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Search Results for all work with filters:

  • 2016
  • transport
  • biomedicin

Work 1-10 of 22

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Article

State of the field: An informatics-based systematic review of the SOD1-G93A amyotrophic lateral sclerosis transgenic mouse model

by Renaid B Kim; Cameron W Irvin; Keval R Tilva; Cassie Mitchell

2016

Subjects
  • Engineering, Biomedical
  • Health Sciences, General
  • Health Sciences, Medicine and Surgery
  • File Download
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Numerous sub-cellular through system-level disturbances have been identified in over 1300 articles examining the superoxide dismutase-1 guanine 93 to alanine (SOD1-G93A) transgenic mouse amyotrophic lateral sclerosis (ALS) pathophysiology. Manual assessment of such a broad literature base is daunting. We performed a comprehensive informatics-based systematic review or field analysis to agnostically compute and map the current state of the field. Text mining of recaptured articles was used to quantify published data topic breadth and frequency. We constructed a nine-category pathophysiological function-based ontology to systematically organize and quantify the field's primary data. Results demonstrated that the distribution of primary research belonging to each category is: systemic measures an motor function, 59%; inflammation, 46%; cellular energetics, 37%; proteomics, 31%; neural excitability, 22%; apoptosis, 20%; oxidative stress, 18%; aberrant cellular chemistry, 14%; axonal transport, 10%. We constructed a SOD1-G93A field map that visually illustrates and categorizes the 85% most frequently assessed sub-topics. Finally, we present the literature-cited significance of frequently published terms and uncover thinly investigated areas. In conclusion, most articles individually examine at least two categories, which is indicative of the numerous underlying pathophysiological interrelationships. An essential future path is examination of cross-category pathophysiological interrelationships and their co-correspondence to homeostatic regulation and disease progression.

Article

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

by Dalin Li; Jean-Paul Achkar; Talin Haritunians; Jonathan P Jacobs; Ken Y Hui; Mauro D'Amato; Stephan Brand; Graham Radford-Smith; Jonas Halfvarson; Jan-Hendrik Niess; Subramaniam Kugathasan; Carsten Buning; L. Philip Schumm; Lambertus Klei; Ashwin Ananthakrishnan; Guy Aumais; Leaonard Baidoo; Marla Dubinsky; Claudio Fiocchi; Jurgen Glas; Raquel Milgram; Deborah D. Proctor; Miguel Regueiro; Lisa A. Simms; Joanne M. Stempak; Stephan R. Targan; Leif Torkvist; Yashoda Sharma; Bernie Devlin; James Borneman; Hakon Hakonarson; Ramnik J. Xavier; Mark Daly; Steven R. Brant; John D. Rioux; Mark S. Silverberg; Judy H. Cho; Jonathan Braun; Dermot P.B. McGovern; Richard H. Duerr

2016

Subjects
  • Biology, Genetics
  • Biology, Microbiology
  • Health Sciences, Immunology
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Background & Aims Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). Methods Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. Results We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10 -13 ). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P =.009) and CD cases (P =.0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10 -16 ) and overweight individuals (P = 6.73 × 10 -16 ). Conclusions Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Article

Posttraumatic stress disorder: A metabolic disorder in disguise?

by Vasiliki Michopoulos; Aimee Vester; Gretchen Neigh

2016

Subjects
  • Psychology, Behavioral
  • Biology, Physiology
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Posttraumatic stress disorder (PTSD) is a heterogeneous psychiatric disorder that affects individuals exposed to trauma and is highly co-morbid with other adverse health outcomes, including cardiovascular disease and obesity. The unique pathophysiological feature of PTSD is the inability to inhibit fear responses, such that individuals suffering from PTSD re-experience traumatic memories and are unable to control psychophysiological responses to trauma-associated stimuli. However, underlying alterations in sympathetic nervous system activity, neuroendocrine systems, and metabolism associated with PTSD are similar to those present in traditional metabolic disorders, such as obesity and diabetes. The current review highlights existing clinical, translational, and preclinical data that support the notion that underneath the primary indication of impaired fear inhibition, PTSD is itself also a metabolic disorder and proposes altered function of inflammatory responses as a common underlying mechanism. The therapeutic implications of treating PTSD as a whole-body condition are significant, as targeting any underlying biological system whose activity is altered in both PTSD and metabolic disorders, (i.e. HPA axis, sympathetic nervous systems, inflammation) may elicit symptomatic relief in individuals suffering from these whole-body adverse outcomes.

Article

The sodium chloride cotransporter (NCC) and epithelial sodium channel (ENaC) associate

by Abinash Mistry; Brandi Wynne; Ling Yu; Victor Tomilin; Qiang Yue; Yiqun Zhou; Otor Al-Khalili; Rickta Mallick; Hui Cai; Abdel Alli; Benjamin Ko; Hui-Fang Bao; Alexa Mattheyses; Oleh Pochynyuk; Franziska Theilig; Douglas Eaton; Robert Hoover Jr

2016

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

The thiazide-sensitive sodium chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) are two of the most important determinants of salt balance and thus systemic blood pressure. Abnormalities in either result in profound changes in blood pressure. There is one segment of the nephron where these two sodium transporters are coexpressed, the second part of the distal convoluted tubule. This is a key part of the aldosterone-sensitive distal nephron, the final regulator of salt handling in the kidney. Aldosterone is the key hormonal regulator for both of these proteins. Despite these shared regulators and coexpression in a key nephron segment, associations between these proteins have not been investigated. After confirming apical localization of these proteins, we demonstrated the presence of functional transport proteins and native association by blue native PAGE. Extensive coimmunoprecipitation experiments demonstrated a consistent interaction of NCC with α-And γ-ENaC. Mammalian two-hybrid studies demonstrated direct binding of NCC to ENaC subunits. Fluorescence resonance energy transfer and immunogold EM studies confirmed that these transport proteins are within appropriate proximity for direct binding. Additionally, we demonstrate that there are functional consequences of this interaction, with inhibition of NCC affecting the function of ENaC. This novel finding of an association between ENaC and NCC could alter our understanding of salt transport in the distal tubule.

Article

Understanding Local Spatial Variation Along the Care Continuum: The Potential Impact of Transportation Vulnerability on HIV Linkage to Care and Viral Suppression in High-Poverty Areas, Atlanta, Georgia

by Neela Goswami; Michelle M. Schmitz; Travis Sanchez; Sharoda Dasgupta; Patrick Sullivan; Hannah Cooper; Deepali Rane; Jane Kelly; Carlos Del Rio; Lance Waller

2016

Subjects
  • Health Sciences, Public Health
  • Health Sciences, Immunology
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Background: Engagement in care is central to reducing mortality for HIV-infected persons and achieving the White House National AIDS Strategy of 80% viral suppression in the US by 2020. Where an HIV-infected person lives impacts his or her ability to achieve viral suppression. Reliable transportation access for healthcare may be a key determinant of this place-suppression relationship. Methods: ZIP code tabulation areas (ZCTAs) were the units of analysis. We used geospatial and ecologic analyses to examine spatial distributions of neighborhood-level variables (eg, transportation accessibility) and associations with: (1) community linkage to care, and (2) community viral suppression. Among Atlanta ZCTAs with data for newly diagnosed HIV cases (2006-2010), we used Moran I to evaluate spatial clustering and linear regression models to evaluate associations between neighborhood variables and outcomes. Results: In 100 ZCTAs with 8413 newly diagnosed HIV-positive residents, a median of 60 HIV cases were diagnosed per ZCTA during the 5-year period. We found significant clustering of ZCTAs with low linkage to care and viral suppression (Moran I = 0.218, P< 0.05). In high-poverty ZCTAs, a 10% point increase in ZCTA-level household vehicle ownership was associated with a 4% point increase in linkage to care (P = 0.02, R2 = 0.16). In low-poverty ZCTAs, a 10% point increase in ZCTA-level household vehicle ownership was associated with a 30% point increase in ZCTA-level viral suppression (P = 0.01, R2 = 0.08). Conclusions: Correlations between transportation variables and community-level care linkage and viral suppression vary by area poverty level and provide opportunities for interventions beyond individual-level factors.

Article

Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

by Ling Chen; Lauren LaRocque LaRocque; Orhan Efe; Juan Wang; Jeff Sands; Janet Klein

2016

Subjects
  • Biology, Physiology
  • File Download
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AIM: This study evaluates the effect of dapagliflozin, a SGLT2 inhibitor, on fluid or electrolyte balance and its effect on urea transporter-A1 (UT-A1), aquaporin-2 (AQP2) and Na-K-2Cl cotransporter (NKCC2) protein abundance in diabetic rats. METHODS: Diabetes mellitus (DM) was induced by injection of streptozotocin into the tail vein. Serum Na+, K+, Cl- concentration, urine Na+, K+, Cl- excretion, blood glucose, urine glucose excretion, urine volume, urine osmolality and urine urea excretion were analyzed after the administration of dapagliflozin. UT-A1, AQP2 and NKCC2 proteins were detected by western blot. RESULTS: Dapagliflozin treatment decreased blood glucose concentration by 38% at day 7 and by 47% at day 14 and increased the urinary glucose excretion rate compared with the untreated diabetic animals. Increased 24-hour urine volume, decreased urine osmolality and hyponatremia, hypokalemia and hypochloremia observed in diabetic rats were attenuated by dapagliflozin treatment. Western blot analysis showed that UT-A1, AQP2 and NKCC2 proteins are upregulated in DM rats over control rats; dapagliflozin treatment results in a further increase in inner medulla tip UT-A1 protein abundance by 42% at day 7 and by 46% at day 14, but it did not affect the DM-induced upregulation of AQP2 and NKCC2 proteins. CONCLUSION: Dapagliflozin treatment augmented the compensatory changes in medullary transport proteins in DM. These changes would tend to conserve solute and water even with persistent glycosuria. Therefore, diabetic rats treated with dapagliflozin have a mild osmotic diuresis compared to nondiabetic animals, but this does not result in an electrolyte disorder or significant volume depletion.

Article

PET Tracers Beyond FDG in Prostate Cancer

by David Schuster; Cristina Nanni; Stefano Fanti

2016

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Radiology
  • Chemistry, Nuclear
  • File Download
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Conventional anatomical imaging with CT and MRI has limitations in the evaluation of prostate cancer. PET is a powerful imaging technique, which can be directed toward molecular targets as diverse as glucose metabolism, density of prostate-specific membrane antigen receptors, and skeletal osteoblastic activity. Although 2-deoxy-2- 18 F-FDG-PET is the mainstay of molecular imaging, FDG has limitations in typically indolent prostate cancer. Yet, there are many useful and emerging PET tracers beyond FDG, which provide added value. These include radiotracers interrogating prostate cancer via molecular mechanisms related to the biology of choline, acetate, amino acids, bombesin, and dihydrotestosterone, among others. Choline is used for cell membrane synthesis and its metabolism is upregulated in prostate cancer. 11 C-choline and 18 F-choline are in wide clinical use outside the United States, and they have proven most beneficial for detection of recurrent prostate cancer. 11 C-acetate is an indirect biomarker of fatty acid synthesis, which is also upregulated in prostate cancer. Imaging of prostate cancer with 11 C-acetate is overall similar to the choline radiotracers yet is not as widely used. Upregulation of amino acid transport in prostate cancer provides the biologic basis for amino acid–based radiotracers. Most recent progress has been made with the nonnatural alicyclic amino acid analogue radiotracer anti-1-amino-3- 18 F-fluorocyclobutane-1-carboxylic acid (FACBC or fluciclovine) also proven most useful for the detection of recurrent prostate cancer. Other emerging PET radiotracers for prostate cancer include the bombesin group directed to the gastrin-releasing peptide receptor, 16β- 18 F-fluoro-5α-dihydrotestosterone (FDHT) that binds to the androgen receptor, and those targeting the vasoactive intestinal polypeptide receptor 1 (VPAC-1) and urokinase plasminogen activator receptor (uPAR), which are also overexpressed in prostate cancer.

Article

Viral forensic genomics reveals the relatedness of classic herpes simplex virus strains KOS, KOS63, and KOS79

by Christopher D. Bowen; Daniel W. Renner; Jacob T Shreve; Yolanda Tafuri; Kimberly M. Payne; Richard Dix; Paul R. Kinchington; Derek Gatherer; Moriah L. Szpara

2016

Subjects
  • Biology, Genetics
  • Biology, Molecular
  • Health Sciences, Opthamology
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Herpes simplex virus 1 (HSV-1) is a widespread global pathogen, of which the strain KOS is one of the most extensively studied. Previous sequence studies revealed that KOS does not cluster with other strains of North American geographic origin, but instead clustered with Asian strains. We sequenced a historical isolate of the original KOS strain, called KOS63, along with a separately isolated strain attributed to the same source individual, termed KOS79. Genomic analyses revealed that KOS63 closely resembled other recently sequenced isolates of KOS and was of Asian origin, but that KOS79 was a genetically unrelated strain that clustered in genetic distance analyses with HSV-1 strains of North American/European origin. These data suggest that the human source of KOS63 and KOS79 could have been infected with two genetically unrelated strains of disparate geographic origins. A PCR RFLP test was developed for rapid identification of these strains.

Article

The Lectin-like Domain of TNF Increases ENaC Open Probability through a Novel Site at the Interface between the Second Transmembrane and C-terminal Domains of the -Subunit

by Rudolf Lucas; Qiang Yue; Abdel Alli; Billie Jeanne Duke; Otor Al-Khalili; Tiffany Thai; Jürg Hamacher; Supriya Sridhar; Iryna Lebedyeva; Huabo Su; Susan Tzotzos; Bernhard Fischer; Armanda Formigao Gameiro; Maria Loose; Trinad Chakraborty; Waheed Shabbir; Mohammed Aufy; Rosa Lemmens-Gruber; Douglas Eaton; Istvan Czikora

2016

Subjects
  • Health Sciences, Pharmacology
  • Health Sciences, Toxicology
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Regulation of the epithelial sodium channel (ENaC), which regulates fluid homeostasis and blood pressure, is complex and remains incompletely understood. The TIP peptide, a mimic of the lectin-like domain of TNF, activates ENaC by binding to glycosylated residues in the extracellular loop of ENaC-α as well as to a hitherto uncharacterized internal site. Molecular docking studies suggested three residues, Val 567 , Glu 568 , and Glu 571 , located at the interface between the second transmembrane and C-terminal domains of ENaC-α, as a critical site for binding of the TIP peptide. We generated Ala replacement mutants in this region of ENaC-α and examined its interaction with TIP peptide (3M, V567A/E568A/E571A; 2M, V567A/E568A; and 1M, E571A). 3M and 2M ENaC-α but not 1M ENaC-α, displayed significantly reduced binding capacity to TIP peptide and to TNF. When overexpressed in H441 cells,3M mutant ENaC-α formed functional channels with similar gating and density characteristics as the WT subunit and efficiently associated with the β and γ subunits in the plasma membrane. We subsequently assayed for increased open probability time and membrane expression, both of which define ENaC activity, following addition of TIP peptide. TIP peptide increased open probability time in H441 cells overexpressing wild type and 1M ENaC-α channels, but not 3M or 2M ENaC-α channels. On the other hand, TIP peptide-mediated reduction in ENaC ubiquitination was similar in cells overexpressing either WT or 3M ENaC-α subunits. In summary, this study has identified a novel site in ENaC-α that is crucial for activation of the open probability of the channel, but not membrane expression, by the lectin-like domain of TNF.

Article

Transport across Schlemm's canal endothelium and the blood-aqueous barrier

by Sietse T. Braakman; James E. Moore; Christopher Ethier; Darryl R. Overby

2016

Subjects
  • Health Sciences, General
  • Engineering, Biomedical
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The majority of trabecular outflow likely crosses Schlemm's canal (SC) endothelium through micron-sized pores, and SC endothelium provides the only continuous cell layer between the anterior chamber and episcleral venous blood. SC endothelium must therefore be sufficiently porous to facilitate outflow, while also being sufficiently restrictive to preserve the blood-aqueous barrier and prevent blood and serum proteins from entering the eye. To understand how SC endothelium satisfies these apparently incompatible functions, we examined how the diameter and density of SC pores affects retrograde diffusion of serum proteins across SC endothelium, i.e. from SC lumen into the juxtacanalicular tissue (JCT). Opposing retrograde diffusion is anterograde bulk flow velocity of aqueous humor passing through pores, estimated to be approximately 5 mm/s. As a result of this relatively large through-pore velocity, a mass transport model predicts that upstream (JCT) concentrations of larger solutes such as albumin are less than 1% of the concentration in SC lumen. However, smaller solutes such as glucose are predicted to have nearly the same concentration in the JCT and SC. In the hypothetical case that, rather than micron-sized pores, SC formed 65 nm fenestrae, as commonly observed in other filtration-active endothelia, the predicted concentration of albumin in the JCT would increase to approximately 50% of that in SC. These results suggest that the size and density of SC pores may have developed to allow SC endothelium to maintain the blood-aqueous barrier while simultaneously facilitating aqueous humor outflow.
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