HeidelbergCement (Germany)

ABSTRACT The Mediterranean, the Irano-Anatolian and the Caucasus regions are known as major biodiversity hotspots with high speciation dynamics in many groups of plants and animals. In order to better understand underlying processes, the situation of the wool carder bee Anthidium loti, a pollinator whose distribution extends from the Mediterranean into Central Asia and Pakistan, was examined. Despite a high level of geographic variation in the colour pattern, it was found that colouration does not correspond to distinct population groups. However, genetic examination of the COI mitochondrial marker and the LW-rhodopsin nuclear one from populations of the entire distribution range revealed that there are two distinct groups: eastern and western. Phylogenetic analysis showed that these two groups belong to monophyletic clades and multiple species delimitation analyses confirmed the presence of two well distinct species within A. loti s.l. Further evidence for the presence of distinct taxa was obtained by a multivariate Discriminant Function Analysis of nine morphometric parameters, which allowed us to correctly assign 93.8% of all specimens to the respective species. Based on these results and the examination of the historical type material, the western population group was assigned to Anthidium loti Perris 1852, and the eastern population group to Anthidium regulare Eversmann 1852, which has previously been regarded as a synonym. The taxonomic status is hereby re-established (stat. resurr.), and a lectotype is designated. This study adds novel evidence to the growing body of knowledge demonstrating a high cryptic diversity in the Mediterranean region.

Neurotrophin (NT) receptor signaling regulates neuronal survival, axonal and dendritic network maintenance, differentiation, and synaptic plasticity. Signaling is initiated by NT binding to the extracellular domain of NT receptor dimers, leading to activation of the receptor and signal propagation intracellularly. How this activating signal is mediated by the single-pass transmembrane (TM) helical domain of the receptor, and what the relation between domain sequence and signaling mechanism is, remains unclear. The structure and dynamics of the TM domain of the receptor dimers in the active and inactive states for intracellular signaling are still elusive, with NMR structures capturing only a single state. Here, we carried out unbiased and enhanced sampling molecular dynamics simulations of the TM domain dimers of the wild-type p75, TrkA and TrkB NT receptors and selected mutants in micelle and bilayer lipid environments at atomistic and coarse-grained levels of representation. The coarse-grained simulations enabled exploration of multiple states of the TM domain dimers and revealed the influence of the lipid environment on the TM helix arrangements. From the simulations, we identify active and inactive TM helix arrangements of the p75 and TrkA receptors that are supported by experimental data and suggest two different signaling mechanisms through the C-terminal regions of the TM helices. For TrkB, a single dominant but less energetically stable arrangement of the TM domain dimer is observed. These findings have implications for mechanistic studies of NT receptor signaling and the design of neuroprotective drugs to stabilize specific states of the TM domain of the receptors.

Abstract Influenza A virus (IAV) causes up to five million cases of severe illness and half a million deaths worldwide each year. While there are a few clinically approved drugs for treating IAV, they are challenged by the rapid evolution of the virus leading to emergence of drug resistance and the adverse effects of the drugs. Targeting host cellular factors that support virus replication could limit resistance, increase the broad-spectrum antiviral properties of drugs, and benefit from repurposing drugs already existing against those factors. However, selecting the right drug-target pairs with low toxicity and minimal adverse effects has been challenging, even though hundreds of cellular host factors have been identified. In this study, we applied a computational and knowledge-based drug-target prioritization approach to identify promising drug-target pairs. We selected five pairs for experimental validation: telmisartan-Angiotensin II receptor, type 1 (AGTR1), metoclopramide hydrochloride-Cholinergic receptor muscarinic 1 (CHRM1), cefepime hydrochloride-phosphogluconate dehydrogenase (PGD), ranolazine dihydrochloride-sodium channel voltage-gated type v alpha subunit (SCN5A), and ofloxacin-topoisomerase II alpha 170kDa (TOP2A). Except for cefepime hydrochloride, all four drugs showed significant plaque reduction in Madin Darby canine kidney (MDCK) cells. In the immunofluorescence assay, metoclopramide hydrochloride, ranolazine dihydrochloride, and telmisartan showed antiviral activity in MDCK and/or adenocarcinoma human alveolar basal epithelial (A549) cell lines. In conclusion, our approach can prioritize and identify drugs with antiviral activity against influenza virus. Refining and strengthening such approaches could be valuable for rapid antiviral discovery and pandemic preparedness.HighlightsComputational drug-target prioritization indicated drugs for validationTelmisartan showed anti-influenza virus activity in MDCK cellsMetoclopramide and ranolazine showed anti-influenza activity in A549 and MDCK cells

There remains widespread doubt among clinicians that mere lifestyle advice and counseling provided in routine care can achieve improvements in health. We aimed to determine the health effects of the largest behavior change program for pre-diabetes globally (the English Diabetes Prevention Programme) when implemented at scale in routine care. We exploited the threshold in glycated hemoglobin (HbA1c) used to decide on program eligibility by applying a regression discontinuity design, one of the most credible quasi-experimental strategies for causal inference, to electronic health data from approximately one-fifth of all primary care practices in England. Program referral led to significant improvements in patients' HbA1c and body mass index. This analysis provides causal, rather than associational, evidence that lifestyle advice and counseling implemented in a national health system can achieve important health improvements.

The needs for research on cementitious materials are reviewed with a focus on Europe. These are considered under 8 topics: clinker production, alternatives to Portland cement, composite cements based on Portland clinker, concrete, admixtures, durability, recycling, digitisation in concrete construction, and, carbon capture and use or storage; finally, the key research questions and their potential for CO2 reduction are summarised in a “Watermelon” diagram with a list of 30 key questions to be addressed (see Appendix).

Abstract Pancreatic carcinoma is one of the most lethal cancers and the absence of efficient therapeutic strategies results in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC impacts initiation, development, and survival of this tumor type. Using patient-derived xenografts of pancreatic carcinoma driven by KRAS and MYC oncogenic transcription, we show that co-inhibition of Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) synergistically induce tumor regression through targeting promoter pause-release, a rate-limiting step in transcription elongation. By comparing the nascent transcriptome with the recruitment of elongation and termination factors along genes, we found that co-inhibition of TOP1 and BRD4, while globally impairing RNA production, disturbs recruitment of proteins involved in termination. Thus, RNA polymerases continue transcribing downstream of genes for hundreds of kilobases leading to readthrough transcription. This pervasive transcription also occurs during replication, perturbing replisome progression and leading to DNA damage. The synergistic effect of TOP1 and BRD4 inhibition is specific for cancer cells leaving normal cells unharmed, highlighting the sensitivity of the tumor to these transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of high transcription and replication.One Sentence SummaryTOP1 and BRD4 inhibitors synergize to selectively kill pancreatic cancerin vivo viareadthrough transcription without emergence of drug resistance