Glaucoma: role of neuroprotective agents

Glaucoma is an optic neuropathy, considered as the second leading cause of blindness worldwide. Glaucoma is characterized by selective death of retinal ganglion cells (RGC) and a progressive loss of vision. Elevated intraocular pressure (IOP) is one of the most important risk factors for developing glaucoma and hence we mainly focus on lowering IOP to arrest the progression of glaucoma. However, many patients continue to demonstrate a clinically downhill course despite the control of initially raised IOP. In fact, some patients develop what is called normal tension glaucoma, not associated to an increased IOP. This emphasizes that several pressure-independent mechanisms are responsible for the development and progression of glaucomatous neuropathy and that high IOP and vascular insufficiency in the optic nerve head are only risk factors for the development of glaucoma, and are not the only target for the treatment of glaucoma. The reason is that the process of RGC death is thought to be biphasic, and the primary injury is followed by a slower secondary degeneration related to a noxious environment surrounding the apoptotic cells. This environment is characterized by changes in the extra-cellular ionic concentrations, increased amounts of free radicals, neurotrophins (NT) depletion and increased glutamate-induced excitotoxicity due to high extra-cellular glutamate levels, which binds to N-methyl-D-aspartate (NMDA) receptors leading to an abnormally high intracellular Ca2+ concentration. Neuroprotection is a process that attempts to preserve the remaining cells that are still vulnerable to damage, and the main aim of neuroprotective therapy is to employ pharmacologic or other means to attenuate the hostility of the environment surrounding the degenerating cells, or to supply the cells with the tools to deal with this aggression, providing resilience to the insult. Several agents have been reported neuroprotective in glaucoma, both in clinical assays, such as Ca2+ channel blockers, and in experimental studies, such as betaxolol, brimonidine, NMDA antagonists, nitric oxide synthase inhibitors, NT and Ginkgo biloba extract. Most neuroprotective agents for glaucoma have proved beneficial effects over RGC, not showing effects over IOP. However, when analyzing classically used medications for glaucoma, it becomes difficult to understand if its effect over the progression of glaucoma is due to neuroprotective pathways or by means of lowering IOP. The ideal anti-glaucoma drug would be one that when applied topically, reduces IOP, but also probes to reach the retina in appropriate amounts, and activates specific receptors in the retina to attenuate RGC death. In this review, we will examine currently advocated neuroprotective drug-based strategies in the potential management of glaucoma

Pervasive contingency and entrenchment in a billion years of Hsp90 evolution [preprint]

Interactions among mutations within a protein have the potential to make molecular evolution contingent and irreversible, but the extent to which epistasis actually shaped historical evolutionary trajectories is unclear. We addressed this question by identifying all amino acid substitutions that occurred during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae and then precisely measuring their fitness effects when introduced into both extant and reconstructed ancestral Hsp90 proteins. We find a pervasive influence of epistasis: of 98 derived states that evolved during history, most were deleterious at times before they happened, and the vast majority also became subsequently entrenched, with the ancestral state becoming deleterious after its substitution. This epistasis was primarily caused by specific interactions among sites rather than a general permissive or restrictive effect on the protein\u27s tolerance to mutation. Our results show that epistasis continually opens and closes windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect the transient internal constraints imposed by a protein\u27s fleeting sequence states

PSR J0026-1955: A curious case of evolutionary subpulse drifting and nulling

PSR J0026-1955 was independently discovered by the Murchison Widefield Array (MWA) recently. The pulsar exhibits subpulse drifting, where the radio emission from a pulsar appears to drift in spin phase within the main pulse profile, and nulling, where the emission ceases briefly. The pulsar showcases a curious case of drift rate evolution as it exhibits rapid changes between the drift modes and a gradual evolution in the drift rate within a mode. Here we report new analysis and results from observations of J0026-1955 made with the upgraded Giant Meterwave Radio Telescope (uGMRT) at 300-500 MHz. We identify two distinct subpulse drifting modes: A and B, with mode A sub-categorised into A0, A1, and A2, depending upon the drift rate evolutionary behaviour. Additionally, the pulsar exhibits short and long nulls, with an estimated overall nulling fraction of ~58%, which is lower than the previously reported value. Our results also provide evidence of subpulse memory across nulls and a consistent behaviour where mode A2 is often followed by a null. We investigate the drift rate modulations of J0026-1955 and put forward two different models to explain the observed drifting behaviour. We suggest that either a change in polar gap screening or a slow relaxation in the spark configuration could possibly drive the evolution in drift rates. J0026-1955 belongs to a rare subset of pulsars which exhibit subpulse drifting, nulling, mode changing, and drift rate evolution. It is, therefore, an ideal test bed for carousel models and to uncover the intricacies of pulsar emission physics.Comment: 14 pages, 10 figures, 1 table. Accepted for publication in MNRA

Status of vitamin D, paratharmone and serum calcium levels in perimenopausal women and their mutual correlation

Background: The present study was carried out with an aim to assess Vitamin D, parathyroid hormone and calcium status in perimenopausal women and to find out their mutual correlation.Methods: The present work was carried out on in the Department of Obstetrics and Gynaecology, in collaboration with Department of Biochemistry at Era's Lucknow Medical College and Hospitals, Lucknow, U.P. 80 healthy females aged 40-50 years were included in the study. Serum vitamin D, parathyroid hormone and calcium levels were assessed. Data was analyzed using ANOVA and Pearson correlation coefficient.Results: Osteopenia and osteoporosis was seen in 33 (41.3%) and 21 (26.3%) women respectively, 50 (62.5%) women had S. vitamin D levels 0.05). Correlation between Vitamin D levels and Parathyroid hormone levels was weak and not significant.Conclusions: The findings of present study highlighted that perimenopausal phase should be regarded as a transition phase where a lot of physiological changes take place resulting in bone mineral density loss and fall in serum hormonal, vitamin and mineral levels. Owing to tremendous continuing changes the relationship between these parameters is vitiated and does not show a systematic change.

A study of role of doppler in gestational hypertension and perinatal outcome

Background: Hypertensive disorder of pregnancy is one of the most common complications that affect the human pregnancy. Hence it is important to identify women at risk of developing gestational hypertension or preeclampsia, its early diagnosis and subsequent consequences due to uteroplacental insufficiency with help of Doppler ultrasound, to improve perinatal outcome. The objective of this study was to study the application of Doppler ultrasound with analysis of blood flow velocity waveform in gestational hypertension and to examine and study the perinatal outcome in pregnancy with altered Doppler indices.Methods: A prospective study was carried out in 50 antenatal patients diagnosed to have gestational hypertension during a period of 12 months to evaluate the role of color Doppler imaging in gestational hypertension in patients more than 28 weeks of gestation, the initial scan was performed immediately after the diagnosis. This study analyzed the blood flow in umbilical artery, maternal uterine artery and fetal middle cerebral artery using Doppler ultrasound.Results: In this study approximately 76% of cases were found in 20-30 years group. 58% showed abnormal umbilical artery Doppler while 42% women had normal umbilical artery Doppler. In this study 23 cases had cerebro-placental index 1. Cases with cerebro-placental index <1 had various complications like preterm delivery, low birth weight, increased chances of still birth, intra uterine death (IUD), increased NICU admission. In this study 31 cases had abnormal uterine artery Doppler which accounts for 62% of total cases, while 38% had normal uterine artery Doppler.Conclusions: Doppler ultrasound can reliably predict any adverse fetal outcome in hypertensive pregnancies and can be a useful tool for decision making in appropriate timing of intervention for delivery

Single-pulse analysis and average emission characteristics of PSR J1820-0427 from observations made with the MWA and uGMRT

We have studied the pulse-to-pulse variability in PSR J1820--0427 and its frequency dependence using high-quality, wide-band observations made from the upgraded Giant Metrewave Radio Telescope (uGMRT; 300-750 MHz) and the Murchison Widefield Array ($\sim$170-200 MHz). The low-frequency data reveal a previously unreported feature in the average profile (at 185 MHz) after accounting for the effects of temporal broadening arising from multi-path scattering due to the Interstellar Medium (ISM). We advance a new method for flux density calibration of beamformed data from the uGMRT and use it to measure the single pulse flux densities across the uGMRT band. Combined with previously published measurements, these flux densities are best fit with a power-law spectrum with a low-frequency turnover. We also use calibrated flux densities to explore the relationship between pulse-to-pulse variability and the spectral index of individual pulses. Our analysis reveals a large scatter in the single-pulse spectral indices and a general tendency for brighter pulses to show a steepening of the spectral index. We also examine the frequency-dependence of the pulse-fluence distribution and its relation to the Stochastic Growth Theory.Comment: 13 pages, 9 figures, 2 tables. Accepted for publication in MNRA

Plasma proteome correlates of lipid and lipoprotein: biomarkers of metabolic diversity and inflammation in children of rural Nepal.

Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL, and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL-cholesterol (HDL-C) concentrations were common, especially in children with subclinical inflammation. Among 982 proteins analyzed, the relative abundance of 11, 12, and 52 plasma proteins was correlated with LDL-cholesterol (r = -0.43∼0.70), triglycerides (r = -0.39∼0.53), and HDL-C (r = -0.49∼0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4∼40%, and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis, and tissue repair lower by 3∼20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease

Latent effects of Hsp90 mutants revealed at reduced expression levels

In natural systems, selection acts on both protein sequence and expression level, but it is unclear how selection integrates over these two dimensions. We recently developed the EMPIRIC approach to systematically determine the fitness effects of all possible point mutants for important regions of essential genes in yeast. Here, we systematically investigated the fitness effects of point mutations in a putative substrate binding loop of yeast Hsp90 (Hsp82) over a broad range of expression strengths. Negative epistasis between reduced expression strength and amino acid substitutions was common, and the endogenous expression strength frequently obscured mutant defects. By analyzing fitness effects at varied expression strengths, we were able to uncover all mutant effects on function. The majority of mutants caused partial functional defects, consistent with this region of Hsp90 contributing to a mutation sensitive and critical process. These results demonstrate that important functional regions of proteins can tolerate mutational defects without experimentally observable impacts on fitness

Perspectives of chalcopyrite-based CIGSe thin-film solar cell: a review

Solar photovoltaic (PV) is empowering, reliable, and ecofriendly technology for harvesting energy which can be assessed from the fact that PV panels with total electricity generation capacity of 505 GW have been installed by the end of 2018. Thin-film solar cells based on copper indium gallium selenide (CIGSe) are promising photovoltaic absorber material owing to an alternative to crystalline silicon (c-Si)-based solar cells because of the huge potential for low-cost solar electricity production with minimal usage of raw materials. The efficiency record of 23.4% was achieved recently in CIGSe solar cells, which was comparable to c-Si solar cells (27.6%). The manufacturing cost of $0.34/W is expected for 15% efficient CIGSe module. The present review article discusses the perspectives of CISe/CIGSe-based thin-film solar cells with the focus on absorber material. Different vacuum and non-vacuum techniques for fabricating these materials are discussed along with the operation of solar cells and their manufacturability. The working mechanism of CIGSe solar cells with the characteristic features of the open-circuit voltage and current density as well as the factors influencing the efficiency in different fabrication techniques are reviewed. Moreover, some strategies toward the improvement of solar cells performance contemplating modified deposition are reviewed. Furthermore, how these strategies can be executed in order to make it cost effective methods is also discussed in detail. Prevailing constrictions for the commercial maturity are deliberated, and future perspectives for improvement at lab as well as industrial scalabilities are outlined