Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a genetic and early-onset neurodegenerative disorder characterized by iron accumulation in the basal ganglia. It is due to mutations in ...Pantothenate Kinase 2 (PANK2), an enzyme that catalyzes the phosphorylation of vitamin B5, first and essential step in coenzyme A (CoA) biosynthesis. Most likely, an unbalance of the neuronal levels of this important cofactor represents the initial trigger of the neurodegenerative process, yet a complete understanding of the connection between PANK2 malfunctioning and neuronal death is lacking. Most PKAN patients carry mutations in both alleles and a loss of function mechanism is proposed to explain the pathology. When PANK2 mutants were analyzed for stability, dimerization capacity, and enzymatic activity in vitro, many of them showed properties like the wild-type form. To further explore this aspect, we overexpressed the wild-type protein, two mutant forms with reduced kinase activity and two retaining the catalytic activity in zebrafish embryos and analyzed the morpho-functional consequences. While the wild-type protein had no effects, all mutant proteins generated phenotypes that partially resembled those observed in
pank2
and
coasy
morphants and were rescued by CoA and vitamin B5 supplementation. The overexpression of PANK2 mutant forms appears to be associated with perturbation in CoA availability, irrespective of their catalytic activity.
Atheromatous carotid plaque rupture is responsible for the majority of ischaemic strokes in the developed world. Plaque rupture has been associated with plaque morphology, plaque components’ ...properties, inflammation and local stress concentration. High resolution multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in vivo. This study combined the recent advances in finite element analysis (FEA) and MRI, and performed stress analysis of five vulnerable carotid plaques based on the geometry derived from in vivo MRI. Image segmentation was based on multi-spectral MRI and co-registered with histology for plaque characterization. Plaque fibrous cap, lipid pool and vessel wall were modelled as isotropic, incompressible hyperelastic materials undergoing large deformation under pulse pressure loading. High stress concentrations were predicted at the shoulders and the thinnest fibrous cap regions of the plaque, and the mean maximal stresses were found to be higher in the ruptured plaques (683.3
kPa) than those in the unruptured plaques (226.9
kPa). The effect of the relative stiffness of fibrous cap to lipid pool on the stress within the cap itself was studied. It was shown that larger relative stiffness of fibrous cap to lipid pool resulted in higher stress within the cap. Thus, it is likely that high stress concentrations in vulnerable plaque may cause plaque rupture and lead to acute ischaemic sequelae. A combination of in vivo high resolution MRI and FEA could potentially act as a useful tool to assess plaque vulnerability and risk stratify patients with carotid atheroma.
IntroductionDegenerative cervical myelopathy (DCM) is a common and disabling condition of symptomatic cervical spinal cord compression secondary to degenerative changes in spinal structures leading ...to a mechanical stress injury of the spinal cord. RECEDE-Myelopathy aims to test the disease-modulating activity of the phosphodiesterase 3/phosphodiesterase 4 inhibitor Ibudilast as an adjuvant to surgical decompression in DCM.Methods and analysisRECEDE-Myelopathy is a multicentre, double-blind, randomised, placebo-controlled trial. Participants will be randomised to receive either 60–100 mg Ibudilast or placebo starting within 10 weeks prior to surgery and continuing for 24 weeks after surgery for a maximum of 34 weeks. Adults with DCM, who have a modified Japanese Orthopaedic Association (mJOA) score 8–14 inclusive and are scheduled for their first decompressive surgery are eligible for inclusion. The coprimary endpoints are pain measured on a visual analogue scale and physical function measured by the mJOA score at 6 months after surgery. Clinical assessments will be undertaken preoperatively, postoperatively and 3, 6 and 12 months after surgery. We hypothesise that adjuvant therapy with Ibudilast leads to a meaningful and additional improvement in either pain or function, as compared with standard routine care.Study designClinical trial protocol V.2.2 October 2020.Ethics and disseminationEthical approval has been obtained from HRA—Wales.The results will be presented at an international and national scientific conferences and in a peer-reviewed journals.Trial registration numberISRCTN Number: ISRCTN16682024.
Aim: To assess the efficacy of foliar application of nutrients, i.e., calcium as calcium chloride and boron as borax on yield and quality of guava (Psidium guajava L.) cv. Lalit fruits. Methodology: ...Nineteen -year- old uniform guava plants planted at 6x6 m apart were selected for investigation. Foliar application of calcium chloride (CaCl2) and borax (Na2 B4O5 (OH)4-8H2O) was done as split dose application during first week of August and second week of September in the year 2017 and 2018. Nine treatments in toto viz., T0 (Control), T1 (Calcium chloride 0.1%), T2 (Calcium chloride 0.2%), T3 (Borax, 0.1%), T4 (Borax 0.2%), T5 (Calcium chloride 0.1% + Borax 0.1%), T6 (Calcium chloride 0.1% + Borax 0.2%), T7 (Calcium chloride 0.2% + Borax 0.1%), T8 (Calcium chloride 0.2% + Borax 0.2%) were applied as foliar feeding. Effect of treatments was recorded on fruit length, fruit width, fruit volume, fruit yield (kg tree-1), fruit specific gravity, total soluble solids, acidity, ascorbic acid, total sugar, reducing sugar and non-reducing sugar content of fruit. Results: Foliar application of calcium chloride @ 0.2% along with borax @ 0.1% was the best treatment combination among the all treatments for improving fruit yield (i.e., from 44.333 kg tree-1 to 61.170 kg tree-1) and quality of guava fruits (viz., TSS 7.613 - 11.6700Brix, ascorbic acid 155.457 - 176.343 mg 100g-1 pulp and total sugars 5.383 - 7.547%) in the environmental conditions akin to environmental conditions of Horticultural Research Farm of Babasaheb Bhimrao Ambedkar University, Lucknow (India). Interpretation: Judicious application of calcium and boron as foliar spray might ameliorate adverse effects of soil and environmental factors and improve production and quality of guava fruits.
Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade of this early proteolytic activity with GM6001, a broad-spectrum matrix metalloproteinase inhibitor, ...results in improved recovery after spinal cord injury. As matrix metalloproteinase-9 is likewise acutely elevated in dogs with naturally occurring spinal cord injuries, we evaluated efficacy of GM6001 solubilized in dimethyl sulfoxide in this second species. Safety and pharmacokinetic studies were conducted in naïve dogs. After confirming safety, subsequent pharmacokinetic analyses demonstrated that a 100 mg/kg subcutaneous dose of GM6001 resulted in plasma concentrations that peaked shortly after administration and were sustained for at least 4 days at levels that produced robust in vitro inhibition of matrix metalloproteinase-9. A randomized, blinded, placebo-controlled study was then conducted to assess efficacy of GM6001 given within 48 hours of spinal cord injury. Dogs were enrolled in 3 groups: GM6001 dissolved in dimethyl sulfoxide (n = 35), dimethyl sulfoxide (n = 37), or saline (n = 41). Matrix metalloproteinase activity was increased in the serum of injured dogs and GM6001 reduced this serum protease activity compared to the other two groups. To assess recovery, dogs were a priori stratified into a severely injured group and a mild-to-moderate injured group, using a Modified Frankel Scale. The Texas Spinal Cord Injury Score was then used to assess long-term motor/sensory function. In dogs with severe spinal cord injuries, those treated with saline had a mean motor score of 2 (95% CI 0-4.0) that was significantly (P<0.05; generalized linear model) less than the estimated mean motor score for dogs receiving dimethyl sulfoxide (mean, 5; 95% CI 2.0-8.0) or GM6001 (mean, 5; 95% CI 2.0-8.0). As there was no independent effect of GM6001, we attribute improved neurological outcomes to dimethyl sulfoxide, a pleotropic agent that may target diverse secondary pathogenic events that emerge in the acutely injured cord.
Senna is an important medicinal plant and is used in many Ayurvedic formulations. Dianthraquinone glucosides are the main bioactive phytochemicals present in leaves and pods of senna. The extraction ...efficiency in terms of yield and composition of the extract of senna prepared using both conventional (cold percolation at room temperature and refluxing) and non conventional (ultrasound and microwave assisted solvent extraction as well as supercritical fluid extraction) techniques were compared in the present study. Also a rapid reverse phase HPLC-PDA detection method was developed and validated for the simultaneous determination of sennoside A and sennoside B in the different extracts of senna leaves. Ultrasound and microwave assisted solvent extraction techniques were more effective in terms of yield and composition of the extracts compared to cold percolation at room temperature and refluxing methods of extraction.
Millets play a key role in the food security of Central Himalayan Region. Evaluation of finger millet Eleusine coracana (L) Gaertn genetic diversity is yet lacking in this region. Hence, the present ...study was conducted with the aim to explore, collect and evaluate the genetic diversity of finger millet in order to identify traitspecific germplasm forcrop improvement. Exploration expeditions were conducted in the finger millet growing areas of Central Himalayan Region i.e., Uttarakhand State of India.Atotal of 314 accessions were collected from altitudinal range of 225 - 2250 m asl. Collected germplasm was grown at one place and evaluated for various phenophysiological traits. Ample diversity was found in pheno-physiological traits viz., flag leaf length (17.91 - 97.92 cm), fag leaf width (0.83 - 1.23), flag leaf angle (19 - 530), peduncle length (9.02 - 45.43 cm), plant height (71.71 - 140.30 cm), days to 50% flowering (66.00 - 98.00), days to 80% maturity (117.00 - 147.00), days to harvesting (141 -149), ear head length (4.16 - 14.61 cm) and 1000 seed weight (1.01 -4.71 g). In addition, these accessions were evaluated for variability in total chlorophyll (1.02 - 6.90 mg.g-1 fresh weight), carotenoids (0.87 - 4.33 mg.g-1 fresh weight) content and lipid peroxidation (0.55 - 7.42 n mol MDA formed. mg-1 protein. hr-1). Seeds of collected germplasm had wide variability in nutritional traits viz., carbohydrate (72.56 - 79.22%), fat (1.31 - 2.52%) and protein (5.66 - 12.96%) content. Principal components responsible for variability were identified. Central Himalayan Region has been found to have enormous diversity of finger millet. Collected germplasm had remarkable ability to withstand varying weather conditions and resistance to environmental/ abiotic stresses. Substantial diversity noticed in different traits might be utilized for crop improvement to develop nutritionally rich and abiotic/ biotic stress tolerant varieties.
The mountain ecosystem of the Central Himalayan Region is known for its diversity of crops and their wild relatives. In spite of adverse climatic conditions, this region is endowed with a rich ...diversity of millets. Hence, the aim of the present study was to explore, collect, conserve and evaluate the diversity of barnyard millet (Echinochloa frumentacea) to find out the extent of diversity available in different traits and the traits responsible for abiotic stress tolerance, and to identify trait-specific accessions for crop improvement and also for the cultivation of millets in the region as well as in other similar agro-ecological regions. A total of 178 accessions were collected and evaluated for a range of morpho-physiological and biochemical traits. Significant variability was noted in days to 50% flowering, days to 80% maturity, 1000 seed weight and yield potential of the germplasm. These traits are considered to be crucial for tailoring new varieties for different agro-climatic conditions. Variations in biochemical traits such as lipid peroxidation (0·552–7·421 nmol malondialdehyde formed/mg protein/h), total glutathione (105·270–423·630 mmol/g fresh weight) and total ascorbate (4·980–9·880 mmol/g fresh weight) content indicate the potential of collected germplasm for abiotic stress tolerance. Principal component analysis also indicated that yield, superoxide dismutase activity, plant height, days to 50% flowering, catalase activity and glutathione content are suitable traits for screening large populations of millet and selection of suitable germplasm for crop improvement and cultivation. Trait-specific accessions identified in the present study could be useful in crop improvement programmes, climate-resilient agriculture and improving food security in areas with limited resources.
Background More than half of all cerebral ischemic events are the result of rupture of extracranial plaques. The clinical determination of carotid plaque vulnerability is currently based solely on ...luminal stenosis; however, it has been increasingly suggested that plaque morphology and biomechanical stress should also be considered. We used finite element analysis based on in vivo magnetic resonance imaging (MRI) to simulate the stress distributions within plaques of asymptomatic and symptomatic individuals. Methods Thirty nonconsecutive subjects (15 symptomatic and 15 asymptomatic) underwent high-resolution multisequence in vivo MRI of the carotid bifurcation. Stress analysis was performed based on the geometry derived from in vivo MRI of the carotid artery at the point of maximal stenosis. The finite element analysis model considered plaque components to be hyperelastic. The peak stresses within the plaques of symptomatic and asymptomatic individuals were compared. Results High stress concentrations were found at the shoulder regions of symptomatic plaques, and the maximal stresses predicted in this group were significantly higher than those in the asymptomatic group (508.2 ± 193.1 vs 269.6 ± 107.9 kPa; P = .004). Conclusions Maximal predicted plaque stresses in symptomatic patients were higher than those predicted in asymptomatic patients by finite element analysis, suggesting the possibility that plaques with higher stresses may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, biomechanical stress analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma. It may help in the identification of patients with asymptomatic carotid atheroma at greatest risk of developing symptoms or mild-to-moderate symptomatic stenoses, which currently fall outside current clinical guidelines for intervention.
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