Publications by authors named "Brian Fowler"

142 Publications

Chromosome-scale genome assembly provides insights into rye biology, evolution and agronomic potential.

Nat Genet 2021 04 18;53(4):564-573. Epub 2021 Mar 18.

Aquatic and Crop Resource Development, National Research Council, Saskatoon, Saskatchewan, Canada.

Rye (Secale cereale L.) is an exceptionally climate-resilient cereal crop, used extensively to produce improved wheat varieties via introgressive hybridization and possessing the entire repertoire of genes necessary to enable hybrid breeding. Rye is allogamous and only recently domesticated, thus giving cultivated ryes access to a diverse and exploitable wild gene pool. To further enhance the agronomic potential of rye, we produced a chromosome-scale annotated assembly of the 7.9-gigabase rye genome and extensively validated its quality by using a suite of molecular genetic resources. We demonstrate applications of this resource with a broad range of investigations. We present findings on cultivated rye's incomplete genetic isolation from wild relatives, mechanisms of genome structural evolution, pathogen resistance, low-temperature tolerance, fertility control systems for hybrid breeding and the yield benefits of rye-wheat introgressions.
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http://dx.doi.org/10.1038/s41588-021-00807-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035072PMC
April 2021

Postoperative Clinical Outcomes Using Standard Variables Following Levator-Mullerectomy Advancement Blepharoptosis Surgery.

J Craniofac Surg 2021 Feb 18. Epub 2021 Feb 18.

Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN.

Abstract: The Muller muscle-conjunctival resection is a common technique used to treat blepharoptosis, but there is variability with the target surgical resection and expected postoperative outcomes measured by marginal reflex distance-1 (MRD1). A Levator-Mullerectomy is a novel surgical approach described by Morris et al to incorporate the levator palpebrae superioris in the same incision as the classic Muller muscle-conjunctival resection in the treatment of blepharoptosis. This a retrospective study of patients who underwent Levator-Mullerectomy for ptosis repair showing the clinical outcomes based on MRD1. Statistical analysis was performed using analysis of variance and a nonparametric Kruskal-Wallis test. One hundred-twelve eyes of 83 patients (29 bilateral cases) with a mean age 64.6 years (7-92 years) were included. The types and prevalence of blepharoptosis were involutional (83%), neurogenic (8.0%), traumatic (3.6%), apraxia (2.7%), and congenital (2.7%). There was no significant difference in clinical outcome based on type of blepharoptosis (P = 0.7). Target resection lengths of 8 mm, 10 mm, and 12 mm were compared with postoperative MRD1 change. The mean change in MRD 1 between 8 mm and 10 mm was found to be statistically significant (P = 0.001 for both) but was not statistically significant for the 12 mm resection (P = 0.8). In patients with blepharoptosis and a positive response to 2.5% phenylephrine can benefit from Levator-Mullerectomy with either an 8 mm or 10 mm resection. This novel surgical approach allows surgeons to produce a more predictable and consistent clinical outcome.
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http://dx.doi.org/10.1097/SCS.0000000000007554DOI Listing
February 2021

A Case of Non-Arteritic Anterior Ischemic Optic Neuropathy with COVID-19.

Cureus 2020 Dec 7;12(12):e11950. Epub 2020 Dec 7.

Ophthalmology, Hamilton Eye Institute, Memphis, USA.

Non-arteritic ischemic optic neuropathy (NAION) is thought to be caused by loss of blood flow to the optic nerve which in turn causes an acute, unilateral and painless vision loss that affects older vasculopathic patients. We report a case of a 43-year-old Hispanic male with the classic presentation of NAION in the setting of a coronavirus disease 2019 (COVID-19) infection. It is well documented that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause hypoxemia and thrombophilia in patients, both of which may contribute to the development of NAION. It is uncertain whether the association of NAION and COVID-19 was causal or coincidental but the purpose of this case report is to argue that there is biological plausibility and to help shed light on potential ophthalmologic complications of COVID-19.
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http://dx.doi.org/10.7759/cureus.11950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785499PMC
December 2020

Teprotumumab in Clinical Practice: Recommendations and Considerations From the OPTIC Trial Investigators.

J Neuroophthalmol 2021 Jan 4;Publish Ahead of Print. Epub 2021 Jan 4.

Department of Surgery (RSD, YW), Division of Ophthalmology, Cedars Sinai Medical Center, Los Angeles, California; State Key Laboratory of Ophthalmology (RSD), Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Department of Ophthalmology (RAD), Casey Eye Institute, Portland, Oregon; Department of Ophthalmology (GJH), Medical College of Wisconsin, Milwaukee, Wisconsin; Bascom Palmer Eye Institute (STW), University of Miami, Miami, Florida; Eye Wellness Center-Neuro-Eye Clinical Trials (JSS, RAT), Inc, Houston, Texas; Hamilton Eye Institute (BF, JF), University of Tennessee Health Science Center, Memphis, Tennessee; and Department of Ophthalmology and Visual Sciences (TJS), Kellogg Eye Center, and Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan.

Background: Thyroid eye disease (TED) is a vision-threatening and debilitating condition that until very recently had no Food and Drug Administration (FDA)-approved medical therapies. Teprotumumab has recently been approved to treat TED. We aim to provide guidance for its use, based on the input of the US investigators who participated in Phase 2 and Phase 3 clinical trials.

Methods: An expert panel was convened on October 11th and November 16th of 2019. All panel members had extensive experience as investigators in the Phase 2 and/or Phase 3 clinical trials of teprotumumab. Consensus among those investigators was reached to determine patient characteristics most appropriate for teprotumumab treatment. Safety guidelines were also reviewed and agreed on.

Results: The authors recommend that teprotumumab be considered first-line therapy for patients with clinically significant ophthalmopathy, including those with disease duration exceeding 9 months. The clinical activity score (CAS) may be useful for longitudinal monitoring but should not be used to determine treatment eligibility. Criteria will likely be expanded after more experience with the drug. Using teprotumumab for patients with TED with substantial signs, symptoms, or morbidity without a CAS score of >4 (e.g., progressive proptosis, diplopia, and early compressive optic neuropathy) or more, could be considered. Diabetes mellitus and inflammatory bowel disease comorbidities should not be exclusionary, but stringent monitoring in these patients is recommended. Drug dosing, administration interval, and duration should adhere to the study protocol: 8 infusions, separated by 3 weeks. Patients with more severe disease may benefit from additional doses. Corticosteroids can be used before or during teprotumumab therapy. Clinical and laboratory monitoring should be consistent with good clinical practice for patients receiving teprotumumab.

Conclusions: Confirming the efficacy of teprotumumab usage outside the narrow parameters of the completed clinical trials will require rigorous scientific validation. As a step in that direction, we believe its on-label usage is appropriately applied to all patients with TED with substantial symptoms or morbidity, as judged by their physician.
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http://dx.doi.org/10.1097/WNO.0000000000001134DOI Listing
January 2021

Identifying Mouse Autoimmune Uveitis from Fundus Photographs Using Deep Learning.

Transl Vis Sci Technol 2020 12 2;9(2):59. Epub 2020 Dec 2.

University of Tennessee Health Science Center, Memphis, TN, USA.

Purpose: To develop a deep learning model for objective evaluation of experimental autoimmune uveitis (EAU), the animal model of posterior uveitis that reveals its essential pathological features via fundus photographs.

Methods: We developed a deep learning construct to identify uveitis using reference mouse fundus images and further categorized the severity levels of disease into mild and severe EAU. We evaluated the performance of the model using the area under the receiver operating characteristic curve (AUC) and confusion matrices. We further assessed the clinical relevance of the model by visualizing the principal components of features at different layers and through the use of gradient-weighted class activation maps, which presented retinal regions having the most significant influence on the model.

Results: Our model was trained, validated, and tested on 1500 fundus images (training, 1200; validation, 150; testing, 150) and achieved an average AUC of 0.98 for identifying the normal, trace (small and local lesions), and disease classes (large and spreading lesions). The AUCs of the model using an independent subset with 180 images were 1.00 (95% confidence interval [CI], 0.99-1.00), 0.97 (95% CI, 0.94-0.99), and 0.96 (95% CI, 0.90-1.00) for the normal, trace and disease classes, respectively.

Conclusions: The proposed deep learning model is able to identify three severity levels of EAU with high accuracy. The model also achieved high accuracy on independent validation subsets, reflecting a substantial degree of generalizability.

Translational Relevance: The proposed model represents an important new tool for use in animal medical research and provides a step toward clinical uveitis identification in clinical practice.
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http://dx.doi.org/10.1167/tvst.9.2.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718814PMC
December 2020

The relationship of the Phantom® Lapidus Intramedullary Nail System to neurologic and tendinous structures in the foot: An anatomic study.

Foot Ankle Surg 2021 Feb 20;27(2):231-234. Epub 2020 May 20.

Graduate Medical Education Department, Wellstar Atlanta Medical Center, United States.

Background: The purpose of our cadaveric study was to determine the proximity of nail insertion and interlocking mechanisms in the Phantom® Lapidus Intramedullary Nail System to neurologic and tendinous structures in the foot.

Methods: We used 10 fresh-frozen human lower-extremity specimen cadavers. For each specimen, the Nail System was inserted as described in the published technique guide. We then performed dissection on the tibialis anterior tendon, extensor hallucis longus tendon, and medial dorsal cutaneous branch of the superficial peroneal nerve and we measured and averaged the distances from each of these structures from the nail.

Results: The tibialis anterior tendon was in closest proximity to the insertion of the proximal medial interlock K-wire with an average distance of 0.4mm from the tendon. The extensor hallucis longus tendon was in closest proximity to nail insertion with an average distance of 1.2mm. The medial dorsal cutaneous branch of the superficial peroneal nerve was in closest proximity to the distal interlock K-wire with an average distance of 7.5mm.

Conclusions: The tibialis anterior tendon, extensor hallucis longus tendon, and the medial dorsal cutaneous branch of the superficial peroneal nerve are at risk with the insertion of the nail system. Blunt dissection should be performed using this system with a path to bone before instrumentation to reduce the risk of nerve and tendon injury in the foot.
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http://dx.doi.org/10.1016/j.fas.2020.04.007DOI Listing
February 2021

Prevalence and predictors of elevated central venous pressure and obstructive sleep apnea in patients with lower extremity chronic venous disease.

J Vasc Surg Venous Lymphat Disord 2020 09 21;8(5):775-782. Epub 2020 Feb 21.

Cardiovascular Medicine, OhioHealth/Riverside Methodist Hospital, Columbus, Ohio.

Background: Chronic venous disease (CVD) is a common vascular disorder with manifestations ranging from asymptomatic spider veins to venous ulcers. Elevated right atrial pressure, otherwise called central venous pressure (CVP), can also result in edema and hyperpigmentation similar to chronic venous insufficiency. Obstructive sleep apnea (OSA) is a known risk factor for elevation of CVP. Prevalence rates of elevated CVP or OSA are unknown in patients presenting with a diagnosis of CVD.

Methods: This is a single-center, retrospective, descriptive study of patients referred to our tertiary care center with a diagnosis of CVD. Each patient was evaluated by simultaneous venous duplex ultrasound (to assess venous reflux) and limited echocardiography of the right side of the heart (to assess elevated CVP). We assessed the prevalence and predictors of elevated CVP in this cohort using multivariate logistic regression.

Results: A total of 264 patients with CVD were evaluated, and of these, 22.7% had elevated CVP and 26.9% had OSA. There was no significant difference in the prevalence of OSA or elevated body mass index in the group with elevated CVP compared with patients with normal CVP. The predictors of elevated CVP were age >64.6 years (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.003-1.05; P = .026), diabetes mellitus (OR, 2.19; 95% CI, 1.05-4.5; P = .035), and right lower extremity Venous Clinical Severity Score of ≥8.5 (OR, 1.098; 95% CI, 1.011-1.193; P = .026). Other predictors included prior history of pulmonary embolism and renal insufficiency.

Conclusions: Compared with the general population, the prevalence of elevated CVP and OSA is significant in this cohort of patients. Age, diabetes, and right lower extremity chronic venous insufficiency symptoms seem to be predictors of elevated CVP. Larger, population-based prevalence studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.jvsv.2019.12.071DOI Listing
September 2020

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

N Engl J Med 2020 01;382(4):341-352

From Cedars-Sinai Medical Center, Los Angeles (R.S.D., A.P.); Johannes Gutenberg University Medical Center, Mainz (G.J.K.), and University Hospital Essen, Essen (A.E.) - both in Germany; Horizon Therapeutics, Lake Forest, IL (S.S., E.H.Z.T., R.P., J.W.S., T.V., R.J.H.); University of Tennessee Health Science Center, Memphis (J.C.F., B.T.F.); University of Pisa, Pisa (C.M., M.M., A.A.), and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (M.S.) - both in Italy; Oregon Health and Sciences University, Portland (R.D.); Medical College of Wisconsin Eye Institute, Milwaukee (G.J.H.); Eye Wellness Center-Neuro-Eye Clinical Trials, Houston (J.S., R.T.); Kellogg Eye Center-Michigan Medicine (C.N., T.J.S.) and University of Michigan Medical School (T.J.S.) - both in Ann Arbor; and Bascom Palmer Eye Institute, Miami (S.W.).

Background: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.

Methods: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).

Results: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.

Conclusions: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).
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http://dx.doi.org/10.1056/NEJMoa1910434DOI Listing
January 2020

Intravascular Papillary Endothelial Hyperplasia of the Orbit: A Case of Masson's Tumor.

Cureus 2019 Dec 1;11(12):e6266. Epub 2019 Dec 1.

Ophthalmology, University of Tennessee Health Science Center, Memphis, USA.

Herein, we present a case of a 64-year-old male presenting with diplopia that was found to have a left orbital Masson's tumor. It is necessary to differentiate it from malignant angiosarcoma as complete excision is often curative. The following case emphasizes the modalities that can be used for diagnosis as well as the appropriate treatments.
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http://dx.doi.org/10.7759/cureus.6266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937477PMC
December 2019

Primary Isolated Lacrimal Gland Amyloidosis: A Case Report and Review of the Literature.

Cureus 2019 Nov 29;11(11):e6258. Epub 2019 Nov 29.

Ophthalmology, University of Tennessee Health Science Center, Memphis, USA.

We report a case of a 42-year-old woman who presented with a one-year history of a painless right orbital mass and right upper lid ptosis. Magnetic resonance imaging (MRI) revealed a superotemporal right orbital mass involving the lacrimal gland, and subsequent tissue biopsy and histopathologic evaluation was consistent with amyloidosis. An otherwise negative workup by hematology/oncology confirmed a diagnosis of primary isolated lacrimal gland amyloidosis. To the best of our knowledge, this is the first documented case of isolated lacrimal gland amyloidosis without immunoglobulin (Ig) light chain restriction on in situ hybridization testing with a report of MRI findings. In addition, this is the second reported case of the disease without Ig light chain restriction on immunohistochemistry staining, and it is the third case with reported MRI results.
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http://dx.doi.org/10.7759/cureus.6258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937473PMC
November 2019

Canthal V-plasty for Floppy Eyelid Surgery.

Plast Reconstr Surg Glob Open 2019 Oct 29;7(10):e2464. Epub 2019 Oct 29.

Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tenn.

The purpose of this article is to present a modified approach to the reconstruction of the upper and lower eyelids in floppy eyelid syndrome. A retrospective chart review was performed on all floppy eyelid patients who underwent simultaneous tightening of the upper and lower eyelid with a lateral tarsal strip, using a V-shaped incision in the lateral canthus, at University of Tennessee Hamilton Eye Institute from 2011 to 2012. Preoperative symptoms, surgical outcomes, complication rates, and postoperative symptoms were recorded. Nine eyes of 7 patients who underwent surgical correction for symptomatic floppy eyelids were included. All patients noted improvement in symptoms postoperatively, after reduction in the laxity of the upper and lower eyelid. Postoperative complications included buried lashes in the lateral canthus in 1 eye and a pyogenic granuloma in the lateral canthus of 1 eye. An excellent cosmetic outcome was noted in 78% (7/9) of eyes. No patients reported dissatisfaction nor required secondary surgical correction. The lateral canthal "V" incision provides an additional approach in the successful management of floppy eyelid syndrome involving the upper and lower eyelids. The design of the incision allows for excellent exposure of the lateral canthus for shortening of the eyelids with tarsal strip fixation, and it preserves the lateral canthal skin and canthus architecture. Further, the "V" incision is easily continued into the eyelid crease for blepharoplasty and ptosis repair when necessary.
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http://dx.doi.org/10.1097/GOX.0000000000002464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6846288PMC
October 2019

Blue rubber bleb nevus syndrome of the orbit and gastrointestinal tract.

Orbit 2020 Dec 12;39(6):456-457. Epub 2019 Nov 12.

Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center , Memphis, Tennessee, USA.

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http://dx.doi.org/10.1080/01676830.2019.1687737DOI Listing
December 2020

Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.

J Hum Genet 2020 Jan 23;65(2):91-98. Epub 2019 Oct 23.

INSERM UMR_S 1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
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http://dx.doi.org/10.1038/s10038-019-0689-yDOI Listing
January 2020

Orbital Pheochromocytoma Metastasis in 2 Patients With Known Pheochromocytoma.

Ophthalmic Plast Reconstr Surg 2019 Nov/Dec;35(6):e131-e134

Hamilton Eye Institute, University of Tennessee Health Science Center.

Two patients with previously diagnosed pheochromocytoma presented with facial pain and ptosis. Imaging revealed orbital lesions. Both patients were referred for surgical evaluation of the orbital mass. Surgical excision was performed for both. Pathology confirmed metastatic pheochromocytoma. Pheochromocytomas commonly metastasize to bone, liver, and other tissues. Five cases of metastasis to orbital bone have been previously described. These 2 cases are unique in that the metastases were not hormonally active, presented soon after initial diagnosis, and were treated palliatively with surgical excision. Previous treatment of orbital bony metastasis used radiotherapy. These cases demonstrate that surgical resection is a viable treatment option in these situations. Orbital metastasis of pheochromocytomas should be considered with the appropriate clinical presentation. These are the first documented cases of intraorbital metastasis, separate from the bony walls. Previously, orbital bony wall metastases were treated with radiation. Surgical excision is a viable option for treatment of such metastases.Orbital involvement should be considered in patients with systemic disease presenting with new ocular findings.
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http://dx.doi.org/10.1097/IOP.0000000000001460DOI Listing
January 2020

Genome-Wide Identification and Characterization of the Wheat Remorin (REM) Family during Cold Acclimation.

Plant Genome 2019 06;12(2)

Remorins (REMs) are plant-specific proteins that play an essential role in plant-microbe interactions. However, their roles in vernalization and abiotic stress responses remain speculative. Most remorins have a variable proline-rich -half and a more conserved -half that is predicted to form coils. A search of the wheat ( L.) database revealed the existence of 20 different genes, which we classified into six groups on the basis of whether they shared a common phylogenetic and structural origin. Analysis of the physical genomic distributions demonstrated that genes are dispersed in the wheat genome and have one to seven introns. Promoter analysis of genes revealed the presence of putative -elements related to diverse functions like development, hormonal regulation, and biotic and abiotic stress responsiveness. Expression levels of genes were measured in plants grown under field and controlled conditions and in response to hormone treatment. Our analyses revealed that 12 members of the REM family are regulated during cold acclimation in wheat in four different tissues (roots, crowns, stems, and leaves), with the highest expression in roots. Differential gene expression was found between wheat cultivars with contrasting degrees of cold tolerance, suggesting the implication of genes in cold response and tolerance. Additionally, eight genes were induced in response to abscisic acid and methyl jasmonate treatment. This genome-wide analysis of genes provides valuable resources for functional analysis aimed at understanding their role in stress adaptation.
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http://dx.doi.org/10.3835/plantgenome2018.06.0040DOI Listing
June 2019

Images in Vascular Medicine. Rat bite fever: A rare case of critical limb ischemia.

Vasc Med 2019 10 22;24(5):465-466. Epub 2019 May 22.

OhioHealth Heart & Vascular Physicians, Columbus, OH, USA.

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http://dx.doi.org/10.1177/1358863X19849619DOI Listing
October 2019

Variation of the minimally invasive CDCR technique.

Orbit 2020 Apr 20;39(2):118-122. Epub 2019 May 20.

Tulane Department of Ophthalmology, Tulane University School of Medicine, New Orleans, LA, USA.

: Traditional (tCDCR) and endoscopic conjunctivodacryocystorhinostomy (eCDCR) are challenging surgical techniques requiring general anesthesia, a facial incision, and a large osteotomy and mucosal flap. Minimally invasive CDCR (miCDCR) techniques eliminate the need for some of the steps in t/eCDCR. Introduced here is a variation of the miCDCR technique using a Naugle-Fleming knurled dilator (NKD) to create the osteotomy and instruments within a central line catheter kit to help easily place or replace a Jones' tube into position within a bony conduit.: This IRB-approved retrospective chart review examined all patients who underwent this miCDCR technique performed by two oculoplastic surgeons at Hamilton Eye Institute at the University of Tennessee Health Sciences Center from 2014 to 2016. Inclusion criteria: need for CDCR (either primary or repeat). Exclusion criteria: loss to follow up prior to six months. Primary endpoints: operative time, incidence of tube migration and complications, and cessation of epiphora.: Sixteen patients (nine men, seven women) were reviewed, with three undergoing bilateral procedure, totaling 19 cases. Age range: 47.0 to 84.0 years, average of 66.6 years (). Ten patients had surgery under local/MAC augmented with IV sedation, and six had general anesthesia (38%). Average operative time was 17.4 min (). One patient (5%) required revision in the six-month immediate post-operative period because of tube migration. All patients had cessation of epiphora.: This procedure can be done safely and quickly without general anesthesia, resulting in a satisfactorily lower rate of tube migration and cessation of epiphora rates.
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http://dx.doi.org/10.1080/01676830.2019.1605612DOI Listing
April 2020

Essential skin shrinkage: cicatricial ectropion, a histopathologic evaluation and clinical analysis.

Orbit 2020 Apr 20;39(2):93-97. Epub 2019 May 20.

Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN, USA.

: To describe common risk factors in patients with Essential Skin Shrinkage (ESS) and identify corresponding histopathologic changes in lower eyelids.: A case-control study was performed after an Internal Review Board approval was obtained. Consecutive patients who underwent surgical repair for ectropion with ESS of the lower eyelid were enrolled along with 10 control patients. Informed consent was obtained on all patients. Fitzpatrick skin type, history of sun exposure and non-melanoma skin cancer was obtained along with relevant physical exam findings. Skin samples obtained during surgical repair were evaluated by light microscopy for the extent of dermal actinic change. Statistical analysis was performed.: Sixteen study subjects and 10 control patients were enrolled. Subjects were found to be predominantly male, older than controls (p = 0.0011) and have Fitzpatrick skin type (FST) I or II while controls had type I, II or III (p = 0.0221). Hours of sun exposure reported by subjects ranged from 23,165 to greater than 125,000 h, versus 1,459 to 46,890 h in controls (p = 0.0002). Nine of 16 (56%) subjects had a history of skin cancer compared to only 3/10 controls (30%) (p = 0.2475). Histopathologic evaluation using the Fritschi scale for dermal actinic damage identified an average grade of 3.6 for subjects and 2.4 for controls (p = 0.0095).: ESS is predominantly seen in male individuals with FST I or II and a history of extensive sun exposure. Histopathologic evaluation shows moderate to severe actinic damage. These individuals frequently have concomitant non-melanoma skin cancer.
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http://dx.doi.org/10.1080/01676830.2019.1600152DOI Listing
April 2020

Eyelid Spontaneous Blink Analysis and Age-Related Changes Through High-Speed Imaging.

Ophthalmic Plast Reconstr Surg 2019 Sep/Oct;35(5):487-490

University of Tennessee.

Purpose: To analyze the spontaneous eyelid blink and sphincter closure activity of the orbicularis oculi by measuring the horizontal eyelid movement.

Methods: Individuals 18+ years of age, any ethnicity, and gender were recruited. Participants completed a questionnaire to determine eligibility. Exclusion criteria included the following: history of facial trauma, nerve palsy, surgery, use of periorbital neuromodulators or filler within the past year, thyroid eye disease, and eyelid or ocular surface disease. Data were collected from participants by decade. Eyelid blinks were recorded using the FPS 1000HD. The motions of 3 spontaneous blinks in primary gaze were recorded. All blinks were reviewed and one chosen for most accurate analysis. Horizontal palpebral fissure width and its changes of open and closed eye measurements were taken using National Institute of Health ImageJ software version 2.0. The data were subjected to SAS version 9.4 analysis using paired t test, t test, and linear models.

Results: One hundred thirty-six patients were recruited. Fourteen patients were excluded; 122 patients were used in analysis. Ages ranged from 22 to 90 years. Participants were divided into 6 groups according to age (20-29, 30-39, 40-49, 50-59, 60-69, and 70+ years of age). The average horizontal fissure length across all ages was 24.23 mm. Average change in horizontal fissure length decreased 1.42 mm among all ages. There was a statistically significant difference comparing age 20-29 decade to age 70+ decade.

Conclusions: Horizontal fissure length changes with eyelid blink and defines 1 component of the eyelid sphincter.
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http://dx.doi.org/10.1097/IOP.0000000000001349DOI Listing
January 2020

Vitamin B , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation.

J Inherit Metab Dis 2019 07 28;42(4):673-685. Epub 2019 Jan 28.

Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Vitamin B (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl-CoA mutase and methionine synthase. Methylmalonyl-CoA mutase is required for the catabolism of certain (branched-chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl-Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl-Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S-adenosylmethionine, the most important cellular methyl-donor. Disruption of methionine synthase has wide-ranging implications for all methylation-dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5-methyltetrahydrofolate as a one-carbon donor. Folate-bound one-carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate-mediated one-carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.
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http://dx.doi.org/10.1002/jimd.12009DOI Listing
July 2019

Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency.

Biochim Biophys Acta Mol Basis Dis 2019 06 22;1865(6):1265-1272. Epub 2019 Jan 22.

Division of Metabolism and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. Electronic address:

Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism. Autosomal recessive pathogenic variations in MCEE reportedly cause methylmalonic aciduria (MMAuria) in eleven patients. We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE. Nine patients were homozygous for the known nonsense variation p.Arg47* (c.139C > T), and one for the novel missense variation p.Ile53Arg (c.158T > G). To understand better the molecular basis of MCEE deficiency, we mapped p.Ile53Arg, and two previously described pathogenic variations p.Lys60Gln and p.Arg143Cys, onto our 1.8 Å structure of wild-type (wt) human MCEE. This revealed potential dimeric assembly disruption by p.Ile53Arg, but no clear defects from p.Lys60Gln or p.Arg143Cys. We solved the structure of MCEE-Arg143Cys to 1.9 Å and found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket. Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with misfolded protein. By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this variation may cause disease. MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity. These studies reveal ten new patients with MCEE deficiency and rationalize misfolding and loss of activity as molecular defects in MCEE-type MMAuria.
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http://dx.doi.org/10.1016/j.bbadis.2019.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525113PMC
June 2019

Ice segregation in the crown of winter cereals: Evidence for extraorgan and extratissue freezing.

Plant Cell Environ 2019 02 19;42(2):701-716. Epub 2018 Nov 19.

Department of Plant Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Meaningful improvements in winter cereal cold hardiness requires a complete model of freezing behaviour in the critical crown organ. Magnetic resonance microimaging diffusion-weighted experiments provided evidence that cold acclimation decreased water content and mobility in the vascular transition zone (VTZ) and the intermediate zone in rye (Secale cereale L. Hazlet) compared with wheat (Triticum aestivum L. Norstar). Differential thermal analysis, ice nucleation, and localization studies identified three distinct exothermic events. A high-temperature exotherm (-3°C to -5°C) corresponded with ice formation and high ice-nucleating activity in the leaf sheath encapsulating the crown. A midtemperature exotherm (-6°C and -8°C) corresponded with cavity ice formation in the VTZ but an absence of ice in the shoot apical meristem (SAM). A low-temperature exotherm corresponded with SAM injury and the killing temperature in wheat (-21°C) and rye (-27°C). The SAM had lower ice-nucleating activity and freezing survival compared with the VTZ when frozen in vitro. The intermediate zone was hypothesized to act as a barrier to ice growth into the SAM. Higher cold hardiness of rye compared with wheat was associated with higher VTZ and intermediate zone desiccation resulting in the formation of ice barriers surrounding the SAM.
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http://dx.doi.org/10.1111/pce.13454DOI Listing
February 2019

Impact of Public Health Responses During a Measles Outbreak in an Amish Community in Ohio: Modeling the Dynamics of Transmission.

Am J Epidemiol 2018 09;187(9):2002-2010

Department of Ecology and Evolutionary Biology, Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, New Jersey.

We quantified measles transmissibility during a measles outbreak in Ohio in 2014 to evaluate the impact of public health responses. Case incidence and the serial interval (time between symptom onset in primary cases and secondary cases) were used to assess trends in the effective reproduction number R (the average number of secondary cases generated per case). A mathematical model was parameterized using early R values to determine the size and duration of the outbreak that would have occurred if containment measures had not been initiated, as well as the impact of vaccination. As containment started, we found a 4-fold decline in R (from approximately 4 to 1) over the course of 2 weeks and maintenance of R < 1 as control measures continued. Under a conservative scenario, the model estimated 8,472 cases (90% confidence interval (CI): 8,447, 8,489) over 195 days (90% CI: 179, 223) without control efforts and 715 cases (90% CI: 103, 1,338) over 128 days (90% CI: 117, 139) when vaccination was included; 7,757 fewer cases (90% CI: 7,130, 8,365) and 67 fewer outbreak days (90% CI: 48, 98) were attributed to vaccination. Vaccination may not account entirely for transmission reductions, suggesting that changes in community behavior (social distancing) and other control efforts (isolation, quarantining) are important. Our findings highlight the benefits of measles outbreak response and of understanding behavior change dynamics.
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http://dx.doi.org/10.1093/aje/kwy082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118071PMC
September 2018

Tissue-specific changes in apoplastic proteins and cell wall structure during cold acclimation of winter wheat crowns.

J Exp Bot 2018 02;69(5):1221-1234

Department of Plant Sciences, University of Saskatchewan, Saskatoon, SK, Canada.

The wheat (Triticum aestivum L.) crown is the critical organ of low temperature stress survival over winter. In cold-acclimated crowns, ice formation in the apoplast causes severe tissue disruption as it grows at the expense of intracellular water. While previous crown studies have shown the vascular transition zone (VTZ) to have a higher freezing sensitivity than the shoot apical meristem (SAM), the mechanism behind the differential freezing response is not fully understood. Cooling cold-acclimated crowns to -10 °C resulted in an absence of VTZ tetrazolium chloride staining, whereas the temperatures at which 50% of the SAM stained positive and 50% of plants recovered (LT50) were similar after cold acclimation for 21 (-16 °C) and 42 d (-20 °C) at 4 °C. Proteomic analysis of the apoplastic fluids identified dehydrins, vernalization-responsive proteins, and cold shock proteins preferentially accumulated in the SAM. In contrast, modifications to the VTZ centered on increases in pathogenesis-related proteins, anti-freeze proteins, and sugar hydrolyzing enzymes. Fourier transform infrared spectroscopy focal plane array analysis identified the biochemical modification of the cell wall to enhance methyl-esterified cross-linking of glucuronoarabinoxylans in the VTZ. These findings indicate that the SAM and VTZ express two distinct tissue-specific apoplastic responses during cold acclimation.
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http://dx.doi.org/10.1093/jxb/erx450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019019PMC
February 2018

Transcriptomic Insights into Phenological Development and Cold Tolerance of Wheat Grown in the Field.

Plant Physiol 2018 03 19;176(3):2376-2394. Epub 2017 Dec 19.

Department of Plant Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A8, Canada

Cold acclimation and winter survival in cereal species is determined by complicated environmentally regulated gene expression. However, studies investigating these complex cold responses are mostly conducted in controlled environments that only consider the responses to single environmental variables. In this study, we have comprehensively profiled global transcriptional responses in crowns of field-grown spring and winter wheat () genotypes and their near-isogenic lines with the alleles swapped. This in-depth analysis revealed multiple signaling, interactive pathways that influence cold tolerance and phenological development to optimize plant growth and development in preparation for a wide range of over-winter stresses. Investigation of genetic differences at the locus revealed that a vernalization requirement maintained a higher level of cold response pathways while genetically promoted floral development. Our results also demonstrated the influence of genetic background on the expression of cold and flowering pathways. The link between delayed shoot apex development and the induction of cold tolerance was reflected by the gradual up-regulation of abscisic acid-dependent and C-REPEAT-BINDING FACTOR pathways. This was accompanied by the down-regulation of key genes involved in meristem development as the autumn progressed. The chromosome location of differentially expressed genes between the winter and spring wheat genetic backgrounds showed a striking pattern of biased gene expression on chromosomes 6A and 6D, indicating a transcriptional regulation at the genome level. This finding adds to the complexity of the genetic cascades and gene interactions that determine the evolutionary patterns of both phenological development and cold tolerance traits in wheat.
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http://dx.doi.org/10.1104/pp.17.01311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841705PMC
March 2018

Manifestations of neurological symptoms and thromboembolism in adults with MTHFR-deficiency.

J Neurol Sci 2017 Dec 6;383:123-127. Epub 2017 Nov 6.

Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Background: Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood.

Objective: We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood.

Methods: Extensive diagnostic work-up including genetic testing was performed in four adult members.

Results: The male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135μmol/L and 231μmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency.

Conclusion: Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.
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http://dx.doi.org/10.1016/j.jns.2017.10.035DOI Listing
December 2017

Effect of Co-segregating Markers on High-Density Genetic Maps and Prediction of Map Expansion Using Machine Learning Algorithms.

Front Plant Sci 2017 23;8:1434. Epub 2017 Aug 23.

Department of Plant Sciences, Crop Development Centre, University of Saskatchewan, SaskatoonSK, Canada.

Advances in sequencing and genotyping methods have enable cost-effective production of high throughput single nucleotide polymorphism (SNP) markers, making them the choice for linkage mapping. As a result, many laboratories have developed high-throughput SNP assays and built high-density genetic maps. However, the number of markers may, by orders of magnitude, exceed the resolution of recombination for a given population size so that only a minority of markers can accurately be ordered. Another issue attached to the so-called 'large p, small n' problem is that high-density genetic maps inevitably result in many markers clustering at the same position (co-segregating markers). While there are a number of related papers, none have addressed the impact of co-segregating markers on genetic maps. In the present study, we investigated the effects of co-segregating markers on high-density genetic map length and marker order using empirical data from two populations of wheat, Mohawk × Cocorit (durum wheat) and Norstar × Cappelle Desprez (bread wheat). The maps of both populations consisted of 85% co-segregating markers. Our study clearly showed that excess of co-segregating markers can lead to map expansion, but has little effect on markers order. To estimate the inflation factor (IF), we generated a total of 24,473 linkage maps (8,203 maps for Mohawk × Cocorit and 16,270 maps for Norstar × Cappelle Desprez). Using seven machine learning algorithms, we were able to predict with an accuracy of 0.7 the map expansion due to the proportion of co-segregating markers. For example in Mohawk × Cocorit, with 10 and 80% co-segregating markers the length of the map inflated by 4.5 and 16.6%, respectively. Similarly, the map of Norstar × Cappelle Desprez expanded by 3.8 and 11.7% with 10 and 80% co-segregating markers. With the increasing number of markers on SNP-chips, the proportion of co-segregating markers in high-density maps will continue to increase making map expansion unavoidable. Therefore, we suggest developers improve linkage mapping algorithms for efficient analysis of high-throughput data. This study outlines a practical strategy to estimate the IF due to the proportion of co-segregating markers and outlines a method to scale the length of the map accordingly.
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http://dx.doi.org/10.3389/fpls.2017.01434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572363PMC
August 2017

Consideration for eliminating conjunctival closure in the enucleation procedure.

Orbit 2017 Oct 25;36(5):322-324. Epub 2017 Jul 25.

b University of Tennessee Health Science Center , Hamilton Eye Institute , Memphis , Tennessee , USA.

To compare post-operative results and complications in patients who undergo enucleation with or without suture closure of the conjunctiva. This was a retrospective chart review study. Review of 50 cases of enucleation surgery at the University of Arkansas for Medical Sciences and Arkansas Children's Hospital between July 2011 and December 2014. Criteria for inclusion in the study were all cases of enucleation that had extraocular muscles attached to a spherical orbital implant with or without conjunctival closure, and at least 2 months of postoperative follow up. Post-operative complications were evaluated. A total of 36 cases fulfilled the criteria for inclusion in the study; 12 cases with direct sutured layered direct closure of Tenon's and then conjunctiva and 24 cases with Tenon's capsule sutured closure but without direct conjunctival sutured closure. No implant complications were identified in either group (p = 1.0). Mean follow-up for all groups was 16.71 months (range 2 to 43 mo., SD 11.94). Mean follow up for the non-closure group was 14.42 months (range 2.25 to 36 mo., SD 10.35). Two cases in the conjunctival closure group developed a conjunctival cyst, affecting prosthesis fit, approximately 3 months postoperatively: no such cysts were identified in the non-conjunctival closure group. Fisher exact test for cyst formation between the two groups was not statistically significant (p = 0.1048). Direct conjunctival closure following enucleation surgery does not appear to increase the risk of extrusion, exposure, or infection. Foregoing direct closure decreases surgical time and reduces cost. It is unclear if this decreases conjunctival cyst formation.
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http://dx.doi.org/10.1080/01676830.2017.1337174DOI Listing
October 2017

Exploring new alleles for frost tolerance in winter rye.

Theor Appl Genet 2017 Oct 20;130(10):2151-2164. Epub 2017 Jul 20.

TUM School of Life Sciences, Plant Breeding, Technical University of Munich, Liesel-Beckmann-Str. 2, 85354, Freising, Germany.

Key Message: Rye genetic resources provide a valuable source of new alleles for the improvement of frost tolerance in rye breeding programs. Frost tolerance is a must-have trait for winter cereal production in northern and continental cropping areas. Genetic resources should harbor promising alleles for the improvement of frost tolerance of winter rye elite lines. For frost tolerance breeding, the identification of quantitative trait loci (QTL) and the choice of optimum genome-based selection methods are essential. We identified genomic regions involved in frost tolerance of winter rye by QTL mapping in a biparental population derived from a highly frost tolerant selection from the Canadian cultivar Puma and the European elite line Lo157. Lines per se and their testcrosses were phenotyped in a controlled freeze test and in multi-location field trials in Russia and Canada. Three QTL on chromosomes 4R, 5R, and 7R were consistently detected across environments. The QTL on 5R is congruent with the genomic region harboring the Frost resistance locus 2 (Fr-2) in Triticeae. The Puma allele at the Fr-R2 locus was found to significantly increase frost tolerance. A comparison of predictive ability obtained from the QTL-based model with different whole-genome prediction models revealed that besides a few large, also small QTL effects contribute to the genomic variance of frost tolerance in rye. Genomic prediction models assigning a high weight to the Fr-R2 locus allow increasing the selection intensity for frost tolerance by genome-based pre-selection of promising candidates.
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http://dx.doi.org/10.1007/s00122-017-2948-7DOI Listing
October 2017

Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B-trafficking proteins ABCD4 and LMBD1.

J Biol Chem 2017 07 1;292(28):11980-11991. Epub 2017 Jun 1.

Division of Metabolism and Children's Research Center, University Children's Hospital, CH-8032 Zurich, Switzerland; Rare Disease Initiative Zurich (radiz), Clinical Research Priority Program for Rare Diseases, University of Zurich, CH-8006 Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, CH-8006 Zurich, Switzerland. Electronic address:

Vitamin B (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes and result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1-ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis.
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http://dx.doi.org/10.1074/jbc.M117.784819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512089PMC
July 2017