Concentration and microbiological utilization of small organic molecules in the Scheldt estuary, the Belgian coastal zone of the North Sea and the English Channel

Concentrations and utilization rates of alanine, aspartate, lysine, glucose, glycollic, acetic and lactic acids have been determined on 6 occasions at least, during a full seasonal cycle in the water column of 3 stations (Scheldt estuary, coastal North Sea and English Channel) with greatly differing biological characteristics. No significant differences in substrate concentration could be detected between the 3 stations, although the rate of utilization of all substrates differed greatly, decreasing in the order estuarine > coastal > open sea environment. This apparent paradox is explained by aid of a simple model showing that the steady state concentration of a particular substrate is independent of its rate of production (and thus of consumption) and depends only on purely physiological characteristics of the bacteria. Using published data for the pertinent physiological parameters of marine bacteria, the model accounts for at least the order of magnitude of substrate concentrations observed, and the absence of important seasonal variation

Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis

AmBisome® (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with Fungizone® (DAmB), the deoxycholate form of AmB, in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 hours after single intravenous (IV) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar, but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6 and 8). After single and multiple dosing, intralesional concentrations were respectively 5- and 20-fold higher compared to those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25 or 12.5 mg/kg (IV), there was a clear correlation between dose level, intralesional AmB concentration and relative reduction in parasite load and lesion size (R2 values > 0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation

Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Delta, Y144Delta, and LLA241/243Delta. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers

Genome wide association study of Preserved Ratio Impaired Spirometry (PRISm)

Background: Preserved Ratio Impaired Spirometry (PRISm) is defined as FEV1 &lt;80% predicted, FEV1/FVC ≥0.70. PRISm is associated with respiratory symptoms and co-morbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated co-morbidities.Methods: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected SNPs reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait Linkage Disequilibrium score regression to estimate genome-wide genetic correlation between PRISM and pulmonary and extra-pulmonary traits. Phenome-wide association studies of top SNPs was performed. Results: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg = 0.62, p-value &lt;0.001) was observed, and genetic correlation with type II diabetes (rg = 0.12, p-value 0.007). PheWAS showed that 18 of 22 signals were associated with diabetic traits and 7 with blood pressure traits.Discussion: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals; rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B) have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extra-pulmonary co-morbidity.<br/

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Concentration and microbiological utilization of small organic molecules in the Scheldt estuary, the Belgian coastal zone of the North Sea and the English Channel

Concentrations and utilization rates of alanine, aspartate, lysine, glucose, glycollic, acetic and lactic acids have been determined on 6 occasions at least, during a full seasonal cycle in the water column of 3 stations (Scheldt estuary, coastal North Sea and English Channel) with greatly differing biological characteristics. No significant differences in substrate concentration could be detected between the 3 stations, although the rate of utilization of all substrates differed greatly, decreasing in the order estuarine > coastal > open sea environment. This apparent paradox is explained by aid of a simple model showing that the steady state concentration of a particular substrate is independent of its rate of production (and thus of consumption) and depends only on purely physiological characteristics of the bacteria. Using published data for the pertinent physiological parameters of marine bacteria, the model accounts for at least the order of magnitude of substrate concentrations observed, and the absence of important seasonal variation

Severe wind gust thresholds for Meteoalarm derived from uniform return periods in ECA&amp;D

In this study we present an alternative wind gust warning guideline for Meteoalarm, the severe weather warning website for Europe. There are unrealistically large differences in levels and issuing frequencies of all warning levels currently in use between neighbouring Meteoalarm countries. This study provides a guide for the Meteoalarm community to review their wind gust warning thresholds. A more uniform warning system is achieved by using one pan-European return period per warning level. The associated return values will be different throughout Europe because they depend on local climate conditions, but they will not change abruptly at country borders as is currently the case for the thresholds. As return values are a measure of the possible danger of an event and its impact on society, they form an ideal basis for a warning system. Validated wind gust measurements from the European Climate Assessment and Dataset (ECA&amp;D, &lt;a href="http://www.ecad.eu" target="_blank"&gt;http://www.ecad.eu&lt;/a&gt;) were used to calculate return values of the annual maximum wind gust. The current thresholds are compared with return values for 3 different return periods: 10 times a year return periods for yellow warnings, 2 yr periods for orange and 5 yr periods for red warnings. So far 10 countries provide wind gust data to ECA&amp;D. Due to the ECA&amp;D completeness requirements and the fact that some countries provided too few stations to be representative for that country, medians of the return values of annual maximum wind gust could be calculated for 6 of the 10 countries. Alternative guideline thresholds are presented for Norway, Ireland, The Netherlands, Germany, the Czech Republic and Spain and the need to distinguish between coastal, inland and mountainous regions is demonstrated. The new thresholds based on uniform return periods differ significantly from the current ones, particularly for coastal and mountainous areas. &lt;br&gt;&lt;br&gt; We are aware of other, sometimes binding factors (e.g. laws) that prevent participating counties from implementing this climatology based warning system