ガーナ，アシャンティ火山帯南部に分布する古原生代変火山岩類のSr-Nd 同位体組成

Neodymium (Nd) and strontium (Sr) isotopic data are presented for Paleoproterozoic metavolcanic rocks in the southern part of the Ashanti volcanic belt of Ghana. The metavolcanic rocks are predominantly basalts/basaltic andesites and andesites with minor dacites. Two types of basalts/basaltic andesites (B/A), Type I and Type II, have been identified. The Type I B/A are stratigraphically overlain by the Type II B/A, followed by the andesites and the dacites. The analyzed volcanic rocks commonly have low initial (87)Sr/(86)Sr ratios consistent with previous studies on Paleoproterozoic rocks from the West African craton. The LREE-depleted, tholeiitic Type I B/A exhibit back-arc basin geochemical signatures and show high positive epsilon Nd (i.e., ε(Nd) (2.1 Ga) = +3.89 to +7.21), which suggest a long term depleted source and also indicate that they were produced in an entirely oceanic environment devoid of influence of continental crust. The isotope signatures are thus consistent with the previously published trace element data of the Type I basalts/basaltic andesites in suggesting that their parent magma was generated from a depleted mantle. The Type I B/A have Nd model ages (T(DM2)) of 1.83–2.09 Ga similar to their formation ages, suggesting that they were juvenile at their time of formation. The andesites and the Type II B/A andesites show LREE-enriched patterns and exhibit characteristics of subduction zone-related magmas, and show initial ε(Nd) (2.1Ga) values of –1.15 to + 1.35 and Nd model ages (T(DM2)) of 2.32–2.58 Ga. The LREE-enriched dacitic porphyry also exhibits characteristics of subduction zone-related magmas, and have initial ε(Nd) (2.1Ga) value of –2.24 and Nd model ages (T(DM2)) of 2.64 Ga. The Nd isotopic data confirms the juvenile character of the Birimian crust, but also suggests some contributions of a pre-Birimian crustal material (or Archean?) in the genesis of some of the metavolcanic rocks. Our isotopic result is consistent with the island arc complex model which views Paleoproteozoic terranes of West Africa in the context of subduction–accretion processes

Preparation of potentially porous, chiral organometallic materials through spontaneous resolution of pincer palladium conformers

Understanding the mechanism by which advanced materials assemble is essential for the design of new materials with desired properties. Here, we report a method to form chiral, potentially porous materials through spontaneous resolution of conformers of a PCP pincer palladium complex ({; ; 2, 6-bis[(di-t-butylphosphino)methyl]phenyl}; ; palladium(II)halide). The crystallisation is controlled by weak hydrogen bonding giving rise to chiral qtz-nets and channel structures, as shown by 16 such crystal structures for X = Cl, and Br with various solvents like pentane and bromobutane. The fourth ligand (in addition to the pincer ligand) on palladium plays a crucial role ; the chloride and the bromide primarily form hexagonal crystals with large 1D channels, whereas the iodide (presumably due to its inferior hydrogen bonding capacity) forms monoclinic crystals without channels. The hexagonal channels are completely hydrophobic and filled with disordered solvent molecules. Upon heating loss of solvent occurs and the hexagonal crystals transform into other non-porous polymorphs. Also by introducing strong acid, the crystallisation process can be directed to a different course, giving several different non-porous polymorphs. In conclusion a number of rules can be formulated dictating the formation of hexagonal channel structures based on pincer palladium complexes. Such rules are important for a rational design of future self-assembling materials with applications in storage and molecular recognition

Potent Dengue virus neutralization by a therapeutic antibody with low monovalent affinity requires bivalent engagement

We recently described our most potently neutralizing monoclonal antibody, E106, which protected against lethal Dengue virus type 1 (DENV-1) infection in mice. To further understand its functional properties, we determined the crystal structure of E106 Fab in complex with domain III (DIII) of DENV-1 envelope (E) protein to 2.45 Å resolution. Analysis of the complex revealed a small antibody-antigen interface with the epitope on DIII composed of nine residues along the lateral ridge and A-strand regions. Despite strong virus neutralizing activity of E106 IgG at picomolar concentrations, E106 Fab exhibited a ∼20,000-fold decrease in virus neutralization and bound isolated DIII, E, or viral particles with only a micromolar monovalent affinity. In comparison, E106 IgG bound DENV-1 virions with nanomolar avidity. The E106 epitope appears readily accessible on virions, as neutralization was largely temperature-independent. Collectively, our data suggest that E106 neutralizes DENV-1 infection through bivalent engagement of adjacent DIII subunits on a single virion. The isolation of anti-flavivirus antibodies that require bivalent binding to inhibit infection efficiently may be a rare event due to the unique icosahedral arrangement of envelope proteins on the virion surface

Rapid and sensitive detection of mycobacterium ulcerans by use of a loop-mediated isothermal amplification test

This work reports the design and evaluation of a rapid loop-mediated isothermal amplification test for detecting Mycobacterium ulcerans DNA based on the multicopy insertion sequence IS2404. The test is robust and specific with a detection limit equivalent to 20 copies of the target sequence (0.01 to 0.1 genome). The test has potential for the diagnosis of Buruli ulcer under field conditions

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p \u3c 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p \u3c 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored

Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring.

BACKGROUND: Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established. METHODOLOGY/PRINCIPAL FINDING: Peripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co-extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone. CONCLUSIONS/SIGNIFICANCE: Our study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine further through longitudinal studies

Combined Inflammatory and Metabolic Defects Reflected by Reduced Serum Protein Levels in Patients with Buruli Ulcer Disease

Buruli ulcer is a skin disease caused by Mycobacterium ulcerans that is spreading in tropical countries, with major public health and economic implications in West Africa. Multi-analyte profiling of serum proteins in patients and endemic controls revealed that Buruli ulcer disease down-regulates the circulating levels of a large array of inflammatory mediators, without impacting on the leukocyte composition of peripheral blood. Notably, several proteins contributing to acute phase reaction, lipid metabolism, coagulation and tissue remodelling were also impacted. Their down-regulation was selective and persisted after the elimination of bacteria with antibiotic therapy. It involved proteins with various functions and origins, suggesting that M. ulcerans infection causes global and chronic defects in the host’s protein metabolism. Accordingly, patients had reduced levels of total serum proteins and blood urea, in the absence of signs of malnutrition, or functional failure of liver or kidney. Interestingly, slow healers had deeper metabolic and coagulation defects at the start of antibiotic therapy. In addition to providing novel insight into Buruli ulcer pathogenesis, our study therefore identifies a unique proteomic signature for this disease

UK and Ireland Joint Advisory Group (JAG) consensus statements for training and certification in diagnostic endoscopic ultrasound (EUS)

Background and Aims: International endoscopy societies vary in their approach for credentialing individuals in endoscopic ultrasound (EUS) to enable independent practice; however, there is no consensus in this or its implementation. In 2019, the Joint Advisory Group on GI Endoscopy (JAG) commissioned a working group to examine the evidence relating to this process for EUS. The aim of this was to develop evidence-based recommendations for EUS training and certification in the UK.Methods: Under the oversight of the JAG quality assurance team, a modified Delphi process was conducted which included major stakeholders from the UK and Ireland. A formal literature review was made, initial questions for study were proposed and recommendations for training and certification in EUS were formulated after a rigorous assessment using the Grading of Recommendation Assessment, Development and Evaluation tool and subjected to electronic voting to identify accepted statements. These were peer reviewed by JAG and relevant stakeholder societies before consensus on the final EUS certification pathway was achieved.Results: 39 initial questions were proposed of which 33 were deemed worthy of assessment and finally formed the key recommendations. The statements covered four key domains, such as: definition of competence (13 statements), acquisition of competence (10), assessment of competence (5) and postcertification mentorship (5). Key recommendations include: (1) minimum of 250 hands-on cases before an assessment for competency can be made, (2) attendance at the JAG basic EUS course, (3) completing a minimum of one formative direct observation of procedural skills (DOPS) every 10 cases to allow the learning curve in EUS training to be adequately studied, (4) competent performance in summative DOPS assessments and (5) a period of mentorship over a 12-month period is recommended as minimum to support and mentor new service providers.Conclusions: An evidence-based certification pathway has been commissioned by JAG to support and quality assure EUS training. This will form the basis to improve quality of training and safety standards in EUS in the UK and Ireland.</p

The exploration of hotel reference prices under dynamic pricing scenarios and different forms of competition

The reference price, used by consumers to evaluate market prices, has tremendous relevance in dynamic pricing. Reconciling current heterogeneous theories and studies on reference prices, this paper analyzes the impact of hotel price sequences on consumers’ reference prices through a lab and a field experiment. Experiment 1 tests the importance of retrospective price evaluations, while Experiment 2 evaluates the impact of three forms of competition: (i) simultaneous behavior, where firms adjust prices simultaneously; (ii) leader-follower behavior, where one firm acts as the leader; and (iii) independent behavior, where each player takes its rival’s strategy as given and seeks to maximize its own profits. The results show that consumers decrease their reference price when competing hotels adjust their prices simultaneously. Relevant managerial implications are drawn for the hospitality industry, which is affected by the presence of online travel agencies that announce the daily rates offered by each competitor