Publications by authors named "Alexander Doyle"

16 Publications

  • Page 1 of 1

Non-lesional mesial temporal lobe epilepsy requires bilateral invasive evaluation.

Epilepsy Behav Rep 2021 27;15:100441. Epub 2021 Mar 27.

Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8508, USA.

Purpose: Mesial temporal lobe epilepsy (MTLE) usually responds well to surgical treatment, although in non-lesional cases up to 50% of patients experience seizure relapse. The possibility of bilateral independent seizure onset should be considered as a reason for epilepsy surgery failure.

Methods: In a cohort of 177 patients who underwent invasive presurgical evaluation with stereo-tactically placed electrodes in two level four epilepsy centers, 29 had non-lesional MTLE. Invasive evaluation results are described.

Results: Among 29 patients with non-lesional MRI and mesial temporal lobe seizure onset recorded during stereo-EEG (SEEG) evaluation, four patients with unilateral preimplantation hypothesis had independent bilateral mesial temporal seizures on SEEG despite of unilateral non-invasive evaluation data. Three of these patients were treated with bitemporal responsive neurostimulator system (RNS). Independent bilateral mesial temporal seizures have been confirmed on RNS ECoG (electrocorticography). The fourth patient underwent right anterior temporal lobectomy.

Conclusion: We propose that patients with non-lesional mesial temporal lobe epilepsy would benefit from bilateral invasive evaluation of mesial temporal structures to predict those patients who would be at most risk for surgical failure. Neurostimulaiton could be an initial treatment option for patients with independent bitemporal seizure onset.
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http://dx.doi.org/10.1016/j.ebr.2021.100441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058515PMC
March 2021

Physical activity status and quality of life in patients with epilepsy - Survey from level four epilepsy monitoring units.

Epilepsy Res 2021 Jul 9;173:106639. Epub 2021 Apr 9.

Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX, 75390, USA. Electronic address:

Purpose: People with epilepsy (PWE) tend to have sedentary lifestyles which may predispose them to a lower perceived quality of life (QOL). Moreover, the relationship between physical activity (PA) and QOL in populations of PWE with high disease burden has been under-studied. The goal of this study was to evaluate PA level and its impact on health-related QOL in PWE who were admitted to Level-4 epilepsy monitoring units (EMU).

Methods: In this prospective observational study, 200 patients from two EMUs in Dallas, Texas completed the following standard surveys: Rapid Assessment of Physical Activity (RAPA), the Quality of Life in Epilepsy (QOLIE-31), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder 7-item (GAD-7) questionnaire. Information on self-reported epilepsy history, severity of disease, and socioeconomic status were also collected. The diagnosis of epilepsy was confirmed by video-EEG monitoring.

Results: Among the 200 who completed the survey, 113 had a diagnosis of epilepsy and 109 of them completed the RAPA. Ninety-two (84 %) of these PWE reported a sedentary level of physical activity (RAPA < 6) and 16 % reported an active level (RAPA ≥ 6). Self-reported QOL was slightly higher in PWE with an active level of PA compared to PWE with a sedentary level of PA (63.8 ± 15.0 vs 53.7 ± 17.9, p = 0.07), even though there was no difference in the severity of self-reported mood symptoms. After controlling for employment and seizure frequency, physical activity level measured by RAPA score was also positively related to QOL (r = 0.39, p = 0.01) and negatively correlated with anxiety symptoms (r = -0.28, p = 0.02) and depression symptoms (r = -0.25, p = 0.04).

Conclusion: The majority of PWE in this survey reported sedentary lifestyles despite most of them being young to middle-aged adults. Higher PA level was associated with fewer self-reported mood symptoms and higher QOL. In conjunction with the literature, these results suggest that PWE with a wide range of disease burden should be encouraged to participate in regular exercise to potentially improve QOL.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106639DOI Listing
July 2021

Human Primary Airway Basal Cells Display a Continuum of Molecular Phases from Health to Disease in COPD.

Am J Respir Cell Mol Biol 2021 Mar 31. Epub 2021 Mar 31.

Lund University, 5193, Molecular Medicine and Gene Therapy, Lund, Sweden;

Airway basal cells are crucial for regeneration of the human lung airway epithelium, and are thought to be important contributors to Chronic Obstructive Pulmonary Disease (COPD) and other lung disorders. In order to reveal how basal cells contribute to disease, and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and Nerve-Growth Factor Receptor (NGFR) expression. The basal cell population was found to be molecularly and functionally heterogeneous in contrast to cultured basal cells. In addition, significant differences were found such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single cell RNA sequencing on primary basal cells from healthy donors and GOLD stage IV COPD patients, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response related genes GADD45B and AHSA1, along with genes involved in the response to hypoxia such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung.
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http://dx.doi.org/10.1165/rcmb.2020-0464OCDOI Listing
March 2021

Comparison of psychiatric comorbidities and impact on quality of life in patients with epilepsy or psychogenic nonepileptic spells.

Epilepsy Behav 2020 01 20;102:106649. Epub 2019 Nov 20.

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA. Electronic address:

Objectives: Psychiatric comorbidity is common in people with epilepsy (PWE) and psychogenic nonepileptic spells (PNES). These comorbidities can be detrimental to quality of life (QOL) and are often underdiagnosed and undertreated. Some types of epilepsy, such as focal temporal lobe epilepsy (TLE), have been associated with higher rates of psychiatric comorbidity. This study examined the impact of psychiatric comorbidity on QOL in patients admitted to two level 4 epilepsy monitoring units (EMUs).

Methods: In this prospective observational study, 200 patients admitted to two level 4 EMUs completed standardized surveys including the Quality of Life in Epilepsy (QOLIE-31-P), Generalized Anxiety Disorder 7-item (GAD-7), Patient Health Questionnaire (PHQ-9), and Beck Depression Inventory-II (BDI-II). Hierarchal multiple regression was performed to assess impact on QOL.

Results: Of the 200 participants, 113 had a diagnosis of epilepsy, 36 had a diagnosis of PNES, and 51 were excluded for nondiagnostic evaluation or dual diagnosis. Of those with epilepsy, 65 had TLE, 28 had focal extratemporal lobe epilepsy (ETLE), and 20 had nonfocal epilepsy. Patients with PNES had higher self-reported anxiety and depression levels (GAD-7: p = 0.04, PHQ-9: p < 0.01; BDI-II: p < 0.01) but similar QOL to PWE (p = 0.78). Using hierarchal multiple regression, symptoms of anxiety and depression were significant predictors of lower QOL in PWE but not in patients with PNES. There was no difference in QOL in those with ETLE and TLE.

Conclusions: Our findings suggest that self-reported anxiety and depression symptoms are common in patients admitted to level 4 EMUs regardless of diagnosis and play an important role in predicting QOL in PWE. Our findings emphasize the importance of routinely screening all EMU patients for psychiatric comorbidity.
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http://dx.doi.org/10.1016/j.yebeh.2019.106649DOI Listing
January 2020

Lin28b controls a neonatal to adult switch in B cell positive selection.

Sci Immunol 2019 09;4(39)

Developmental Immunology Unit, Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, 22242 Lund, Sweden.

The ability of B-1 cells to become positively selected into the mature B cell pool, despite being weakly self-reactive, has puzzled the field since its initial discovery. Here, we explore changes in B cell positive selection as a function of developmental time by exploiting a link between CD5 surface levels and the natural occurrence of self-reactive B cell receptors (BCRs) in BCR wild-type mice. We show that the heterochronic RNA binding protein Lin28b potentiates a neonatal mode of B cell selection characterized by enhanced overall positive selection in general and the developmental progression of CD5 immature B cells in particular. Lin28b achieves this by amplifying the CD19/PI3K/c-Myc positive feedback loop, and ectopic Lin28b expression restores both positive selection and mature B cell numbers in CD19 adult mice. Thus, the temporally restricted expression of relaxes the rules for B cell selection during ontogeny by modulating tonic signaling. We propose that this neonatal mode of B cell selection represents a cell-intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody-mediated immunity throughout life.
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http://dx.doi.org/10.1126/sciimmunol.aax4453DOI Listing
September 2019

Cannabis and Epilepsy.

J Dual Diagn 2020 Jan-Mar;16(1):75-82. Epub 2019 Aug 6.

Department of Neurology, UTSW Epilepsy Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

In recent years, the use of cannabidiol in the treatment of refractory epilepsy has been increasingly investigated and has been gaining public support as a novel way to treat these disorders. Marijuana has been used for medical purposes for thousands of years, and a lot of research has been conducted over the last several decades into the chemistry and pharmacology of marijuana and its many compounds, including cannabidiol. Using PubMed, we performed a review of the literature regarding the history of cannabinoid use in treating epilepsy. There are historical and recent scientific developments that support the use of cannabidiol in rare severe epilepsy syndromes.
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http://dx.doi.org/10.1080/15504263.2019.1645372DOI Listing
August 2019

Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration.

Cell Rep 2017 Dec;21(12):3514-3523

Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84, Lund, Sweden. Electronic address:

The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis. In contrast, when challenged through transplantation, Hlf-deficient HSCs showed an impaired ability to reconstitute hematopoiesis and became gradually exhausted upon serial transplantation. Transcriptional profiling of Hlf-deficient HSCs revealed changes associated with enhanced cellular activation, and cell-cycle analysis demonstrated a significant reduction of quiescent HSCs. Accordingly, toxic insults targeting dividing cells completely eradicated the HSC pool in Hlf-deficient mice. In summary, our findings point to HLF as a critical regulator of HSC quiescence and as an essential factor for maintaining the HSC pool during regeneration.
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http://dx.doi.org/10.1016/j.celrep.2017.11.084DOI Listing
December 2017

Preoxygenation and apneic oxygenation using Transnasal Humidified Rapid-Insufflation Ventilatory Exchange for emergency intubation.

J Crit Care 2016 12 23;36:8-12. Epub 2016 Jun 23.

Department of Anaesthesia and Critical Care, Queen Elizabeth Hospital, King's Lynn, UK. Electronic address:

Purpose: Hypoxia is one of the leading causes of anesthesia-related injury. In response to the limitations of conventional preoxygenation, Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) has been used as a method of providing both preoxygenation and apneic oxygenation during intubation.

Materials And Methods: In this prospective, observational study, THRIVE was introduced in a critical care unit (CCU), operating room (OR), and emergency department (ED) during emergency intubation of patients at high risk of hypoxia. Linear regression analysis tested for correlation between apnea time or body mass index and hemoglobin saturation (Spo).

Results: Across 71 sequential patients, the interquartile range for apnea time and decrease in Spo were 60 to 125 seconds and 0% to 3%, respectively. Significant desaturation occurred in 5 (7%) patients. There was no evidence of correlation between apnea time or body mass index and Spo (R=0.04 and 0.08 for CCU/ED and OR and 0.01 and 0.04 CCU/ED and OR, respectively). There were no complications reported from using THRIVE.

Conclusions: This study demonstrated that preoxygenation and apneic oxygenation using THRIVE were associated with a low incidence of desaturation during emergency intubation of patients at high risk of hypoxia in the CCU, OR, and ED. THRIVE has the potential to minimize the risk of hypoxia in these patient groups.
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http://dx.doi.org/10.1016/j.jcrc.2016.06.011DOI Listing
December 2016

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

Elife 2015 10 27;4. Epub 2015 Oct 27.

Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States.

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.
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http://dx.doi.org/10.7554/eLife.08648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621743PMC
October 2015

Genome Sequences of Mycobacteriophages AlanGrant, Baee, Corofin, OrangeOswald, and Vincenzo, New Members of Cluster B.

Genome Announc 2015 Jun 18;3(3). Epub 2015 Jun 18.

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

AlanGrant, Baee, Corofin, OrangeOswald, and Vincenzo are newly isolated phages of Mycobacterium smegmatis mc(2)155 discovered in Pittsburgh, Pennsylvania, USA. All five phages share nucleotide similarity with cluster B mycobacteriophages but span considerable diversity with Corofin and OrangeOswald in subcluster B3, AlanGrant and Vincenzo in subcluster B4, and Baee in subcluster B5.
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http://dx.doi.org/10.1128/genomeA.00586-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472886PMC
June 2015

The simultaneous use of a heat and moisture exchanger and a heated humidifier causes critical airway occlusion in less than 24 hours.

J Crit Care 2015 Aug 8;30(4):863.e1-3. Epub 2015 Apr 8.

Department of Anaesthesia and Critical Care, Queen Elizabeth Hospital, Gayton Road, Kings Lynn, Norfolk, UK, PE30 4ET. Electronic address:

Purpose: Heat and moisture exchangers (HMEs) and heated humidifiers (HHs) may be used together inadvertently. Such an incident occurred at our institution resulting in airway occlusion.

Material And Methods: A bench-top study was conducted to compare the incidence of airway occlusion when using (1) no airway humidification, (2) HME alone, (3) HH alone, and (4) both HME and HH in combination as part of a standard breathing circuit.

Results: The simultaneous use of a HME and a HH was associated with a reduction in tidal volume (no airway humidification, P ≤ .05; HME alone, P ≤ .01; and HH alone, P ≤ .01) and an increased incidence of airway occlusion (no airway humidification, 0/7; HME alone, 0/7; HH alone, 0/7; and HME and HH in combination, 7/7; P < .0001).

Conclusions: The use of a HME and a HH in combination is likely to result in airway occlusion. Precautions should be taken to ensure that both systems are not used together in clinical practice.
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http://dx.doi.org/10.1016/j.jcrc.2015.03.033DOI Listing
August 2015

Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections.

J Am Coll Cardiol 2015 Apr;65(13):1324-1336

Department of Cardiology, University Hospital Antwerp, Antwerp, Belgium.

Background: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-β signaling.

Objectives: This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis.

Methods: We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done.

Results: Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands.

Conclusions: Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.
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http://dx.doi.org/10.1016/j.jacc.2015.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380321PMC
April 2015

Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

Mol Ther 2015 May 6;23(5):835-844. Epub 2015 Feb 6.

Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden; Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden. Electronic address:

Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.
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http://dx.doi.org/10.1038/mt.2015.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427872PMC
May 2015

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome.

Eur J Hum Genet 2015 Feb 16;23(2):224-8. Epub 2014 Apr 16.

Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS.
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http://dx.doi.org/10.1038/ejhg.2014.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297897PMC
February 2015

Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.

Nat Genet 2012 Nov 30;44(11):1249-54. Epub 2012 Sep 30.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.
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http://dx.doi.org/10.1038/ng.2421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545695PMC
November 2012

Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways.

FASEB J 2011 Jan 8;25(1):99-110. Epub 2010 Sep 8.

Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.

Cachectic muscle wasting is a frequent complication of many inflammatory conditions, due primarily to excessive muscle catabolism. However, the pathogenesis and intervention strategies against it remain to be established. Here, we tested the hypothesis that Toll-like receptor 4 (TLR4) is a master regulator of inflammatory muscle catabolism. We demonstrate that TLR4 activation by lipopolysaccharide (LPS) induces C2C12 myotube atrophy via up-regulating autophagosome formation and the expression of ubiquitin ligase atrogin-1/MAFbx and MuRF1. TLR4-mediated activation of p38 MAPK is necessary and sufficient for the up-regulation of atrogin1/MAFbx and autophagosomes, resulting in myotube atrophy. Similarly, LPS up-regulates muscle autophagosome formation and ubiquitin ligase expression in mice. Importantly, autophagy inhibitor 3-methyladenine completely abolishes LPS-induced muscle proteolysis, while proteasome inhibitor lactacystin partially blocks it. Furthermore, TLR4 knockout or p38 MAPK inhibition abolishes LPS-induced muscle proteolysis. Thus, TLR4 mediates LPS-induced muscle catabolism via coordinate activation of the ubiquitin-proteasome and the autophagy-lysosomal pathways.
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http://dx.doi.org/10.1096/fj.10-164152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005430PMC
January 2011