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The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification. Main problem in this context is that compounds with very low solubility and slow intrinsic dissolution in the intestinal environment will cause significant bioavailability problems if their solid oral dosage forms are emptied from the stomach undisintegrated. Also very low plasma profiles may result under these circumstances. Such cases can occur accidentally and are not resultant of non-compliance. Thus, limitation for one case per study only as suggested in the guideline is not justified.
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
Two new species of aulacid wasps, Pristaulacus iuliae Turrisi & Nobile sp. nov. from South India (Karnataka) and Pristaulacus ninae sp. nov. from Peninsular Malaysia (Pahang), are described, figured and compared with most related species. Based on the present addition, the Indomalayan area currently includes 27 species of Pristaulacus Kieffer out of 61 known from the whole Oriental Region, which is however a largely underestimated number. An identification key to species and an updated checklist of Pristaulacus occurring in the Indomalayan area are provided.
The enigmatic ‘y-larvae’ (Thecostraca: Facetotecta) are microscopic marine planktonic crustaceans that were discovered more than a century ago, yet to this day their adults remain unknown. Despite occurring locally in large diversities, and therefore presumably being of ecological importance, only 17 species have been described globally, rendering it practically impossible to identify any y-larval specimen from any locality. The fact that species have been based on different life stages (nauplii and/or cyprids) further hampers identification. Y-larvae include many forms with planktotrophic (feeding) nauplii and even more with lecithotrophic (non-feeding) nauplii. At one coral-reef locality on the shore of Sesoko Island (Okinawa, Japan), extensive fieldwork in 2018 and 2019 confirmed an enormous taxonomic diversity of y-larvae there. Here, we present morphological diagnoses and an identification key for 34 lecithotrophic y-naupliar types (or morphospecies), which will correspond minimally to the same number of species when described. As a temporary measure, all are referred to by alphabetical parataxonomic designations, except for three that have been formally described already within the genus Hansenocaris Itô, 1985. To this should be added an additional 7–9 planktotrophic y-naupliar morphospecies, which are only treated briefly. Most often, y-larval taxonomy has been based on the cyprid stage, but the large morphological diversity of y-nauplii suggests that nauplii are at least as important for taxonomy. Lecithotrophic y-nauplii display a multitude of body shapes, the form-evolution of which is discussed here with reference to a recent molecular phylogeny of Facetotecta partly based on material from the same site. An indirect estimate of the relative abundances of all 34 lecithotrophic y-naupliar morphospecies is presented, based on laboratory-reared final-instar specimens. This treatment is intended as a step towards a proper taxonomy and a revised classification of Facetotecta, which will involve detailed descriptions of both nauplii and cyprids. Until such work progresses, the present overview of the y-naupliar fauna of a single Okinawan locality known to be a hotspot of y-larval diversity is offered as a baseline for further surveys of Facetotecta elsewhere in the Indo-West Pacific and beyond.
Highlights
• NCoR1 is the most highly expressed endothelial corepressor.
• Loss of NCoR1 promotes angiogenic function in endothelial cells.
• Loss of NCoR1 promotes a tip cell position during angiogenic sprouting.
Abstract
Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCOR1 promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCOR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
In a year marked by challenging market dynamics, the importance of ESG investments remains unwavering. But the wave of ESG regulations and requests generates a demand for more scalable ways to collect and analyze ESG data. The rise of AI could mark a turning point in an industry heavily burdened by reporting requirements, and unlock the true potential of ESG for businesses and investors alike.
Yes, they are. The securities services industry is at a tipping point of its digital transformation and will now see industry solutions to scale. We identify three fundamental drivers being adopted more broadly: cloud migration, data, and digitization. This triage also drives the scaling of Clearstream’s digital infrastructure D7, one of the leading digital infrastructures globally.
This study explores high-frequency cross-asset lead-lag relationships for various market microstructure dimensions. Utilizing data from stocks, futures, and exchange traded products, the findings uncover significant lead-lag patterns, particularly among fundamentally related instruments. Our results demonstrate that knowledge about lead-lag relationships can be leveraged for forecasting short-term changes in financial markets.
Nowadays, firms lack information to derive the share of wallet, a vital metric that identifies how much additional spending a firm could capture from each customer. However, decoding Blockchain data enables observing all transactions of each wallet, respectively customer, on the Ethereum NFT market. To shed light on the share of wallet, we analyzed 22.7 million transactions from over 1.3 million customers across eight competing firms on the Ethereum NFT market.
Highlights
• TAM polarization induces CP RNA.
• CP RNA expression is regulated by HIF-2 and STAT1.
• CP RNA is transferred from TAMs to HT1080 cells.
• CP RNA is translated by HT1080 cells and protects from ferroptosis.
• Co-cultured HT1080 cells decrease iron and lipid peroxidation.
Abstract
Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.