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Article ; Online: Skeletal CH

Tang, Wenxian / Silva, Mickael / Hakimov, Khaiyom / Zhang, Xiaoyuan / Hlaing, Ponnya / Cenker, Emre / AlRamadan, Abdullah S / Turner, James W G / Farooq, Aamir / Im, Hong G / Sarathy, S Mani

ACS omega

2024 Volume 9, Issue 10, Page(s) 11255–11265

Abstract: Methanol is a promising renewable fuel for achieving a better engine combustion efficiency and lower exhaust emissions. Under exhaust gas recirculation conditions, trace amounts of nitrogen oxides have been shown to participate in fuel oxidation and ... ...

Abstract	Methanol is a promising renewable fuel for achieving a better engine combustion efficiency and lower exhaust emissions. Under exhaust gas recirculation conditions, trace amounts of nitrogen oxides have been shown to participate in fuel oxidation and impact the ignition characteristics significantly. Despite numerous studies that analyzed the methanol/NO
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c06488
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Article ; Online: Processing of Real-World, Dynamic Natural Stimuli in Autism is Linked to Corticobasal Function.

Webster, Paula J / Frum, Chris / Kurowski-Burt, Amy / Bauer, Christopher E / Wen, Sijin / Ramadan, Jad H / Baker, Kathryn A / Lewis, James W

Autism research : official journal of the International Society for Autism Research

2020 Volume 13, Issue 4, Page(s) 539–549

Abstract: Many individuals with autism spectrum disorder (ASD) have been shown to perceive everyday sensory information differently compared to peers without autism. Research examining these sensory differences has primarily utilized nonnatural stimuli or natural ... ...

Abstract	Many individuals with autism spectrum disorder (ASD) have been shown to perceive everyday sensory information differently compared to peers without autism. Research examining these sensory differences has primarily utilized nonnatural stimuli or natural stimuli using static photos with few having utilized dynamic, real-world nonverbal stimuli. Therefore, in this study, we used functional magnetic resonance imaging to characterize brain activation of individuals with high-functioning autism when viewing and listening to a video of a real-world scene (a person bouncing a ball) and anticipating the bounce. We investigated both multisensory and unisensory processing and hypothesized that individuals with ASD would show differential activation in (a) primary auditory and visual sensory cortical and association areas, and in (b) cortical and subcortical regions where auditory and visual information is integrated (e.g. temporal-parietal junction, pulvinar, superior colliculus). Contrary to our hypotheses, the whole-brain analysis revealed similar activation between the groups in these brain regions. However, compared to controls the ASD group showed significant hypoactivation in the left intraparietal sulcus and left putamen/globus pallidus. We theorize that this hypoactivation reflected underconnectivity for mediating spatiotemporal processing of the visual biological motion stimuli with the task demands of anticipating the timing of the bounce event. The paradigm thus may have tapped into a specific left-lateralized aberrant corticobasal circuit or loop involved in initiating or inhibiting motor responses. This was consistent with a dual "when versus where" psychophysical model of corticobasal function, which may reflect core differences in sensory processing of real-world, nonverbal natural stimuli in ASD. Autism Res 2020, 13: 539-549. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: To understand how individuals with autism perceive the real-world, using magnetic resonance imaging we examined brain activation in individuals with autism while watching a video of someone bouncing a basketball. Those with autism had similar activation to controls in auditory and visual sensory brain regions, but less activation in an area that processes information about body movements and in a region involved in modulating movements. These areas are important for understanding the actions of others and developing social skills.
MeSH term(s)	Acoustic Stimulation/methods ; Adolescent ; Adult ; Auditory Perception/physiology ; Autism Spectrum Disorder/physiopathology ; Brain/physiopathology ; Brain Mapping/methods ; Child ; Female ; Humans ; Magnetic Resonance Imaging/methods ; Male ; Mental Processes/physiology ; Photic Stimulation/methods ; Visual Perception/physiology ; Young Adult
Language	English
Publishing date	2020-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2481338-2
ISSN	1939-3806 ; 1939-3792
ISSN (online)	1939-3806
ISSN	1939-3792
DOI	10.1002/aur.2250
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Article ; Online: Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma.

Puram, Sidharth V / Mints, Michael / Pal, Ananya / Qi, Zongtai / Reeb, Ashley / Gelev, Kyla / Barrett, Thomas F / Gerndt, Sophie / Liu, Ping / Parikh, Anuraag S / Ramadan, Salma / Law, Travis / Mroz, Edmund A / Rocco, James W / Adkins, Doug / Thorstad, Wade L / Gay, Hiram A / Ding, Li / Paniello, Randal C /

Pipkorn, Patrik / Jackson, Ryan S / Wang, Xiaowei / Mazul, Angela / Chernock, Rebecca / Zevallos, Jose P / Silva-Fisher, Jessica / Tirosh, Itay

Nature genetics

2023 Volume 55, Issue 4, Page(s) 640–650

Abstract: Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular ... ...

Abstract	Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.
MeSH term(s)	Humans ; Squamous Cell Carcinoma of Head and Neck/complications ; Head and Neck Neoplasms/complications ; Carcinoma, Squamous Cell/genetics ; Human Papillomavirus Viruses ; Papillomavirus Infections/complications ; Papillomavirus Infections/genetics ; Oropharyngeal Neoplasms/genetics ; Oropharyngeal Neoplasms/metabolism ; Genomics ; Papillomaviridae/genetics
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01357-3
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Article ; Online: Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification.

Reilly, Molly B / Tekieli, Tessa / Cros, Cyril / Aguilar, G Robert / Lao, James / Toker, Itai Antoine / Vidal, Berta / Leyva-Díaz, Eduardo / Bhattacharya, Abhishek / Cook, Steven J / Smith, Jayson J / Kovacevic, Ismar / Gulez, Burcu / Fernandez, Robert W / Bradford, Elisabeth F / Ramadan, Yasmin H / Kratsios, Paschalis / Bao, Zhirong / Hobert, Oliver

PLoS genetics

2022 Volume 18, Issue 9, Page(s) e1010372

Abstract: Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the ... ...

Abstract	Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 14 homeobox genes in 24 distinct neuron classes that are mostly unrelated by location, function and lineage history. 12 of these 24 neuron classes had no homeobox gene function ascribed to them before, while in the other 12 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analyses, 113 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism ; Cell Differentiation/genetics ; DNA-Binding Proteins/genetics ; Employment ; Gene Expression Regulation, Developmental ; Genes, Homeobox/genetics ; Neurons/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Caenorhabditis elegans Proteins ; DNA-Binding Proteins ; Transcription Factors
Language	English
Publishing date	2022-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010372
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Article ; Online: Abnormal corneal nerve morphology and brain volume in patients with schizophrenia.

Scientific reports

2022 Volume 12, Issue 1, Page(s) 1870

Abstract: Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its ... ...

Abstract	Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its relationship to cognitive dysfunction and symptom severity in schizophrenia. Thirty-six subjects with schizophrenia and 26 controls underwent assessment of cognitive function, symptom severity, CCM and MRI brain volumetry. Subjects with schizophrenia had lower cognitive function (P ≤ 0.01), corneal nerve fiber density (CNFD), length (CNFL), branch density (CNBD), CNBD:CNFD ratio (P < 0.0001) and cingulate gyrus volume (P < 0.05) but comparable volume of whole brain (P = 0.61), cortical gray matter (P = 0.99), ventricle (P = 0.47), hippocampus (P = 0.10) and amygdala (P = 0.68). Corneal nerve measures and cingulate gyrus volume showed no association with symptom severity (P = 0.35-0.86 and P = 0.50) or cognitive function (P = 0.35-0.86 and P = 0.49). Corneal nerve measures were not associated with metabolic syndrome (P = 0.61-0.64) or diabetes (P = 0.057-0.54). The area under the ROC curve distinguishing subjects with schizophrenia from controls was 88% for CNFL, 84% for CNBD and CNBD:CNFD ratio, 79% for CNFD and 73% for the cingulate gyrus volume. This study has identified a reduction in corneal nerve fibers and cingulate gyrus volume in schizophrenia, but no association with symptom severity or cognitive dysfunction. Corneal nerve loss identified using CCM may act as a rapid non-invasive surrogate marker of neurodegeneration in patients with schizophrenia.
MeSH term(s)	Adult ; Brain/diagnostic imaging ; Brain/pathology ; Brain/physiopathology ; Case-Control Studies ; Cognition ; Cornea/innervation ; Cross-Sectional Studies ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Microscopy, Confocal ; Middle Aged ; Nerve Fibers/pathology ; Organ Size ; Predictive Value of Tests ; Reproducibility of Results ; Schizophrenia/diagnostic imaging ; Schizophrenia/pathology ; Schizophrenia/physiopathology ; Schizophrenic Psychology ; Severity of Illness Index ; Young Adult
Language	English
Publishing date	2022-02-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-05609-w
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Article ; Online: Novel hardening bone putty enhances sternal closure and accelerates postoperative recovery.

Vasanthan, Vishnu / Hassanabad, Ali Fatehi / Kang, Sean / Dundas, Jameson / Ramadan, Darlene / Holloway, Daniel / Adams, Corey / Ahsan, Muhammad / Fedak, Paul W M

The Journal of thoracic and cardiovascular surgery

2022 Volume 166, Issue 5, Page(s) e430–e443

Abstract: Objectives: Regaining and maintaining sternal stability are key to recovery after cardiac surgery and resuming baseline quality of life. Montage (ABYRX) is a moldable, calcium phosphate-based putty that adheres to bleeding bone, hardens after ... ...

Abstract	Objectives: Regaining and maintaining sternal stability are key to recovery after cardiac surgery and resuming baseline quality of life. Montage (ABYRX) is a moldable, calcium phosphate-based putty that adheres to bleeding bone, hardens after application, and is resorbed and replaced with bone during the remodeling process. We evaluate the feasibility, safety, and efficacy of enhanced sternal closure with this novel putty to accelerate recovery in patients after sternotomy. Methods: A single-center, single-blinded, randomized controlled trial was performed (NCT03365843). Patients undergoing elective cardiac surgery via sternotomy received sternal closure with either Montage bone putty and wire cerclage (enhanced sternal closure; n = 33) or wire cerclage alone (control; n = 27). Standardized patient-reported outcomes assessed health-related quality of life (EQ-5D Index) and physical disability (Health Assessment Questionnaire). A Likert-type 11-point scale quantified pain. Spirometry assessed respiratory function. Patients reached 6-week follow-up, with 1-year follow-up for safety end points. Results: There were no device-related adverse events. Enhanced sternal closure improved physical functional recovery (reduced Healthcare Index and Quality) and quality of life (increased EQ-5D Index) at day 5/discharge, week 2, and week 4. Enhanced sternal closure reduced incisional pain while resting, breathing, sleeping, and walking at day 5/discharge. Enhanced sternal closure reduced chest wall and back pain at day 3 and day 5 discharge. A higher proportion of patients with enhanced sternal closure recovered to 60% of their baseline forced vital capacity by day 5/discharge. Enhanced sternal closure shortened hospital stay. Conclusions: Enhanced sternal closure improves and accelerates postoperative recovery compared with conventional wire closure. Earlier discharge may provide substantial cost benefits for the healthcare system.
MeSH term(s)	Humans ; Quality of Life ; Treatment Outcome ; Wound Closure Techniques/adverse effects ; Wound Healing ; Sternum/surgery ; Sternotomy/adverse effects ; Pain/etiology ; Bone Wires
Language	English
Publishing date	2022-09-17
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3104-5
ISSN	1097-685X ; 0022-5223
ISSN (online)	1097-685X
ISSN	0022-5223
DOI	10.1016/j.jtcvs.2022.09.016
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Article ; Online: Abnormal corneal nerve morphology and brain volume in patients with schizophrenia

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 9

Abstract: Abstract Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its ... ...

Abstract	Abstract Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its relationship to cognitive dysfunction and symptom severity in schizophrenia. Thirty-six subjects with schizophrenia and 26 controls underwent assessment of cognitive function, symptom severity, CCM and MRI brain volumetry. Subjects with schizophrenia had lower cognitive function (P ≤ 0.01), corneal nerve fiber density (CNFD), length (CNFL), branch density (CNBD), CNBD:CNFD ratio (P < 0.0001) and cingulate gyrus volume (P < 0.05) but comparable volume of whole brain (P = 0.61), cortical gray matter (P = 0.99), ventricle (P = 0.47), hippocampus (P = 0.10) and amygdala (P = 0.68). Corneal nerve measures and cingulate gyrus volume showed no association with symptom severity (P = 0.35–0.86 and P = 0.50) or cognitive function (P = 0.35–0.86 and P = 0.49). Corneal nerve measures were not associated with metabolic syndrome (P = 0.61–0.64) or diabetes (P = 0.057–0.54). The area under the ROC curve distinguishing subjects with schizophrenia from controls was 88% for CNFL, 84% for CNBD and CNBD:CNFD ratio, 79% for CNFD and 73% for the cingulate gyrus volume. This study has identified a reduction in corneal nerve fibers and cingulate gyrus volume in schizophrenia, but no association with symptom severity or cognitive dysfunction. Corneal nerve loss identified using CCM may act as a rapid non-invasive surrogate marker of neurodegeneration in patients with schizophrenia.
Keywords	Medicine ; R ; Science ; Q
Subject code	150 ; 616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The central role of calcium in the effects of cytokines on beta-cell function: Implications for type 1 and type 2 diabetes

Ramadan, James W / Steiner, Stephen R / O’Neill, Christina M / Nunemaker, Craig S

Cell calcium. 2011 Dec., v. 50, no. 6

2011

Abstract: The appropriate regulation of intracellular calcium is a requirement for proper cell function and survival. This review focuses on the effects of proinflammatory cytokines on calcium regulation in the insulin-producing pancreatic beta-cell and how normal ...

Abstract	The appropriate regulation of intracellular calcium is a requirement for proper cell function and survival. This review focuses on the effects of proinflammatory cytokines on calcium regulation in the insulin-producing pancreatic beta-cell and how normal stimulus-secretion coupling, organelle function, and overall beta-cell viability are impacted. Proinflammatory cytokines are increasingly thought to contribute to beta-cell dysfunction not only in type 1 diabetes (T1D), but also in the progression of type 2 diabetes (T2D). Cytokine-induced disruptions in calcium handling result in reduced insulin release in response to glucose stimulation. Cytokines can alter intracellular calcium levels by depleting calcium from the endoplasmic reticulum (ER) and by increasing calcium influx from the extracellular space. Depleting ER calcium leads to protein misfolding and activation of the ER stress response. Disrupting intracellular calcium may also affect organelles, including the mitochondria and the nucleus. As a chronic condition, cytokine-induced calcium disruptions may lead to beta-cell death in T1D and T2D, although possible protective effects are also discussed. Calcium is thus central to both normal and pathological cell processes. Because the tight regulation of intracellular calcium is crucial to homeostasis, measuring the dynamics of calcium may serve as a good indicator of overall beta-cell function.
Keywords	calcium ; cytokines ; endoplasmic reticulum ; extracellular space ; glucose ; homeostasis ; insulin ; insulin-dependent diabetes mellitus ; islets of Langerhans ; mitochondria ; noninsulin-dependent diabetes mellitus ; protective effect ; stress response ; viability
Language	English
Dates of publication	2011-12
Size	p. 481-490.
Publishing place	Elsevier India Pvt Ltd.
Document type	Article
ZDB-ID	757687-0
ISSN	1532-1991 ; 0143-4160
ISSN (online)	1532-1991
ISSN	0143-4160
DOI	10.1016/j.ceca.2011.08.005
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes.

Ramadan, James W / Steiner, Stephen R / O'Neill, Christina M / Nunemaker, Craig S

Cell calcium

2011 Volume 50, Issue 6, Page(s) 481–490

Abstract	The appropriate regulation of intracellular calcium is a requirement for proper cell function and survival. This review focuses on the effects of proinflammatory cytokines on calcium regulation in the insulin-producing pancreatic beta-cell and how normal stimulus-secretion coupling, organelle function, and overall beta-cell viability are impacted. Proinflammatory cytokines are increasingly thought to contribute to beta-cell dysfunction not only in type 1 diabetes (T1D), but also in the progression of type 2 diabetes (T2D). Cytokine-induced disruptions in calcium handling result in reduced insulin release in response to glucose stimulation. Cytokines can alter intracellular calcium levels by depleting calcium from the endoplasmic reticulum (ER) and by increasing calcium influx from the extracellular space. Depleting ER calcium leads to protein misfolding and activation of the ER stress response. Disrupting intracellular calcium may also affect organelles, including the mitochondria and the nucleus. As a chronic condition, cytokine-induced calcium disruptions may lead to beta-cell death in T1D and T2D, although possible protective effects are also discussed. Calcium is thus central to both normal and pathological cell processes. Because the tight regulation of intracellular calcium is crucial to homeostasis, measuring the dynamics of calcium may serve as a good indicator of overall beta-cell function.
MeSH term(s)	Animals ; Calcium/metabolism ; Calcium/physiology ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cytokines/pharmacology ; Cytokines/physiology ; Diabetes Mellitus, Type 1/etiology ; Diabetes Mellitus, Type 2/etiology ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress ; Glucose/metabolism ; Homeostasis ; Humans ; Insulin/metabolism ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/physiology ; Islets of Langerhans/metabolism ; Islets of Langerhans/physiology ; Mitochondria/metabolism
Chemical Substances	Cytokines ; Insulin ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2011-09-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	757687-0
ISSN	1532-1991 ; 0143-4160
ISSN (online)	1532-1991
ISSN	0143-4160
DOI	10.1016/j.ceca.2011.08.005
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Article ; Online: An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.

Sharma, Poonam R / Mackey, Aaron J / Dejene, Eden A / Ramadan, James W / Langefeld, Carl D / Palmer, Nicholette D / Taylor, Kent D / Wagenknecht, Lynne E / Watanabe, Richard M / Rich, Stephen S / Nunemaker, Craig S

Endocrinology

2015 Volume 156, Issue 9, Page(s) 3147–3156

Abstract: Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell ... ...

Abstract	Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.
MeSH term(s)	Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Factor XIII/genetics ; Factor XIII/metabolism ; Gene Expression Profiling ; Genome-Wide Association Study ; Humans ; Inflammation/metabolism ; Interleukin-1beta ; Interleukin-6 ; Islets of Langerhans/metabolism ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Oligonucleotide Array Sequence Analysis ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Stress, Physiological
Chemical Substances	Carrier Proteins ; Interleukin-1beta ; Interleukin-6 ; Klhl6 protein, mouse ; Membrane Proteins ; Tiarp protein, mouse ; Factor XIII (9013-56-3) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk2 protein, mouse (EC 2.7.11.1) ; Pamr1 protein, mouse (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2015-1203
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Full text online

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In stock of ZB MED Cologne/Königswinter

Order via subito