High-resolution benthic foraminiferal records of the last glacial termination in the northern North Atlantic

Large oceanic changes occurred during the last transition from glacial to interglacial conditions (Termination I), which significantly affected pelagic and benthic environments. This study presents results of a quantitative investigation of benthic foraminifera at four sites distributed along a north-south transect across the northern North Atlantic with a high temporal resolution (k 200 years). Benthic foraminifera are examined in samples (1-2 cm sampling intervals) from four long sediment cores located in the southern Fram Strait, the Greenland-Iceland-Norwegian Sea (GIN Sea), and the Rockall Plateau. The most prominent species of benthic foraminifera include Oridorsalis nnlbolzatlls, Cibicidoides wl~ellerstoufi,C assidulina spp. group, P!jrgo rotalaria, Globocassidrrliiza sllbg-lobosa and tubes of agglutinated taxa. In each core, the climatic amelioration at Termination I is recorded to have occurred in two steps. A first INDAR maximum (INDividuals Accumulation Rate = ind/cm2 ky; GIN Sea: average 3,000-6,000 ind/cm2 ky, Rockall Plateau: average 150 ind/cm2 ky) is followed by a period of lower values. A second maximum reveals slightly lower values than the older maximum. Interglacial INDAR values average 700 ind/cm2 ky for the GIN Sea and 200 ind/cm2 ky on the Rockall Plateau. This is roughly twice that of typical glacial values. Meltwater events, identified by stable isotope data and sea-surface temperature reconstructions based on planktic foraminiferal transfer functions, are marked by an increase in endobenthic and opportunistic species. A decrease of reconstructed sea-surface temperatures appears synchronous with the relative INDAR minimum that occurs between the two INDAR maxima. The results indicate a close coupling of sea-surface processes to the benthic realm ("pelagic-benthic coupling") with a longitudinally variable strength. The climate signal at the Rockall Plateau revealed by the fossil benthic foraminifera shows a lower amplitude than that of the GIN Sea. The second, younger INDAR maximum is characterized by an increased abundance of epibenthic species at all core locations, suggesting extended lateral bottom currents. In comparison with various palaeo-climatological data sets, the variability of fossil benthic foraminiferal abundances in the GIN Sea show a distinct coherence with changes of atmospheric temperatures, sea-surface temperatures and the postglacial sea level rise. The variability of the benthic foraminiferal fauna is principally in phase with climate change events

Anforderungen an wissenschaftliche Informationsinfrastrukturen

Der Bedarf an geeigneten Informationsinfrastrukturen für die digitalen Ergebnisse in der Wissenschaft erfährt zunehmend an Bedeutung und Aufmerksamkeit. Auf politischer, infrastruktureller und organisatorischer Ebene bemühen sich zahlreiche nationale und internationale Initiativen darum, Lösungen zu finden, um Forschungsdaten langfristig zu sichern und den Zugang zu ihnen zu ermöglichen oder zu erleichtern. Ein essentielles Kernelement einer funktionierenden wissenschaftlichen Informationsversorgung ist die Akzeptanz der Wissenschaftlerinnen und Wissenschaftler von solchen Systemen sowohl als Nutzer, als auch als Zulieferer. Eine Akzeptanz hängt im Wesentlichen an der Funktionalität und Zuverlässigkeit solcher Informationssysteme sowie deren Ausmaß und Qualität an Service und assoziierten Dienstleistungen. Diese Anforderungen wiederum orientieren sich eng an den durchaus sehr spezifischen Ansprüchen einzelner wissenschaftlicher Disziplinen. Um solche Herausforderungen zu meistern, gilt es, die anstehenden Aufgaben zu benennen und Akteure, die über die nötige Expertise und das Vertrauen verfügen, konstruktiv und offen mit in die Diskussion einzubeziehen. Diese beinhaltet, traditionelle und bewährte Ansätze und Methoden zu hinterfragen und im Kontext der digitalen Möglichkeiten und Potenziale neu zu bewerten. Insbesondere auch wissenschaftliche Bibliotheken könnten und sollten im Umfeld der Informationsinfrastrukturen hierbei eine entscheidende Rolle spielen.

Anforderungen an wissenschaftliche Informationsinfrastrukturen

"Der Bedarf an geeigneten Informationsinfrastrukturen für die digitalen Ergebnisse in der Wissenschaft erfährt zunehmend an Bedeutung und Aufmerksamkeit. Auf politischer, infrastruktureller und organisatorischer Ebene bemühen sich zahlreiche nationale und internationale Initiativen darum, Lösungen zu finden, um Forschungsdaten langfristig zu sichern und den Zugang zu ihnen zu ermöglichen oder zu erleichtern. Ein essentielles Kernelement einer funktionierenden wissenschaftlichen Informationsversorgung ist die Akzeptanz der Wissenschaftlerinnen und Wissenschaftler von solchen Systemen sowohl als Nutzer, als auch als Zulieferer. Eine Akzeptanz hängt im Wesentlichen an der Funktionalität und Zuverlässigkeit solcher Informationssysteme sowie deren Ausmaß und Qualität an Service und assoziierten Dienstleistungen. Diese Anforderungen wiederum orientieren sich eng an den durchaus sehr spezifischen Ansprüchen einzelner wissenschaftlicher Disziplinen. Um solche Herausforderungen zu meistern, gilt es, die anstehenden Aufgaben zu benennen und Akteure, die über die nötige Expertise und das Vertrauen verfügen, konstruktiv und offen mit in die Diskussion einzubeziehen. Diese beinhaltet, traditionelle und bewährte Ansätze und Methoden zu hinterfragen und im Kontext der digitalen Möglichkeiten und Potenziale neu zu bewerten. Insbesondere auch wissenschaftliche Bibliotheken könnten und sollten im Umfeld der Informationsinfrastrukturen hierbei eine entscheidende Rolle spielen." [Autorenreferat

High-throughput roll-to-roll production of polymer biochips for multiplexed DNA detection in point-of-care diagnostics

Roll-to-roll UV nanoimprint lithography has superior advantages for high-throughput manufacturing of micro- or nano-structures on flexible polymer foils with various geometries and configurations. Our pilot line provides large-scale structure imprinting for cost-effective polymer biochips (4500 biochips/hour), enabling rapid and multiplexed detections. A complete high-volume process chain of the technology for producing structures like μ-sized, triangular optical out-couplers or capillary channels (width: from 1 μm to 2 mm, height: from 200 nm up to 100 μm) to obtain biochips (width: 25 mm, length: 75 mm, height: 100 μm to 1.5 mm) was described. The imprinting process was performed with custom-developed resins on polymer foils with resin thicknesses ranging between 125–190 μm. The produced chips were tested in a commercial point-of-care diagnostic system for multiplexed DNA analysis of methicillin resistant Staphylococcus aureus (e.g., mecA, mecC gene detections). Specific target DNA capturing was based on hybridisation between surface bound DNA probes and biotinylated targets from the sample. The immobilised biotinylated targets subsequently bind streptavidin–horseradish peroxidase conjugates, which in turn generate light upon incubation with a chemiluminescent substrate. To enhance the light out-coupling thus to improve the system performance, optical structures were integrated into the design. The limits-of-detection of mecA (25 bp) for chips with and without structures were calculated as 0.06 and 0.07 μM, respectively. Further, foil-based chips with fluidic channels were DNA functionalised in our roll-to-roll micro-array spotter following the imprinting. This straightforward approach of sequential imprinting and multiplexed DNA functionalisation on a single foil was also realised for the first time. The corresponding foil-based chips were able to detect mecA gene DNA sequences down to a 0.25 μM concentration.This research was supported by R2R BIOFLUIDICS project (http://www.r2r-biofluidics.eu/) under Horizon 2020 European Union (EU) Research and Innovation Programme with grant agreement no 646260. The research was also partially supported by NextGenMicrofluidics project (https:// www. nextgenmicrofluidics.eu/) under HORIZON2020 with grant agreement no 862092. The authors cordially thank Gerburg Schider & Gerhard Mohr, Markus Postl, Paul Patter and Alexander Wheeldon (JOANNEUM RESEARCH – Materials, Weiz, Austria) for revising the manuscript, preparing all the chip and R2R pilot line illustrations, taking the photographs and providing technical support, respectively. The authors are also grateful to Christian Wolf and Johannes Götz (JOANNEUM RESEARCH – Materials, Weiz, Austria) for their supports in the fluidic design and R2R UV-NIL structuring, respectively. We further kindly thank Alba Simon Munoz and Robert Fay (SCIENION AG, Berlin, Germany) for providing the illustration of the R2R micro-spotting line. PT specially thanks Ege Ozgun (NANOTAM, Bilkent University, Ankara, Turkey) for critically reading the manuscript

Neuropathic pain caused by miswiring and abnormal end organ targeting

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.The research leading to these results has received funding from the following sources: an ERC Advanced Investigator grant to R.K. (Pain Plasticity 294293); grants from the Deutsche Forschungsgemeinschaft to R.K. (SFB1158, projects B01, B06), to T.K. (SFB1158, project B08), to S.G.L. (SFB1158, project A01) and to V.G. (SFB1158, project A03); a grant to B.O. (project number 371923335); and grant CIDEGENT/2020/052 from Generalitat Valenciana to F.J.T. R.K. is a member of the Molecular Medicine Partnership Unit of the European Molecular Biology Laboratory and Medical Faculty Heidelberg. V.G. and T.A.N. were partially supported by a post-doctoral fellowship and physician scientist fellowship, respectively, from the Medical Faculty Heidelberg. D.M. was partially supported by a post-doctoral fellowship from Excellence Cluster CellNetworks. We acknowledge support from the Interdisciplinary Neurobehavioral Core (INBC) for the behavioural experiments, the data storage service SDS@hd and bwMLS&WISO HPC supported by the state of Baden-Württemberg and the German Research Foundation (DFG) through grants INST 35/1314-1 FUGG and INST 35/1134-1 FUGG, respectively.Peer reviewe

Genotype–phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype–phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype–phenotype correlations encouraging further analyses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01332-1

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes:findings from the ENIGMA Epigenetics Working Group

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions