Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin

With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4–5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC50) against the Chinese Hamster Ovary cell line of 57–65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial

Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land

There is limited information on the exposure to pesticides experienced by UK residents living near agricultural land. This study aimed to investigate their pesticide exposure in relation to spray events. Farmers treating crops with captan, chlormequat, chlorpyrifos or cypermethrin provided spray event information. Adults and children residing ≤100 m from sprayed fields provided first-morning void urine samples during and outwith the spray season. Selected samples (1–2 days after a spray event and at other times (background samples)) were analysed and creatinine adjusted. Generalised Linear Mixed Models were used to investigate if urinary biomarkers of these pesticides were elevated after spray events. The final data set for statistical analysis contained 1518 urine samples from 140 participants, consisting of 523 spray event and 995 background samples which were analysed for pesticide urinary biomarkers. For captan and cypermethrin, the proportion of values below the limit of detection was greater than 80%, with no difference between spray event and background samples. For chlormequat and chlorpyrifos, the geometric mean urinary biomarker concentrations following spray events were 15.4 μg/g creatinine and 2.5 μg/g creatinine, respectively, compared with 16.5 μg/g creatinine and 3.0 μg/g creatinine for background samples within the spraying season. Outwith the spraying season, concentrations for chlorpyrifos were the same as those within spraying season backgrounds, but for chlormequat, lower concentrations were observed outwith the spraying season (12.3 μg/g creatinine). Overall, we observed no evidence indicative of additional urinary pesticide biomarker excretion as a result of spray events, suggesting that sources other than local spraying are responsible for the relatively low urinary pesticide biomarkers detected in the study population

Ice and firn heterogeneity within Larsen C Ice Shelf from borehole optical televiewing

Research was funded by the UK Natural Environmental Research Council grants NE/L006707/1 and NE/L005409/1 and a HEFCW/Aberystwyth University Capital Equipment Grant to B.H. Data will be available via the project website (www.projectmidas.org) and the UK Polar Data Centre (https://www.bas.ac.uk/data/uk-pdc/) from mid-2017.We use borehole optical televiewing (OPTV) to explore the internal structure of Larsen C Ice Shelf (LCIS). We report a suite of five ~90 m long OPTV logs, recording a light-emitting diode-illuminated, geometrically correct image of the borehole wall, from the northern and central sectors of LCIS collected during austral spring 2014 and 2015. We use a thresholding-based technique to estimate the refrozen ice content of the ice column and exploit a recently calibrated density-luminosity relationship to reveal its structure. All sites are dense and strongly influenced by surface melt, with frequent refrozen ice layers and mean densities, between the depths of 1.87 and 90 m, ranging from 862 to 894 kg m−3. We define four distinct units that comprise LCIS and relate these to ice provenance, dynamic history, and past melt events. These units are in situ meteoric ice with infiltration ice (U1), meteoric ice which has undergone enhanced densification (U2), thick refrozen ice (U3), and advected continental ice (U4). We show that the OPTV-derived pattern of firn air content is consistent with previous estimates, but that a significant proportion of firn air is contained within U4, which we interpret to have been deposited inland of the grounding line. The structure of LCIS is strongly influenced by the E-W gradient in föhn-driven melting, with sites close to the Antarctic Peninsula being predominantly composed of refrozen ice. Melting is also substantial toward the ice shelf center with >40% of the overall imaged ice column being composed of refrozen ice.Publisher PDFPeer reviewe

Geochemistry and oxygen isotope composition of main-group pallasites and olivine-rich clasts in mesosiderites: Implications for the "Great Dunite Shortage" and HED-mesosiderite connection

Evidence from iron meteorites indicates that a large number of differentiated planetesimals formed early in Solar System history. These bodies should have had well-developed olivine-rich mantles and consequentially such materials ought to be abundant both as asteroids and meteorites, which they are not. To investigate this “Great Dunite Shortage” we have undertaken a geochemical and oxygen isotope study of main-group pallasites and dunitic rocks from mesosiderites. Oxygen isotope analysis of 24 main-group pallasites (103 replicates) yielded a mean Δ17O value of −0.187 ± 0.016‰ (2σ), which is fully resolved from the HED Δ17O value of −0.246 ± 0.014 (2σ) obtained in our earlier study and demonstrates that both groups represent distinct populations and were derived from separate parent bodies. Our results show no evidence for Δ17O bimodality within the main-group pallasites, as suggested by a number of previous studies. Olivine-rich materials from the Vaca Muerta, Mount Padbury and Lamont mesosiderites, and from two related dunites (NWA 2968 and NWA 3329), have Δ17O values within error of the mesosiderite average. This indicates that these olivine-rich materials are co-genetic with other mesosiderite clasts and are not fragments from an isotopically distinct pallasite-like impactor. Despite its extreme lithologic diversity the mesosiderite parent body was essentially homogeneous with respect to Δ17O, a feature best explained by an early phase of large-scale melting (magma ocean), followed by prolonged igneous differentiation. Based on the results of magma ocean modeling studies, we infer that Mg-rich olivines in mesosiderites formed as cumulates in high-level chambers and do not represent samples of the underlying mantle. By analogy, recently documented Mg-rich olivines in howardites may have a similar origin. Although the Dawn mission did not detect mesosiderite-like material on Vesta, evidence linking the mesosiderites and HEDs includes: (i) their nearly identical oxygen isotope compositions; (ii) the presence in both of coarse-grained Mg-rich olivines; (iii) both have synchronous Lu-Hf and Mn-Cr ages; (iv) there are compositional similarities between the metal in both; and (v) mesosiderite-like material has been identified in a howardite breccia. The source of the mesosiderites remains an outstanding question in meteorite science. The underrepresentation of olivine-rich materials amongst both asteroids and meteorites results from a range of factors. However, evidence from pallasites and mesosiderites indicates that the most important reason for this olivine shortage lies in the early, catastrophic destruction of planetesimals in the terrestrial planet-forming region and the subsequent preferential loss of their olivine-rich mantles

Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer's disease

Neuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer’s disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer’s disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer’s progression. However, the extent of retinal involvement in Alzheimer’s models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer’s mouse models, Tg2576, 3xTg-AD and APPNL-G-F. Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer’s models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer’s models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer’s disease

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis.

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy

Effect of treatment of clinical seizures vs electrographic seizures in full-term and near-term neonates : a randomized clinical trial

Importance: Seizures in the neonatal period are associated with increased mortality and morbidity. Bedside amplitude-integrated electroencephalography (aEEG) has facilitated the detection of electrographic seizures; however, whether these seizures should be treated remains uncertain. Objective: To determine if the active management of electrographic and clinical seizures in encephalopathic term or near-term neonates improves survival free of severe disability at 2 years of age compared with only treating clinically detected seizures. Design, Setting, and Participants: This randomized clinical trial was conducted in tertiary newborn intensive care units recruited from 2012 to 2016 and followed up until 2 years of age. Participants included neonates with encephalopathy at 35 weeks’ gestation or more and younger than 48 hours old. Data analysis was completed in April 2021. Interventions: Randomization was to an electrographic seizure group (ESG) in which seizures detected on aEEG were treated in addition to clinical seizures or a clinical seizure group (CSG) in which only seizures detected clinically were treated. Main Outcomes and Measures: Primary outcome was death or severe disability at 2 years, defined as scores in any developmental domain more than 2 SD below the Australian mean assessed with Bayley Scales of Neonate and Toddler Development, 3rd ed (BSID-III), or the presence of cerebral palsy, blindness, or deafness. Secondary outcomes included magnetic resonance imaging brain injury score at 5 to 14 days, time to full suck feeds, and individual domain scores on BSID-III at 2 years. Results: Of 212 randomized neonates, the mean (SD) gestational age was 39.2 (1.7) weeks and 122 (58%) were male; 152 (72%) had moderate to severe hypoxic-ischemic encephalopathy (HIE) and 147 (84%) had electrographic seizures. A total of 86 neonates were included in the ESG group and 86 were included in the CSG group. Ten of 86 (9%) neonates in the ESG and 4 of 86 (4%) in the CSG died before the 2-year assessment. The odds of the primary outcome were not significantly different in the ESG group compared with the CSG group (ESG, 38 of 86 [44%] vs CSG, 27 of 86 [31%]; odds ratio [OR], 1.83; 95% CI, 0.96 to 3.49; P = .14). There was also no significant difference in those with HIE (OR, 1.77; 95% CI, 0.84 to 3.73; P = .26). There was evidence that cognitive outcomes were worse in the ESG (mean [SD] scores, ESG: 97.4 [17.7] vs CSG: 103.8 [17.3]; mean difference, −6.5 [95% CI, −1.2 to −11.8]; P = .01). There was little evidence of a difference in secondary outcomes, including time to suck feeds, seizure burden, or brain injury score. Conclusions and Relevance: Treating electrographic and clinical seizures with currently used anticonvulsants did not significantly reduce the rate of death or disability at 2 years in a heterogeneous group of neonates with seizures

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Monitoring Greenland ice sheet buoyancy-driven calving discharge using glacial earthquakes

Since the 2000s, Greenland ice sheet mass loss has been accelerating, followed by increasing numbers of glacial earthquakes (GEs) at near-grounded glaciers. GEs are caused by calving of km-scale icebergs which capsize against the terminus. Seismic record inversion allows a reconstruction of the history of GE sources which captures capsize dynamics through iceberg-to-terminus contact. When compared with a catalog of contact forces from an iceberg capsize model, seismic force history accurately computes calving volumes while the earthquake magnitude fails to uniquely characterize iceberg size, giving errors up to 1 km ³ . Calving determined from GEs recorded ateight glaciers in 1993–2013 accounts for up to 21% of the associated discharge and 6% of the Greenland mass loss. The proportion of discharge attributed to capsizing calving may be underestimated by at least 10% as numerous events could not be identified by standard seismic detections (Olsen and Nettles, 2018). While calving production tends to stabilize in East Greenland, Western glaciers have released more and larger icebergs since 2010 and have become major contributors to Greenland dynamic discharge. Production of GEs and calving behavior are controlled by glacier geometry with bigger icebergs being produced when the terminus advances in deepening water. We illustrate how GEs can help in partitioning and monitoring Greenland mass loss and characterizing capsize dynamics

A Web-Based Psychoeducational Intervention for Adolescent Depression:Design and Development of MoodHwb

Background: Depression is common in adolescence and leads to distress and impairment in individuals, families and carers. Treatment and prevention guidelines highlight the key role of information and evidence-based psychosocial interventions not only for individuals but also for their families and carers. Engaging young people in prevention and early intervention programs is a challenge, and early treatment and prevention of adolescent depression is a major public health concern. There has been growing interest in psychoeducational interventions to provide accurate information about health issues and to enhance and develop self-management skills. However, for adolescents with, or at high risk of depression, there is a lack of engaging Web-based psychoeducation programs that have been developed with user input and in line with research guidelines and targeted at both the individual and their family or carer. There are also few studies published on the process of development of Web-based psychoeducational interventions. Objective: The aim of this study was to describe the process underlying the design and development of MoodHwb (HwbHwyliau in Welsh): a Web-based psychoeducation multimedia program for young people with, or at high risk of, depression and their families, carers, friends, and professionals. Methods: The initial prototype was informed by (1) a systematic review of psychoeducational interventions for adolescent depression; (2) findings from semistructured interviews and focus groups conducted with adolescents (with depressive symptoms or at high risk), parents or carers, and professionals working with young people; and (3) workshops and discussions with a multimedia company and experts (in clinical, research, and multimedia work). Twelve interviews were completed (four each with young people, parents or carers, and professionals) and six focus groups (three with young people, one with parents and carers, one with professionals, and one with academics). Results: Key themes from the interviews and focus groups were: aims of the program, design and content issues, and integration and context of the program. The prototype was designed to be person-centered, multiplatform, engaging, interactive, and bilingual. It included mood-monitoring and goal-setting components and was available as a Web-based program and an app for mobile technologies. Conclusions: MoodHwb is a Web-based psychoeducational intervention developed for young people with, or at high risk of, depression and their families and carers. It was developed with user input using qualitative methods as well as user-centered design and educational and psychological theory. Further research is needed to evaluate the effectiveness of the program in a randomized controlled trial. If found to be effective, it could be implemented in health, education, youth and social services, and charities, to not only help young people but also families, carers, friends, and professionals involved in their care