Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer

Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovarian cancer and compounds in preclinical research, and olaparib, a PARP inhibitor targeting DNA damage repair, is a promising approach. P8-D6 induces DNA damage that can be repaired by base excision repair or homologous recombination in which PARP plays a major role. This study analyzed benefits of combining P8-D6 and olaparib treatment in 2D and 3D cultures with ovarian cancer cells. Measurement of viability, cytotoxicity and caspase activity were used to assess therapy efficacy and to calculate the combination index (CI). Further DNA damage was quantified using the biomarkers RAD51 and γH2A.X. The combinational treatment led to an increased caspase activity and reduced viability. CI values partially show synergisms in combinations at 100 nM and 500 nM P8-D6. More DNA damage accumulated, and spheroids lost their membrane integrity due to the combinational treatment. While maintaining the same therapy efficacy as single-drug therapy, doses of P8-D6 and olaparib can be reduced in combinational treatments. Synergisms can be seen in some tested combinations. In summary, the combination therapy indicates benefits and acts synergistic at 100 nM and 500 nM P8-D6

Unexpected fish and squid in the central Arctic deep scattering layer

The retreating ice cover of the Central Arctic Ocean (CAO) fuels speculations on future fisheries. However, very little is known about the existence of harvestable fish stocks in this 3.3 million–square kilometer ecosystem around the North Pole. Crossing the Eurasian Basin, we documented an uninterrupted 3170-kilometer-long deep scattering layer (DSL) with zooplankton and small fish in the Atlantic water layer at 100- to 500-meter depth. Diel vertical migration of this central Arctic DSL was lacking most of the year when daily light variation was absent. Unexpectedly, the DSL also contained low abundances of Atlantic cod, along with lanternfish, armhook squid, and Arctic endemic ice cod. The Atlantic cod originated from Norwegian spawning grounds and had lived in Arctic water temperature for up to 6 years. The potential fish abundance was far below commercially sustainable levels and is expected to remain so because of the low productivity of the CAO

2022 Upgrade and Improved Low Frequency Camera Sensitivity for CMB Observation at the South Pole

Constraining the Galactic foregrounds with multi-frequency Cosmic Microwave Background (CMB) observations is an essential step towards ultimately reaching the sensitivity to measure primordial gravitational waves (PGWs), the sign of inflation after the Big-Bang that would be imprinted on the CMB. The BICEP Array telescope is a set of multi-frequency cameras designed to constrain the energy scale of inflation through CMB B-mode searches while also controlling the polarized galactic foregrounds. The lowest frequency BICEP Array receiver (BA1) has been observing from the South Pole since 2020 and provides 30 GHz and 40 GHz data to characterize the Galactic synchrotron in our CMB maps. In this paper, we present the design of the BA1 detectors and the full optical characterization of the camera including the on-sky performance at the South Pole. The paper also introduces the design challenges during the first observing season including the effect of out-of-band photons on detectors performance. It also describes the tests done to diagnose that effect and the new upgrade to minimize these photons, as well as installing more dichroic detectors during the 2022 deployment season to improve the BA1 sensitivity. We finally report background noise measurements of the detectors with the goal of having photon noise dominated detectors in both optical channels. BA1 achieves an improvement in mapping speed compared to the previous deployment season.Comment: Proceedings of SPIE Astronomical Telescopes + Instrumentation 2022 (AS22

Analysis of Temperature-to-Polarization Leakage in BICEP3 and Keck CMB Data from 2016 to 2018

The Bicep/Keck Array experiment is a series of small-aperture refracting telescopes observing degree-scale Cosmic Microwave Background polarization from the South Pole in search of a primordial B-mode signature. As a pair differencing experiment, an important systematic that must be controlled is the differential beam response between the co-located, orthogonally polarized detectors. We use high-fidelity, in-situ measurements of the beam response to estimate the temperature-to-polarization (T → P) leakage in our latest data including observations from 2016 through 2018. This includes three years of Bicep3 observing at 95 GHz, and multifrequency data from Keck Array. Here we present band-averaged far-field beam maps, differential beam mismatch, and residual beam power (after filtering out the leading difference modes via deprojection) for these receivers. We show preliminary results of "beam map simulations," which use these beam maps to observe a simulated temperature (no Q/U) sky to estimate T → P leakage in our real data

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7

Planck early results XX : New light on anomalous microwave emission from spinning dust grains

Peer reviewe

Planck intermediate results. XXIII. Galactic plane emission components derived from Planck with ancillary data

Planck data when combined with ancillary data provide a unique opportunity to separate the diffuse emission components of the inner Galaxy. The purpose of the paper is to elucidate the morphology of the various emission components in the strong star-formation region lying inside the solar radius and to clarify the relationship between the various components. The region of the Galactic plane covered is l = 300\ub0 \u2192 0\ub0 \u2192 60\ub0 wherestar-formation is highest and the emission is strong enough to make meaningful component separation. The latitude widths in this longitude range lie between 1 and 2, which correspond to FWHM z-widths of 100-200 pc at a typical distance of 6 kpc. The four emission components studied here are synchrotron, free-free, anomalous microwave emission (AME), and thermal (vibrational) dust emission. These components are identified by constructing spectral energy distributions (SEDs) at positions along the Galactic plane using the wide frequency coverage of Planck (28.4-857GHz) in combination with low-frequency radio data at 0.408-2.3 GHz plus WMAP data at 23-94 GHz, along with far-infrared (FIR) data from COBE-DIRBE and IRAS. The free-free component is determined from radio recombination line (RRL) data. AME is found to be comparable in brightness to the free-free emission on the Galactic plane in the frequency range 20-40 GHz with a width in latitude similar to that of the thermal dust; it comprises 45 \ub1 1% of the total 28.4 GHz emission in the longitude range l = 300\ub0 \u2192 0\ub0 \u2192 60\ub0. The free-free component is the narrowest, reflecting the fact that it is produced by current star-formation as traced by the narrow distribution of OB stars. It is the dominant emission on the plane between 60 and 100 GHz. RRLs from this ionized gas are used to assess its distance, leading to a free-free z-width of FWHM 48 100 pc. The narrow synchrotron component has a low-frequency brightness spectral index \u3b2synch 48 -2.7 that is similar to the broad synchrotron component indicating that they are both populated by the cosmic ray electrons of the same spectral index. The width of this narrow synchrotron component is significantly larger than that of the other three components, suggesting that it is generated in an assembly of older supernova remnants that have expanded to sizes of order 150 pc in 3 7 105 yr; pulsars of a similar age have a similar spread in latitude. The thermal dust is identified in the SEDs with average parameters of Tdust = 20.4 \ub1 0.4 K, \u3b2FIR = 1.94 \ub1 0.03 (> 353 GHz), and \u3b2mm = 1.67 \ub1 0.02 (< 353 GHz). The latitude distributions of gamma-rays, CO, and the emission in high-frequency Planck bands have similar widths, showing that they are all indicators of the total gaseous matter on the plane in the inner Galaxy. \ua9 ESO, 2015

Planck 2015 results: XXV. Diffuse low-frequency Galactic foregrounds

We discuss the Galactic foreground emission between 20 and 100 GHz based on observations by Planck and WMAP. The total intensity in this part of the spectrum is dominated by free-free and spinning dust emission, whereas the polarized intensity is dominated by synchrotron emission. The Commander component-separation tool has been used to separate the various astrophysical processes in total intensity. Comparison with radio recombination line templates verifies the recovery of the free-free emission along the Galactic plane. Comparison of the high-latitude H\u3b1 emission with our free-free map shows residuals that correlate with dust optical depth, consistent with a fraction (\ue2\u2030 30%) of H\u3b1 having been scattered by high-latitude dust. We highlight a number of diffuse spinning dust morphological features at high latitude. There is substantial spatial variation in the spinning dust spectrum, with the emission peak (in I\u3bd) ranging from below 20 GHz to more than 50 GHz. There is a strong tendency for the spinning dust component near many prominent H ii regions to have a higher peak frequency, suggesting that this increase in peak frequency is associated with dust in the photo-dissociation regions around the nebulae. The emissivity of spinning dust in these diffuse regions is of the same order as previous detections in the literature. Over the entire sky, the Commander solution finds more anomalous microwave emission (AME) than the WMAP component maps, at the expense of synchrotron and free-free emission. This can be explained by the difficulty in separating multiple broadband components with a limited number of frequency maps. Future surveys, particularly at 5-20 GHz, will greatly improve the separation by constraining the synchrotron spectrum. We combine Planck and WMAP data to make the highest signal-to-noise ratio maps yet of the intensity of the all-sky polarized synchrotron emission at frequencies above a few GHz. Most of the high-latitude polarized emission is associated with distinct large-scale loops and spurs, and we re-discuss their structure. We argue that nearly all the emission at 40deg &gt; l &gt;-90deg is part of the Loop I structure, and show that the emission extends much further in to the southern Galactic hemisphere than previously recognised, giving Loop I an ovoid rather than circular outline. However, it does not continue as far as the "Fermi bubble/microwave haze", making it less probable that these are part of the same structure. We identify a number of new faint features in the polarized sky, including a dearth of polarized synchrotron emission directly correlated with a narrow, roughly 20deg long filament seen in H\u3b1 at high Galactic latitude. Finally, we look for evidence of polarized AME, however many AME regions are significantly contaminated by polarized synchrotron emission, and we find a 2\u3c3 upper limit of 1.6% in the Perseus region

Provisioning of public charging infrastructure for E-cars taking into account ideal-typical charging needs

Die Bundesregierung verfolgt das Ziel, bis 2020 eine Million Elektrofahrzeuge auf Deutschlands Straßen zu bringen. Für diese großflächige Einführung von Elektromobilität ist neben elektrischen Fahrzeugen, die mittlerweile auf dem Markt verfügbar sind, auch (private und öffentlich zugängliche) Ladeinfrastruktur notwendig. Seit einigen Jahren arbeiten Privatwirtschaft, öffentliche Hand und Wissenschaft daran, die Herausforderung der Bereitstellung der „richtigen“ Ladeinfrastruktur zu lösen. In der vorliegenden Arbeit erfolgt eine institutionenökonomische Untersuchung der Fragen, die sich im Kontext der Bereitstellung von öffentlich zugänglicher und privater Ladeinfrastruktur stellen. Soweit möglich werden Handlungsempfehlungen an die öffentliche Hand zu Anpassungen des institutionellen Rahmens abgeleitet, die eine aus gesamtwirtschaftlicher Perspektive effiziente Bereitstellung von Ladeinfrastruktur fördern. Zunächst werden drei aus Nutzersicht idealtypische Ladebedarfe hergeleitet, die unterschiedliche Anforderungen an Angebotskonzepte zur Deckung der Ladebedarfe stellen und anhand derer die Analyse der Bereitstellungsfragen erfolgt: • Ein flächendeckendes Angebot von Schnellladeinfrastruktur ist notwendig, um Nutzern von Elektrofahrzeugen Mobilitätsoptionen zu eröffnen. • Eine verlässliche Lademöglichkeit am regelmäßigen Parkort jedes Nutzers ist essenziell, um „Alltagsmobilität“ zu ermöglichen. • Möglichkeiten zur Zwischendurchladung können das Ladeinfrastruktursystem an unregelmäßigen Parkorten ergänzen. Die Bereitstellung eines Schnellladenetzwerkes durch einen zentralen Akteur mit öffentlichem Zielsystem erscheint vorteilhaft gegenüber einer wettbewerblichen Bereitstellung. Im Gegensatz dazu ist die Herausforderung bei der Bereitstellung von Möglichkeiten zur regelmäßigen Ladung die Koordination mit dem Parkraum, so dass die Bereitstellung von Ladeinfrastruktur durch die (dezentralen) Stellplatzbereitsteller erfolgen sollte. Im öffentlichen Raum sind die Gemeinden gefordert, über die Ausgestaltung differenzierter Nutzungsregeln zuverlässige Ladeangebote für „Laternenparker“ zu entwickeln. Im privaten Bereich erscheint es zielführend, Nutzern ein Anrecht auf Ladeinfrastrukturbereitstellung gegenüber Stellplatzinhabern zu gewähren. Die Bereitstellung von Ladeinfrastruktur zur Zwischendurchladung an unregelmäßigen Parkorten ist von niedrigerer Bedeutung für das gesamte Elektromobilitätssystem. Darüber hinaus haben Stellplatzbereitsteller an den Parkorten grundsätzlich wirksame Anreize, effizient Ladeinfrastrukturangebote zur Zwischendurchladung bereitzustellen. Die öffentliche Hand kann die Komplexität und Kosten in den drei Bereichen durch die Einführung von technischen Standards sowie Regeln zu Betrieb und Strombelieferung von Ladeinfrastruktur reduzieren. Bei einer finanziellen Förderung der Ladeinfrastrukturbereitstellung durch die öffentliche Hand sind Nachfrageverschiebungen aufgrund von Substitutionsbeziehungen zwischen verschiedenen Ladeangeboten zu berücksichtigen.The German federal government has committed to quantitative targets regarding the e-mobility market development by 2020. The provision of (private and publicly accessible) charging infrastructure is seen as one of the main challenges to achieve these targets. This dissertation identifies and examines questions that arise in the context of providing charging infrastructure from the perspective of institutional economics. As far as possible policy recommendations for an efficient provision of charging infrastructure are derived. In the first step the dissertation identifies three ideal types of charging needs from a customer’s perspective: • A nation-wide fast charging network is required to provide comprehensive mobility options for users. • Users need a reliable charging facility at their regular parking spot to be able to cover their every day mobility needs. • Charging facilities at occasional parking spots can selectively further enhance the charging infrastructure system. The analyses show that the provision of a fast charging network should be coordinated centrally. In contrast it should be the parking spot providers to decide upon charging facility installation for regular use on their premises. Local authorities will need to develop differentiated rules for usage and allocation of charging facilities on public parking space to guarantee the required level of reliability for users. Users that regularly use private parking spots should be entitled to demand the installation of charging facilities of their landlords or employers. Charging infrastructure at occasional parking spots is of less priority for the overall e mobility system and parking spot providers have incentives to provide an adequate level of charging infrastructure. It is shown that the public authorities can clearly reduce the costs of providing charging infrastructure by enforcing technical standards as well as establishing rules on how charging infrastructure is provided with electricity. In case the public authorities subsidize the provision of charging infrastructure it should take into account substitution effects between the demand for different types of charging infrastructure