Publications by authors named "Pinky Agarwal"

67 Publications

Vision, challenges and opportunities for a Plant Cell Atlas.

Elife 2021 09 7;10. Epub 2021 Sep 7.

Division of Evolutionary Biology, National Institute for Basic Biology, Okazaki, Japan.

With growing populations and pressing environmental problems, future economies will be increasingly plant-based. Now is the time to reimagine plant science as a critical component of fundamental science, agriculture, environmental stewardship, energy, technology and healthcare. This effort requires a conceptual and technological framework to identify and map all cell types, and to comprehensively annotate the localization and organization of molecules at cellular and tissue levels. This framework, called the Plant Cell Atlas (PCA), will be critical for understanding and engineering plant development, physiology and environmental responses. A workshop was convened to discuss the purpose and utility of such an initiative, resulting in a roadmap that acknowledges the current knowledge gaps and technical challenges, and underscores how the PCA initiative can help to overcome them.
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http://dx.doi.org/10.7554/eLife.66877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423441PMC
September 2021

A Multi-center Genome-wide Association Study of Cervical Dystonia.

Mov Disord 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Lübeck, Lübeck, Germany.

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility.

Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach.

Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal.

Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823).

Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28732DOI Listing
July 2021

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

Eur J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background And Purpose: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.

Methods: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.

Results: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.

Conclusions: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.
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http://dx.doi.org/10.1111/ene.15031DOI Listing
July 2021

Predictors of survival in older adults hospitalized with COVID-19.

Neurol Sci 2021 Oct 3;42(10):3953-3958. Epub 2021 Jul 3.

EvergreenHealth Medical Center, Evergreen Neuroscience Institute, Kirkland, WA, USA.

Objective: This study was designed to investigate clinical characteristics associated with mortality and predictors of survival in older adults hospitalized with COVID-19 with a focus on neurological comorbidities and presenting neurological manifestations.

Methods: We compared clinical characteristics in an age- and gender-matched sample of 75 deceased and 75 recovered patients (M = 78) hospitalized with COVID-19 and developed a logistic regression to predict likelihood of survival.

Results: Deceased patients were more like to have dementia, altered mental status (AMS), acute respiratory distress syndrome (ARDS), sepsis, mechanical ventilation, and balance difficulties; higher heart rate, respiratory rate, blood urea nitrogen, creatinine, and absolute neutrophils; lower oxygen saturation and absolute lymphocytes; and shorter length of hospitalization. Logistic regression based on three mortality predictors (ARDS, AMS, and length of hospitalization) correctly predicted 87% of the outcome (89% sensitivity at 85% specificity).

Conclusions: Dementia and AMS were strong predictors of death in older adults hospitalized with COVID-19. Our findings add to the rapidly growing neurology of COVID-19 literature and underscore the importance of early recognition and the incorporation of a mental status examination into the medical assessment of COVID-19.
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http://dx.doi.org/10.1007/s10072-021-05435-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253673PMC
October 2021

Uptake of telehealth in Parkinson's disease clinical care and research during the COVID-19 pandemic.

Parkinsonism Relat Disord 2021 05 11;86:97-100. Epub 2021 Apr 11.

Parkinson Disease and Movement Disorders Centre, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada. Electronic address:

Introduction: Traditionally, medical care and research in Parkinson's disease (PD) have been conducted with in-person encounters. The recent COVID-19 pandemic has profoundly impacted the delivery of in-person clinical care and clinical research. We conducted an online survey of active clinician members of the Parkinson Study Group (PSG) to evaluate the adoption of various non-face-to-face methods in clinical practice and research in PD during the COVID-19 pandemic.

Methods: We conducted a survey using the open-access online SurveyMonkey tool (http://www.surveymonkey.com). The survey had 27 items and was designed to elucidate clinical/research care before and during the COVID-19 pandemic. The survey was sent to 414 active PSG members with weekly reminders and it remained accessible for 30 days from May 2020.

Results: We received 142 responses, of which 133 (93.7%) provided demographic data. The clinical use of virtual visits via synchronous video conferencing increased from 39.5% pre-COVID-19 to 94.6% during the COVID-19 pandemic. Lack of access for patients (68.2%) and patient resistance (51.4%) were the top barriers for its use. Approximately 70% respondents stated that 75-100% of their research activities were suspended during the COVID-19 pandemic. Many sites had to fill out protocol deviations (38.2%), protocol exceptions (25.5%) or change their research profile due to layoffs (16.8%). The overall use of video conferencing increased from 30.3% to 64.1%.

Conclusion: The current results suggest a need for flexibility in conducting office visits and clinical trials in PD patients. Technology has the potential to enhance patient care and convenience, when in-person visits can be challenging.
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http://dx.doi.org/10.1016/j.parkreldis.2021.03.032DOI Listing
May 2021

Silencing of an Ubiquitin Ligase Increases Grain Width and Weight in Rice.

Front Genet 2020 12;11:600378. Epub 2021 Jan 12.

National Institute of Plant Genome Research, New Delhi, India.

Many quantitative trait loci (QTLs) have been identified by molecular genetic studies which control grain size by regulating grain width, length, and/or thickness. () is one such QTL that codes for a RING-type E3 ubiquitin ligase and increases grain size by regulating grain width through ubiquitin-mediated degradation of unknown substrates. A natural variation (single-nucleotide polymorphism at the 346 position) in the functional domain-coding region of in rice genotypes has been shown to cause an increase in grain width/weight in rice. However, this variation is absent in rice genotypes. In this study, we report that reduced expression of can alter grain size, even though natural sequence variation is not responsible for increased grain size in rice genotypes. shows high expression in seed development stages and the protein localizes to the nucleus and cytoplasm. Downregulation of by RNAi technology results in wider and heavier grains. Microscopic observation of grain morphology suggests that OsGW2 determines grain size by influencing both cell expansion and cell proliferation in spikelet hull. Using transcriptome analysis, upregulated genes related to grain size regulation have been identified among 1,426 differentially expressed genes in an _RNAi transgenic line. These results reveal that is a negative regulator of grain size in rice and affects both cell number and cell size in spikelet hull.
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http://dx.doi.org/10.3389/fgene.2020.600378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835794PMC
January 2021

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

Neurology 2021 01 12;96(4):e563-e574. Epub 2020 Oct 12.

From the Departments of Biomedical Engineering (A.G.S., S.B.B.) and Neurology (A.G.S.), Case Western University School of Medicine; Neurological Institute (A.G.S.), University Hospitals Cleveland; Neurology Service (A.G.S.), Louis Stokes Cleveland VA Medical Center, OH; Department of Neurology (L.S., G.K.-B., A.F., S. Factor, H.A.J.), Human Genetics (H.A.J.), and Pediatrics (H.A.J.), Emory University School of Medicine, Atlanta, GA; Institute of Neurogenetics (C.K., J.J., S.L., N.B., A.M., T.B.), University of Lübeck, Germany; Department of Neurology (M.V., E.R., C.B.), Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology (J.J.), Baylor College of Medicine, Houston, TX; Neurology and Neurosurgery (J.J.-S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neurology (N.P.), Henry Ford Health System, West Bloomfield, MI; Department of Psychiatry and Neurology (L.M.), Baylor College of Medicine, Houston, TX; Department of Neurological Sciences (C.C.), Rush University Medical Center, Chicago, IL; Department of Neurology (R.L.B.), University of Rochester, NY; Department of Neurology (B.D.B.), University of Colorado School of Medicine, Aurora; Department of Neurology (I.M., A.W.S.), Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville; Department of Neurology (S.G.R.), University of Maryland School of Medicine, Baltimore; University of Tennessee Health Science Center (M.S.L.), Memphis; Department of Neurosciences (A.B.), Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome; IRCCS Neuromed (G.F.), Pozzilli, Italy; The University of Alabama at Birmingham (N.S.); Methodist Neurological Institute (W.O.), Houston, TX; Department of Neurology (S.P.R.), University of New Mexico Health Sciences Center, Albuquerque; Department of Neurology (R.S.-P.), Mount Sinai Beth Israel, New York, NY; Lou Ruvo Center for Brain Health (Z.M.), Cleveland Clinic, Las Vegas, NV; Booth Gardner Parkinson's Care Center (P.A.), Kirkland, WA; Mayo Clinic (C.A.), Scottsdale, AZ; Andre Barbeau Movement Disorders Unit (S.C.), Montreal University Hospital Center (CHUM); Movement Disorder Clinic (S.H.F.), Toronto Western Hospital, Division of Neurology University of Toronto, Canada; UC Davis School of Medicine (A.B.), Sacramento; The Parkinson's and Movement Disorder Institute (D.T.), Orange Coast Memorial Medical Center, Fountain Valley, CA; Department of Medicine (O.S.), Medical Genetics, and Pediatrics, University of Alberta, Canada; Department of Neurology (S. Frank), Beth Israel Deaconess Medical Center, Boston, MA; and Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy (J.P.), Washington University School of Medicine, St Louis, MO.

Objective: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia.

Methods: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition.

Results: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics.

Conclusion: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.
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http://dx.doi.org/10.1212/WNL.0000000000011049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905789PMC
January 2021

SUPER STARCHY1/ONAC025 participates in rice grain filling.

Plant Direct 2020 Sep 4;4(9):e00249. Epub 2020 Sep 4.

National Institute of Plant Genome Research New Delhi India.

NAC transcription factors (TFs) are known for their role in development and stress. This article attempts to functionally validate the role of rice / () during seed development. The gene is seed-specific and its promoter directs reporter expression in the developing endosperm and embryo in rice transgenic plants. Furthermore, rice transgenic plants ectopically expressing / have a plantlet lethal phenotype with hampered vegetative growth, but increased tillers and an altered shoot apical meristem structure. The vegetative cells of these plantlets are filled with distinct starch granules. RNAseq analysis of two independent plantlets reveals the differential expression of reproductive and photosynthetic genes. A comparison with seed development transcriptome indicates differential regulation of many seed-related genes by SS1/ ONAC025. Genes involved in starch biosynthesis, especially amylopectin and those encoding seed storage proteins, and regulating seed size are also differentially expressed. In conjunction, / shows highest expression in rice. As a TF, SS1/ ONAC025 is a transcriptional repressor localized to endoplasmic reticulum and nucleus. The article shows that / is a seed-specific gene promoting grain filling in rice, and negatively affecting vegetative growth.
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http://dx.doi.org/10.1002/pld3.249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507516PMC
September 2020

Altered mental status in 71 deaths due to COVID-19.

Int J Neurosci 2020 Oct 1:1-4. Epub 2020 Oct 1.

Evergreen Neuroscience Institute, Evergreen Health Medical Center, Kirkland, WA, USA.

Objective: The purpose of this study was to investigate the occurrence of neurologic symptoms with a focus on altered mental status in a sample of deaths due to COVID-19.

Methods: We reviewed neurologic symptoms in 71 deaths due to COVID-19 at the first US hospital with reported cases, of which 66 (93%) had medical comorbidities, 47 (66%) came from assisted living facilities or nursing homes and 35 (49%) had baseline dementia.

Results: Sixty-one patients (86%) demonstrated neurologic symptoms at hospital admission. Altered mental status was seen in 47 patients (66%) and represented the most common neurologic symptom. Seven patients (10%) were comatose at hospital admission and 5 (7%) presented with altered mental status without respiratory symptoms. Three patients had seizures and two had strokes. Hypertension (61%), cardiovascular disease (59%), and dementia (49%) were the most common comorbidities associated with death due to COVID-19 in our sample.

Conclusions: Neurologic symptoms, particularly altered mental status, are very common in COVID-19 patients with high risk of mortality. In a small subset of patients, altered mental status is the defining feature of disease presentation. A mental status examination should be incorporated in the medical assessment of COVID-19.
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http://dx.doi.org/10.1080/00207454.2020.1825422DOI Listing
October 2020

Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor.

Tremor Other Hyperkinet Mov (N Y) 2020 08 14;10:29. Epub 2020 Aug 14.

Cala Health, Burlingame, CA, US.

Highlights: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients.

Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use.

Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey.

Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of 'severe' or 'moderate' patients improving to 'mild' or 'slight'. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported.

Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients.
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http://dx.doi.org/10.5334/tohm.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427656PMC
August 2020

Neurological manifestations in 404 COVID-19 patients in Washington State.

J Neurol 2021 Mar 6;268(3):770-772. Epub 2020 Aug 6.

Evergreen Health Neuroscience Institute, Kirkland, WA, USA.

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http://dx.doi.org/10.1007/s00415-020-10087-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407444PMC
March 2021

Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study.

J Neurol Neurosurg Psychiatry 2020 03 17;91(3):314-320. Epub 2019 Dec 17.

Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.

Objective: Isolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients.

Methods: Patients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread.

Results: 487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009).

Conclusions: Initial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.
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http://dx.doi.org/10.1136/jnnp-2019-321794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024047PMC
March 2020

Depression and Anxiety in Parkinson Disease.

Clin Geriatr Med 2020 02 10;36(1):93-104. Epub 2019 Sep 10.

Booth Gardner Parkinson's Care Center, Evergreen Neuroscience Institute, 12039 NE 128th St, MS-77, Kirkland, WA 98034, USA; University of Washington, Seattle, WA, USA. Electronic address:

Depression and anxiety are common neuropsychiatric manifestations of Parkinson disease. However, they are often under-recognized because the somatic symptoms of depression often overlap with the motor symptoms of Parkinson disease and there is low self-reporting. Clinicians need to be vigilant about early detection and treatment of anxiety and depression in the patient with Parkinson disease. The development of new therapeutic strategies, including diet, exercise, and counseling along with antidepressants provide a holistic approach to management.
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http://dx.doi.org/10.1016/j.cger.2019.09.012DOI Listing
February 2020

Mediator subunit OsMED14_1 plays an important role in rice development.

Plant J 2020 03 12;101(6):1411-1429. Epub 2019 Dec 12.

National Institute of Plant Genome Research (NIPGR), Aruna Asaf Ali Marg, New Delhi, 110067, India.

Mediator, a multisubunit co-activator complex, regulates transcription in eukaryotes and is involved in diverse processes in Arabidopsis through its different subunits. Here, we have explored developmental aspects of one of the rice Mediator subunit gene OsMED14_1. We analyzed its expression pattern through RNA in situ hybridization and pOsMED14_1:GUS transgenics that showed its expression in roots, leaves, anthers and seeds prominently at younger stages, indicating possible involvement of this subunit in multiple aspects of rice development. To understand the developmental roles of OsMED14_1 in rice, we generated and studied RNAi-based knockdown rice plants that showed multiple effects including less height, narrower leaves and culms with reduced vasculature, lesser lateral root branching, defective microspore development, reduced panicle branching and seed set, and smaller seeds. Histological analyses showed that slender organs were caused by reduction in both cell number and cell size in OsMED14_1 knockdown plants. Flow cytometric analyses and expression analyses of cell cycle-related genes revealed that defective cell-cycle progression led to these defects. Expression analyses of auxin-related genes and indole-3-acetic acid (IAA) immunolocalization study indicated altered auxin level in these knockdown plants. Reduction of lateral root branching in knockdown plants was corrected by exogenous IAA supplement. OsMED14_1 physically interacts with transcription factors YABBY5, TAPETUM DEGENERATION RETARDATION (TDR) and MADS29, possibly regulating auxin homeostasis and ultimately leading to lateral organ/leaf, microspore and seed development.
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http://dx.doi.org/10.1111/tpj.14605DOI Listing
March 2020

Transcription factor OsNF-YB9 regulates reproductive growth and development in rice.

Planta 2019 Dec 3;250(6):1849-1865. Epub 2019 Sep 3.

National Institute of Plant Genome Research, New Delhi, 110067, India.

Main Conclusion: OsNF-YB9 controls heading by affecting expression of regulators of flowering. It affects the development of the reproductive meristem by interacting with MADS1 and controlling expression of hormone-related genes. Nuclear Factor-Y (NF-Y) family of transcription factors takes part in many aspects of growth and development in eukaryotes. They have been classified into three subunit classes, namely, NF-YA, NF-YB and NF-YC. In plants, this transcription factor family is much diverged and takes part in several developmental processes and stress. We investigated NF-Y subunit genes of rice (Oryza sativa) and found OsNF-YB9 as the closest homologue of LEAFY COTYLEDON1. OsNF-YB9 delayed the heading date when ectopically expressed in rice. Expression of several heading date regulating genes such as Hd1, Ehd1, Hd3a and RFT1 were altered. OsNF-YB9 overexpression also resulted in morphological defects in the reproductive organs and led to pseudovivipary. OsNF-YB9 interacted with MADS1, a key regulator of floral development. This NF-Y subunit acted upstream to several transcription factors as well as signalling proteins involved in brassinosteroid and gibberellic acid metabolism and cell cycle. OsNF-YB9 and OsNF-YC12 interacted in planta and the latter also delayed heading in rice upon overexpression suggesting its involvement in a similar pathway. Our data provide new insights into the rice heading date pathway integrating these OsNF-Y subunit members to the network. These features can be exploited to improve vegetative growth and yield of rice plants in future.
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http://dx.doi.org/10.1007/s00425-019-03268-2DOI Listing
December 2019

Analysis of Rice Proteins with DLN Repressor Motif/S.

Int J Mol Sci 2019 Mar 30;20(7). Epub 2019 Mar 30.

National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi-110067, India.

Transcriptional regulation includes both activation and repression of downstream genes. In plants, a well-established class of repressors are proteins with an ERF-associated amphiphilic repression/EAR domain. They contain either DLNxxP or LxLxL as the identifying hexapeptide motif. In rice (), we have identified a total of 266 DLN repressor proteins, with the former motif and its modifications thereof comprising 227 transcription factors and 39 transcriptional regulators. Apart from DLNxxP motif conservation, DLNxP and DLNxxxP motifs with variable numbers/positions of proline and those without any proline conservation have been identified. Most of the DLN repressome proteins have a single DLN motif, with higher relative percentage in the C-terminal region. We have designed a simple yeast-based experiment wherein a DLN motif can successfully cause strong repression of downstream reporter genes, when fused to a transcriptional activator of rice or yeast. The DLN hexapeptide motif is essential for repression, and at least two "DLN" residues cause maximal repression. Comparatively, rice has more DLN repressor encoding genes than Arabidopsis, and DLNSPP motif from rice is 40% stronger than the known Arabidopsis SRDX motif. The study reports a straightforward assay to analyze repressor activity, along with the identification of a strong DLN repressor from rice.
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http://dx.doi.org/10.3390/ijms20071600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479872PMC
March 2019

May the Fittest Protein Evolve: Favoring the Plant-Specific Origin and Expansion of NAC Transcription Factors.

Bioessays 2018 08 25;40(8):e1800018. Epub 2018 Jun 25.

National Institute of Plant Genome Research, Aruna Asaf Ali Marg, New Delhi-110067, India.

Plant-specific NAC transcription factors (TFs) evolve during the transition from aquatic to terrestrial plant life and are amplified to become one of the biggest TF families. This is because they regulate genes involved in water conductance and cell support. They also control flower and fruit formation. The review presented here focuses on various properties, regulatory intricacies, and developmental roles of NAC family members. Processes controlled by NACs depend majorly on their transcriptional properties. NACs can function as both activators and/or repressors. Additionally, their homo/hetero dimerization abilities can also affect DNA binding and activation properties. The active protein levels are dependent on the regulatory cascades. Because NACs regulate both development and stress responses in plants, in-depth knowledge about them has the potential to help guide future crop improvement studies.
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http://dx.doi.org/10.1002/bies.201800018DOI Listing
August 2018

ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study): A Randomized Clinical Trial.

JAMA Neurol 2017 08;74(8):941-949

Adamas Pharmaceuticals Inc, Emeryville, California.

Importance: Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need.

Objective: To evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD.

Design, Setting, And Participants: A randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact.

Interventions: Patients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks.

Main Outcomes And Measures: The primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo).

Results: A total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%).

Conclusions And Relevance: ADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia.

Trial Registration: clinicaltrials.gov Identifier: NCT02136914.
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http://dx.doi.org/10.1001/jamaneurol.2017.0943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710325PMC
August 2017

Brain iron concentrations in regions of interest and relation with serum iron levels in Parkinson disease.

J Neurol Sci 2017 Jul 23;378:38-44. Epub 2017 Apr 23.

University of Utah School of Medicine, Clinical Radiology, Salt Lake City, UT 84132, United States.

Brain iron has been previously found elevated in the substantia nigra pars compacta (SNpc), but not in other brain regions, of Parkinson's disease (PD) patients. However, iron in circulation has been recently observed to be lower than normal in PD patients. The regional selectivity of iron deposition in brain as well as the relationship between SNpc brain iron and serum iron within PD patients has not been completely elucidated. In this pilot study we measured brain iron in six regions of interest (ROIs) as well as serum iron and serum ferritin, in 24 PD patients and 27 age- gender-matched controls. Brain iron was measured on magnetic resonance imaging (MRI) with a T2 prime (T2') method. Difference in brain iron deposition between PD cases and controls for the six ROIs were calculated. SNpc/white matter brain iron ratios and SNpc/serum iron ratios were calculated for each study participant, and differences between PD patients and controls were tested. PD patients overall had higher brain iron than controls in the SNpc. PD patients had significantly higher SNpc/white matter brain iron ratios than controls, and significantly higher brain SNpc iron/serum iron ratios than controls. These results indicate that PD patients' iron metabolism is disrupted toward a higher partitioning of iron to the brain SNpc at the expenses of iron in the circulation.
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http://dx.doi.org/10.1016/j.jns.2017.04.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609675PMC
July 2017

Emerging functions of multi-protein complex Mediator with special emphasis on plants.

Crit Rev Biochem Mol Biol 2017 10 19;52(5):475-502. Epub 2017 May 19.

a National Institute of Plant Genome Research (NIPGR) , New Delhi , India.

Mediator is a multi-subunit protein complex which is involved in transcriptional regulation in yeast and other eukaryotes. As a co-activator, it connects information from transcriptional activators/repressors to transcriptional machinery including RNA polymerase II and general transcription factors. It is not only involved in transcription initiation but also has important roles to play in transcription elongation and termination. Functional attributes of different Mediator subunits have been largely defined in yeast and mammalian systems earlier, while such studies in plants have gained momentum recently. Mediator regulates various processes related to plant development and is also involved in biotic and abiotic stress response. Thus, plant Mediator, like yeast and mammalian Mediator complex, is indispensable for plant growth and survival. Interaction of its multiple subunits with other regulatory proteins and their ectopic expression or knockdown in model plant like Arabidopsis and certain crop plants are paving the way to biochemical analysis and unravel molecular mechanisms of action of Mediator in plants.
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http://dx.doi.org/10.1080/10409238.2017.1325830DOI Listing
October 2017

Management of lower urinary tract symptoms in Parkinson's disease in the neurology clinic.

Int J Neurosci 2017 Dec 25;127(12):1136-1149. Epub 2017 May 25.

b Booth Gardner Parkinson's Care Center , Evergreen Neuroscience Institute , Kirkland , WA , USA.

This clinical review aims to evaluate lower urinary tract symptoms (LUTS) in Parkinson's disease (PD) patients and the current treatment options available for these symptoms in a neurology setting. The review also addresses when referral to urology is appropriate. A literature search was conducted using the keywords 'LUTS', 'non-motor symptoms', 'overactive bladder', 'Parkinson's disease' and 'urinary symptoms' using the Medline/Pubmed search engine. Data collected ranged from 2000 to present with emphasis on recent publications. This review was conducted because LUTS in PD has a major impact on quality of life and is associated with early institutionalization. Emphasis is placed on treating overactive bladder with conservative strategies and medical management in the neurology setting. Quality of life can be improved and institutionalization can be delayed with a multimodal approach to bladder care.
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http://dx.doi.org/10.1080/00207454.2017.1327857DOI Listing
December 2017

Optimizing extended-release carbidopa/levodopa in Parkinson disease: Consensus on conversion from standard therapy.

Neurol Clin Pract 2017 Feb;7(1):86-93

University of Cincinnati (AJE), OH; Georgetown University Hospital (FLP), Washington, DC; Case Western Reserve University (BLW), Cleveland, OH; Medical College of Georgia (JCM), Augusta University; University of Toledo College of Medicine (LWE), OH; Columbia University (CHW), New York, NY; Evergreen Hospital Medical Center (PA), Kirkland, WA; Parkinson's Institute and Clinical Center (RD), Sunnyvale, CA; Methodist Neurological Institute (WGO), Houston, TX; The Movement Disorder Clinic of Oklahoma (KJK), Tulsa; and Coastal Neurological Medical Group, Inc. (DES), La Jolla, CA.

Purpose Of Review: To help clinicians optimize the conversion of a patient's Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD).

Recent Findings: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice.

Summary: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient's preconversion levodopa daily dosage and choosing a division of doses to address the patient's motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.
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http://dx.doi.org/10.1212/CPJ.0000000000000316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310207PMC
February 2017

Three Rice NAC Transcription Factors Heteromerize and Are Associated with Seed Size.

Front Plant Sci 2016 7;7:1638. Epub 2016 Nov 7.

National Institute of Plant Genome Research New Delhi, India.

NACs are plant-specific transcription factors (TFs) involved in multiple aspects of development and stress. In rice, three NAC TF encoding genes, namely , and express specifically during seed development, at extremely high levels. They exhibit significantly strong association with seed size/weight with the sequence variations located in the upstream regulatory region. Concomitantly, their expression pattern/levels during seed development vary amongst different accessions with variation in seed size. The alterations in the promoter sequences of the three genes, amongst the five rice accessions, correlate with the expression levels to a certain extent only. In terms of transcriptional properties, the three NAC TFs can activate and/or suppress downstream genes, though to different extents. Only ONAC026 is localized to the nucleus while ONAC020 and ONAC023 are targeted to the ER and cytoplasm, respectively. Interestingly, these two proteins interact with ONAC026 and the dimers localize in the nucleus. -splicing between and results in three additional forms of . The transcriptional properties including activation, repression, subcellular localization and heterodimerization of spliced forms of ONAC020 and ONAC026 are different, indicating toward their role as competitors. The analysis presented in this paper helps to conclude that the three genes, which are associated with seed size, have independent as well as overlapping roles during the process and can be exploited as potential targets for crop improvement.
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http://dx.doi.org/10.3389/fpls.2016.01638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098391PMC
November 2016

An Efficient Strategy Combining SSR Markers- and Advanced QTL-seq-driven QTL Mapping Unravels Candidate Genes Regulating Grain Weight in Rice.

Front Plant Sci 2016 26;7:1535. Epub 2016 Oct 26.

National Institute of Plant Genome Research (NIPGR) New Delhi, India.

Development and use of genome-wide informative simple sequence repeat (SSR) markers and novel integrated genomic strategies are vital to drive genomics-assisted breeding applications and for efficient dissection of quantitative trait loci (QTLs) underlying complex traits in rice. The present study developed 6244 genome-wide informative SSR markers exhibiting fragment length polymorphism based on repeat-unit variations among genomic sequences of 11 , and wild rice accessions. These markers were mapped on diverse coding and non-coding sequence components of known cloned/candidate genes annotated from 12 chromosomes and revealed a much higher amplification (97%) and polymorphic potential (88%) along with wider genetic/functional diversity level (16-74% with a mean 53%) especially among accessions belonging to cultivar group, suggesting their utility in large-scale genomics-assisted breeding applications in rice. A high-density 3791 SSR markers-anchored genetic linkage map (IR 64 × Sonasal) spanning 2060 cM total map-length with an average inter-marker distance of 0.54 cM was generated. This reference genetic map identified six major genomic regions harboring robust QTLs (31% combined phenotypic variation explained with a 5.7-8.7 LOD) governing grain weight on six rice chromosomes. One strong grain weight major QTL region () was narrowed-down by integrating traditional QTL mapping with high-resolution QTL region-specific integrated SSR and single nucleotide polymorphism markers-based QTL-seq analysis and differential expression profiling. This led us to delineate two natural allelic variants in two known -regulatory elements (RAV1AAT and CARGCW8GAT) of glycosyl hydrolase and serine carboxypeptidase genes exhibiting pronounced seed-specific differential regulation in low (Sonasal) and high (IR 64) grain weight mapping parental accessions. Our genome-wide SSR marker resource (polymorphic within/between diverse cultivar groups) and integrated genomic strategy can efficiently scan functionally relevant potential molecular tags (markers, candidate genes and alleles) regulating complex agronomic traits (grain weight) and expedite marker-assisted genetic enhancement in rice.
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http://dx.doi.org/10.3389/fpls.2016.01535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080349PMC
October 2016

Clinical and demographic characteristics related to onset site and spread of cervical dystonia.

Mov Disord 2016 12 18;31(12):1874-1882. Epub 2016 Oct 18.

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: Clinical characteristics of isolated idiopathic cervical dystonia such as onset site and spread to and from additional body regions have been addressed in single-site studies with limited data and incomplete or variable dissociation of focal and segmental subtypes. The objectives of this study were to characterize the clinical characteristics and demographics of isolated idiopathic cervical dystonia in the largest standardized multicenter cohort.

Methods: The Dystonia Coalition, through a consortium of 37 recruiting sites in North America, Europe, and Australia, recruited 1477 participants with focal (60.7%) or segmental (39.3%) cervical dystonia on examination. Clinical and demographic characteristics were evaluated in terms of the body region of dystonia onset and spread.

Results: Site of dystonia onset was: (1) focal neck only (78.5%), (2) focal onset elsewhere with later segmental spread to neck (13.3%), and (3) segmental onset with initial neck involvement (8.2%). Frequency of spread from focal cervical to segmental dystonia (22.8%) was consistent with prior reports, but frequency of segmental onset with initial neck involvement was substantially higher than the 3% previously reported. Cervical dystonia with focal neck onset, more than other subtypes, was associated with spread and tremor of any type. Sensory tricks were less frequent in cervical dystonia with segmental components, and segmental cervical onset occurred at an older age.

Conclusions: Subgroups had modest but significant differences in the clinical characteristics that may represent different clinical entities or pathophysiologic subtypes. These findings are critical for design and implementation of studies to describe, treat, or modify disease progression in idiopathic isolated cervical dystonia. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154862PMC
December 2016

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

JAMA 2016 Jul;316(1):40-50

Boston University Medical Campus, Boston, Massachusetts.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.

Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.

Main Outcomes And Measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.

Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.

Conclusions And Relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifier: NCT01795859.
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http://dx.doi.org/10.1001/jama.2016.8655DOI Listing
July 2016

Smoking and haptoglobin phenotype modulate serum ferritin and haptoglobin levels in Parkinson disease.

J Neural Transm (Vienna) 2016 11 27;123(11):1319-1330. Epub 2016 Jun 27.

Department of Family and Public Health, University of California San Diego, 9500 Gilman Drive #0725, La Jolla, CA, 92093, USA.

The phenotype Hp 2-1 of haptoglobin has been previously associated with increased risk of Parkinson disease (PD) and with serum iron abnormalities in PD patients. Tobacco smoking has been consistently observed in epidemiology studies to be inversely related to PD risk, with mechanisms that remain uncertain. We recently observed that the protective effect of smoking on PD risk is stronger among subjects of haptoglobin Hp 2-2 and Hp 1-1 phenotypes, and weaker among subjects of haptoglobin Hp 2-1 phenotype. In this PD case-control study, we investigated whether tobacco smoking was associated with changes in serum haptoglobin and ferritin concentration that depended on haptoglobin phenotype among 106 PD patients and 238 controls without PD or other neurodegenerative disorders. Serum ferritin concentration, serum haptoglobin concentration, haptoglobin phenotype, and smoking data information of cases and controls were obtained. Differences in haptoglobin and ferritin concentration by smoking status and pack-years of smoking were calculated as well as regression between pack-years and haptoglobin and ferritin concentration, and the effect of haptoglobin phenotype on these parameters. Tobacco smoking was associated with an elevation in serum haptoglobin concentration, especially among healthy controls of haptoglobin Hp 2-2 phenotype, and with an elevation in ferritin concentration especially among PD patients of haptoglobin Hp 2-1 phenotype. These findings suggest that an elevation in haptoglobin concentration, preferentially among subjects of haptoglobin Hp 2-2 phenotype, could be a contributing factor to the protective effect of smoking on PD risk.
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http://dx.doi.org/10.1007/s00702-016-1590-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096643PMC
November 2016

Clinical and genetic features of cervical dystonia in a large multicenter cohort.

Neurol Genet 2016 Jun 11;2(3):e69. Epub 2016 Apr 11.

Departments of Neurology and Anatomy & Neurobiology (M.S.L., S.R.V., J.X., M.M.T.), University of Tennessee Health Science Center, Memphis, TN; Department of Neurology (J.S.P., L.J.W.), Washington University School of Medicine, St. Louis, MO; Departments of Neurology (A.R.R.), Human Genetics, and Pediatrics (H.A.J.), School of Medicine, Emory University, Atlanta, GA; Department of Neurology (P.H.), Vanderbilt University, Nashville, TN; Department of Neurological Sciences (C.L.C.), Rush University, Chicago, IL; Institute of Neurogenetics (A.W., J. Junker), University of Lübeck, Germany; Department of Neurology (J. Jankovic), Baylor College of Medicine, Houston, TX; Department of Neurology (R.L.B.), University of Rochester, NY; Department of Neurology (S.G.R.), University of Maryland, Baltimore, MD; Department of Neurology (R.L.R.), University of Florida, Gainesville, FL; Department of Neurology (B.D.B.), University of Colorado Denver School of Medicine, Aurora, CO; Center of Excellence in Neuroscience (S.C.), University of Montreal, QC, Canada; Mirken Department of Neurology (L.S.), Mt. Sinai Beth Israel Medical Center, New York, NY; Booth Gardner Parkinson's Care Center (P.A.), Kirkland, WA; and Department of Neurology (N.P.S.), University of Alabama at Birmingham, AL.

Objective: To characterize the clinical and genetic features of cervical dystonia (CD).

Methods: Participants enrolled in the Dystonia Coalition biorepository (NCT01373424) with initial manifestation as CD were included in this study (n = 1,000). Data intake included demographics, family history, and the Global Dystonia Rating Scale. Participants were screened for sequence variants (SVs) in GNAL, THAP1, and Exon 5 of TOR1A.

Results: The majority of participants were Caucasian (95%) and female (75%). The mean age at onset and disease duration were 45.5 ± 13.6 and 14.6 ± 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. The remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. Family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic SVs in THAP1, TOR1A, and GNAL were identified in 8 participants (0.8%). Two individuals harbored novel missense SVs in Exon 5 of TOR1A. Synonymous and noncoding SVs in THAP1 and GNAL were identified in 4% of the cohort.

Conclusions: Head tremor, laryngeal dystonia, and psychiatric comorbidities are more common in female participants with CD. Coding and noncoding variants in GNAL, THAP1, and TOR1A make small contributions to the pathogenesis of CD.
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http://dx.doi.org/10.1212/NXG.0000000000000069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830199PMC
June 2016

Genome-wide generation and use of informative intron-spanning and intron-length polymorphism markers for high-throughput genetic analysis in rice.

Sci Rep 2016 Apr 1;6:23765. Epub 2016 Apr 1.

National Institute of Plant Genome Research (NIPGR), Aruna Asaf Ali Marg, New Delhi 110067, India.

We developed genome-wide 84634 ISM (intron-spanning marker) and 16510 InDel-fragment length polymorphism-based ILP (intron-length polymorphism) markers from genes physically mapped on 12 rice chromosomes. These genic markers revealed much higher amplification-efficiency (80%) and polymorphic-potential (66%) among rice accessions even by a cost-effective agarose gel-based assay. A wider level of functional molecular diversity (17-79%) and well-defined precise admixed genetic structure was assayed by 3052 genome-wide markers in a structured population of indica, japonica, aromatic and wild rice. Six major grain weight QTLs (11.9-21.6% phenotypic variation explained) were mapped on five rice chromosomes of a high-density (inter-marker distance: 0.98 cM) genetic linkage map (IR 64 x Sonasal) anchored with 2785 known/candidate gene-derived ISM and ILP markers. The designing of multiple ISM and ILP markers (2 to 4 markers/gene) in an individual gene will broaden the user-preference to select suitable primer combination for efficient assaying of functional allelic variation/diversity and realistic estimation of differential gene expression profiles among rice accessions. The genomic information generated in our study is made publicly accessible through a user-friendly web-resource, "Oryza ISM-ILP marker" database. The known/candidate gene-derived ISM and ILP markers can be enormously deployed to identify functionally relevant trait-associated molecular tags by optimal-resource expenses, leading towards genomics-assisted crop improvement in rice.
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http://dx.doi.org/10.1038/srep23765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817136PMC
April 2016

An Integrated Genomic Strategy Delineates Candidate Mediator Genes Regulating Grain Size and Weight in Rice.

Sci Rep 2016 Mar 22;6:23253. Epub 2016 Mar 22.

National Institute of Plant Genome Research (NIPGR), Aruna Asaf Ali Marg, New Delhi 110067, India.

The present study deployed a Mediator (MED) genes-mediated integrated genomic strategy for understanding the complex genetic architecture of grain size/weight quantitative trait in rice. The targeted multiplex amplicon resequencing of 55 MED genes annotated from whole rice genome in 384 accessions discovered 3971 SNPs, which were structurally and functionally annotated in diverse coding and non-coding sequence-components of genes. Association analysis, using the genotyping information of 3971 SNPs in a structured population of 384 accessions (with 50-100 kb linkage disequilibrium decay), detected 10 MED gene-derived SNPs significantly associated (46% combined phenotypic variation explained) with grain length, width and weight in rice. Of these, one strong grain weight-associated non-synonymous SNP (G/A)-carrying OsMED4_2 gene was validated successfully in low- and high-grain weight parental accessions and homozygous individuals of a rice mapping population. The seed-specific expression, including differential up/down-regulation of three grain size/weight-associated MED genes (including OsMED4_2) in six low and high-grain weight rice accessions was evident. Altogether, combinatorial genomic approach involving haplotype-based association analysis delineated diverse functionally relevant natural SNP-allelic variants in 10 MED genes, including three potential novel SNP haplotypes in an OsMED4_2 gene governing grain size/weight differentiation in rice. These molecular tags have potential to accelerate genomics-assisted crop improvement in rice.
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http://dx.doi.org/10.1038/srep23253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802383PMC
March 2016
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