Relative Genetic and Environmental Contributions to Variations in Human Retinal Electrical Responses Quantified in a Twin Study

Purpose To estimate heritability of parameters of human retinal electrophysiology and to explore which parameters change with age. Design Prospective, classic twin study. Participants Adult monozygotic and dizygotic twin pairs recruited from the TwinsUK cohort. Methods Electroretinogram responses were recorded using conductive fiber electrodes in response to stimuli incorporating standards set by the International Society for the Clinical Electrophysiology of Vision. These parameters were extracted; in addition, photopic negative-response (PhNR; originating from retinal ganglion cells) and i-wave components were extracted from responses to the photopic single flash. Parameter values were averaged from both eyes. Main Outcome Measures Mean values were calculated for the cohort. Correlation coefficients with age were calculated (averaging parameters from both twins from each pair). Coefficients of intrapair correlation were calculated for monozygotic and dizygotic twins. Age-adjusted heritability estimates were derived using standard maximum likelihood structural equation twin modeling. Results Responses were recorded from 210 participants in total (59 monozygotic and 46 dizygotic twin pairs). Ninety-three percent were women. Mean age for the cohort was 62.4 years (standard deviation, 11.4 years). In general, response amplitudes correlated negatively, and implicit times positively, with age. Correlations were statistically significant (P < 0.05) and moderate or strong (coefficient, >0.35) for the following parameters: scotopic standard and bright-flash a-wave implicit times, photopic 30-Hz flicker and single-flash b-wave implicit times, and PhNR and i-wave implicit times. Intrapair correlations were higher for monozygotic than dizygotic twins, suggesting important genetic influences. Age-adjusted estimates of heritability were significant for all parameters (except scotopic dim-flash b-wave implicit time), ranging from 0.34 to 0.85. Highest estimates were for photopic single-flash a-wave and b-wave amplitudes (0.84 and 0.85, respectively). Conclusions This study explored heritability of retinal electrophysiologic parameters and included measurements reflecting ganglion cell function. Most parameters showed significant heritability, indicating that genetic factors are important, determining up to 85% of the variance in some cone system response parameters. Scotopic responses tended to show lower heritability (possibly relating to greater rod system susceptibility to environmental factors). Future studies can explore the identity of these genetic factors, improving our understanding of how they shape retinal function

Screening of marigold (Tagetes erecta L.) cultivars for drought stress based on vegetative and physiological characteristics

Drought tolerance is an important genotypic character to be exploited for the plant cultivar selection under water deficit conditions. In the recent study, we examined the response of two marigold cultivars (Inca and Bonanza) under different regimes of drought stress. The aim was to determine the best performing cultivar under water/drought stress. Three irrigation treatments include; 4 days (T1), 6 days (T2) and 8 days (T3) in comparison to control 1 day (T0) interval were imposed. Response characters under study were morphological, physiological and anatomical. Complete Randomized Design (CRD) with four replications in two factorial arrangements was followed for experiment layout. The results revealed that increasing water stress adversely affect plant height, in both cultivars. Both cultivars showed a decreasing trend to the number of flowers under water stress. Total chlorophyll contents including a, b were also showed reduction under prolonged drought treatment in both cultivars from (2.7 mg g-1 FW) to (1 mg g-1 FW). Overall, the performance of cultivar (cv.) Inca was satisfactory under water stress regimes. These results are helpful for selecting drought tolerant marigold cultivars in water scarce areas.  Â

Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5\u27-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P \u3c 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P \u3c 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms

Purpose Both rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones. Methods ERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m−2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m−2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. Results Mean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p < 0.0001). We found no significant correlation of b/a ratio with age. Conclusions Over 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background

Revisiting the Indus Basin Model for an energy sustainable Pakistan

Water is vital and an essential entity directly and indirectly for all living creatures from their birth, whereas electrical energy has a dominant role in the growth of society in general and for human beings in particular. Optimal use of water and production of electrical energy at minimum cost are potential research challenges. Hydraulic energy is one of the cheapest and the most exploited renewable energy resource for power generation worldwide, and is in line with the seventh United Nations Sustainable Development Goal (SDG 7). The Indus basin is a trans-boundary basin, and its modeling has been a source of interest for scientists and policymakers. Indus Basin Model Revised (IBMR) has many variants, all focusing on optimal use of water for irrigation purposes. In this paper, the modified IBMR model is proposed addressing both agriculture and power generation aspects simultaneously. This model optimizes the Consumer Producer Surplus (CPS) by considering different water inflow probabilities. A parameter has been introduced in the modified objective function to manipulate the supply of water to agriculture and hydropower generation. The proposed model has been implemented in Generic Algebraic Modeling System (GAMS) and case studies have been investigated in presence and absence of power generation. The results obtained show that, with incorporation of hydropower, basin wide income is increased up to 11.83% using 50% exceedance probability, and results are in agreement with reference power generation estimated by National Transmission and Dispatch Company (NTDC). The SDG 7 targets ensure the reasonable, dependable, sustainable and contemporary energy access to all. The current research is focusing on how Pakistan would achieve the SDG 7 targets. By 2040, it is anticipated that Pakistan’s energy mix will have around 40% of hydropower and 16% of renewable energy

The chelation of colonic luminal iron by a unique sodium alginate for the improvement of gastrointestinal health

Scope: Iron is an essential nutrient. However, in animal models, excess unabsorbed dietary iron residing within the colonic lumen has been shown to exacerbate inflammatory bowel disease and intestinal cancer. Therefore, the aims of this study were to screen a panel of alginates to identify a therapeutic that can chelate this pool of iron and thus be beneficial for intestinal health. Methods and results: Using several in vitro intestinal models, it is evident that only one alginate (Manucol LD) of the panel tested was able to inhibit intracellular iron accumulation as assessed by iron-mediated ferritin induction, transferrin receptor expression, intracellular 59Fe concentrations, and iron flux across a Caco-2 monolayer. Additionally, Manucol LD suppressed iron absorption in mice, which was associated with increased fecal iron levels indicating iron chelation within the gastrointestinal tract. Furthermore, the bioactivity of Manucol LD was found to be highly dependent on both its molecular weight and its unique compositional sequence. Conclusion: Manucol LD could be useful for the chelation of this detrimental pool of unabsorbed iron and it could be fortified in foods to enhance intestinal health.</p

Electrical responses from human retinal cone pathways associate with a common genetic polymorphism implicated in myopia

SignificanceMyopia prevalence has increased dramatically over recent decades. Genome-wide association studies have identified numerous loci, but mechanisms by which genotypic identity confers myopia susceptibility are unknown. The common variant most strongly associated with myopia is near a gene encoding retinal gap junctions. We analyzed retinal electrophysiological responses from 186 twins genotyped at this locus, finding association between cone-driven, but not rod-driven, electroretinogram signals and allelic genotype. Examination of responses to further, nonstandard testing protocols, together with recordings from patients with selective loss of bipolar cell signals, points to an effect on cone-driven hyperpolarizing ("OFF") signals. The pattern of retinal expression of this gene appears consistent with these findings, which support a potential role for altered cone-driven signaling in myopia development

Design, Performance, and Calibration of the CMS Hadron-Outer Calorimeter

The CMS hadron calorimeter is a sampling calorimeter with brass absorber and plastic scintillator tiles with wavelength shifting fibres for carrying the light to the readout device. The barrel hadron calorimeter is complemented with an outer calorimeter to ensure high energy shower containment in the calorimeter. Fabrication, testing and calibration of the outer hadron calorimeter are carried out keeping in mind its importance in the energy measurement of jets in view of linearity and resolution. It will provide a net improvement in missing \et measurements at LHC energies. The outer hadron calorimeter will also be used for the muon trigger in coincidence with other muon chambers in CMS

Metal-Ligand Proton Tautomerism, Electron Transfer, and C(sp3)-H Activation by a 4-Pyridinyl-Pincer Iridium Hydride Complex

The para-N-pyridyl-based PCP pincer proligand 3,5-bis(di-tert-butylphosphinomethyl)-2,6-dimethylpyridine (pN-tBuPCP-H) was synthesized and metalated to give the iridium complex (pN-tBuPCP)IrHCl (2-H). In marked contrast with its phenyl-based congeners, e.g., (tBuPCP)IrHCl and derivatives, 2-H is highly air-sensitive and reacts with oxidants such as ferrocenium, trityl cation, and benzoquinone. These oxidations ultimately lead to intramolecular activation of a phosphino-t-butyl C(sp3)-H bond and cyclometalation. Considering the greater electronegativity of N than C, 2-H is expected to be less easily oxidized than simple PCP derivatives; cyclic voltammetry and DFT calculations support this expectation. However, 2-H is calculated to undergo metal-ligand-proton tautomerism (MLPT) to give an N-protonated complex that can be described with resonance forms representing a zwitterionic complex (with a negative charge on Ir) and a p-N-pyridylidene (a remote N-heterocyclic carbene) Ir(I) complex. One-electron oxidation of this tautomer is calculated to be dramatically more favorable than direct oxidation of 2-H (ΔΔG° = −31.3 kcal/mol). The resulting Ir(II) oxidation product is easily deprotonated to give metalloradical 2• which is observed by NMR spectroscopy. 2• can be further oxidized to give cationic Ir(III) complex, 2+, which can oxidatively add a phosphino-t-butyl C-H bond and undergo deprotonation to give the observed cyclometalated product. DFT calculations indicate that less sterically hindered analogues of 2+ would preferentially undergo intermolecular addition of C(sp3)-H bonds, for example, of n-alkanes. The resulting iridium alkyl complexes could undergo facile β-H elimination to afford olefin, thereby completing a catalytic cycle for alkane dehydrogenation driven by one-electron oxidation and deprotonation, enabled by MLPT. © 2023 The Authors. Published by American Chemical Society