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Search Results for all work with filters:

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Work 1-7 of 7

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Article

Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

by David Ellison; Andrew Mugler; Matthew D. Brennan; Sung Hoon Lee; Robert J. Huebner; Eliah R. Shamir; Laura A. Woo; Joseph Kim; Patrick Amar; Ilya Nemenman; Andrew J. Ewald; Andre Levchenko

2016

Subjects
  • Biology, Cell
  • Biology, Microbiology
  • File Download
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Abstract:Close

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and little is known about how multicellular signal processing modulates single-cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored whether cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow epidermal growth factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.

Article

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study

by Michael A. Pulsipher; Brent R. Logan; Pintip Chitphakdithai; Deidre M. Kiefer; Marcie L. Riches; J. Douglas Rizzo; Paola Anderlini; Susan F. Leitman; Ann Haight; Edmund Waller

2019

Subjects
  • Biology, Cell
  • Health Sciences, Immunology
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34 + level before apheresis compared with younger RDs (age > 60, 59 × 10 6 /L; age 41 to 60, 81 × 10 6 /L; age 18 to 40, 121 × 10 6 /L; P <.001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P <.001) and higher collection volumes (52% versus 32% > 24 L, P <.001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 10 9 /L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P =.01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P <.001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P =.004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

Article

The chloride-bicarbonate exchanger pendrin is increased in the kidney of the pregnant rat

by Crystal A. West; Jill W. Verlander; Susan Wall; Chris Baylis

2015

Subjects
  • Biology, Physiology
  • Biology, Cell
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Abstract:Close

New Findings: What is the central question of this study? Pregnancy requires a robust plasma volume expansion driven by renal sodium retention. In the late-pregnant kidney, the aldosterone-responsive epithelial Na+ channel is increased, whereas the sodium-chloride cotransporter is decreased. Pendrin has been shown to support sodium reabsorption in the distal nephron and compensate for loss of the sodium-chloride cotransporter. We investigated the expression and abundance of pendrin in the pregnant kidney. What is the main finding and its importance? Pendrin protein, apical localization and thiazide sensitivity are increased in pregnancy. This implicates a possible role for pendrin in supporting the renal sodium chloride reabsorption and plasma volume expansion of pregnancy. Pregnancy is characterized by cumulative plasma volume expansion as a result of renal sodium retention, driven by activation of aldosterone. We previously reported that the abundance and activity of the aldosterone-responsive epithelial Na+ channel is increased, whereas the sodium-chloride cotransporter (NCC) is decreased in the kidney of the late-pregnant rat. The chloride-bicarbonate exchanger pendrin is also aldosterone responsive and has been shown to support activity of the aldosterone-responsive epithelial Na+ channel and compensate for the loss of NCC. Additionally, pendrin coupled to the sodium-dependent chloride-bicarbonate exchanger (NDCBE) mediates thiazide-sensitive sodium reabsorption in the cortical collecting duct. In this study, we investigated pendrin and NDCBE transcript expression, pendrin protein abundance, pendrin cellular localization and thiazide sensitivity in virgin, mid-pregnant and late-pregnant rats to test the hypothesis that increased pendrin activity might occur in pregnancy. By RT-PCR, NDCBE and pendrin mRNA expression was unchanged from virgins, whereas pendrin protein abundance determined by Western blotting was increased in both mid- and late-pregnant rats. The apical localization of pendrin was also increased in late-pregnant rats compared with virgins by immunohistochemistry. Pregnant rats displayed an increased natriuretic response to hydrochlorothiazide compared with virgins. Given that NCC expression is decreased in late pregnancy, an increased thiazide sensitivity may be due to inhibition of upregulated pendrin-NDCBE-coupled sodium reabsorption. Thus, increased pendrin in pregnant rats may compensate for the decreased NCC and aid in the renal sodium chloride reabsorption of pregnancy.

Article

Pendrin abundance, subcellular distribution, and function are unaffected by either alpha ENaC gene ablation or by increasing ENaC channel activity

by Johannes Loffing; Vladimir Pech; Dominique Loffing-Cueni; Delaney C. Abood; Young Hee Kim; Chao Chen; Truyen D. Pham; Jill W. Verlander; Susan Wall

2023

Subjects
  • Biology, Physiology
  • Biology, Cell
  • File Download
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Abstract:Close

The intercalated cell Cl−/HCO3− exchanger, pendrin, modulates ENaC subunit abundance and function. Whether ENaC modulates pendrin abundance and function is however unknown. Because αENaC mRNA has been detected in pendrin-positive intercalated cells, we hypothesized that ENaC, or more specifically the αENaC subunit, modulates intercalated cell function. The purpose of this study was therefore to determine if αENaC is expressed at the protein level in pendrin-positive intercalated cells and to determine if αENaC gene ablation or constitutively upregulating ENaC activity changes pendrin abundance, subcellular distribution, and/or function. We observed diffuse, cytoplasmic αENaC label in pendrin-positive intercalated cells from both mice and rats, with much lower label intensity in pendrin-negative, type A intercalated cells. However, while αENaC gene ablation within principal and intercalated cells of the CCD reduced Cl− absorption, it did not change pendrin abundance or subcellular distribution in aldosterone-treated mice. Further experiments used a mouse model of Liddle’s syndrome to explore the effect of increasing ENaC channel activity on pendrin abundance and function. The Liddle’s variant did not increase either total or apical plasma membrane pendrin abundance in aldosterone-treated or in NaCl-restricted mice. Similarly, while the Liddle’s mutation increased total Cl− absorption in CCDs from aldosterone-treated mice, it did not significantly affect the change in Cl− absorption seen with pendrin gene ablation. We conclude that in rats and mice, αENaC localizes to pendrin-positive ICs where its physiological role remains to be determined. While pendrin modulates ENaC abundance, subcellular distribution, and function, ENaC does not have a similar effect on pendrin.

Article

Impact of perioperative blood transfusion on survival in pancreatic neuroendocrine tumor patients: analysis from the US Neuroendocrine Study Group

by Paula Marincola Smith; Jordan Baechle; Carmen C. Solorzano; Marcus Tan; Alexandra A. Lopez-Aguiar; Mary Dillhoff; Eliza Beal; George Poultsides; John G. D. Cannon; Flavio G. Rocha; Angelena Crown; Clifford Cho; Megan Beems; Emily R. Winslow; Victoria R. Rendell; Bradley A. Krasnick; Ryan C. Fields; Shishir Maithel; Christina E. Bailey; Kamran Idrees

2020

Subjects
  • Health Sciences, Oncology
  • Biology, Cell
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

Background Packed red blood cell (PRBC) transfusion has been associated with worse survival in multiple malignancies but its impact on pancreatic neuroendocrine tumors (PNETs) is unknown. The aim of this study was to determine the impact of PRBC transfusion on survival following PNET resection. Methods A retrospective cohort study of PNET patients was performed using the US Neuroendocrine Tumor Study Group database. Demographic and clinical factors were compared. Kaplan–Meier and log-rank analyses were performed. Factors associated with transfusion, overall (OS), recurrence-free (RFS) and progression-free survival (PFS) were assessed by logistic regression. Results Of 1129 patients with surgically resected PNETs, 156 (13.8%) received perioperative PRBC transfusion. Transfused patients had higher ASA Class, lower preoperative hemoglobin, larger tumors, more nodal involvement, and increased major complications (all p < 0.010). Transfused patients had worse median OS (116 vs 150 months, p < 0.001), worse RFS (83 vs 128 months, p < 0.01) in curatively resected (n = 1047), and worse PFS (11 vs 24 months, p = 0.110) in non-curatively resected (n = 82) patients. On multivariable analysis, transfusion was associated with worse OS (HR 1.80, p = 0.011) when controlling for TNM stage, tumor grade, final resection status, and pre-operative anemia. Conclusion PRBC transfusion is associated with worse survival for patients undergoing PNET resection.

Article

Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation

by Frederick R. Adler; Alexander R. A. Anderson; Abhinav Bhushan; Paul Bogdan; Jose Javier Bravo-Cordero; Amy Brock; Yun Chen; Edna Cukierman; Kathleen E DelGiorno; Gerald V Denis; Meghan C Ferrall-Fairbanks; Zev Jordan Gartner; Ronald N Germain; Deborah M Gordon; Ginger Hunter; Mohit Kumar Jolly; Loukia Georgiou Karacosta; Karthikeyan Mythreye; Parag Katira; Rajan P Kulkarni; Matthew L Kutys; Arthur D Lander; Ashley M Laughney; Herbert Levine; Emil Lou; Pedro R Lowenstein; Kristyn S Masters; Dana Pe’er; Shelly R Peyton; Manu Platt; Jeremy E Purvis; Gerald Quon; Jennifer K Richer; Nicole C Riddle; Analiz Rodriguez; Joshua C Snyder; Gregory Lee Szeto; Claire J Tomlin; Itai Yanai; Ioannis K Zervantonakis; Hannah Dueck

2023

Subjects
  • Biology, Cell
  • Health Sciences, Oncology
  • Engineering, Biomedical
  • File Download
  • View Abstract

Abstract:Close

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Article

Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation

by Xiaoqian Qian; Jeff Sands; Xiang Song; Guangping Chen

2016

Subjects
  • Biology, Physiology
  • Biology, Cell
  • File Download
  • View Abstract

Abstract:Close

Two urea transporters, UT-A1 and UT-A3, are expressed in the kidney terminal inner medullary collecting duct (IMCD) and are important for the production of concentrated urine. UT-A1, as the largest isoform of all UT-A urea transporters, has gained much attention and been extensively studied; however, the role and the regulation of UT-A3 are less explored. In this study, we investigated UT-A3 regulation by glycosylation modification. A site-directed mutagenesis verified a single glycosylation site in UT-A3 at Asn279. Loss of the glycosylation reduced forskolin-stimulated UT-A3 cell membrane expression and urea transport activity. UT-A3 has two glycosylation forms, 45 and 65 kDa. Using sugar-specific binding lectins, the UT-A3 glycosylation profile was examined. The 45-kDa form was pulled down by lectin concanavalin A (Con A) and Galant husnivalis lectin (GNL), indicating an immature glycan with a high amount of mannose (Man), whereas the 65-kDa form is a mature glycan composed of acetylglucosamine (GlcNAc) and poly-N-acetyllactosame (poly-LacNAc) that was pulled down by wheat germ agglutinin (WGA) and tomato lectin, respectively. Interestingly, the mature form of UT-A3 glycan contains significant amounts of sialic acid. We explored the enzymes responsible for directing UT-A3 sialylation. Sialyltransferase ST6GalI, but not ST3GalIV, catabolizes UT-A3 α2,6-sialylation. Activation of protein kinase C (PKC) by PDB treatment promoted UT-A3 glycan sialylation and membrane surface expression. The PKC inhibitor chelerythrine blocks ST6GalI-induced UT-A3 sialylation. Increased sialylation by ST6GalI increased UT-A3 protein stability and urea transport activity. Collectively, our study reveals a novel mechanism of UT-A3 regulation by ST6GalI-mediated sialylation modification that may play an important role in kidney urea reabsorption and the urinary concentrating mechanism.
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