Publications by authors named "Tulsi Patel"

36 Publications

is a non-lethal modifier of the mosaic eye phenotype in .

MicroPubl Biol 2021 Jan 18;2021. Epub 2021 Jan 18.

University of Detroit Mercy, Detroit, MI USA.

Genetic screens have been used to identify genes involved in the regulation of different biological processes. We identified growth mutants in a Flp/FRT screen using the eye to identify conditional regulators of cell growth and cell division. One mutant identified from this screen, , was mapped and characterized by researchers in undergraduate genetics labs as part of the Fly-CURE. We find that is a non-lethal genetic modifier of the mosaic eye phenotype.
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http://dx.doi.org/10.17912/micropub.biology.000359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812380PMC
January 2021

Quantitative analysis of particulate matter release during orthodontic procedures: a pilot study.

Br Dent J 2020 Nov 12. Epub 2020 Nov 12.

Barts and The London School of Medicine and Dentistry, Orthodontics, Institute of Dentistry, Queen Mary University of London, London, E1 2AD, UK.

Introduction Transmission of SARS-CoV-2 through aerosol has been suggested, particularly in the presence of highly concentrated aerosols in enclosed environments. It is accepted that aerosols are produced during a range of dental procedures, posing potential risks to both dental practitioners and patients. There has been little agreement concerning aerosol transmission associated with orthodontics and associated mitigation.Methods Orthodontic procedures were simulated in a closed side-surgery using a dental manikin on an acrylic model using composite-based adhesive. Adhesive removal representing debonding was undertaken using a 1:1 contra-angle handpiece (W&H Synea Vision WK-56 LT, Bürmoos, Austria) and fast handpiece with variation in air and water flow. The removal of acid etch was also simulated with the use of combined 3-in-1 air-water syringe. An optical particle sizer (OPS 3330, TSI Inc., Minnesota, USA) and a portable scanning mobility particle sizer (NanoScan SMPS Nanoparticle Sizer 3910, TSI Inc., Minnesota, USA) were both used to assess particulate matter ranging in dimension from 0.08 to 10 μm.Results Standard debonding procedure (involving air but no water) was associated with clear increase in the 'very small' and 'small' (0.26-0.9 μm) particles but only for a short period. Debonding procedures without supplementary air coolant appeared to produce similar levels of aerosol to standard debonding. Debonding in association with water tended to produce large increases in aerosol levels, producing particles of all sizes throughout the experiment. The use of water and a fast handpiece led to the most significant increase in particles. Combined use of the 3-in-1 air-water syringe did not result in any detectable increase in the aerosol levels.Conclusions Particulate matter was released during orthodontic debonding, although the concentration and volume was markedly less than that associated with the use of a fast handpiece. No increase in particulates was associated with prolonged use of a 3-in-1 air-water syringe. Particulate levels reduced to baseline levels over a short period (approximately five minutes). Further research within alternative, open environments and without air exchange systems is required.
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http://dx.doi.org/10.1038/s41415-020-2280-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658615PMC
November 2020

Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy.

Acta Neuropathol Commun 2020 10 22;8(1):172. Epub 2020 Oct 22.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer's disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (n = 2008, n = 1037, n = 971) and Thal phase amyloid plaque scores (n = 1786, n = 1018, n = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46-4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = - 0.822, 95% CI - 1.439 to - 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = - 0.995, 95% CI - 1.773 to - 0.218, p = 0.012) than LBD-NP patients (ß = - 0.292, 95% CI - 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = - 0.638, 95% CI - 1.139 to - 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.
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http://dx.doi.org/10.1186/s40478-020-01050-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579984PMC
October 2020

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice.

Front Immunol 2020 15;11:573677. Epub 2020 Sep 15.

Department of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United States.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein-kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi's may have potential for therapeutic use for systemic and NPSLE.
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http://dx.doi.org/10.3389/fimmu.2020.573677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522287PMC
September 2020

Correction to: Deciphering cellular transcriptional alterations in Alzheimer's disease brains.

Mol Neurodegener 2020 09 15;15(1):54. Epub 2020 Sep 15.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13024-020-00403-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490892PMC
September 2020

The efficacy of an extraoral scavenging device on reduction of splatter contamination during dental aerosol generating procedures: an exploratory study.

Br Dent J 2020 Sep 11. Epub 2020 Sep 11.

Post-CCST Speciality Registrar in Orthodontics, Barts Health NHS Trust, The Royal London Dental Hospital, London, UK.

Introduction This study was conducted in light of the SARS-CoV-2 pandemic, which brought UK dentistry to a standstill. The market has seen a recent influx of unproven extraoral scavengers (EOSs), which claim to reduce the risk of particulate spread.Aims To investigate the efficacy of a commercially available EOS device on contamination reduction during dental aerosol generating procedures (AGPs). The secondary aim was to investigate differences between open and closed dental operatories.Method Dental procedures were simulated on a dental manikin using citric acid (10%) added to the water lines with universal indicating paper (UIP) placed in strategic locations in the operatory, on the clinician and assistant. Chromatic change related to settling of splatter containing citric acid on the UIP was analysed to calculate percentage intensity of splatter contamination.Results EOSs resulted in 20% reduction in frequency and 75% reduction in mean intensity of contamination of operatory sites. There was a 33% and 76% reduction in mean intensity contamination for clinician and assistant, respectively. Use of rubber dam and four-handed dentistry resulted in further reduction.Discussion This exploratory study demonstrates contamination by splatter in a simulated dental setting. The concern in dentistry regarding aerosol requires further quantitative investigation of smaller particles.Conclusions The routine use of four-handed dentistry and rubber dam should continue where possible to maximise risk mitigation during AGPs. However, on the basis of our findings, the use of an EOS device can further mitigate the magnitude and concentration of splatter.
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http://dx.doi.org/10.1038/s41415-020-2112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484927PMC
September 2020

Deciphering cellular transcriptional alterations in Alzheimer's disease brains.

Mol Neurodegener 2020 07 13;15(1):38. Epub 2020 Jul 13.

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer's disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.
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http://dx.doi.org/10.1186/s13024-020-00392-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359236PMC
July 2020

Covalent and non-covalent strategies for the immobilization of Tobacco Etch Virus protease (TEVp) on superparamagnetic nanoparticles.

J Biotechnol 2020 Oct 30;322:1-9. Epub 2020 Jun 30.

Department of Chemistry, East Carolina University, Greenville, NC, 27858-4353, United States. Electronic address:

Proteases with highly specific activities have numerous applications, including the cleavage of affinity tags (Flag; HA; His6X) and solubility promoting partners (GST; MBP) within the context of protein isolation and purification schemes. However, commercially sourced proteases such as Tobacco Etch Virus protease (TEVp) and Human Rhinovirus (HRV) 3C protease are typically applied as single use aliquots, which limits their cost-effectiveness. In addition, the presence of residual proteases in downstream applications can complicate analysis of the protein of interest. Thus, the creation of immobilized, reusable site-specific proteases would be of significant value to the life science community. In this work, we explore two strategies for the immobilization of TEV protease onto superparamagnetic iron oxide nanoparticles (SPIONs). In one strategy, a MBP-TEVp-Streptavidin fusion protein is immobilized on biotin-functionalized SPIONs. In a second strategy, TEV protease is covalently coupled onto SPIONs directly, via amine-mediated attachment, and indirectly, via HALO-tag mediated attachment. We demonstrate activity of our immobilized proteases in the presence of a MBP-GFP fusion protein containing the TEV protease target sequence (ENLYFQ|S). We then analyze time-dependent activity, longevity, and reuse of these immobilized protein preparations, comparing each approach. The protease immobilization strategies described in this work may be useful tools for simplifying challenging protein purification protocols, in addition to providing general methods for enzyme immobilization on SPIONs.
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http://dx.doi.org/10.1016/j.jbiotec.2020.06.021DOI Listing
October 2020

A comparison study: Periodontal practice approach of dentists and dental hygienists.

Int J Dent Hyg 2020 Aug 15;18(3):314-321. Epub 2020 May 15.

Department of Periodontics & Dental Hygiene, The University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA.

Objectives: The aim of this study was to investigate periodontal practice methods of dentists and dental hygienists to compare their knowledge and treatment approach in managing periodontal disease.

Methods: An electronic survey was designed to assess and capture three aspects of data: (a) knowledge of periodontics; (b) practice approaches in non-surgical periodontal therapy; and (c) factors affecting clinical care. The survey was distributed to dentists and dental hygienists who graduated from the same dental school within 5 years (2012-2016). Results were analysed by chi-square test, Fisher's exact test and logistic regression model.

Results: Out of total 117 participants, 111 of them reported their profession (n = 77 in the dental programme, n = 34 in the dental hygiene programme). The results showed no statistical difference in basic periodontal knowledge between dentists and dental hygienists (P = .12). Only 13% of the surveyed population identified appropriate recall intervals for periodontal maintenance and more dental hygienists reported periodontal re-evaluations being performed within their offices compared with dentists (91% vs 70%, P = .02). Almost half of the participants who reportedly performed periodontal re-evaluations (46%) charged for the re-evaluation procedure, despite it not being covered by dental insurance. More hygienists reported being familiar with and performing adjunct therapy compared to dentists in the study (P < .01).

Conclusion: In general, dentists and hygienists in the study were found to have similar periodontal knowledge and practice approaches. However, differences in performing periodontal re-evaluation and adjunct therapy were significant. Further studies are needed to investigate clinical barriers that impact evidence-based periodontal care.
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http://dx.doi.org/10.1111/idh.12441DOI Listing
August 2020

Venous Thromboembolism Treatment and Prevention in Cancer Patients: Can We Use Pills Yet?

Curr Treat Options Oncol 2020 04 23;21(5):43. Epub 2020 Apr 23.

Division of Gynecologic Oncology, Carilion Clinic, 1 Riverside Circle, Suite 300, Roanoke, VA, 24016, USA.

Opinion Statement: Cancer increases a patient's risk for developing a venous thromboembolism (VTE) and is a relatively common finding in this population. Traditionally, anticoagulants used to treat VTE have included low molecular weight heparin (LMWH) or vitamin K antagonists (VKA). However, within the last several years, a newer class of anticoagulant, the direct oral anticoagulants (DOACs), has emerged as a potential option for pharmacologic thromboprophylaxis and for treatment of VTE in patients with cancer. While data is still limited and evolving, DOACs offer several benefits that are worth considering, including ease of administration and similar efficacy compared to LMWH in preventing recurrent VTE. However, some studies have reported a notable risk of increased bleeding associated with the use of DOACs. Additional studies are underway to evaluate the role of DOACs compared to LMWH in the setting of cancer. In our practice, based on existing data, we have been using DOACs for the chronic treatment of acute VTE and prevention of recurrent VTE in patients who do not have contraindications to anticoagulation and do not have severe renal insufficiency (creatinine clearance < 30 mL/min). For cancer patients admitted to the hospital with an acute medical illness, we use LMWH for primary prevention of VTE. In the perioperative setting, for patients undergoing major surgery with an active cancer, we prefer pharmacologic thromboprophylaxis with LMWH, although there is some emerging evidence that DOACs may be safe in this setting.
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http://dx.doi.org/10.1007/s11864-020-00744-wDOI Listing
April 2020

Development of endometrial stromal sarcoma in a patient undergoing in vitro fertilization: A case report.

Gynecol Oncol Rep 2020 May 30;32:100541. Epub 2020 Jan 30.

Department of Obstetrics and Gynecology, Virginia Tech Carilion Clinic, United States.

Development of endometrial stromal sarcoma during in vitro fertilization (IVF) is rare. We encountered a case of endometrial stromal sarcoma (ESS) presenting as a new endometrial mass in a patient undergoing donor egg IVF, despite normal imaging and exams prior to and throughout treatment. To our knowledge, this is the only report describing the rapid growth of ESS during IVF treatment. When diagnosing an endometrial stromal sarcoma, it is important for the clinician and patient to be aware that full histologic inspection is required to distinguish it from a benign neoplasm. Given the need for a hysterectomy for definitive diagnosis, this case presents ethical challenges and potential for patient distress.
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http://dx.doi.org/10.1016/j.gore.2020.100541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038005PMC
May 2020

Characterization of Admission Medication Reconciliations Performed by Pharmacists in a Pediatric Institution: Resource Allocation.

J Pediatr Pharmacol Ther 2020 ;25(2):139-148

Background: Compared with adults, children may be at greater risk of medication errors and potential adverse effects. The American Academy of Pediatrics recommends developing mechanisms for proactively identifying patients at risk for medication-related adverse events and failed reconciliation. This study's primary purpose was to evaluate pediatric patients admitted to identify risk factors requiring pharmacist intervention during medication reconciliation (MedRec).

Methods: This prospective study included pediatric patients admitted during the study time frame until the target population of 500 patient encounters was achieved. During each admission, pharmacy staff completed a medication history, after which a pediatric pharmacist completed a MedRec, as is standard hospital practice. The primary outcome was identification of factors for high-risk transitions of care during pediatric admissions based on the need for pharmacist interventions during the MedRec process.

Results: In total, 331 interventions were made for 127 patients (median 2; range, 1-12). Of the 331 interventions, 196 (59.2%) were classified as being of moderate or significant severity. Although patients with at least 2 home medications were significantly more likely to require any intervention (p < 0.0001), patients with 5 or more home medications were more likely to have a significant intervention.

Conclusion: Identifying patients with home medications could allow for focused efforts to intervene. Also, patients admitted to the PICU or those with cardiology- or endocrinology-related diagnoses should be prioritized for MedRec process, because of the likelihood of requiring multiple home medications. This strategy should be tailored to individual pediatric institutions based on internal quality control assessments and available resources.
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http://dx.doi.org/10.5863/1551-6776-25.2.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025743PMC
January 2020

Correction: Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.

Transl Psychiatry 2019 Jun 11;9(1):167. Epub 2019 Jun 11.

Human Genetics Group, University of Nottingham, Nottingham, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41398-019-0503-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559959PMC
June 2019

Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.

Transl Psychiatry 2019 05 24;9(1):154. Epub 2019 May 24.

Institute of Neuroscience Biomedical Research Building Campus for Ageing and Vitality Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.

Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer's disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer's Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.
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http://dx.doi.org/10.1038/s41398-019-0485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534556PMC
May 2019

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization.

Mol Cell Proteomics 2019 Mar 22;18(3):504-519. Epub 2020 Sep 22.

Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, South Carolina 29209;. Electronic address:

The fumarate ester dimethyl fumarate (DMF) has been introduced recently as a treatment for relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition that results in neuronal demyelination and axonal loss. DMF is known to act by depleting intracellular glutathione and modifying thiols on Keap1 protein, resulting in the stabilization of the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. We have previously shown that DMF reacts with a wide range of protein thiols, suggesting that the complete mechanisms of action of DMF are unknown. Here, we investigated other intracellular thiol residues that may also be irreversibly modified by DMF in neurons and astrocytes. Using mass spectrometry, we identified 24 novel proteins that were modified by DMF in neurons and astrocytes, including cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). Using an in vitro functional assay, we demonstrated that DMF-modified cofilin-1 loses its activity and generates less monomeric actin, potentially inhibiting its cytoskeletal remodeling activity, which could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. We found that the oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, our work provides new insights into the mechanisms supporting the neuroprotective and remyelination benefits associated with DMF treatment in addition to the antioxidant response by Nrf2.
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http://dx.doi.org/10.1074/mcp.RA118.000922DOI Listing
March 2019

Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization.

Mol Cell Proteomics 2019 03 26;18(3):504-519. Epub 2018 Dec 26.

From the ‡Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, South Carolina 29209;

The fumarate ester dimethyl fumarate (DMF) has been introduced recently as a treatment for relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition that results in neuronal demyelination and axonal loss. DMF is known to act by depleting intracellular glutathione and modifying thiols on Keap1 protein, resulting in the stabilization of the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. We have previously shown that DMF reacts with a wide range of protein thiols, suggesting that the complete mechanisms of action of DMF are unknown. Here, we investigated other intracellular thiol residues that may also be irreversibly modified by DMF in neurons and astrocytes. Using mass spectrometry, we identified 24 novel proteins that were modified by DMF in neurons and astrocytes, including cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). Using an functional assay, we demonstrated that DMF-modified cofilin-1 loses its activity and generates less monomeric actin, potentially inhibiting its cytoskeletal remodeling activity, which could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. We found that the oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, our work provides new insights into the mechanisms supporting the neuroprotective and remyelination benefits associated with DMF treatment in addition to the antioxidant response by Nrf2.
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http://dx.doi.org/10.1074/mcp.RA118.000922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398201PMC
March 2019

Observations of extensive gene expression differences in the cerebellum and potential relevance to Alzheimer's disease.

BMC Res Notes 2018 Sep 4;11(1):646. Epub 2018 Sep 4.

Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.

Objectives: In order to determine how gene expression is altered in disease it is of fundamental importance that the global distribution of gene expression levels across the disease-free brain are understood and how differences between tissue types might inform tissue choice for investigation of altered expression in disease state. The aim of this pilot project was to use RNA-sequencing to investigate gene expression differences between five general areas of post-mortem human brain (frontal, temporal, occipital, parietal and cerebellum), and in particular changes in gene expression in the cerebellum compared to cortex regions for genes relevant to Alzheimer's disease, as the cerebellum is largely preserved from disease pathology and could be an area of interest for neuroprotective pathways.

Results: General gene expression profiles were found to be similar between cortical regions of the brain, however the cerebellum presented a distinct expression profile. Focused exploration of gene expression for genes associated with Alzheimer's disease suggest that those involved in the immunity pathway show little expression in the brain. Furthermore some Alzheimer's disease associated genes display significantly different expression in the cerebellum compared with other brain regions, which might indicate potential neuroprotective measures.
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http://dx.doi.org/10.1186/s13104-018-3732-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123947PMC
September 2018

Genotyping of the Alzheimer's Disease Genome-Wide Association Study Index Single Nucleotide Polymorphisms in the Brains for Dementia Research Cohort.

J Alzheimers Dis 2018 ;64(2):355-362

Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.

The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOEɛ4 allele was identified (p = 3.99×10-12). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert et al. GWAS meta-analysis was observed.
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http://dx.doi.org/10.3233/JAD-180191DOI Listing
July 2019

Experiencing abortion rights in India through issues of autonomy and legality: A few controversies.

Authors:
Tulsi Patel

Glob Public Health 2018 Jun 17;13(6):702-710. Epub 2018 Jan 17.

a Department of Sociology , Delhi School of Economics, University of Delhi , Delhi , India.

Abortion laws in India, like other laws, are premised on the 1861 British Penal Code. The Medical Termination of Pregnancy Act was passed in 1971 to circumvent the criminality clause around abortion. Yet the law continues to render invisible women's right to choose. Legal procedures have often hindered in permitting abortion, resulting in the death of a mother or the foetus. Despite the latest techno-medical advances, the laws have remained stagnant or rather restrictive, complicated further by selective female foetus abortions. Legal resistance to abortion-seeking after 20 weeks gestation adversely affects women, depriving them of autonomy of choice. In this paper, raising important gender, health and ethical issues are illustrated through a recent legal case in India. Feminist campaigns against the legal mindset in India are emerging.
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http://dx.doi.org/10.1080/17441692.2018.1424920DOI Listing
June 2018

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease.

Neurobiol Aging 2018 02 10;62:244.e1-244.e8. Epub 2017 Oct 10.

Human Genetics Group, University of Nottingham, Nottingham, UK. Electronic address:

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995122PMC
February 2018

Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease.

J Alzheimers Dis Rep 2017 Sep 13;1(1):97-108. Epub 2017 Sep 13.

School of Biosciences, University of Nottingham, Nottingham, UK.

A number of genetic loci associate with early onset Alzheimer's disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2β confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared using a pyrosequencing platform. We identified significant group-wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3'UTR of RIN3 (CpG1  = 0.019, CpG2  = 0.018, CpG3  = 0.012, CpG4  = 0.009, CpG5  = 0.002, CpG6  = 0.018, and CpG7  = 0.013, respectively; AD/Control  = 22/26; Male/Female  = 27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of β, , , or genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the promoter in one AD individual only (22% reduction in methylation,  = 2.0E-10; Control  = 26, AD  = 25, Male/Female  = 29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD.
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http://dx.doi.org/10.3233/ADR-170015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159661PMC
September 2017

Proteinuria in Patients Undergoing Renal Cancer Surgery: Impact on Overall Survival and Stability of Renal Function.

Eur Urol Focus 2016 Dec 10;2(6):616-622. Epub 2016 Feb 10.

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Background: Proteinuria is included in the Kidney Disease: Improving Global Outcomes (KDIGO) risk stratification for chronic kidney disease (CKD) in the general population. However, the importance of proteinuria in patients with renal cancer has not been adequately studied.

Objective: To evaluate the prognostic impact of preoperative proteinuria on overall survival (OS) and renal function stability (RFS) for patients managed with renal cancer surgery.

Design, Setting, And Participants: From 1999 to 2008, 977 patients who underwent renal cancer surgery had preoperative data recorded for the glomerular filtration rate (GFR) estimated using the CKD Epidemiology Collaboration equation (G1 ≥90, G2 60-89, G3a 45-59, G3b 30-44, G4 15-29, and G5 <15ml/min/1.73 m) and proteinuria status according to a dipstick assay (A, negative or trace protein; A, ≥30mg/dl). Median follow-up was 8.7 yr (range 7.0-10.7).

Intervention: Renal cancer surgery.

Outcome Measurements And Statistical Analysis: OS and RFS (avoidance of a decline in GFR of ≥50% and of dialysis) were analyzed using the Kaplan-Meier method. We performed multivariable Cox regression to evaluate independent predictors for both outcomes.

Results And Limitations: The 326 patients (33%) with A proteinuria status had compromised 5-yr OS compared with A patients (65% vs 77%; p<0.001). They also had lower RFS at 5 yr (72% vs 86%; p<0.001). However, significant differences in OS according to proteinuria status were only observed in the G1, G2, and G3a groups, and differences in RFS in the G3a group. On multivariable analysis for all patients and for the G1, G2, and G3a groups, proteinuria was an independent prognostic factor for OS (both p<0.05). On multivariable analysis for all patients and for those in the G3a group, proteinuria was an independent prognostic factor for RFS (both p<0.05). Limitations include the retrospective study design and potential ascertainment bias.

Conclusions: Proteinuria appears to be a significant and independent predictor of OS and RFS in patients undergoing renal cancer surgery, particularly for certain cohorts, and should be sensibly incorporated into routine management. Further studies, ideally prospective, are required to evaluate the importance of the degree of proteinuria. The generalizability of our findings will also require further investigation.

Patient Summary: Protein in the urine (proteinuria) is a sign of kidney damage, and kidney cancer patients with proteinuria have worse outcomes after surgery. Assessment of proteinuria should be routinely included in the preoperative evaluation of patients with kidney cancer.
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http://dx.doi.org/10.1016/j.euf.2016.01.003DOI Listing
December 2016

Coordinated control of terminal differentiation and restriction of cellular plasticity.

Elife 2017 04 19;6. Epub 2017 Apr 19.

Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University, New York, United States.

The acquisition of a specific cellular identity is usually paralleled by a restriction of cellular plasticity. Whether and how these two processes are coordinated is poorly understood. Transcription factors called terminal selectors activate identity-specific effector genes during neuronal differentiation to define the structural and functional properties of a neuron. To study restriction of plasticity, we ectopically expressed CHE-1, a terminal selector of ASE sensory neuron identity. In undifferentiated cells, ectopic expression of CHE-1 results in activation of ASE neuron type-specific effector genes. Once cells differentiate, their plasticity is restricted and ectopic expression of CHE-1 no longer results in activation of ASE effector genes. In striking contrast, removal of the respective terminal selectors of other sensory, inter-, or motor neuron types now enables ectopically expressed CHE-1 to activate its ASE-specific effector genes, indicating that terminal selectors not only activate effector gene batteries but also control the restriction of cellular plasticity. Terminal selectors mediate this restriction at least partially by organizing chromatin. The chromatin structure of a CHE-1 target locus is less compact in neurons that lack their resident terminal selector and genetic epistasis studies with H3K9 methyltransferases suggest that this chromatin modification acts downstream of a terminal selector to restrict plasticity. Taken together, terminal selectors activate identity-specific genes and make non-identity-defining genes less accessible, thereby serving as a checkpoint to coordinate identity specification with restriction of cellular plasticity.
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http://dx.doi.org/10.7554/eLife.24100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397285PMC
April 2017

Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array.

Neurobiol Aging 2017 01 23;49:215.e1-215.e8. Epub 2016 Sep 23.

School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.

We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995152PMC
January 2017

Preoperative Prediction and Postoperative Surgeon Assessment of Volume Preservation Associated With Partial Nephrectomy: Comparison With Measured Volume Preservation.

Urology 2016 07 29;93:124-9. Epub 2016 Mar 29.

Glickman Urological Kidney Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Objective: To evaluate whether surgeons can predict the percent parenchymal mass that will be preserved by partial nephrectomy (PN) based on preoperative imaging, which could have potential utility for preoperative surgical planning and patient counseling. The proportion of preserved viable parenchyma following PN is the primary determinant of functional recovery. However, direct measurement of parenchymal volume preservation (VP) can be complex and time consuming.

Materials And Methods: For patients managed with PN at our institution (2007-2014), we randomly selected 45 with a third in each of low, intermediate, or high R.E.N.A.L. complexity groups. All patients had recorded postoperative surgeon assessment of volume preservation (SAVP) and measured VP based on preoperative or postoperative computed tomography. Nine clinical providers predicted VP based solely on review of preoperative imaging while blinded to SAVP and measured VP. Clinical experience of the providers ranged from medical students to experienced urologic surgeons.

Results: Median age was 66 years, median tumor size was 4.0 cm, and median R.E.N.A.L. was 8. Median measured VP was 81% (interquartile range of 74-89%). Preoperative prediction of VP correlated poorly with measured VP among the different surgeons (mean correlation coefficient, R = 0.34, range = 0.24-0.40). Surgeon experience provided minimal incremental improvement. Correlation between R.E.N.A.L. and measured VP was also marginal (R = 0.43). In contrast, correlation between postoperative SAVP and measured VP was much more robust (R = 0.75, P <.001).

Conclusion: Preoperative prediction of VP and R.E.N.A.L. score correlated poorly with measured VP for patients managed with PN. In contrast, postoperative SAVP provided a relatively reliable estimate of VP, and should be considered an acceptable substitute in most clinical circumstances.
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http://dx.doi.org/10.1016/j.urology.2016.02.055DOI Listing
July 2016

Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease.

Neurobiol Aging 2016 Mar 29;39:220.e1-7. Epub 2015 Dec 29.

Schools of Life Sciences and Medicine, Human Genetics, University of Nottingham, Nottingham, UK. Electronic address:

Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155438PMC
March 2016

Reproductive Ethics in Commercial Surrogacy: Decision-Making in IVF Clinics in New Delhi, India.

J Bioeth Inq 2015 Sep 2;12(3):491-501. Epub 2015 Jul 2.

Department of Obstetrics and Gynaecology, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, 8200, Aarhus N, Denmark.

As a neo-liberal economy, India has become one of the new health tourism destinations, with commercial gestational surrogacy as an expanding market. Yet the Indian Assisted Reproductive Technology (ART) Bill has been pending for five years, and the guidelines issued by the Indian Council of Medical Research are somewhat vague and contradictory, resulting in self-regulated practices of fertility clinics. This paper broadly looks at clinical ethics in reproduction in the practice of surrogacy and decision-making in various procedures. Through empirical research in New Delhi, the capital of India, from December 2011 to November 2012, issues of decision-making on embryo transfer, fetal reduction, and mode of delivery were identified. Interviews were carried out with doctors in eighteen ART clinics, agents from four agencies, and fourteen surrogates. In aiming to fulfil the commissioning parents' demands, doctors were willing to go to the greatest extent possible in their medical practice. Autonomy and decision-making regarding choice of the number of embryos to transfer and the mode of delivery lay neither with commissioning parents nor surrogate mothers but mostly with doctors. In order to ensure higher success rates, surrogates faced the risk of multiple pregnancy and fetal reduction with little information regarding the risks involved. In the globalized market of commercial surrogacy in India, and with clinics compromising on ethics, there is an urgent need for formulation of regulative law for the clinical practice and maintenance of principles of reproductive ethics in order to ensure that the interests of surrogate mothers are safeguarded.
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http://dx.doi.org/10.1007/s11673-015-9642-8DOI Listing
September 2015

Informed consent in medical decision-making in commercial gestational surrogacy: a mixed methods study in New Delhi, India.

Acta Obstet Gynecol Scand 2015 May 4;94(5):465-72. Epub 2015 Feb 4.

Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark.

Objective: To investigate ethical issues in informed consent for decisions regarding embryo transfer and fetal reduction in commercial gestational surrogacy.

Design: Mixed methods study employing observations, an interview-guide and semi-structured interviews.

Setting: Fertility clinics and agencies in Delhi, India, between December 2011 and December 2012.

Population: Doctors providing conceptive technologies to commissioning couples and carrying out surrogacy procedures; surrogate mothers; agents functioning as links for surrogacy.

Methods: Interviews using semi-structured interview guides were carried out among 20 doctors in 18 fertility clinics, five agents from four agencies and 14 surrogate mothers. Surrogate mothers were interviewed both individually and in the presence of doctors and agents. Data on socio-economic context and experiences among and between various actors in the surrogacy process were coded to identify categories of ethical concern. Numerical and grounded theory-oriented analyses were used.

Main Outcome Measures: Informed consent, number of embryos transferred, fetal reduction, conflict of interest among the involved parties.

Results: None of the 14 surrogate mothers were able to explain the risks involved in embryo transfer and fetal reduction. The majority of the doctors took unilateral decisions about embryo transfer and fetal reduction. The commissioning parents were usually only indirectly involved. In the qualitative analysis, difficulties in explaining procedures, autonomy, self-payment of fertility treatment and conflicts of interest were the main themes.

Conclusions: Clinical procedural decisions were primarily made by the doctors. Surrogate mothers were not adequately informed. There is a need for regulation on decision-making procedures to safeguard the interests of surrogate mothers.
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http://dx.doi.org/10.1111/aogs.12576DOI Listing
May 2015