Plasmodium falciparum Cysteine-Rich Protective Antigen (CyRPA) Elicits Detectable Levels of Invasion-Inhibitory Antibodies during Natural Infection in Humans.

Plasmodium falciparum cysteine-rich protective antigen (CyRPA) is a conserved component of an essential erythrocyte invasion complex (RH5/Ripr/CyRPA) and a target of potent cross-strain parasite-neutralizing antibodies. While naturally acquired human RH5 antibodies have been functionally characterized, there are no similar reports on CyRPA. Thus, we analyzed the parasite-neutralizing activity of naturally acquired human CyRPA antibodies. In this regard, CyRPA human antibodies were measured and purified from malaria-infected plasma obtained from patients in central India and analyzed for their parasite neutralizing activity via in vitro growth inhibition assays (GIA). We report that, despite being susceptible to antibodies, CyRPA is a highly conserved antigen that does not appear to be under substantial immune selection pressure, as a very low acquisition rate for anti-CyRPA antibodies was reported in malaria-exposed Indians. We demonstrate for the first time that the small amounts of natural CyRPA antibodies exhibited functional parasite-neutralizing activity and that a CyRPA-based vaccine formulation induces highly potent antibodies in rabbits. Importantly, the vaccine-induced CyRPA antibodies exhibited a robust 50% inhibitory concentration (IC50) of 21.96 µg/ml, which is comparable to the IC50 of antibodies against the leading blood-stage vaccine candidate, reticulocyte-binding-like homologous protein 5 (RH5). Our data support CyRPA as a unique vaccine target that is highly susceptible to immune attack but is highly conserved compared to other leading candidates such as MSP-1 and AMA-1, further substantiating its promise as a leading blood-stage vaccine candidate.

Intrinsic efficiency limits in low-bandgap non-fullerene acceptor organic solar cells.

In bulk heterojunction (BHJ) organic solar cells (OSCs) both the electron affinity (EA) and ionization energy (IE) offsets at the donor-acceptor interface should equally control exciton dissociation. Here, we demonstrate that in low-bandgap non-fullerene acceptor (NFA) BHJs ultrafast donor-to-acceptor energy transfer precedes hole transfer from the acceptor to the donor and thus renders the EA offset virtually unimportant. Moreover, sizeable bulk IE offsets of about 0.5 eV are needed for efficient charge transfer and high internal quantum efficiencies, since energy level bending at the donor-NFA interface caused by the acceptors' quadrupole moments prevents efficient exciton-to-charge-transfer state conversion at low IE offsets. The same bending, however, is the origin of the barrier-less charge transfer state to free charge conversion. Our results provide a comprehensive picture of the photophysics of NFA-based blends, and show that sizeable bulk IE offsets are essential to design efficient BHJ OSCs based on low-bandgap NFAs.

Antibody Combinations Targeting the Essential Antigens CyRPA, RH5, and MSP-119 Potently Neutralize Plasmodium falciparum Clinical Isolates From India and Africa.

BACKGROUND: Targeting multiple key antigens that mediate distinct Plasmodium falciparum erythrocyte invasion pathways is an attractive approach for the development of blood-stage malaria vaccines. However, the challenge is to identify antigen cocktails that elicit potent strain-transcending parasite-neutralizing antibodies efficacious at low immunoglobulin G concentrations feasible to achieve through vaccination. Previous reports have screened inhibitory antibodies primarily against well adapted laboratory parasite clones. However, validation of the parasite-neutralizing efficacy against clinical isolates with minimal in vitro cultivation is equally significant to better ascertain their prospective in vivo potency. METHODS: We evaluated the parasite-neutralizing activity of different antibodies individually and in combinations against laboratory adapted clones and clinical isolates. Clinical isolates were collected from Central India and Mozambique, Africa, and characterized for their invasion properties and genetic diversity of invasion ligands. RESULTS: In our portfolio, we evaluated 25 triple antibody combinations and identified the MSP-Fu+CyRPA+RH5 antibody combination to elicit maximal parasite neutralization against P. falciparum clinical isolates with variable properties that underwent minimal in vitro cultivation. CONCLUSIONS: The MSP-Fu+CyRPA+RH5 combination exhibited highly robust parasite neutralization against P. falciparum clones and clinical isolates, thus substantiating them as promising candidate antigens and establishing a proof of principle for the development of a combinatorial P. falciparum blood-stage malaria vaccine.

Prevalence of afebrile parasitaemia due to Plasmodium falciparum & P. vivax in district Balaghat (Madhya Pradesh): Implication for malaria control.

BACKGROUND & OBJECTIVES: Balaghat district in Central India is a highly malarious district where both Plasmodium falciparum and P. vivax are prevalent. In this district, the persistence of malaria was on an increase and not responsive to intervention measures even though there was no drug resistance. This study was undertaken by conducting mass screening to determine the prevalence of malaria among particularly vulnerable tribe of Balaghat, for developing evidence-based intervention measures for malaria control in hard to reach areas. METHODS: This prospective study was carried out during 2013-2014 by conducting mass survey of the population in 10 villages of Birsa community health centre (CHC) and 12 villages of Baihar CHC. Finger-pricked blood smears were collected from all consenting individuals with or without fever for microscopic examination. RESULTS: In the febrile group, the slide positivity rate (SPR) and slide falciparum rate (SFR) were 32.4 and 28.9 per cent, respectively, with 89.4 per cent P. falciparum, while in the afebrile individuals also, the SPR and SFR were high (29 and 26%, respectively), but these were significantly lower than that of febrile group. The gametocyte carriers were significantly higher (odds ratio 1.67, 95% confidence interval 1.25-2.25, P=0.0004) in afebrile patients when compared with febrile group. Vector incrimination showed the presence of four sporozoite-positive Anopheles culicifacies out of 1953 assayed. INTERPRETATION & CONCLUSIONS: Plasmodium falciparum malaria was high in young children (up to 8 years) as compared to the adult in both afebrile and febrile group in Balaghat district. High prevalence of gametocyte was observed in all age groups among the afebrile cases. The identification of afebrile malaria parasitaemia is an important challenge for the malaria elimination initiatives. A strong malaria surveillance system is fundamental to both programme design and implementation.

Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum.

Transmission blocking malaria vaccines are aimed to block the development and maturity of sexual stages of parasite within mosquitoes. The vaccine candidate antigens (Pfs25, Pfs48/45, Pfs230) that have shown transmission blocking immunity in model systems are in different stages of development. These antigens are immunogenic with limited genetic diversity. Pfs25 is a leading candidate and currently in phase I clinical trial. Efforts are now focused on the cost-effective production of potent antigens using safe adjuvants and optimization of vaccine delivery system that are capable of inducing strong immune responses. This review addresses the potential usefulness, development strategies, challenges, clinical trials and current status of Plasmodium falciparum sexual stage malaria vaccine candidate antigens for the development of transmission-blocking vaccines.

Spray deposited copper zinc tin sulphide (Cu2ZnSnS4) film as a counter electrode in dye sensitized solar cells.

Stoichiometric thin films of Cu2ZnSnS4 (CZTS) were deposited by the spray technique on a FTO coated glass substrate, with post-annealing in a H2S environment to improve the film properties. CZTS films were used as a counter electrode (CE) in Dye-Sensitized Solar Cells (DSCs) with N719 dye and an iodine electrolyte. The DSC of 0.25 cm(2) area using a CE of CZTS film annealed in a H2S environment under AM 1.5G illumination (100 mW cm(-2)) exhibited a short circuit current density (JSC) = 18.63 mA cm(-2), an open circuit voltage (VOC) = 0.65 V and a fill factor (FF) = 0.53, resulting in an overall power conversion efficiency (PCE) = 6.4%. While the DSC using as deposited CZTS film as a CE showed the PCE = 3.7% with JSC = 13.38 mA cm(-2), VOC = 0.57 V and FF = 0.48. Thus, the spray deposited CZTS films can play an important role as a CE in the large area DSC fabrication.

Current status and applications of genus Geobacillus in the production of industrially important products-a review.

The genus Geobacillus is one of the most important genera which mainly comprises gram-positive thermophilic bacterial strains including obligate aerobes, denitrifiers and facultative anaerobes having capability of endospore formation as well. The genus Geobacillus is widely distributed in nature and mostly abundant in extreme locations such as cool soils, hot springs, hydrothermal vents, marine trenches, hay composts and dairy plants. Due to plasticity towards environmental adaptation, the Geobacillus sp. shows remarkable genome diversification and acquired many beneficial properties, which facilitates their exploitation for many biotechnological applications. Many thermophiles are of biotechnological importance and having considerable interest in commercial applications for the production of industrially important products. Recently, due to catabolic versatility especially in the degradation of hemicellulose and starch containing agricultural waste and rapid growth rates, these microorganisms show potential for the production of biofuels, thermostable enzymes and bioremediation. This review mainly summarizes the status of Geobacillus sp. including its notable properties, biotechnological studies and its potential application in the production of industrially important products.

Comparative evaluation of TonoPen AVIA, Goldmann applanation tonometry and non-contact tonometry.

To compare the tonometric recordings of the Tono-Pen AVIA (TPA) with intraocular pressure (IOP) recordings made with Goldmann applanation tonometry (GAT) and non-contact tonometry (NCT). This prospective, observational, comparative case series consisted of 180 eyes of 180 subjects (50 patients with glaucoma and 130 healthy controls). NCT was performed first, followed by GAT and TPA measurement after a 5-min break. The mean age of the patients enrolled in the study was 43.99±16.67 years. The limits of agreement (confidence interval 95%) as calculated from the Bland-Altman plots for TPA-GAT and TPA-NCT were +8.7 to -7.7 and +8.6 to -9.6 mmHg in glaucoma patients. In healthy subjects these values were +4.8 to -5.1 and +6.2 to -5.2 mmHg, respectively. TPA tends to overestimate IOP compared to GAT at central corneal thickness (CCT) greater than 520 µm and underestimate IOP at CCT less than 510 µm. TPA overestimates IOP in comparison to NCT in subjects with CCT greater than 456 µm. Due to wide limits of agreement, TPA cannot be used interchangeably with GAT and NCT in the serial monitoring of glaucoma patients. Central corneal thickness has a significant influence on the IOP readings measured by Tono-Pen AVIA.

Dopant-Assisted Matrix Stabilization Enables Thermoelectric Performance Enhancement in n-Type Quantum Dot Films.

Efficient thermoelectric generators require further progress in developing n-type semiconductors that combine low thermal conductivity with high electrical conductivity. By embedding colloidal quantum dots (CQDs) in a metal halide matrix (QDMH), the metal halide matrix can enhance phonon scattering, thus suppressing thermal transport; however, simultaneously achieving high electrical conductivity in such systems has previously been limited by the deleterious impact of a large density of interfaces on charge transport. Therefore, new strategies are needed to improve charge carrier transport without sacrificing matrix-enabled low thermal transport. Here, we report the use of chemical doping in the solution state to improve electron transport while maintaining low thermal transport in QDMH films. By incorporating cesium carbonate (Cs2CO3) salts as a dopant prior to matrix formation, we find that the dopant stabilizes the matrix in colloidal inks and enables efficient n-type doping in QDMH films. As a result, this strategy leads to an enhanced n-type thermoelectric behavior in solution-processed QDMH films near room temperature, with a thermal conductivity of 0.25 W m-1 K-1-significantly lower than in prior films based on organic-ligand-cross-linked CQD films (>0.6 W m-1 K-1) and spark-plasma-sintered CQD systems (>1 W m-1 K-1). This study provides a pathway to developing efficient n-type thermoelectric materials with low thermal conductivity using single-step deposition and low-temperature processing.

18.4 % Organic Solar Cells Using a High Ionization Energy Self-Assembled Monolayer as Hole-Extraction Interlayer.

Self-assembled monolayers (SAMs) based on Br-2PACz ([2-(3,6-dibromo-9H-carbazol-9-yl)ethyl]phosphonic acid) 2PACz ([2-(9H-Carbazol-9-yl)ethyl]phosphonic acid) and MeO-2PACz ([2-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl]phosphonic acid) molecules were investigated as hole-extracting interlayers in organic photovoltaics (OPVs). The highest occupied molecular orbital (HOMO) energies of these SAMs were measured at -6.01 and -5.30 eV for Br-2PACz and MeO-2PACz, respectively, and found to induce significant changes in the work function (WF) of indium-tin-oxide (ITO) electrodes upon chemical functionalization. OPV cells based on PM6 (poly[(2,6-(4,8-bis(5-(2-ethylhexyl-3-fluoro)thiophen-2-yl)-benzo[1,2-b:4,5-b']dithiophene))-alt-(5,5-(1',3'-di-2-thienyl-5',7'-bis(2-ethylhexyl)benzo[1',2'-c:4',5'-c']dithiophene-4,8-dione)]) : BTP-eC9 : PC71 BM ([6,6]-phenyl-C71-butyric acid methyl ester) using ITO/Br-2PACz anodes exhibited a maximum power conversion efficiency (PCE) of 18.4 %, outperforming devices with ITO/MeO-2PACz (14.5 %) and ITO/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT : PSS) (17.5 %). The higher PCE was found to originate from the much higher WF of ITO/Br-2PACz (-5.81 eV) compared to ITO/MeO-2PACz (4.58 eV) and ITO/PEDOT : PSS (4.9 eV), resulting in lower interface resistance, improved hole transport/extraction, lower trap-assisted recombination, and longer carrier lifetimes. Importantly, the ITO/Br-2PACz electrode was chemically stable, and after removal of the SAM it could be recycled and reused to construct fresh OPVs with equally impressive performance.

Some data quality issues at ClinicalTrials.gov.

BACKGROUND: Clinical trial registries have been established as a form of public accountability. Sponsors ought to register their trials promptly and accurately, but this is not always done. Some of the problems include non-registration of trials, registration of trials with incomplete information, and non-reporting of trial results on time. In this study we enumerate or quantify some quality issues with respect to Principal Investigator (PI) and Responsible Party data. METHODS: We analyzed interventional trials registered with ClinicalTrials.gov. Using certain selection criteria, we started with 112,013 records, and then applied further filters. The trial had to (a) start between 1 January 2005 and 31 December 2014, (b) include a "drug" or "biological" in the "intervention" field, (c) be registered with an American authority, and (d) list a real person's name as investigator and also his or her role in the study. RESULTS: We identified four categories of errors in the ClinicalTrials.gov records. First, some data were missing. The name of the investigator, or his or her role, was missing in 12% of 35,121 trials. In examining 71,359 pairs of names and roles, 17% of the "names" were found to be not those of real persons, but instead junk information. Second, there were variations in a large number of names. We identified 19 categories of variants. We determined that 13% of the names had variants that could not be resolved using a program. Third, some trials listed many PIs each, although only one such person holds overall responsibility for the trial and therefore not more than one person should be listed as PI. Fourth, in examining whether the PI's name was available as part of the Responsible Party tag, we found that in 1221 (3.5%) of 35,121 trials, the Responsible Party tag is absent. CONCLUSIONS: We have outlined four categories of problems with data hosted by ClinicalTrials.gov and have quantified three of them. We also suggest how these errors could be prevented in future. It is important to carry out various kinds of audits of trial registries, in order to identify lacunae in the records, that they be addressed.

Systemic Associations of Childhood Glaucoma: A Review.

PURPOSE: To review systemic associations of childhood glaucoma. METHODS: Patients younger than 15 years and diagnosed as having glaucoma were divided into four groups: isolated primary congenital glaucoma, glaucoma with other congenital ocular anomalies, congenital glaucoma with known systemic diseases, and secondary glaucoma. Prevalence and type of systemic associations in each group were studied. RESULTS: A retrospective analysis of 371 patients diagnosed as having glaucoma was done. In the primary congenital glaucoma group, 13 of 218 (5.9%) patients had an associated systemic illness: congenital heart disease and global developmental delay were the most common systemic manifestations. In the congenital ocular anomalies group, 10 of 63 (15.8%) patients had an associated systemic illness. Axenfeld-Reiger syndrome, aniridia, and Peters' anomaly frequently had systemic comorbidities with congenital heart disease. In the known systemic diseases group, all 18 (100%) patients had systemic manifestations of an associated syndrome: Sturge-Weber and Down syndrome were the most frequent. In the secondary glaucoma group, 9 of 72 (12.5%) patients had systemic involvement, which was often seen as the most common cause after congenital cataract surgery. These children had congenital heart disease and global developmental delay as a consequence of congenital rubella and congenital cytomegalovirus infection. CONCLUSIONS: The study found that 12.9% of patients with childhood glaucoma had an associated systemic abnormality. Patients with congenital glaucoma and other ocular anomalies have a three times higher risk of an underlying systemic anomaly than patients with isolated primary congenital glaucoma. A team comprising an ophthalmologist, pediatrician, and anesthesiologist is recommended to treat these cases. [J Pediatr Ophthalmol Strabismus. 2018;55(6):397-402.].

Sympatric distribution of Plasmodium ovale curtisi and P. ovale wallikeri in India: implication for the diagnosis of malaria and its control.

BACKGROUND: We report the first evidence of sympatric distribution of Plasmodium ovale curtisi and P. ovale wallikeri from India. METHODS: Fingerprick blood samples were collected from fever cases in district Bastar, Chhattisgarh State for malaria screening by microscopy and PCR. RESULTS: Two cases of mono infection of P. ovale, and a fatal case of cerebral malaria with a mixed infection of P. vivax, P. falciparum and P. ovale were confirmed by PCR. Sequencing analysis revealed the presence of P. ovale curtisi and P. ovale wallikeri. CONCLUSIONS: This study highlights the need of molecular diagnosis of malaria cases in forested areas for treatment and control.

Plasmonic effect of spray-deposited Au nanoparticles on the performance of inverted organic solar cells.

Gold nanoparticles with varying sizes were prepared by the spray process under an electric field (DC voltages of 0 V and 1 kV applied to the nozzle) for studying their role in inverted organic solar cells (ITO/Au/ZnO/P3HT:PCBM/Ag). The application of electric field during the spray process resulted in a smaller size (35 nm as compared to 70 nm without the electric field) of the nanoparticles with more uniform distribution. This gave rise to a difference in the surface plasmon resonance (SPR) effect created by the gold nanoparticles (Au NPs), which then affected the solar cell performance. The photovoltaic performances of plasmonic inverted organic solar cells (ITO/Au/ZnO/P3HT:PCBM/Ag) using spray-deposited Au and ZnO layers (both at 1 kV) showed improved efficiency. Fast exciton quenching in the P3HT:PCBM layer was achieved by using a spray-deposited Au layer in between ITO and ZnO layers. The absorption spectra and internal power conversion efficiency (IPCE) curve showed that the Au nanoparticles provide significant plasmonic broadband light absorption enhancement which resulted in the enhancement of the JSC value. Maximum efficiency of 3.6% was achieved for the inverted organic solar cell (IOSC) with an exceptionally high short circuit current density of ∼15 mA cm(-2) which is due to the additional photon absorption and the corresponding increase observed in the IPCE spectrum. The spray technique can be easily applied for the direct formation of Au nanoparticles in the fabrication of IOSC with improved performance over a large area.

Application of anterior segment optical coherence tomography in glaucoma.

Optical coherence tomography (OCT) is a cross-sectional, three-dimensional, high-resolution imaging modality that uses low coherence interferometry to achieve axial resolution in the range of 3-20 µm. Two OCT platforms have been developed: time domain (TD-OCT) and spectral (or Fourier) domain (SD/FD-OCT). Visante anterior segment OCT (Carl Zeiss Meditec) is a TD-OCT widely used for anterior segment imaging. The SD-OCT systems with both posterior and anterior segment imaging capabilities include the RTVue, iVue (Optovue), the Cirrus (Carl Zeiss Meditec), and the Spectralis (Heidelberg Engineering, Inc.). Each of the SD-OCTs has a wavelength in the range of 820-879 nm. Anterior segment OCT is a non-contact method providing high resolution tomographic cross-sectional imaging of anterior segment structures. Anterior segment OCT provides qualitative and quantitative assessment of the anterior segment structures important to the pathogenesis and the anatomical variations of glaucoma, and the approach to and success of treatment. We summarize the clinical applications of anterior segment OCT in glaucoma.

Mechanism of magnesium activation of calcium-activated potassium channels.

Large-conductance (BK type) Ca(2+)-dependent K(+) channels are essential for modulating muscle contraction and neuronal activities such as synaptic transmission and hearing. BK channels are activated by membrane depolarization and intracellular Ca(2+) and Mg(2+) (refs 6-10). The energy provided by voltage, Ca(2+) and Mg(2+) binding are additive in activating the channel, suggesting that these signals open the activation gate through independent pathways. Here we report a molecular investigation of a Mg(2+)-dependent activation mechanism. Using a combined site-directed mutagenesis and structural analysis, we demonstrate that a structurally new Mg(2+)-binding site in the RCK/Rossman fold domain -- an intracellular structural motif that immediately follows the activation gate S6 helix -- is responsible for Mg(2+)-dependent activation. Mutations that impair or abolish Mg(2+) sensitivity do not affect Ca(2+) sensitivity, and vice versa. These results indicate distinct structural pathways for Mg(2+)- and Ca(2+)-dependent activation and suggest a possible mechanism for the coupling between Mg(2+) binding and channel opening.