expression level of MDR1 mRNA did not change significantly. With DOX, the RI and P-gp expression increased slightly, and the MDR1 mRNA expression level gradually increased to the BIU-87/DOX level. AqMDRs can grow stably at drug concentrations slightly higher than the IC50 of sensitive strains, which sensitive strains cannot survive. Conclusions: P-gp transfer between cells gradually increases with longer coculturing of drug-resistant and sensitive strains. The drug resistance of AqMDRs decreases without drug intervention, but with drug intervention, cells can maintain resistance and gradually develop into stable drug-resistant cells.
Carolina D'alesio, Grazia Bellese, Maria Cristina Gagliani, Anastasia Lechiara, Martina Dameri, Elena Grasselli, Luisa Lanfrancone, Katia Cortese, Patrizio Castagnola
Published: 9 April 2019
Biology Open, Volume 8; doi:10.1242/bio.038323

Abstract:The chromodomain helicase DNA-binding 4 (CHD4), a member of the nucleosome remodeling and deacetylases (NuRD) complex, has been identified as an oncogene that modulates proliferation and migration of breast cancers (BC). ERBB2 is an oncogenic driver in 20-30% of BC in which its overexpression leads to increased chemoresistance. Here we investigated whether CHD4 depletion affects the ERBB2 cascade and autophagy, which represents a mechanism of resistance against Trastuzumab (Tz), a therapeutic anti-ERBB2 antibody. We show that CHD4 depletion in two ERBB2+ BC cell lines strongly inhibits cell proliferation, induces p27KIP1 upregulation, Tyr1248 ERBB2 phosphorylation, ERK1/2 and AKT dephosphorylation, and downregulation of both ERBB2 and PI3K levels. Moreover, CHD4 silencing impairs late stages of autophagy, resulting in increased levels of LC3 II and SQSTM1/p62, lysosomal enlargement and accumulation of autolysosomes (ALs). Importantly, we show that CHD4 depletion and concomitant treatment with Tz prevent cell proliferation in vitro. Our results suggest that CHD4 plays a critical role in modulating cell proliferation, ERBB2 signaling cascade and autophagy and provide new insights on CHD4 as a potential target for the treatment of ERBB2+ BC.
Viju Vijayan Pillai, Luiz G. Siqueira, Moubani Das, Tiffany G. Kei, Lan N. Tu, Anthony W. Herren, Brett S. Phinney, Soon Hon Cheong, Peter J. Hansen, Vimal Selvaraj
Published: 5 April 2019
Biology Open; doi:10.1242/bio.037937

Abstract:Trophectoderm of blastocysts mediate early events in fetal-maternal communication enabling implantation and establishment of a functional placenta. Inadequate or impaired developmental events linked to trophoblasts directly impact early embryo survival and successful implantation during a crucial period that corresponds high incidence of pregnancy losses in dairy cows. As yet, the molecular basis of bovine trophectoderm development and signaling towards initiation of implantation remains poorly understood. In this study, we developed methods for culturing undifferentiated bovine blastocyst-derived trophoblasts and used both transcriptomics and proteomics in early colonies to categorize and elucidate their functional characteristics. A total of 9270 transcripts and 1418 proteins were identified and analyzed based on absolute abundance. We profiled an extensive list of growth factors, cytokines and other relevant factors that can effectively influence paracrine communication in the uterine microenvironment. Functional categorization and analysis revealed novel information on structural organization, extracellular matrix composition, cell junction and adhesion components, transcription networks, and metabolic preferences. Our data showcase the fundamental physiology of bovine trophectoderm and indicate hallmarks of the self-renewing undifferentiated state akin to trophoblast stem cells described in other species. Functional features uncovered are essential for understanding early events in bovine pregnancy towards initiation of implantation.