Formation of partially embedded Au nanostructures: Ion beam irradiation on thin film.

The Au partially embedded nanostructure (PEN) is synthesized by ion irradiation on an Au thin film deposited on a glass substrate using a 50 keV Ar ion. Scanning electron microscopy results show ion beam-induced restructuring from irregularly shaped nanostructures (NSs) to spherical Au NSs, and further ion irradiation leads to the formation of well-separated spherical nanoparticles. Higuchi's algorithm of surface analysis is utilized to find the evolution of surface morphology with ion irradiation in terms of the Hurst exponent and fractal dimension. The Au PEN is evidenced by Rutherford backscattering spectrometry and optical studies. Also, the depth of the mechanism behind synthesized PEN is explained on the basis of theoretical simulations, namely, a unified thermal spike and a Monte Carlo simulation consisting of dynamic compositional changes (TRIDYN). Another set of plasmonic NSs was formed on the surface by thermal annealing of the Au film on the substrate. Glucose sensing has been studied on the two types of plasmonic layers: nanoparticles on the surface and PEN. The results reveal the sensing responses of both types of plasmonic layers. However, PEN retains its plasmonic behavior as the NSs are still present after washing with water, which demonstrates the potential for reusability. RESEARCH HIGHLIGHTS: Synthesis of PENs by ion irradiation Utilization of Higuchi's algorithm to explore the surface morphology. Unified thermal spike and TRIDYN simulations being used to explain the results. Glucose is only used as a test case for reusability of substrate.

Theoretical study of highly efficient all-inorganic Sb2S3-on-Si monolithically integrated (2-T) and mechanically stacked (4-T) tandem solar cells using SCAPS-1D.

The power conversion efficiency of all-inorganic Sb2S3-on-Si two-terminal (2-T) monolithically integrated and four-terminal (4-T) mechanically stacked tandem solar cells are investigated. A one-dimensional solar cell capacitance simulator (SCAPS-1D) has been used to simulate the stand-alone antimony trisulfide (Sb2S3) top sub-cell, silicon (Si) bottom sub-cell, 2-T monolithic, and 4-T mechanically stacked tandem solar cells. The stand-alone sub-cells are optimized by extensive studies, including interface defects density, bulk defects density, absorber layer thickness, and series resistance. The power conversion efficiency (PCE) of simulated stand-alone sub-cells is compared and verified with the existing literature. A current matching condition is established to characterize the 2-T monolithic Sb2S3-on-Si tandem cell. A filtered spectrum has been utilized for bottom sub-cell measurement in the tandem solar cells. The best-simulated PCE of Sb2S3-on-Si 2-T monolithic and 4-T tandem cells is 30.22% and 29.30%, respectively. The simulation results presented in this paper open an opportunity for the scientific community to consider Sb2S3 as a potential top sub-cell material in Sb2S3-on-Si tandem solar cells with high PCE.

Performance analysis of n-TiO2/p-Cu2O, n-TiO2/p-WS2/p-Cu2O, and n-TiO2/p-WS2 heterojunction solar cells through numerical modelling.

A new hetero-structure of n-TiO2/p-WS2/p-Cu2O is proposed as a potential candidate for solar energy generation using tungsten disulfide (WS2) as an absorber layer. The proposed device performance is simulated by employing a one-dimensional solar cell capacitance simulator (SCAPS-1D). The numerical simulation studies compared the performances of n-TiO2/p-Cu2O, n-TiO2/p-WS2/p-Cu2O, and n-TiO2/p-WS2 hetero-structures based on various physical parameters like interface defects density, bulk defects density, absorber layer thickness, series resistance, shunt resistance, and operating temperature. In our simulation investigations, we found that interface defects pose a formidable impact on heterojunction devices. Interface defects closer to the front surface severely deteriorate the performances than the back surface. The bandgap of the absorber layer influences the performances of the solar cells. A closer comparison between n-TiO2/p-Cu2O and n-TiO2/p-WS2 heterojunction solar cells (HJSCs) revealed that the latter (n-TiO2/p-WS2) has nearly 182% better performance than the former (n-TiO2/p-Cu2O) devices. Additionally, the performance of the n-TiO2/p-WS2 solar cell is further boosted by ~ 139% in the presence of a hole transport layer of p-Cu2O. The best-simulated efficiency of the proposed new hetero-structure (n-TiO2/p-WS2/p-Cu2O) solar cell is 28.86%. Moreover, these optimized physical parameters may shed light on "easy to apply" new path for fabrication of a non-toxic, environment-friendly, and highly efficient novel thin-film heterojunction (n-TiO2/p-WS2/p-Cu2O) solar cell.

Insulin-like growth factor-2 regulates basal retinal insulin receptor activity.

The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina.

Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits.

Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) (n = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 µg · h/ml to 183.53 µg · h/ml. Within the multidose study, mean AUCs ranged from 2.53 µg · h/ml to 29.89 µg · h/ml. AUCs correlated linearly within the dosage range (r = 0.97; P = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.

Mechanisms involved in epigenetic down-regulation of Gfap under maternal hypothyroidism.

Thyroid hormones (TH) of maternal origin are crucial regulator of mammalian brain development during embryonic period. Although maternal TH deficiency during the critical periods of embryonic neo-cortical development often results in irreversible clinical outcomes, the fundamental basis of these abnormalities at a molecular level is still obscure. One of the key developmental process affected by maternal TH insufficiency is the delay in astrocyte maturation. Glial fibrillary acidic protein (Gfap) is a predominant cell marker of mature astrocyte and is regulated by TH status. Inspite, of being a TH responsive gene during neocortical development the mechanistic basis of Gfap transcriptional regulation by TH has remained elusive. In this study using rat model of maternal hypothyroidism, we provide evidence for an epigenetic silencing of Gfap under TH insufficiency and its recovery upon TH supplementation. Our results demonstrate increased DNA methylation coupled with decreased histone acetylation at the Gfap promoter leading to suppression of Gfap expression under maternal hypothyroidism. In concordance, we also observed a significant increase in histone deacetylase (HDAC) activity in neocortex of TH deficient embryos. Collectively, these results provide novel insight into the role of TH regulated epigenetic mechanisms, including DNA methylation, and histone modifications, which are critically important in mediating precise temporal neural gene regulation.

Candidate genes of flavonoid biosynthesis in Selaginella bryopteris (L.) Baker identified by RNA-Seq.

In the present study, de novo transcriptome analysis of Selaginella bryopteris in frond and root was performed to understand the regulation of flavonoid (FL) biosynthesis. High-quality data of 5.84 and 5.86 Gb was generated for frond and root, respectively, that assembled into 94,713 and 81,567 transcripts. A total of 87,471 and 73,395 unigenes were obtained from frond and root, respectively. A total of 41,267 and 31,048 CDS of frond and root, respectively, were annotated by BLASTX, which showed maximum hits against S. moellendorffii. Out of 11,285 differentially expressed genes, a total of 5639 genes were found to be down-regulated and 5628 genes up-regulated in frond as compared to those in root. In silico analysis of expression of genes in frond as compared to that in root was done for those related to phenylpropanoid (PP)/FL biosynthesis along with transcription factors (TFs) after DESeq and MapMan-based information. Results showed that genes of PP/FL biosynthesis pathway namely SbCHS, SbCHI, SbF3H, SbF3'H, SbDFR, SbUF3GT, SbCCOAMT, and SbCATOMT and TFs (SbMYB1, SbMYB2, SbMYB3, SbBHLH1, and SbWD40-5) were up-regulated in frond in comparison to those in root. Further, this in silico expression data was validated by RT-PCR analysis which showed predominant expression of most of these genes in frond and indicated their importance in the biosynthesis of flavonoids in S. bryopteris. A total of 9074 simple sequence repeats (SSRs) were also identified for frond and 3811 SSRs for root; these can be used for experimental validation.

CLINICAL EVALUATION OF THE RAPID ACCESS VITREAL INJECTION GUIDE: A Handheld Instrument for Assisting Intravitreal Injections.

PURPOSE: The Rapid Access Vitreal Injection (RAVI) guide combines the function of an eyelid speculum and measuring caliper into a single instrument for assisting intravitreal injections. This study clinically evaluated the RAVI guide with respect to patient acceptance, complication rates, and operative goals. METHODS: A prospective study was performed on 54 patients undergoing intravitreal injections using the RAVI guide (n = 32) or the speculum/caliper (n = 22). Device-related pain was assessed using the Wong-Baker scoring system, scaled from 0 (no pain) to 10 (agonizing pain). RESULTS: Mean device-related pain score did not differ significantly between the 2 groups, with scores of 0.6 and 0.7 for the RAVI guide and speculum groups, respectively. The rate of significant pain (score of ≥2) was twice as high in the speculum group (7 of 22, 32%) compared with the RAVI guide group (5 of 32, 16%), but this difference was not statistically significant (P = 0.19, Fisher's exact test). Operative goals of avoiding needle touch to lashes/lids and guiding needle insertion to the intended site were achieved in all patients. CONCLUSION: The RAVI guide appeared equivalent to the eyelid speculum in achieving operative goals, with similarly low pain scores. It has the potential for facilitating efficient, accurate, and safe intravitreal injections.

Transcriptome profiling of the salt-stress response in Triticum aestivum cv. Kharchia Local.

Kharchia Local wheat variety is an Indian salt tolerant land race known for its tolerance to salinity. However, there is a lack of detailed information regarding molecular mechanism imparting tolerance to high salinity in this bread wheat. In the present study, differential root transcriptome analysis identifying salt stress responsive gene networks and functional annotation under salt stress in Kharchia Local was performed. A total of 453,882 reads were obtained after quality filtering, using Roche 454-GS FLX Titanium sequencing technology. From these reads 22,241 ESTs were generated out of which, 17,911 unigenes were obtained. A total of 14,898 unigenes were annotated against nr protein database. Seventy seven transcription factors families in 826 unigenes and 11,002 SSRs in 6,939 unigenes were identified. Kyoto Encyclopedia of Genes and Genomes database identified 310 metabolic pathways. The expression pattern of few selected genes was compared during the time course of salt stress treatment between salt-tolerant (Kharchia Local) and susceptible (HD2687). The transcriptome data is the first report, which offers an insight into the mechanisms and genes involved in salt tolerance. This information can be used to improve salt tolerance in elite wheat cultivars and to develop tolerant germplasm for other cereal crops.

Pharmacokinetic evaluation of avicularin using a model-based development approach.

The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two-compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5-mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans.

Cytotoxic 1,5-diaryl-3-oxo-1,5-pentadienes: an assessment and comparison of membrane permeability using Caco-2 and MDCK monolayers.

A number of cytotoxic conjugated unsaturated ketones were screened for their membrane permeability characteristics using Caco-2 and MDCK cells with the view of finding promising leads for in vivo evaluations. 3b-e and 4a-b demonstrated high permeability characteristics. In particular, 4a emerged as a promising lead which showed excellent apparent permeability (P(app): 54.70) and efflux ratio (ER: 0.15) values. In general, the relative apparent permeabilities of these enones are similar in both bioassays.

Outer retinal structure after closed-globe blunt ocular trauma.

PURPOSE: To evaluate outer retinal structural abnormalities in patients with visual deficits after closed-globe blunt ocular trauma. METHODS: Nine subjects with visual complaints after closed-globe blunt ocular trauma were examined between 1 month after trauma and 6 years after trauma. Spectral domain optical coherence tomography was used to assess the outer retinal architecture, whereas adaptive optics scanning light ophthalmoscopy was used to analyze the photoreceptor mosaic integrity. RESULTS: Visual deficits ranged from central scotomas to decreased visual acuity. Spectral domain optical coherence tomography defects included focal foveal photoreceptor lesions, variable attenuation of the interdigitation zone, and mottling of the outer segment band, with one subject having normal outer retinal structure. Adaptive optics scanning light ophthalmoscopy revealed disruption of the photoreceptor mosaic in all subjects, variably manifesting as foveal focal discontinuities, perifoveal hyporeflective cones, and paracentral regions of selective cone loss. CONCLUSION: We observe persistent outer retinal disruption in subjects with visual complaints after closed-globe blunt ocular trauma, albeit to a variable degree. Adaptive optics scanning light ophthalmoscopy imaging allows the assessment of photoreceptor structure at a level of detail not resolvable using spectral domain optical coherence tomography or other current clinical imaging tools. Multimodal imaging seems to be useful in revealing the cause of visual complaints in patients after closed-globe blunt ocular trauma. Future studies are needed to better understand how photoreceptor structure changes longitudinally in response to various traumas.

Largazole pharmacokinetics in rats by LC-MS/MS.

A highly sensitive and specific LC-MS/MS method for the quantitation of largazole thiol, the active species of the marine-derived preclinical histone deacetylase inhibitor, largazole (prodrug), was developed and validated. Largazole thiol was extracted with ethyl acetate from human or rat plasma along with the internal standard, harmine. Samples were separated on an Onyx Monolithic C18 column by a stepwise gradient elution with 0.1% formic acid in methanol and 0.1% aqueous formic acid employing multiple reaction monitoring (MRM) detection. Linear calibration curves were obtained in the range of 12.5-400 ng/mL with 200 µL of human plasma. The overall intra-day precision was from 3.87% to 12.6%, and the inter-day precision was from 7.12% to 9.8%. The accuracy at low, medium and high concentrations ranged from 101.55% to 105.84%. Plasma protein bindings of largazole thiol in human and rat plasma as determined by an ultrafiltration method were 90.13% and 77.14%, respectively. Plasma drug concentrations were measured by this LC-MS/MS method. The pharmacokinetics of largazole thiol in rats was studied following i.v. administration at 10 mg/kg and found to follow a two-compartment model. Largazole thiol was rapidly eliminated from systemic circulation within 2 h. The established LC-MS/MS method is suitable for the analysis of largazole thiol in human plasma, as well.

3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs: a novel cluster of antimalarials targeting the liver stage of Plasmodium falciparum.

Drug resistance is a major challenge in antimalarial chemotherapy. In addition, a complete cure of malaria requires intervention at various stages in the development of the parasite within the host. There are only a few antimalarials that target the liver stage of the Plasmodium species which is an essential part of the life cycle of the malarial parasite. We report a series of antimalarial 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs 1-5, a number of which exhibit potent in vitro growth-inhibiting properties towards drug-sensitive D6 and drug-resistant C235 strains of Plasmodium falciparum as well as inhibiting the liver stage development of the malarial life cycle. The compounds 2b (IC50: 165 ng/mL), 3b (IC50: 186 ng/mL), 5c (IC50: 159 ng/mL) and 5d (IC50: 93.5 ng/mL) emerged as lead molecules that inhibit liver stage Plasmodium berghei and are significantly more potent than chloroquine (IC50: >2000 ng/mL) and mefloquine (IC50: >2000 ng/mL) in this screen. All the compounds that showed potent inhibitory activity against the P. berghei liver stage were nontoxic to human HepG2 liver cells (IC50: >2000 ng/mL). The compounds 5a and 5b exhibit comparable metabolic stability as chloroquine and mefloquine in human plasma and the most potent compound 5d demonstrated suitable permeability characteristics using the MDCK monolayer. These results emphasize the value of 3,5-bis(benzylidene)-4-piperidones as novel antimalarials for further drug development.

Acute exudative polymorphous vitelliform maculopathy in a patient with Lyme disease.

Acute exudative polymorphous vitelli-form maculopathy (AEPVM) is a rare condition of unclear etiology that has been seen in association with respiratory and viral infections. It has also been reported as a paraneoplastic phenomenon in older individuals. The authors report the first case of AEPVM associated with Lyme disease with over 3.5 years of follow-up. Multimodality serial imaging suggested the lesions began as multiple serous detachments followed by accumulation of photoreceptor outer segments in the subretinal space that gradually resolved over time and gave rise to the characteristic fundus findings at various stages.

From a cytotoxic agent to the discovery of a novel antimalarial agent.

A novel cytotoxin 3,5-bis(4-chlorobenzylidene)-1-[4-{2-(4-morpholinyl)ethoxy}phenyl-carbonyl]-4-piperidone hydrochloride 2 demonstrated potent antimalarial properties with IC(50) values of 0.60 and 1.97 µM against the drug sensitive D6 strain and the C235 drug-resistant strain of Plasmodium falciparum. This compound concentrates in red blood cells, lowers glutathione concentrations in erythrocytes and permeates across CACO-2 cells. These data reveal 2 to be a promising lead compound in the quest for novel antimalarial agents.

Ocular hypertension following intravitreal anti-vascular endothelial growth factor agents.

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in adults over the age of 65 years. The advent of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections has revolutionized the management of exudative AMD. However, multiple case series of sustained elevated intraocular pressure (IOP) after intravitreal injections of anti-VEGF agents have been reported. Sustained elevated IOP has been reported with all anti-VEGF agents being used in ophthalmology and even in patients without any prior history of glaucoma. No clear correlations to injection frequency or patient characteristics have emerged from the multiple reports so far, but it appears that patients with pre-existing glaucoma or ocular hypertension and those receiving a greater number of injections with shorter injection intervals may be at a higher risk for developing ocular hypertension related to anti-VEGF agents. Until future studies elucidate the pathophysiology of sustained IOP following anti-VEGF injections, it is prudent to recognize the possibility of elevations in IOP in association with anti-VEGF therapy. Treating physicians should look for subtle optic nerve head changes and IOP measurements suspicious for glaucoma and have a low threshold for treating elevated IOP if the patient is likely to require multiple intravitreal anti-VEGF injections. Ocular hypertension following anti-VEGF injections appears to be amenable to anti-glaucoma treatment and every effort should be made to preserve the peripheral vision in these patients where central vision is already threatened by exudative AMD.

A protocol to remove colored metabolites and other inhibitors from plant tissues to facilitate RNA isolation suitable for downstream applications.

This work developed a protocol to remove colored metabolites and other interfering substances to facilitate RNA isolation. These metabolites otherwise hinder RNA isolation and downstream applications. The developed protocol used sodium dodecyl sulphate, ethylenediamine tetra-acetic acid, and ethanol in a definite ratio that removed the said metabolites from the tissue and aided isolation of RNA using the existing methods. The protocol was developed for red colored roots of Arnebia euchroma and was extended to other colored tissues [rhizome of Rheum australe (Himalayan Rhubarb) and taproot of Daucus carota (purple carrot)] with success. Without inclusion of our protocol, the existing methods could not isolate good quality RNA from these tissues. RNA isolated by the developed protocol had A(260/280) ratio of 1.88-1.93, A(260/230) ratio of 1.94-2.0, and RNA integrity number of 6.3-8.0. RNA was amenable to downstream applications such as reverse-transcription polymerase chain reaction and primer extension assay.