Molecular insights into the regulation of rice kernel elongation

A large number of rice agronomic traits are complex, multi factorial and polygenic. As the mechanisms and genes determining grain size and yield are largely unknown, the identification of regulatory genes related to grain development remains a preeminent approach in rice genetic studies and breeding programs. Genes regulating cell proliferation and expansion in spikelet hulls and participating in endosperm development are the main controllers of rice kernel elongation and grain size. We review here and discuss recent findings on genes controlling rice grain size and the mechanisms, epialleles, epigenomic variation, and assessment of controlling genes using genome-editing tools relating to kernel elongation

The Photopic Negative Response: An Objective Measure of Retinal Ganglion Cell Function in Patients With Leber's Hereditary Optic Neuropathy

Purpose: The photopic negative response (PhNR) is a slow negative component of a flash photopic full-field ERG that has been shown to be specific for retinal ganglion cell (RGC) activity. Direct evaluation of RGC function is desirable in patients with Leber's hereditary optic neuropathy (LHON) in which the loss of central acuity can make it difficult to monitor patients with standard metrics. The purpose of this study was to evaluate the use of PhNR as an objective noninvasive clinical metric in LHON.Methods: Full-field photopic ERG recordings were collected in subjects with the mt.11778G>A/ND4 LHON mutation using a red on blue stimulus. The PhNR was identified using a computer-based automated detection system, and data were manually examined to remove movement artifacts.Results: The PhNR amplitude was compared between controls (n = 13), carriers (n = 17), and affected (n = 6). Mean PhNR amplitude decreased significantly across groups (P < 0.0001). Post hoc Tukey's test revealed a significant decrease in PhNR amplitude between carriers and controls (P < 0.05) and between carriers and affected (P < 0.01).Conclusions: We are able to demonstrate that the PhNR amplitude is significantly decreased in patients affected by LHON compared to carriers in a well-described pedigree. Surprisingly, there was also a decrease in PhNR in carriers, suggesting potential subclinical RGC dysfunction in some carriers. This is important in patients affected with LHON who typically have a dense central scotoma. The PhNR may be a useful objective outcome measure for future clinical trials

Kinin B1 Receptor Enhances the Oxidative Stress in a Rat Model of Insulin Resistance: Outcome in Hypertension, Allodynia and Metabolic Complications

BACKGROUND: Kinin B(1) receptor (B(1)R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B(1)R activation could perpetuate the oxidative stress which leads to diabetic complications. METHODS AND FINDINGS: Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B(1)R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B(1)R expression, aortic superoxide anion (O(2)(*-)) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O(2)(*-), NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B(1)R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O(2)(*-) in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10-100 microM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe(8)]des-Arg(9)-BK (20 microM; B(1)R agonist). Data show that the greater aortic O(2)(*-) production induced by the B(1)R agonist was blocked only by apocynin. CONCLUSIONS: Activation of kinin B(1)R increased O(2)(*-) through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B(1)R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B(1)R gene expression in this model

Biomedical Discovery Acceleration, with Applications to Craniofacial Development

The profusion of high-throughput instruments and the explosion of new results in the scientific literature, particularly in molecular biomedicine, is both a blessing and a curse to the bench researcher. Even knowledgeable and experienced scientists can benefit from computational tools that help navigate this vast and rapidly evolving terrain. In this paper, we describe a novel computational approach to this challenge, a knowledge-based system that combines reading, reasoning, and reporting methods to facilitate analysis of experimental data. Reading methods extract information from external resources, either by parsing structured data or using biomedical language processing to extract information from unstructured data, and track knowledge provenance. Reasoning methods enrich the knowledge that results from reading by, for example, noting two genes that are annotated to the same ontology term or database entry. Reasoning is also used to combine all sources into a knowledge network that represents the integration of all sorts of relationships between a pair of genes, and to calculate a combined reliability score. Reporting methods combine the knowledge network with a congruent network constructed from experimental data and visualize the combined network in a tool that facilitates the knowledge-based analysis of that data. An implementation of this approach, called the Hanalyzer, is demonstrated on a large-scale gene expression array dataset relevant to craniofacial development. The use of the tool was critical in the creation of hypotheses regarding the roles of four genes never previously characterized as involved in craniofacial development; each of these hypotheses was validated by further experimental work

Why Pleiotropic Interventions are Needed for Alzheimer's Disease

Alzheimer's disease (AD) involves a complex pathological cascade thought to be initially triggered by the accumulation of β-amyloid (Aβ) peptide aggregates or aberrant amyloid precursor protein (APP) processing. Much is known of the factors initiating the disease process decades prior to the onset of cognitive deficits, but an unclear understanding of events immediately preceding and precipitating cognitive decline is a major factor limiting the rapid development of adequate prevention and treatment strategies. Multiple pathways are known to contribute to cognitive deficits by disruption of neuronal signal transduction pathways involved in memory. These pathways are altered by aberrant signaling, inflammation, oxidative damage, tau pathology, neuron loss, and synapse loss. We need to develop stage-specific interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Aβ production and accumulation, and oxidative damage), but also address damage from these pathways that will not be reversed by targeting prodromal pathways. This approach would not only focus on blocking early events in pathogenesis, but also adequately correct for loss of synapses, substrates for neuroprotective pathways (e.g., docosahexaenoic acid), defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting). Monotherapy targeting early single steps in this complicated cascade may explain disappointments in trials with agents inhibiting production, clearance, or aggregation of the initiating Aβ peptide or its aggregates. Both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions during the “prodromal” period prior to conversion to “mild cognitive impairment (MCI).” Furthermore, many of the pathological events are no longer proceeding in series, but are going on in parallel. By the MCI stage, we stand a greater chance of success by considering pleiotropic drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284–286, 2006)

Role of Transforming Growth Factor Signalling in Marrow Stem Cell Differentiation

Bone marrow stem cells have the ability to self renew and differentiate into a multitude of different cell types. Of the various cell potentials, the endothelial differentiation process has been the least understood due to highly context dependent methods of regulation. It was previously found that following mesodermal induction, endothelial precursors emerged in association with inhibited transforming growth factor beta (TGFβ) signalling. To better understand the role of TGFβ signalling in the differentiation process, we treated bone marrow mononuclear cells with either a TGFβ pathway inhibitor, GW788388, or exogenous activating ligand, TGFβ1, and characterized the expression levels of various cellular markers. We demonstrate that neither treatment leads directly to an endothelial phenotype. Instead, we propose a two-step process of TGFβ and bone morphogenic protein (BMP) signalling cross-talk, that could potentially be responsible for endothelial differentiation of bone marrow derived stem cells. Our ability to derive functional endothelial cells from postnatal stem cells may impact multiple fields of research, including the study of vascular regeneration and understanding the mechanisms underlying vascular disease

Ab interno trabeculectomy with trabectome: Outcomes in African American versus Caucasian patients

Objective: To compare the intraocular pressure-lowering efficacy and complication rate of ab interno trabeculectomy with the Trabectome between African American (AA) and Caucasian patients with open-angle glaucoma.Methods: A total of 164 patients (82 AA and 82 Caucasian) who underwent ab interno trabeculectomy over an 8-year period were included in this prospective, case-control study. The Neomedix database was used to look for AA or Caucasian patients with open-angle glaucoma who underwent Trabectome with or without phacoemulsification.Results: The average IOP of AA patients was reduced from 21.2 ± 6.8 mm Hg to 16.1 ± 4.1 mm Hg at 12 M (p \u3c 0.01), and the mean number of glaucoma medications was reduced from 2.4 ± 1.3 to 2.0 ± 1.4 (p = 0.13). Among Caucasians, the mean IOP was reduced from 21.2 ± 6.8 mm Hg to 15.7 ± 4.2 mm Hg at 12 M (p \u3c 0.01), and the number of medications dropped from 2.4 ± 1.2 to 1.7 ± 1.3 (p \u3c 0.01). No statistically significant difference was found between these 2 race groups in IOP, number of medications, and complications. For complications with Trabectome alone, 13% of AA and 9% of Caucasian patients needed secondary surgery. There was only 1 case of hypotony which was in the AA group. For complications with Trabectome combined with phacoemulsification, 4% of AA as well as 4% of Caucasian patients required secondary surgery. There was only 1 case of hypotony which was in the Caucasian group.Conclusion: Ab interno trabeculectomy with Trabectome is associated with a reduction in IOP in both race groups with a similar complication and survival profiles