Report and preliminary results of SONNE cruise SO175, Miami - Bremerhaven, 12.11 - 30.12.2003 : (GAP, Gibraltar Arc Processes)

Expedition SO175 using FS Sonne aimed for a multidisciplinerary geoscientific approach with an international group of researchers. Methods covered the entire span from geophysical data acquisition (seafloor mapping, echography, seismic reflection), sediment coring at sites of active fluid venting, in situ heat flow measurements across the entire length of the Gibraltar thrust wedge, the deformation front, landslide bodies, and mud volcanoes, and finally the deployment of a long-term pore pressure probe. Video-supported operations helped to identify fluid vent sites, regions with tectonic activity, and other attractive high priority targets. Qualitative and quantitative examinations took place on board and are continued on land with respect to pore pressure variation, geomicrobiology, sediment- and fluid mobilization, geochemical processes, faunal assemblages (e.g. cold water corals), and gas hydrates (flammable methane-ice-crystals). Main focus of the expedition has been a better understanding of interaction between dynamic processes in a seismically active region region with slow plate convergence. In the context of earthquake nucleation and subduction zone processes, the SO175 research programme had a variety of goals, such as: • To test the frictional behaviour of the abyssal plain sediments. • To explore the temperature field of the 1755 thrust earthquake event via heat flow measurements. • To assess the role of fluid venting and gas hydrate processes control slope stability and mud volcanic activity along the Iberian continental margin. • To measure isotope geochemistry of pore waters and carbonates of deep fluids. • To quantify microbial activity in Gibraltar wedge sediments. • To test whether microseismicity in the area corresponds to in situ pore pressure changes. • To find out if enhanced heat flow max be indicative of active subduction. Initial tentative results during the cruise suggest that there is a component of active thrusting at the base of the wedge, as attested by heat flow data. Based on mostly geochemical evidence, mud volcanism was found less active than previously assumed. Highlights from post-cruise research include the successful deployment of the long-term station and high frictional resistance of all incoming sediment on the three abyssal plains

Liquid polystyrene: a room-temperature photocurable soft lithography compatible pour-and-cure-type polystyrene

Materials matter in microfluidics. Since the introduction of soft lithography as a prototyping technique and polydimethylsiloxane (PDMS) as material of choice the microfluidics community has settled with using this material almost exclusively. However{,} for many applications PDMS is not an ideal material given its limited solvent resistance and hydrophobicity which makes it especially disadvantageous for certain cell-based assays. For these applications polystyrene (PS) would be a better choice. PS has been used in biology research and analytics for decades and numerous protocols have been developed and optimized for it. However{,} PS has not found widespread use in microfluidics mainly because{,} being a thermoplastic material{,} it is typically structured using industrial polymer replication techniques. This makes PS unsuitable for prototyping. In this paper{,} we introduce a new structuring method for PS which is compatible with soft lithography prototyping. We develop a liquid PS prepolymer which we term as {"}Liquid Polystyrene{"} (liqPS). liqPS is a viscous free-flowing liquid which can be cured by visible light exposure using soft replication templates{,} e.g.{,} made from PDMS. Using liqPS prototyping microfluidic systems in PS is as easy as prototyping microfluidic systems in PDMS. We demonstrate that cured liqPS is (chemically and physically) identical to commercial PS. Comparative studies on mouse fibroblasts L929 showed that liqPS cannot be distinguished from commercial PS in such experiments. Researchers can develop and optimize microfluidic structures using liqPS and soft lithography. Once the device is to be commercialized it can be manufactured using scalable industrial polymer replication techniques in PS - the material is the same in both cases. Therefore{,} liqPS effectively closes the gap between {"}microfluidic prototyping{"} and {"}industrial microfluidics{"} by providing a common material

Cognitive behavioral therapy for insomnia in patients with mental disorders and comorbid insomnia: A systematic review and meta-analysis.

Almost 70% of patients with mental disorders report sleep difficulties and 30% fulfill the criteria for insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia according to current treatment guidelines. Despite this circumstance, insomnia is frequently treated only pharmacologically especially in patients with mental disorders. The aim of the present meta-analysis was to quantify the effects of CBT-I in patients with mental disorders and comorbid insomnia on two outcome parameters: the severity of insomnia and mental health. The databases PubMed, CINHAL (Ebsco) und PsycINFO (Ovid) were searched for randomized controlled trials on adult patients with comorbid insomnia and any mental disorder comparing CBT-I to placebo, waitlist or treatment as usual using self-rating questionnaires as outcomes for either insomnia or mental health or both. The search resulted in 1994 records after duplicate removal of which 22 fulfilled the inclusion criteria and were included for the meta-analysis. The comorbidities were depression (eight studies, 491 patients), post-traumatic stress disorder (PTSD, four studies, 216 patients), alcohol dependency (three studies, 79 patients), bipolar disorder (one study, 58 patients), psychosis (one study, 50 patients) and mixed comorbidities within one study (five studies, 189 patients). The effect sizes for the reduction of insomnia severity post treatment were 0.5 (confidence interval, CI, 0.3-0.8) for patients with depression, 1.5 (CI 1.0-1.9) for patients with PTSD, 1.4 (CI 0.9-1.9) for patients with alcohol dependency, 1.2 (CI 0.8-1.7) for patients with psychosis/bipolar disorder, and 0.8 (CI 0.1-1.6) for patients with mixed comorbidities. Effect sizes for the reduction of insomnia severity were moderate to large at follow-up. Regarding the effects on comorbid symptom severity, effect sizes directly after treatment were 0.5 (CI 0.1-0.8) for depression, 1.3 (CI 0.6-1.9) for PTSD, 0.9 (CI 0.3-1.4) for alcohol dependency in only one study, 0.3 (CI -0.1 - 0.7, insignificant) for psychosis/bipolar, and 0.8 (CI 0.1-1.5) for mixed comorbidities. There were no significant effects on comorbid symptoms at follow-up. Together, these significant, stable medium to large effects indicate that CBT-I is an effective treatment for patients with insomnia and a comorbid mental disorder, especially depression, PTSD and alcohol dependency. CBT-I is also an effective add-on treatment with the aim of improving mental health in patients with depression, PTSD, and symptom severity in outpatients with mixed diagnoses. Thus, in patients with mental disorders and comorbid insomnia, given the many side effects of medication, CBT-I should be considered as a first-line treatment

The hierarchy of coupled sleep oscillations reverses with aging in humans.

A well-orchestrated coupling hierarchy of slow waves and spindles during slow wave sleep supports memory consolidation. In old age, duration of slow wave sleep and number of coupling events decreases. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N=340, 237 female, 103 male) spanning most of the human lifespan (ages 15-83). We find that, instead of changing abruptly, spindles gradually shift from being driven by-, to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow wave frequency, and starts around midlife (∼age 40-48), with an established reversed hierarchy at age 56-83. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using phase slope index (PSI) and number of coupling events, is associated with blood plasma glial fibrillary acidic protein (GFAP) levels, a marker for astrocyte activation. Data-driven models suggest decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a back-shift of the coupling hierarchy (PSI) towards a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.Significance StatementEvidence accumulates that sleep disturbances and cognitive decline are bi-directionally and causally linked forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human lifespan and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human lifespan

Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice

Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research

Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice.

Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Making sense of big data in health research: Towards an EU action plan.

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans

Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors. Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.Peer Reviewe

Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer

Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible toward transformation by activated PIK3CAH1047R but refractory to oncogenic KrasG12D. Using genome-wide transposon screens and genetic loss-of-function experiments, we discover context-dependent genetic interactions that drive extrahepatic cholangiocarcinoma (ECC) and show that PI3K signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts with the pancreas, where oncogenic Kras in concert with p53 loss is a key cancer driver. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development. These studies provide a mechanistic link between PI3K signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor subtype