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Hyponatraemia is the most common electrolyte disturbance observed in hospital inpatients. We report a 90-year-old woman admitted generally unwell following a fall with marked confusion. Examination revealed a tender suprapubic region, and investigations observed elevated inflammatory markers and bacteriuria. Admission investigations demonstrated a serum sodium of 110 mmol/L with associated serum osmolality 236 mmol/kg and urine osmolality 346 mmol/kg. She was treated for hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone (SIADH) and urosepsis. However, her serum sodium failed to normalise despite fluid restriction, necessitating treatment with demeclocycline and hypertonic saline. Despite slow reversal of hyponatraemia over 1 month, the patient developed generalised seizures with pontine and thalamic changes on MRI consistent with osmotic demyelination syndrome (ODS). This case highlights the risk of ODS, a rare but devastating consequence of hyponatraemia treatment, despite cautious sodium correction.

Funder: Canadian Institutes of Health Research (Grant: FRN-142349) Natural Sciences and Engineering Research Council of Canada (Grant: RGPIN 05871-2014), Cells replicate and segregate their DNA with precision. Previous studies showed that these regulated cell-cycle processes were present in the last eukaryotic common ancestor and that their core molecular parts are conserved across eukaryotes. However, some metamonad parasites have secondarily lost components of the DNA processing and segregation apparatuses. To clarify the evolutionary history of these systems in these unusual eukaryotes, we generated a genome assembly for the free-living metamonad Carpediemonas membranifera and carried out a comparative genomics analysis. Here, we show that parasitic and free-living metamonads harbor an incomplete set of proteins for processing and segregating DNA. Unexpectedly, Carpediemonas species are further streamlined, lacking the origin recognition complex, Cdc6 and most structural kinetochore subunits. Carpediemonas species are thus the first known eukaryotes that appear to lack this suite of conserved complexes, suggesting that they likely rely on yet-to-be-discovered or alternative mechanisms to carry out these fundamental processes.

Self-medication of pain with alcohol is prevalent, and expectancies for alcohol analgesia (EAA) likely influence pain relief and alcohol consumption. Hazardous alcohol use has been associated with greater delay discounting rates; however, little is known about the relationship between delay discounting and EAA. Therefore, the present study examined sex differences in associations between delay discounting and EAA. Healthy drinkers without chronic pain (N = 53) completed measures of EAA, alcohol use, and alcohol outcome expectancies. A five-trial adjusting-delay discounting task (DDT) for monetary outcomes was also administered. Regression analyses revealed that sex moderated the relationship between delay discounting and EAA. Steeper delay discounting rates were associated with weaker EAA among men when adjusting for average alcohol consumption. Among women, nonsignificant associations between delay discounting rates and EAA were observed. These findings provide initial evidence of sex differences in associations between delay discounting and EAA. The directionality of these associations was unexpected and may have implications for patterns of self-medication with alcohol. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Members of the α-thymosin family have long been studied for their immunostimulating properties. Among them, the danger-associated molecular patterns (DAMPs) prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) have been shown to act as immunomodulators in vitro, due to their ability to promote T helper type 1 (Th1) responses. Recently, we verified these findings in vivo, showing that both proTα and proTα(100-109) enhance antitumor-reactive T cell-mediated responses. Methods: In view of the eventual use of proTα and proTα(100-109) in humans, we investigated their safety profile in silico, in human leukocytes and cancer cell lines in vitro, and in immunocompetent mice in vivo, in comparison to the proTα derivative thymosin alpha 1 (Τα1), a 28-mer peptide extensively studied for its safety in clinical trials. Results: In silico prediction via computational tools showed that all three peptide sequences likely are non-toxic or do not induce allergic regions. In vitro, pro- Tα, proTα(100-109) and Tα1 did not affect the viability of human cancer cell lines and healthy donor-derived leukocytes, did not promote apoptosis or alter cell cycle distribution. Furthermore, mice injected with proTα, proTα(100-109) and Tα1 at doses equivalent to the suggested dose regimen of Tα1 in humans, did not show signs of acute toxicity, whereas proTα and proTα(100-109) increased the levels of proinflammatory and Th1- type cytokines in their peripheral blood. Conclusion: Our preliminary findings suggest that proTα and proTα(100-109), even at high concentrations, are non-toxic in vitro and in an acute toxicity model in vivo; moreover, we show that the two peptides retain their immunomodulatory properties in vivo and, eventually, could be considered for therapeutic use in humans.

PURPOSE Adams-Oliver syndrome is a rare, inherited disorder of embryologic development that affects multiple systems. Ocular manifestations have been poorly characterized due to the low prevalence and high mortality of the disease when it is associated with internal organ and/or ophthalmic manifestations. We present a case of Adams-Oliver syndrome in a 13-year-old patient whose multimodal retinal imaging findings helped direct management. METHODS Case report reviewing medical records and imaging. PATIENTS Single patient. RESULTS Visual acuity upon presentation was 20/40 in each eye. Ultra-widefield fluorescein angiography revealed peripheral non-perfusion with terminal vascular bulbs, as well as leakage from a temporal fibrovascular complex in the left eye. Fundus autofluorescence imaging showed hyperautofluorescence associated with optic disc drusen and the fibrovascular complex. Treatment with targeted laser photocoagulation was associated with regression of the neovascularization. CONCLUSIONS Retinal manifestations of Adams-Oliver syndrome as observed with ultra-widefield fundus imaging may resemble those of familial exudative vitreoretinopathy and retinopathy of prematurity. Treatment of avascular retina with panretinal photocoagulation can be considered.

BackgroundEnvironmental water samples are increasingly recognised as an important reservoir of antimicrobial resistance (AMR) genes. Polymerase chain reaction (PCR) and next generation sequencing (NGS) offer a potentially inclusive surveillance platform for a wide range of AMR genes. However, molecular methods are dependent upon the extraction of DNA of high yield and quality. Current options for DNA extraction from complex environmental matrices for downstream molecular applications are either expensive or low yielding. We present here a novel magnetic bead-based DNA extraction method, for the detection of antimicrobial resistance genes (ARGs) from river water in Malawi, named MagnaExtract. MethodsMagnaExtract involves initial filtration of 250ml freshwater, followed by an overnight incubation of the filter in 15ml buffered peptone water (BPW), common procedure in microbiology laboratories. 200{micro}l is then taken for a boil (95{degrees}C) and spin step and mixed with magnetic beads to bind DNA. Following washes with ethanol, the DNA is eluted in nuclease-free water. To determine the effectiveness of this method, 98 freshwater samples were collected from two rivers in Southern Malawi, and DNA was isolated using the MagnaExtract method, two commercial Qiagen (Germany) kits; PowerWater and DNeasy Blood and tissue, alongside a boil and spin of BPW, and a boil and spin from bacterial isolate grown on agar media. All samples were screened with a high-resolution melt (HRM) PCR panel previously validated for the detection of third generation cephalosporin and carbapenem ARGs. We compared the DNA yield obtained using all extraction methods, as well as the identification of each ARG. ResultsDNA yield using MagnaExtract was statistically greater than both boil and spin methods and DNeasy Blood & Tissue (Qiagen, Germany). DNA yield was slightly lower than using PowerWater (Qiagen) but the difference was not statistically significant. MagnaExtract was the only method to identify ARGs in all 98 water samples compared with PowerWater (n=82), DNeasy (n=95) boilate of BPW (n=75) and boilate of bacterial isolate (n=87). The most commonly detected ARG was OXA-48 (n=93). In addition, we found overnight incubation in non-selective enrichment broth (BPW) to promote the growth of bacteria harbouring extended spectrum beta lactamase (ESBL) genes and reduction in the detection of carbapenemase genes. ConclusionThe MagnaExtract approach offers a simple, affordable, high yielding DNA extraction method for the detection of ARGs isolated from river water samples.

In the first results from an ongoing global cancer screening data repository, screening program organization was better overall in Europe compared to other continents; however, there were substantial gaps in implementation across both high- and low-resource settings. The CanScreen5 project is a global cancer screening data repository that aims to report the status and performance of breast, cervical and colorectal cancer screening programs using a harmonized set of criteria and indicators. Data collected mainly from the Ministry of Health in each country underwent quality validation and ultimately became publicly available through a Web-based portal. Until September 2022, 84 participating countries reported data for breast (n = 57), cervical (n = 75) or colorectal (n = 51) cancer screening programs in the repository. Substantial heterogeneity was observed regarding program organization and performance. Reported screening coverage ranged from 1.7% (Bangladesh) to 85.5% (England, United Kingdom) for breast cancer, from 2.1% (Cote d'Ivoire) to 86.3% (Sweden) for cervical cancer, and from 0.6% (Hungary) to 64.5% (the Netherlands) for colorectal cancer screening programs. Large variability was observed regarding compliance to further assessment of screening programs and detection rates reported for precancers and cancers. A concern is lack of data to estimate performance indicators across the screening continuum. This underscores the need for programs to incorporate quality assurance protocols supported by robust information systems. Program organization requires improvement in resource-limited settings, where screening is likely to be resource-stratified and tailored to country-specific situations.

The capability of synthesized zeolite A (SZ) to immobilize Ag ions (Ag-SZ) and Ag nanoparticles (AgNp-SZ) were comparatively studied. A novel approach of in situ biosynthesized AgNP-incorporated synthesized zeolite A (AgNp-SZ) was synthesized at an optimum volume of 0.4 mL of the Orthosiphon aristatus (O. aristatus) leaves plant extract (5%) using an in situ approach. In comparison, Ag-SZ was produced by loading the synthesized zeolite with Ag ions. All synthesized materials were characterized for their morphologies and physicochemical properties. The characterization analyses validate that the biosynthesized AgNP (

Thorium mineralization is frequently hosted in carbonate-bearing rocks, and thorium commonly substitutes into the structures of carbonate-bearing minerals that have precipitated from or been modified by hydrothermal fluids. Given this common association, it is reasonable to consider the hypothesis that the presence of carbonate ligands in hydrothermal solutions promotes the transport of Th through the formation of stable aqueous complexes. Our ability to evaluate this hypothesis, however, is hindered by the lack of experimental data for Th-carbonate species at conditions beyond ambient. The low-temperature data indicate that carbonate is a strong complexing agent for Th. In this contribution, we investigate the solubility of Th in carbonate-bearing fluids relevant to natural systems (0.05–0.5 m NaHCO3/Na2CO3; pHT ~ 7.8–9.8) at elevated temperature (175–250 °C). We demonstrate that, in contrast to the behavior of Th at low temperature, the stability of Th-carbonate complexes is not sufficient for them to predominate at these conditions. Instead, the solubility of Th is governed by hydrolysis reactions. Under the experimental conditions investigated, the predominant hydroxyl complexes are Th(OH)40 and Th(OH)5−. Thermodynamic formation constants were derived for these species at the temperatures considered in our experiments (log β4 = 43.34 and 44.31 at 175 and 200 °C, respectively, and log β5 = 46.15 and 47.9 at 225 and 250 °C, respectively) to permit forward modeling of Th mobility in natural systems. Our study indicates that carbonate ions are unlikely to play a role in transporting Th in hydrothermal fluids. Summarizing the results of this study and our previous studies of the solubility of Th in hydrothermal fluids, we conclude that SO42− is the primary ligand responsible for the hydrothermal transport of Th.

Rare earth elements (REEs) mobilize, fractionate, and are re-distributed during supergene processes, and thus provide a powerful tool with which to quantitatively reconstruct the effects of chemical weathering. Moreover, under certain conditions, the REEs can concentrate to levels in the regolith sufficient to form giant regolith-hosted REE deposits, that are now responsible for much of the World’s production of heavy REEs (HREEs). Understanding the supergene behavior of the REEs is an important first step towards applying the REEs as a geochemical tool and meeting the growing global demand of the REEs. Thermodynamic calculations predict that dissolution of the main REE minerals in REE-rich protoliths, namely synchysite-(Y), gadolinite-(Y), hingganite-(Y), yttrialite-(Y), allanite-(Ce), eudialyte, chevkinite-(Ce), britholite, euxenite and loparite-(Ce), should occur spontaneously during weathering. It therefore follows that a high abundance of these minerals in the protolith implies high mobility of the REEs during weathering and consequently a high potential for the discovery of economic REE resources. Dissolution of apatite is promoted by metamictization or structural distortion and could be also important at low pH. In contrast, some LREE-fluorocarbonate minerals, notably bastnasite-(Ce) and parisite-(Ce), and monazite-(Ce) are likely thermodynamically stable in acidic environments. Thus, they would be preserved in the regolith. Zircon, titanite, aeschynite, fergusonite, and xenotime-(Y) are resistant to acidic dissolution, consistent with their common occurrence as residual minerals. In the cases of the world-class regolith-hosted REE deposits in South China, the groundwater is mildly acidic to circumneutral and carbonate-rich. The REEs are consequently transported dominantly as hydrated cations and carbonate complexes, depending on the pH. The general inheritance of the REE pattern of the regolith groundwater in the clay-sorbed fraction in the regolith indicates that the REEs in regolith are scavenged from the regolith groundwater. Elemental anomalies of specific REEs in the clay-sorbed fraction are very likely caused by an anomalously high REECO3+ fraction in the corresponding regolith groundwater, suggesting a preferential uptake of the REECO3+ complexes by the clay minerals, feasibly by halloysite through intercalation as interlayer complexes. This reaction is expected to be particularly important for the sorption and enrichment of the HREEs in the regolith. Depending on the pH and carbonate concentration of the water, surface complexation on clay minerals or interlayer intercalation particularly in halloysite control the pattern of REE enrichment. Mixing of the regolith groundwater with the alkaline and carbonate-rich aquifer groundwater increases the pH and carbonate concentration and, in turn, affects the ability of the mixed water to transport the HREEs. Interplay of aqueous complexation with the regolith mineralogy significantly affects the REE fractionation and re-distribution during groundwater-regolith interaction.

This essay analyzes the scientific evidence that forms the basis of bioactive materials, covering the fundamental understanding of bioactivity phenomena and correlation with the mechanisms of biocompatibility of biomaterials. This is a detailed assessment of performance in areas such as bone-induction, cell adhesion, immunomodulation, thrombogenicity and antimicrobial behavior. Bioactivity is the modulation of biological activity by characteristics of the interfacial region that incorporates the material surface and the immediate local host tissue. Although the term ‘bioactive material’ is widely used and has a well understood general meaning, it would be useful now to concentrate on this interfacial region, considered as ‘the bioactivity zone’. Bioactivity phenomena are either due to topographical/micromechanical characteristics, or to biologically active species that are presented in the bioactivity zone. Examples of topographical/micromechanical effects are the modulation of the osteoblast – osteoclast balance, nanotopographical regulation of cell adhesion, and bactericidal nanostructures. Regulation of bioactivity by biologically active species include their influence, especially of metal ions, on signaling pathways in bone formation, the role of cell adhesion molecules and bioactive peptides in cell attachment, macrophage polarization by immunoregulatory molecules and antimicrobial peptides. While much experimental data exists to demonstrate the potential of such phenomena, there are considerable barriers to their effective clinical translation. This essay shows that there is solid scientific evidence of the existence of bioactivity mechanisms that are associated with some types of biomaterials, especially when the material is modified in a manner designed to specifically induce that activity.

Carbocationic intermediates play an important role in the construction of complex molecules, from biosynthetic pathways in nature to the synthesis of natural products by organic chemists. Herein, a brief introduction that surveys C–C bond forming reactions of vinyl carbocations is highlighted. The discussion of experimental work commences with the development of a main group-catalyzed approach towards accessing vinylated esters through the trapping of vinyl carbocations with silyl ketene acetals. Next, a Claisen-type rearrangement is discussed, which is a result of trapping vinyl carbocations with allyl ethers to form an allyl vinyl oxonium intermediate in situ that can subsequently rearrange. Finally, the last method that is highlighted includes the development of an asymmetric C–H insertion reaction of vinyl carbocations to forge bicyclic products in a highly enantioselective fashion.

La Trobe University Faculty of Science, Technology and Engineering Murray Darling Freshwater Research CentreMDFRC item.Wetlands in many inland catchments are being subjected to increasing salinity. To expand our limited understanding of how increasing salinity will alter carbon and nutrient dynamics in freshwater sediments, we carried out microcosm experiments to examine the acute effects of increasing salinity on the anaerobic cycling of carbon, nutrients (N, P, and S), metals (Fe and Mn), and microbial community structure in sediments from a non-salt-impacted freshwater wetland. Sediments were collected from a wetland on the River Murray floodplain, south eastern Australia and incubated with NaCl concentrations ranging from 0 to 100 mmol L-1. Increasing NaCl concentration led to the immediate release of between about 80 and 190 µmol L-1 ammonium and 235 to 3300 µmol L-1 Fe(II) from the sediments, the amount released `increasing with NaCl concentration. Conversely, net phosphate release decreased with increasing NaCl concentration. The overall microbial community structure, determined from phospholipid fatty acid profiles, changed only at the highest NaCl loadings, with evidence of a decrease in microbial diversity. Bacterial community structure, determined by examining terminal restriction fragment length polymorphism (T-RFLP) of the bacterial 16S rRNA gene, showed little response to increasing NaCl concentration. Conversely, the archaeal (methanogen) population, determined by examining T-RFLP of the archaeal 16S rRNA gene, showed significant changes with increasing NaCl loading. This shift corresponded with a significant decrease in methane production from salt-impacted sediments and therefore shows a linkage between microbial community structure and an ecosystem process.

A theoretical treatment on the oxide-controlled dwell fatigue crack growth of a γ’ strengthened nickel-based superalloys is presented. In particular, this study investigates the influence of an externally applied load and variations in the γ’ dispersion on the grain boundary oxide growth kinetics. A dislocation-based viscoplastic constitutive description for high temperature deformation is used to simulate the stress state evolution in the vicinity of a crack at elevated temperature. The viscoplastic model explicitly accounts for multimodal γ’ particle size distributions. A multicomponent mass transport formulation is used to simulate the formation/evolution of an oxide wedge ahead of the crack tip, where stress-assisted vacancy diffusion is assumed to operate. The resulting set of constitutive and mass transport equations have been implemented within a finite element scheme. Comparison of predicted compositional fields across the matrix/oxide interface are compared with experiments and shown to be in good agreement. Simulations indicate that the presence of a fine γ’ size distribution has a strong influence on the predicted ow stress of the material and consequently on the relaxation in the vicinity of the crack-tip/oxide wedge. It is shown that a unimodal dispersion leads to reduced oxide growth rates (parabolic behavior) when compared to a bimodal one. Stability conditions for oxide formation are investigated and is associated with the prediction of compressive stresses within the oxide layer just ahead of the crack tip, which become progressively negative as the oxide wedge develops. However, mechanical equilibrium requirements induce tensile stresses at the tip of the oxide wedge, where failure of the oxide is predicted. The time taken to reach this critical stress for oxide failure has been calculated, from which dwell crack growth rates are computationally derived. The predicted rates are shown to be in good agreement with available experimental data.

The Nova-Bollinger Ni-Cu sulfide ore deposit is the first economic Ni-Cu-Co sulfide deposit to have been discovered in the Albany-Fraser orogen in Western Australia. The host rocks are mafic-ultramafic intrusive cumulates subdivided into two connected intrusions, designated Upper and Lower. The Upper Intrusion is bowl-shaped and modally layered with alternating peridotite and norite mesocumulate layers, with a Basal Series of dominantly orthocumulate mafic lithologies. The Lower Intrusion is a much thinner, semiconformable chonolith (flattened tube-shaped intrusion) consisting of mostly unlayered mafic to ultramafic orthocumulates. The Lower Intrusion hosts all the high-grade mineralization and most of the disseminated ores. A distinctive plagioclase-bearing lherzolite containing both orthopyroxene and olivine as cumulus phases is a characteristic of the Lower Intrusion and the Basal Series of the Upper. The intrusions differ slightly in olivine and spinel chemistry, the differences being largely attributable to the more orthocumulate character of the Lower Intrusion. Sector zoning in Cr content of pyroxenes is observed in the Lower Intrusion and in the lower marginal zone of the Upper and is attributed to crystallization under supercooled conditions. Symplectite pyroxene-spinel-amphibole coronas at olivine-plagioclase contacts are ubiquitous and are attributed to near-solidus peritectic reaction between olivine, plagioclase, and liquid during and after high-pressure emplacement, consistent with high Al contents in igneous pyroxenes and estimates of the peak regional metamorphism. Original cumulus olivines had compositions around Fo86 and were variably Ni depleted, interpreted as the result of preintrusion equilibration with sulfide liquid. The Upper and Lower Intrusion rocks represent cumulates from a similar parental magma, a high-Al tholeiite with MgO between 10 and 12%, low TiO2 (0.5–0.6%), and high Al2O3 (14–17%). Modeling using alphaMELTS indicates a primary water content of around 2 wt %. The cumulates of both intrusions were derived via multiple magma pulses of liquid-olivine-sulfide slurries with variable amounts of orthopyroxene emplaced into the deep crust at pressures of around 0.7 GPa during the peak of regional metamorphism. The intrusions developed initially as a bifurcating sill, the lower arm developing into the ore-bearing Lower Intrusion chonolith and the upper arm inflating into the cyclically layered Upper Intrusion.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was −4.04 (0.48) mg/g dry weight for deferiprone vs −4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, −0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

The production of hydrogen (H2) from the pyrolysis–catalytic steam reforming of polyethylene, polystyrene (PS) and polyethylene terephthalate waste plastics was investigated using a two-stage reactor. The highest yield of hydrogen (125 mmol/gplastic) was obtained with PS at a catalyst temperature of 900°C and steam input weight hourly space velocity of 7.59 g/(h/gcatalyst) with a 10 wt% nickel/aluminium oxide (Ni/Al2O3) catalyst. Further investigation using PS showed that the process parameters of high catalyst temperature (900°C) and optimised steam input rate significantly increased the yield of hydrogen. Examination of several different catalysts (nickel/aluminium oxide, iron/aluminium oxide, copper/aluminium oxide, cobalt/aluminium oxide) showed that nickel/aluminium oxide had by far the highest catalytic activity and selectivity towards the yield of hydrogen.

To evaluate the visual outcomes and the affect of timing of surgical repair of fovea-splitting rhegmatogenous retinal detachments.A retrospective, consecutive cohort from multiple surgeons at a single center. Fovea status (fovea-on, fovea-splitting, or fovea-off) was classified by preoperative optical coherence tomography. The primary outcome measure was the visual acuity at the last follow-up that was further correlated with the timing of surgical repair.One hundred and ninety-five eyes were included with 62 fovea-on, 65 fovea-splitting, and 68 fovea-off detachments. The mean preoperative logarithm of the minimum angle of resolution visual acuity for fovea-on, fovea-splitting, and fovea-off groups was 0.16 ± 0.21, 0.70 ± 0.56, and 1.67 ± 0.87, respectively (P =0.001). Mean postoperative logarithm of the minimum angle of resolution visual acuity for fovea-on, fovea-splitting, and fovea-off groups were 0.07 ± 0.13, 0.10 ± 0.15, and 0.20 ± 0.22, respectively (P =0.001). A statistically significant difference in mean postoperative logMAR visual acuity was found between fovea-off and fovea-on groups (P = 0.003) and between fovea-off and fovea-splitting groups (P = 0.013), however not between fovea-on and fovea-splitting groups (P = 0.827). Visual acuity improved when repair was performed earlier after presentation for fovea-on (R = 0.378, P = 0.002) and fovea-off groups (R = 0.277, P = 0.022), but not for the fovea-splitting group (R = 0.089, P = 0.481).We described the favorable visual outcomes of surgery for fovea-splitting rhegmatogenous retinal detachment and correlated these with the timing of surgical repair, which may help guide the management of this urgent, vision-threatening condition.

A mathematical model for the catalytic autothermal reforming (ATR) reaction of synthetic crude glycerol to hydrogen in a fixed bed tubular reactor (FBTR) and over an in-house developed metal oxide catalyst is presented in this work. The heterogeneous model equations account for a two-phase system of solid catalyst and bulk feed gas. Also, the ATR of crude glycerol reaction scheme and intrinsic kinetic rate model over an active, selective, and stable nickel-based catalyst were integrated in the developed model. Also, the model was validated using experimental data generated in our labs for the ATR of synthetic crude glycerol. The modelling results adequately described the detailed gas product composition and distribution, temperature profiles, and conversion propagation in the axial direction of the fixed bed reactor over a wide range of reaction temperature (773−923 K) and weight-time (12.71−158.23 g cat·min·molC−1). The crude glycerol conversion predicted with the model showing a close resemblance to those obtained experimentally with an average absolute deviation (AAD) of less than 8%. The maximum crude glycerol conversion and hydrogen yield were found to be 92% and 3 mol hydrogen/mol crude glycerol, respectively. Also, the gas product concentration profile in the reactor was adequately described (90%) accuracy with a hydrogen concentration of 39 vol%.

Lewis-acid mediated allylations of β-alkoxy N-tosyl imines lead to 3-alkoxy homoallylic N-tosyl amines with anti diastereoselectivity. Diastereoselectivity and yields of reactions are comparable between two methods of Hosomi-Sakurai allylations. Observed selectivity trends and computational evidence suggest that 1,3 asymmetric induction occurs through the formation of a six- membered ring chelate which adopts a half-chair-like conformation. The product ratios of allylations to β-alkoxy N-tosyl imines are dependent on conformation preferences of the chelate and stereoelectronic interactions in the transition-state structures. Debenzylation and detosylation of these allylation products result in anti 1,3-amino alcohols, a privileged motif in synthetic and natural bioactive compounds.

Purpose To report the efficacy of photodynamic therapy (PDT) for management of retinal hemangioblastoma. Design Retrospective case series. Participants Seventeen patients with retinal hemangioblastoma treated with PDT. Methods The medical records of 17 patients with retinal hemangioblastoma treated with PDT were reviewed, and treatment outcomes were assessed. Photodynamic therapy was performed with 6 mg/m2 body surface area of verteporfin infused intravenously over 10 minutes activated by 50 J/cm2 laser light at 689 nm for 83 or 166 seconds. Main Outcome Measures Tumor control, subretinal and intraretinal fluid resolution, and visual outcome. Results Eighteen retinal hemangioblastomas in 17 eyes were treated with PDT. Median patient age was 31 years (mean, 36 years; range, 7–66 years), and median follow-up was 51 months (mean, 61 months; range, 2–144 months). Genetic testing confirmed von Hippel-Lindau disease in 8 of 17 patients (47%). The tumors were unilateral in all patients and unifocal in most patients (n = 13/17 [76%]). The tumor median basal diameter was 3.5 mm (mean, 3.4 mm; range, 1.5–6.0 mm) and median thickness was 2.1 mm (mean, 2.3 mm; range, 1.0–5.0 mm). The tumor location was juxtapapillary in 9 of 18 cases (50%). Associated findings included subretinal fluid (n = 14/17 [82%]) and macular edema (n = 12/17 [71%]). The median number of PDT sessions was 1.5 (mean, 1.8; range, 1.0–4.0). Standard duration of PDT (83 seconds) was used in all cases except 2, in which double duration (166 seconds) was used. Outcomes revealed tumor control in 13 of 18 tumors (72%), partial or complete resolution of subretinal fluid in 10 of 14 eyes (71%), and partial or complete resolution of macular edema in 7 of 12 eyes (58%), and stable or improved visual acuity in 12 of 17 eyes (71%). Photodynamic therapy-related transient exudative response was noted in 4 of 17 eyes (24%). Conclusions Photodynamic therapy is an effective treatment for both juxtapapillary and peripheral retinal hemangioblastomas, providing satisfactory rates of tumor control and visual stabilization and improvement. Patients should be monitored for PDT-related transient exudative response.

Plasma membrane tension is known to regulate many cell functions, such as motility and membrane trafficking. Membrane tether pulling is an effective method for measuring the apparent membrane tension of cells and exploring membrane-cytoskeleton interactions. In this article, the mechanical properties of HP1α-depleted MCF7 breast cancer cells are explored in comparison to controls, by pulling membrane tethers using optical tweezers. These studies were inspired by previous findings that a loss of HP1α correlates with an increase in the invasive potential of malignant cancer cells. Specifically, the membrane tension and force relaxation curves for tethers pulled from MCF7 breast cancer cells with HP1α knockdown and their matched controls were measured, and shown to be significantly different.

Purpose:\ud Low-dose whole lung radiotherapy (LDLR) has been proposed as a treatment for patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling and mechanisms of action.\ud \ud Materials and methods:\ud Female C57BL/6 mice were treated with intranasal bleomycin sulphate (7.5 or 11.25 units/kg, day 0), then exposed to whole lung radiation therapy (0.5, 1.0, 1.5 Gy or sham, day 3). Bodyweight was measured daily and lung tissue harvested for histology and flow cytometry on day 10. Computed tomography (CT) lung imaging was performed pre-radiation (day 3) and pre-endpoint (day 10).\ud \ud Results:\ud Bleomycin caused pneumonitis of variable severity which correlated with weight loss. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight and a proportion of these mice exhibited less severe histopathological lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. Additionally, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids. Overall, bleomycin-treated mice exhibited significantly higher percentages of non-aerated lung in left than right lungs and LDLR (1.0 Gy) limited further reductions in aerated lung volume in right but not left lungs. LDLR at 0.5 and 1.5 Gy did not improve bodyweight, flow cytometric or radiological readouts of bleomycin-induced pneumonitis.\ud \ud Conclusions:\ud Our data support the concept that LDLR can ameliorate acute inflammatory lung injury, identify 1.0 Gy as the most effective dose and provide evidence that it is more effective in the context of moderate than severe pneumonitis. Mechanistically, LDLR at 1.0 Gy significantly suppressed bleomycin-induced accumulation of pulmonary interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids.

Most tungsten (W) and tin (Sn) deposits are associated with highly evolved granites derived from the anatexis of metasedimentary rocks. They are commonly separated in both space and time, and in the rare cases where the W and Sn mineralization are part of a single deposit, the two metals are temporally separate. The factors controlling this behavior, however, are not well understood. Our compilation of whole-rock geochemical data for W- and Sn-related granites in major W-Sn metallogenic belts shows that the Sn-related granites are generally the products of higher-temperature partial melting (~800 °C) than the W-related granites (~750 °C). Thermodynamic modeling of partial melting and metal partitioning shows that W is incorporated into the magma formed during low-temperature muscovite-dehydration melting, whereas most of the Sn is released into the magma at a higher temperature during biotite-dehydration melting; the Sn of the magma may be increased significantly if melt is extracted prior to biotite melting. At the same degree of partial melting, the concentrations of the two metals in the partial melt are controlled by their concentration in the protolith. Thus, the nature of the protolith and the melting temperature and subsequent evolution of the magma all influence the metallogenic potential of a magma and, in combination, helped control the spatial and temporal segregation of W and Sn deposits in all major W-Sn metallogenic belts.

Background: The pharmacological response and the therapeutic efficacy of a drug depends on the interactions with plasma proteins. Methodology: The interaction of bovine serum albumin (BSA) with the metal complexes of antihypertensive drugs, Zn(II)/sartan complexes (candesartan, valsartan and losartan), was investigated using fluorescence quenching determinations at different temperatures. Results: The binding studies of the compounds with BSA showed static quenching and moderate binding with calculated constants in the range of 104–106 M-1, indicating potent serum distribution via albumins. In all cases, negative values of free energy are indicative of spontaneous processes and the stabilization of BSA/compound complexes through hydrogen bonding and van der Waals forces. The results for the sartans agree with the reported pharmacokinetics studies. Conclusion: It has been determined that the three sartans and the Zn complexes could be transported and distributed by albumin.

Nanoparticles (NPs) have a variety of applications in different fields. Green method of NP synthesis is an exciting field and recently has gained more attention. In many green methods, plant extracts are used, and in a few studies, animal milk has been used to synthesize metal NPs. Many studies have aimed to synthesize silver nanoparticles (Ag NP) for agricultural use, however, there are many other applications where green NPs can be used. In this work, we examined the electrochemical behavior of Ag NPs synthesized using cow and goat milk at two different temperatures. Synthesized NPs at temperatures of 25 and 37°C were characterized using UV-Vis spectroscopy, Fourier Transform Infra-Red measurements, dynamic light scattering measurements, scanning electron microscopy, energy dispersive x-ray spectroscopy, and x-ray diffraction spectroscopy. Cyclic voltammetry experiments were performed using two buffer systems: the phosphate, and Tris-HCl, at pH = 7.4. The results showed that the average size of Ag NPs made using goat milk does not change significantly with temperature compared to Ag NPs made using cow milk. Here we demonstrate that Ag NPs synthesized display redox properties that have potential to use in applications relevant to other fields such as biosensing, electrocatalysis, and nanoelectronics.

The environmental availability of mineral nutrients plays a role in the adaptation and evolution of soil fungi and fungus-plant symbiotic systems. As nutrient availability is different from soil to soil, it is expected that the most adapted fungi can express multiple genes to promote different mechanisms of mineral attack and of metabolic routes to maximize the use of nutrient resources at the lowest energy cost. Microcosm experiments of Paxillus involutus growing on muscovite, phlogopite and K-exchanged vermiculite as K sources were carried out for 21 days. Gene expression analysis indicated that the level of K-deprivation stress was muscovite > phlogopite >> K-vermiculite. Genes and functions overexpressed in the experiments indicated meaningful metabolic activities including K extraction and transport. SEM-EDS and micro-XRD (∼1.15 mm resolution) analysis of mineral surfaces and chemical analysis of agar and mycelium indicated weathering processes and K uptake in good agreement with gene expression analysis. In many areas, P. involutus caused physical damage to the minerals without any apparent chemical attack, consisting of tracks of different depth, from

The synthesis, structural characterization and photophysical properties of a series of platinum(II) complexes of benzannulated pincer-type diarylamido ligands are described. The ligands all contain tricyclic phenanthridine (3,4-benzoquinoline) rings as donor arms, which were elaborated into N∧N−∧O-coordinating β-enaminoketonato chelates via partial condensation with acetylacetone. The proligands are easily deprotonated, and metallation can be achieved under mild conditions using simple Pt(II) salts and Ag2O as a base. The resulting Pt(II) complexes exhibit strong metal-to-ligand charge-transfer absorptions in the region of ∼450–575 nm and are phosphorescent in solution at room temperature, emitting bright orange light (λmax ∼ 600 nm) with quantum yields of up to 16% and excited-state lifetimes on the order of ∼20 μs, representing significant improvements to these photophysical properties compared with many previously reported N∧N∧O or N∧N∧N-ligated systems. Computational modelling reveals that the lowest-lying triplet state is populated efficiently thanks to strong coupling between singlet and triplet excited state manifolds, as in cyclometallated compounds of Pt(II). Substituents (CH3, tBu, or CF3) in the 2-position of the phenanthridinyl unit are found to have little influence on the optical properties, but the emission is severely quenched when a methyl substituent is introduced ortho to the coordinating nitrogen. Molecular distortions in the excited state are shown to be primarily responsible for the quenching in this complex.

Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues’ levels. This study’s goal was to determine whether ALDO’s biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO’s biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG’s MR (thereby activating the ultrashort feedback loop) reduced CYP11B2’s activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO’s biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO’s circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.

Background The etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain’s susceptibility is not known. Objective We aimed to determine the mechanism underlying the unique susceptibility to anaphylaxis in C3H/HeJ mice. We tested the role of deleterious Toll-like receptor 4 (Tlr4) or dedicator of cytokinesis 8 (Dock8) mutations in this strain because both genes have been associated with food allergy. Methods We generated C3H/HeJ mice with corrected Dock8 or Tlr4 alleles and sensitized and challenged them with peanut. We then characterized the antibody response to sensitization, anaphylaxis response to both oral and systemic peanut challenge, gut microbiome, and biomarkers of gut permeability. Results In contrast to C3H/HeJ mice, C57BL/6 mice were resistant to anaphylaxis after oral peanut challenge; however, both strains undergo anaphylaxis with intraperitoneal challenge. Restoring Tlr4 or Dock8 function in C3H/HeJ mice did not protect from anaphylaxis. Instead, we discovered enhanced gut permeability resulting in ingested allergens in the bloodstream in C3H/HeJ mice compared to C57BL/6 mice, which correlated with an increased number of goblet cells in the small intestine. Conclusions Our work highlights the potential importance of gut permeability in driving anaphylaxis to ingested food allergens; it also indicates that genetic loci outside of Tlr4 and Dock8 are responsible for the oral anaphylactic susceptibility of C3H/HeJ mice.

Non-equilibrium thermodynamics describe the current–voltage characteristics of electrochemical devices. For conventional electrode–electrolyte interfaces, the local activation overpotential is used to describe the electrostatic potential step between the two materials as a current is generated. However, the activation overpotential for the metal/mixed ionic-electronic conducting (MIEC) composite electrodes studied in this work originates at the MIEC–gas interface. Moreover, we have studied the effects of non-equilibrium on the electrostatic surface potential and evaluated its influence over electrode kinetics. By investigating two phase (2PB) and three phase boundary (3PB) reactions at the Ni/Ce1−xGdxO2−δ (Ni/CGO) electrode, we have demonstrated that the driving force for coupled ion-electron transfer is held at the CGO–gas interface for both reaction pathways. We also determined that the rate of coupled ion-electron transfer via the 3PB scales with the availability of free sites on the metallic surface, revealing a Sabatier-like relationship with regards to the selection of metallic phases. Finally, we demonstrated how the theory of the electrostatic surface potential can be applied to other systems outside of the well-studied H2/H2O electrode environment. These findings therefore provide an insight into the design of future electrode structures for a range of electrochemical devices.

We describe a synthetic approach to achieving columnar stacked mesogens of aromatic electron donors (D) and acceptors (A) as an orthogonal strategy to segregate charge carrying channels in films. An unusual columnar liquid crystalline mesogen was designed, such that a planar naphthalenediimide acceptor flanked by two bent-shaped phenothiazine donor moieties self-assembled into a liquid crystalline phase. The use of different shapes in the D–A–D arrangement could allow segregated charge transport columns, thus limiting both intercolumnar and intramolecular D–A interactions. In solution, the mesogen showed independent optical and electronic properties of its constituent D and A components and annealed films of the columnar liquid crystalline material showed a near doubling of photocurrent generation compared to amorphousfilms.

Transfer hydrogenation (TH) is a powerful synthetic tool in the production of secondary alcohols from ketones by using a non-H2 hydrogen source along with metal catalysts. Among homogeneous catalysts, Ru(II) complexes are the most efficient catalysts. In our research, six novel ruthenium(II) complexes bearing bipyridine-based ligands [Ru(L1)Cl2] (1), [Ru(L1)(PPh3)Cl]Cl (2) and [Ru(L2)Cl2] (3) and N-heterocyclic carbene-supported pyridine (NCN) ligands [RuCp(L3)]PF6 (4), [RuCp*(L3)]PF6 (5), and [Ru(p-cymene)(L3)Cl]PF6 (6) (where L1 = 6,6′-bis(aminomethyl)-2,2′-bipyridine, L2 = 6,6′-bis(dimethylaminomethyl)-2,2′-bipyridine and L3 = 1,3-bis(2-methylpyridyl)imidazolium bromide) were synthesised and characterised by NMR spectroscopy, HRMS, and X-ray crystallography. The catalytic transfer hydrogenation of 28 ketones in 2-propanol at 80 °C in the presence of KOtBu (5 mol%) was demonstrated and the effect of ligands is highlighted. The results show that catalyst 1 exhibits improved TH efficiency compared to the commercially available Milstein catalyst and displays higher catalytic activity than 2 due to the steric effect from PPh3. From a combination of kinetic data and Eyring analysis, a zero-order dependence on the acetophenone substrate is observed, implying a rate-limiting hydride transfer step, leading to the proposed inner-sphere hydride transfer mechanism.

Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

OBJECTIVES In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine. METHODS One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.

DNA ligase 1 (LIG1, Cdc9 in yeast) finalizes eukaryotic nuclear DNA replication by sealing Okazaki fragments using DNA end-joining reactions that strongly discriminate against incorrectly paired DNA substrates. Whether intrinsic ligation fidelity contributes to the accuracy of replication of the nuclear genome is unknown. Here, we show that an engineered low-fidelity LIG1Cdc9 variant confers a novel mutator phenotype in yeast typified by the accumulation of single base insertion mutations in homonucleotide runs. The rate at which these additions are generated increases upon concomitant inactivation of DNA mismatch repair, or by inactivation of the Fen1Rad27 Okazaki fragment maturation (OFM) nuclease. Biochemical and structural data establish that LIG1Cdc9 normally avoids erroneous ligation of DNA polymerase slippage products, and this protection is compromised by mutation of a LIG1Cdc9 high-fidelity metal binding site. Collectively, our data indicate that high-fidelity DNA ligation is required to prevent insertion mutations, and that this may be particularly critical following strand displacement synthesis during the completion of OFM., DNA ligase 1 (LIG1) finalizes eukaryotic nuclear DNA synthesis by sealing Okazaki fragments using DNA end-joining reactions. Here the authors, by studying an engineered low-fidelity LIG1, reveal that LIG1 is a highly accurate DNA ligase in vivo.

In photonic integrated circuits (PICs), optical isolators and circulators are essential to prevent lasers from backreflections and to reroute the light flow. In this paper, an integrated polarization-independent device that can be operated as an optical isolator or an optical circulator, based on an InP membrane on silicon platform, is demonstrated. A cerium-doped yttrium iron garnet die is adhesively bonded on a Mach–Zehnder interferometer, in combination with four polarization converters. The device shows maximum optical isolations of 27.0 dB for transverse-electric (TE)-mode input and 34.0 dB for transverse-magnetic TM-mode input. The device also works as a four-port optical circulator. Optical isolations of at least 18.6 dB and 16.4 dB are measured between each circulator port pair for TE- and TM-mode input, respectively. This work could remove the optical interfaces between laser and isolator for robust production. It also provides a step forward toward a multifunctional and high-density PIC.

SARS-CoV-2 and other coronaviruses pose major threats to global health, yet computational efforts to understand them have largely overlooked the process of budding, a key part of the coronavirus life cycle. When expressed together, coronavirus M and E proteins are sufficient to facilitate budding into the ER-Golgi intermediate compartment (ERGIC). To help elucidate budding, we ran atomistic molecular dynamics (MD) simulations using the Feig laboratory’s refined structural models of the SARS-CoV-2 M protein dimer and E protein pentamer. Our MD simulations consisted of M protein dimers and E protein pentamers in patches of membrane. By examining where these proteins induced membrane curvature in silico, we obtained insights around how the budding process may occur. Multiple M protein dimers acted together to induce global membrane curvature through protein-lipid interactions while E protein pentamers kept the membrane planar. These results could eventually help guide development of antiviral therapeutics which inhibit coronavirus budding.

GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995).Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts.In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization.Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

G-Protein coupled D2 autoreceptors expressed on dopamine neurons (D2Rs) inhibit transmitter release and cell firing at axonal endings and somatodendritic compartments. Mechanistic details of somatodendritic dopamine release remain unresolved, partly due to insufficient information on the subcellular distribution of D2Rs. Previous studies localizing D2Rs have been hindered by a dearth of antibodies validated for specificity in D2R knockout animals and have been limited by the small sampling areas imaged by electron microscopy. This study utilized sub-diffraction fluorescence microscopy and electron microscopy to examine D2 receptors in a superecliptic pHlourin GFP (SEP) epitope tagged D2 receptor knockin mouse. Incubating live slices with an anti-SEP antibody achieved the selective labeling of plasma membrane associated receptors for immunofluorescent imaging over a large area of the substantia nigra pars compacta (SNc). SEP-D2Rs appeared as puncta-like structures along the surface of dendrites and soma of dopamine neurons visualized by antibodies to tyrosine hydroxylase (TH). TH-associated SEP-D2Rs displayed a cell surface density of 0.66 puncta per μm(2), which corresponds to an average frequency of 1 punctum every 1.50 μm. Separate ultrastructural experiments using silver-enhanced immunogold revealed that membrane-bound particles represented 28% of total D2Rs in putative dopamine cells within the SNc. Structures immediately adjacent to dendritic membrane gold particles were unmyelinated axons or axon varicosities (40%), astrocytes (19%), other dendrites (7%), or profiles unidentified (34%) in single sections. Some apposed profiles also expressed D2Rs. Fluorescent and ultrastructural analyses also provided the first visualization of membrane-D2Rs at the axon initial segment, a compartment critical for action potential generation. The punctate appearance of anti-SEP staining indicates there is a population of D2Rs organized in discrete signaling sites along the plasma membrane, and for the first time a quantitative estimate of spatial frequency is provided.

Background CNIH3 is an AMPA receptor (AMPAR) auxiliary protein prominently expressed in the dorsal hippocampus (dHPC), a region that plays a critical role in spatial memory and synaptic plasticity. However, the effects of CNIH3 on AMPAR-dependent synaptic function and behavior have not been investigated. Methods We assessed a gain-of-function model of Cnih3 overexpression in the dHPC and generated and characterized a line of Cnih3−/− C57BL/6 mice. We assessed spatial memory through behavioral assays, protein levels of AMPAR subunits and synaptic proteins by immunoblotting, and long-term potentiation in electrophysiological recordings. We also utilized a super-resolution imaging workflow, SEQUIN (Synaptic Evaluation and Quantification by Imaging of Nanostructure), for analysis of nanoscale synaptic connectivity in the dHPC. Results Overexpression of Cnih3 in the dHPC improved short-term spatial memory in female mice but not in male mice. Cnih3−/− female mice exhibited weakened short-term spatial memory, reduced dHPC synapse density, enhanced expression of calcium-impermeable AMPAR (GluA2-containing) subunits in synaptosomes, and attenuated long-term potentiation maintenance compared with Cnih3+/+ control mice; Cnih3−/− males were unaffected. Further investigation revealed that deficiencies in spatial memory and changes in AMPAR composition and synaptic plasticity were most pronounced during the metestrus phase of the estrous cycle in female Cnih3−/− mice. Conclusions This study identified a novel effect of sex and estrous on CNIH3’s role in spatial memory and synaptic plasticity. Manipulation of CNIH3 unmasked sexually dimorphic effects on spatial memory, synaptic function, AMPAR composition, and hippocampal plasticity. These findings reinforce the importance of considering sex as a biological variable in studies of memory and hippocampal synaptic function.

Hydrogen peroxide (H2O2) is a well-known oxidizing agent often used as a remedy by consumers to treat algae and root decay from presumed root disease on interior plants, as well as to encourage root growth and health. To characterize the phytotoxic effects and define the safe concentration threshold for H2O2 use on ‘Vivaldi’ hybrid phalaenopsis orchid (hybrid Phalaenopsis), root systems were dipped for 3 minutes in 0%, 3%, 6%, or 12% H2O2 one time and observed in greenhouse conditions for the following 27 days. Root systems of each plant were assessed over time for percent visible root damage; ratings of root health on a scale of 1 to 5 points, with 5 points indicating “very healthy”; and final fresh and dry weights. To determine when symptoms manifested above the root zone, foliage and flower damage was evaluated over time by assessing percent visible foliage damage, ratings of foliage health, percent foliar wilt, flower/bud count, and final foliage and flower fresh and dry weights. Over the evaluation period, the root health rating of the ‘Vivaldi’ hybrid phalaenopsis orchids treated with 12% H2O2 decreased from 5 to 1.13, whereas those treated with 3% H2O2 only decreased from 5 to 4.13. H2O2 concentrations of 6% and 12% damaged root health permanently, whereas the 3% H2O2 concentration only caused minor damage to overall root health. However, algae were not killed at the 3% rate. Neither foliage nor flowers were seriously affected during the 3 weeks after application, but foliage wilt did result in the 6% and 12% treatments by week 4. As H2O2 concentration increased, fresh weights decreased in roots and leaves. Although a single 3% H2O2 root dip did not result in severe symptoms of phytotoxicity, the treatment’s long-term plant health effects are unknown. Because the 3% H2O2 root dip caused minor plant health setbacks and failed to subdue algae populations in the root zone, consumers should be wary of using H2O2 to improve orchid (Orchidaceae) root health and should instead focus on altering care and watering practices.

The Lake Michigan Ozone Study 2017 (LMOS 2017) was a collaborative multiagency field study targeting ozone chemistry, meteorology, and air quality observations in the southern Lake Michigan area. The primary objective of LMOS 2017 was to provide measurements to improve air quality modeling of the complex meteorological and chemical environment in the region. LMOS 2017 science questions included spatiotemporal assessment of nitrogen oxides (NOx = NO + NO2) and volatile organic compounds (VOC) emission sources and their influence on ozone episodes; the role of lake breezes; contribution of new remote sensing tools such as GeoTASO, Pandora, and TEMPO to air quality management; and evaluation of photochemical grid models. The observing strategy included GeoTASO on board the NASA UC-12 aircraft capturing NO2 and formaldehyde columns, an in situ profiling aircraft, two ground-based coastal enhanced monitoring locations, continuous NO2 columns from coastal Pandora instruments, and an instrumented research vessel. Local photochemical ozone production was observed on 2 June, 9–12 June, and 14–16 June, providing insights on the processes relevant to state and federal air quality management. The LMOS 2017 aircraft mapped significant spatial and temporal variation of NO2 emissions as well as polluted layers with rapid ozone formation occurring in a shallow layer near the Lake Michigan surface. Meteorological characteristics of the lake breeze were observed in detail and measurements of ozone, NOx, nitric acid, hydrogen peroxide, VOC, oxygenated VOC (OVOC), and fine particulate matter (PM2.5) composition were conducted. This article summarizes the study design, directs readers to the campaign data repository, and presents a summary of findings.

Multiple-choice testing with dichotomous scoring is one of the most common assessment methods utilized in undergraduate education. Determining students’ perceptions toward different types of multiple-choice testing formats is important for effective assessment. The present study compared two alternative multiple-choice testing formats used in a second-year required chemistry course: (i) Immediate Feedback Assessment Technique (IFAT®) and (ii) Personal Point Allocation (PPA). Both testing methods allow for partial credit, but only the IFAT® provides immediate feedback on students’ responses. Both survey and interview data indicated that, overall, most students preferred IFAT® to the PPA testing method. These positive ratings were related to potential increase in reward, ease of use, and confidence. IFAT® was also perceived to be less stress producing and anxiety provoking than PPA. Interview data not only supported these findings, but also indicated individual differences in preference for each of these two methods. Additionally, students’ feedback on strategies used for either testing method and suggestions on how to improve the methods are discussed.

Methane activation over NiO/Ce0.82Zr0.18O2 catalysts synthesized by combustion synthesis is studied by in-situ IR spectroscopy and correlated to the properties and oxygen speciation of the catalyst. Through XRD, H2-TPR, and pyridine adsorption followed by FTIR spectroscopy, the reducibility and Lewis acidity of the catalysts are assessed. In-situ FTIR spectroscopy is used to monitor the methane activation on catalyst surfaces. Complex IR features of methane-derived surface species are observed and are attributed to the formation of surface alkyl/alkoxy, aldehyde, formate/carbonate, and aromatic species. A data analysis algorithm is developed to evaluate the evolution of different surface species over time. The formation of formate and carbonate species is driven by adsorbed surface oxygen, while less reactive oxygen species associated with NiO allow for the production of aromatics and alkoxy intermediates. By tuning the reducibility and Lewis acidity of the catalyst, the selectivity to alkoxy intermediates can be improved.

Interleukin-6 (IL-6) has been implicated in the pathogenesis of inflammatory events including those seen with COVID-19 patients. Positive clinical responses to monoclonal antibodies directed against IL-6 receptors (IL-6Rs) suggest that interference with IL-6-dependent activation of pro-inflammatory pathways offers a useful approach to therapy. We exposed IL-6 to hypochlorous acid (HOCl) in vitro at concentrations reported to develop in vivo. After HOCl treatment, binding of IL-6 to IL-6R was reduced in a dose-dependent manner using a bioassay with human cells engineered to provide a luminescence response to signal transduction upon receptor activation. Similar results followed the exposure of IL-6 to N-chlorotaurine (NCT) and hypobromous acid (HOBr), two other reactive species produced in vivo. SDS-PAGE analysis of HOCl-treated IL-6 showed little to no fragmentation or aggregation up to 1.75 mM HOCl, suggesting that the modifications induced at concentrations below 1.75 mM took place on the intact protein. Mass spectrometry of trypsin-digested fragments identified oxidative changes to two amino acid residues, methionine 161 and tryptophan 157, both of which have been implicated in receptor binding of the cytokine. Our findings suggest that exogenous HOCl and NCT might bring about beneficial effects in the treatment of COVID-19. Further studies on how HOCl and HOBr and their halogenated amine derivatives interact with IL-6 and related cytokines in vivo may open up alternative therapeutic interventions with these compounds in COVID-19 and other hyperinflammatory diseases.

Mycobacterium tuberculosis (Mtb) cells are known to synthesize very long chain (C60-90) structurally complex mycolic acids with various functional groups. In this study, we applied linear ion-trap (LIT) multiple-stage mass spectrometry (MSn), combined with high-resolution mass spectrometry to study the mechanisms underlying the fragmentation processes of mycolic acid standards desorbed as lithiated adduct ions by ESI. This is followed by structural characterization of a Mtb mycolic acid family (Bovine strain). Using the insight fragmentation processes gained from the study, we are able to achieve a near complete characterization of the whole mycolic acid family, revealing the identity of the α-alkyl chain, the location of the functional groups including methyl, methoxy, and keto groups along the meroaldehyde chain in each lipid species. This study showcased the power of LIT MSn toward structural determination of complex lipids in a mixture, which would be otherwise very difficult to define using other analytical techniques.

Heteronuclear complexes are highly active catalysts in alternating ring opening copolymerizations (ROCOP) of cyclohexene oxide (CHO)/carbon dioxide or CHO/phthalic anhydride (PA). In this contribution, a series of new trinuclear complexes is investigated through a structure activity study that reveals the influences of ligand electronic properties and metal selection over the catalytic activity and linkage selectivity. The fastest catalyst shows high activity for CHO/CO2ROCOP at low pressure (1 bar CO2pressure) and features the ligand coordinated to two Zn(II) centers and with inexpensive and abundant Na(I) (TOF = 1084 h–1, catalyst/CHO 1:4000, 1 bar, 100 °C). High CHO/PA copolymerization activity is achieved with the combination of two Mg(II) and one Na(I) center (TOF = 142 h–1, catalyst/PA/CHO 1:200:4000, 100 °C); further the catalyst undergoes “switchable” epoxide/anhydride ROCOP and epoxide ring opening polymerization (ROP), allowing for controlled polyether block formation. Polymerization kinetic investigations reveal the influences of the ligand electronics, complex stability and metal–metal separation, and their influences over the retention of high activity throughout the catalysis. The findings should help in guiding future polymerization catalyst design, facilitate block polymer production, and inspire other CO2utilization processes.

Aim: This study investigated the screening, characterization and identification of sophorolipid-producing yeast isolated from palm oil effluent polluted soil. Place and Duration: Two soil samples impacted with palm oil mill effluent were obtained from Elibrada and Rumuche in Emohua Local Government Area, Rivers State, Nigeria, between March 2020 and September 2021. Methodology: The soil samples were analyzed for physicochemical, geotechnical and microbiological qualities. The yeast isolates were identified using biochemical and 16S ITS molecular approaches. The isolates were screened for hydrocarbon degradation and sophorolipid production. The sophorolipid production was evaluated using emulsification index (E24), haemolytic activity, oil spread activity, drop collapse and blue agar plate assay (Cetyl trimethyl ammonium bromide CTAB Method). Results: The pH of the Palm oil mill effluent -impacted soil ranged between pH 6.18 to 6.34 the electrical conductivity value for Elibrada and Rumuche were 20.84 µS/cm and 80.19 µS/cm respectively while that of the unpolluted soil was 220.13 µS/cm. Permeability of the soil from Elibrada was 2.7 cm/s, Rumuche had 1.3 cm/s while the unpolluted soil had 5.6 cm/s. Total organic carbon for soil samples from Rumuche was 4.92%, Elibrada had 6.13% while the unpolluted soil had 8.74%. Oil and grease component for the Rumuche soil was 10500 mg/kg, Elibrada had 7200 mg/kg and the unpolluted soil had 28.0 mg/kg. Total fungal count for Rumuche soil samples was 3.8 × 104 CFU/g while Elibrada had 3.2 × 104 CFU/g. Eighty percent (80%) of the isolates were Candida spp. while 20% were Saccharomyces sp. There were four bands separated which were denoted as ITS 600bp and a Ladder L which was 500bp. The phylogenetic construct showed that the Y8 was 70.2% similar to Candida parapsilosis. The isolate Y3 was 95.8% similar to Candida haemulonis. Isolate Y9 had 100% similarity with Pichia kudriavzevii while Y13 had a 97.4% identity with Saccharomyces cerevisiae the GENBANK accession numbers were Candida haemulonis MW182014, Candida parapsilosis MW182015, Pichia kudriavzevii MW182016 and Saccharomyces cerevisiae MW182017. Conclusion: There is an increasing concern to develop a process for microbial isolation and characterization for effective biotechnological advancement using impacted environmental media as a bioresource.