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Adenine and cytosine base editors (ABE, CBE) allow for precision genome engineering. Here, Base Editor Activity Reporter (BEAR), a plasmid-based fluorescent tool is introduced, which can be applied to report on ABE and CBE editing in a virtually unrestricted sequence context or to label base edited cells for enrichment. Using BEAR-enrichment, we increase the yield of base editing performed by nuclease inactive base editors to the level of the nickase versions while maintaining significantly lower indel background. Furthermore, by exploiting the semi-high-throughput potential of BEAR, we examine whether increased fidelity SpCas9 variants can be used to decrease SpCas9-dependent off-target effects of ABE and CBE. Comparing them on the same target sets reveals that CBE remains active on sequences, where increased fidelity mutations and/or mismatches decrease the activity of ABE. Our results suggest that the deaminase domain of ABE is less effective to act on rather transiently separated target DNA strands, than that of CBE explaining its lower mismatch tolerance., Base editors allow for precision engineering of the genome. Here, the authors present BEAR, a plasmid-based fluorescence assay for the measurement of CBE and ABE activity, to reveal the mechanism underlying their differences and to increase the yield of edited cells with reduced indel background.

Pigment epithelium-derived factor (PEDF) is a serin protease inhibitor and a potent inhibitor of angiogenesis. Its serum level has significant associations with metabolic parameters. However, little is known about the association between PEDF levels and lipid parameters in renal transplanted (TX) patients. Therefore, our aim was to investigate the relationship between PEDF level and lipid parameters in TX patients.Seventy TX patients (47 males, 23 females, mean age 51.7 ± 12.4 years) and 34 healthy controls were enrolled. We examined the serum creatinine, C-reactive protein, fasting glucose and lipid parameters right before, then 1 and 6 months after TX. High-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) activities were measured spectrophotometrically. Lipoprotein subfractions were determined by Lipoprint. PEDF and oxidized low-density liporotein (oxLDL) levels were measured by ELISA.Before transplantation, patients had had a significantly higher PEDF level compared to control subjects (PEDF may play an important role in the increased oxidative stress and enhanced atherogenesis in renal transplant patients.

The widespread use of Cas12a (formerly Cpf1) nucleases for genome engineering is limited by their requirement for a rather long TTTV protospacer adjacent motif (PAM) sequence. Here we have aimed to loosen these PAM constraints and have generated new PAM mutant variants of the four Cas12a orthologs that are active in mammalian and plant cells, by combining the mutations of their corresponding RR and RVR variants with altered PAM specificities. LbCas12a-RVRR showing the highest activity was selected for an in-depth characterization of its PAM preferences in mammalian cells, using a plasmid-based assay. The consensus PAM sequence of LbCas12a-RVRR resembles a TNTN motif, but also includes TACV, TTCV CTCV and CCCV. The D156R mutation in improved LbCas12a (impLbCas12a) was found to further increase the activity of that variant in a PAM-dependent manner. Due to the overlapping but still different PAM preferences of impLbCas12a and the recently reported enAsCas12a variant, they complement each other to provide increased efficiency for genome editing and transcriptome modulating applications.

Superfluid $^4$He (He-II) is a widely studied model system for exploring finite-size effects in strongly confined geometries. Here, we study He-II confined in mm-scale channels of 25 and 50 nm height at high pressures using a nanofluidic Helmholtz resonator. We find that the superfluid density is measurably suppressed in the confined geometry from the transition temperature down to 0.6 K. Importantly, this suppression can be accounted for by roton-like thermal excitation with an energy gap of 5 K. We show that the surface-bound excitations lead to the previously unexplained lack of finite-size scaling of suppression of the superfluid density., Comment: Version 2: 14 pages (5 + 9 supplemental material; 3 + 10 figures). Accepted to Phys. Rev. Lett

Introduction Everyday social interactions are based on Theory of Mind (ToM) or mentalizing, whose complex processes are involved in understanding, representing one’s own and other people’s mental states. ToM is supposed to have two systems. The implicit ToM seems to be a fast, automatic, non-verbal processing. The explicit ToM is characterized by a slower, but more flexible processing, which is mostly verbal, interpretative. Several studies have described explicit ToM deficit in schizophrenic patients. Less research has investigated implicit ToM in patients, however recently, there has been a growing number of articles examining implicit ToM of patients with schizophrenia. Objectives The aim of our systematic review and meta-analysis is to summarize the results of the implicit ToM in schizophrenia. Methods A systematic search was performed in four major databases. We included 11 publications. 7 studies; and 5 studies were included the quantitative synthesis and the qualitative synthesis, respectively. Results We found significant differences in accuracy, reaction time and brain activation patterns during implicit ToM between schizophrenic patients and controls. The systematic review revealed further alterations in visual scanning, cue fixation, face looking time, and difficulties in perspective taking. Conclusions Based on our results implicit ToM is affected in schizophrenia in addition to explicit ToM deficit. However, based on these results we cannot exclude the possibility, that implicit ToM or at least some elements of it might be relatively unaffected (e.g. detection of intentionality), however its effectiveness is limited by non-mentalizing deficits (e.g. certain neurocognitive impairments). Our results may have important implications for the remediation of mentalizing skills. Disclosure The research is supported by the Hungarian National Excellence Centrum Grant (FIKP II) and Hungarian Brain Research Program (KTIA-13-NAP-A-II/12).

Abstract: Capgras symptom is characterized by the delusional belief that a person significant to the patient has been replaced by a ‘double’ or ‘impostor’. Capgras symptom was discussed to be associated with violent behavior. We report here the cases of two male patients with schizophrenia paranoid type, where parricide was connected to Capgras delusion. It is important to emphasize that in our observed cases, non-adherence played an essential role in the development of violent behavior, parricide. Orv Hetil. 2019; 160(42): 1673–1676.

Starting from a historic perspective, we discuss the use of second sound in experimental investigations of quantized vorticity and quantum turbulence in the two-fluid temperature regime of superfluid $$^4$$ He. Starting with the theoretical prediction of second sound by Tisza and Landau and its experimental discovery by Peshkov, we briefly review the pioneering experiments of Hall, Vinen and others that have contributed in an essential way to our current understanding of quantum turbulence in superfluid $$^4$$ He, with an emphasis on relevant research performed over the last two decades in our laboratory in Prague. We then propose further dedicated experiments where second sound can be used both as a generator and detector of quantum turbulence.

Thermal counterflow in superfluid $$^4$$ He (He II) was studied numerically using the vortex filament model in a spherically symmetric geometry (as resulting from a point heat source). It is found that for the range of temperatures and velocities studied, turbulent tangle of the quantised vortices develops only for sufficiently low temperatures, hinting at the existence of a critical temperature, and only for velocities bounded from above (and presumably from below). A velocity–temperature phase diagram is presented. A simple physical model is proposed that qualitatively explains both observations.

Dynamical backaction resulting from radiation pressure forces in optomechanical systems has proven to be a versatile tool for manipulating mechanical vibrations. Notably, dynamical backaction has resulted in the cooling of a mechanical resonator to its ground-state, driving phonon lasing, the generation of entangled states, and observation of the optical-spring effect. In certain magnetic materials, mechanical vibrations can interact with magnetic excitations (magnons) via the magnetostrictive interaction, resulting in an analogous magnon-induced dynamical backaction. In this article, we directly observe the impact of magnon-induced dynamical backaction on a spherical magnetic sample's mechanical vibrations. Moreover, dynamical backaction effects play a crucial role in many recent theoretical proposals; thus, our work provides the foundation for future experimental work pursuing many of these theoretical proposals., Accepted version with appendices

Introduction Previous neuroimaging studies of individuals with nonsyndromic oral clefts have revealed subtle brain structural differences compared to matched controls. Additional studies strongly suggest that the higher incidence of neuropsychiatric issues observed in these individuals may be explained by these neuroanatomical differences. Currently there are no studies that have assessed the overall empirical evidence of the effect of oral clefts on the brain. Objectives Our aim was to summarize available evidence on potential brain structure differences in individuals with nonsyndromic oral clefts and their matched controls. In the current presentation, we discuss the results of regional brain structural differences. Methods Five databases were systematically searched in September 2020 for case-control studies that reported neuroimaging in healthy individuals and individuals with nonsyndromic oral clefts. Duplicate study selection, data extraction, random effects meta-analyses of mean differences (MDs) and their 95% confidence intervals were performed in order to compare regional brain MRI volumes. Results We have identified 245 records following the database searches, from which 12 records met the inclusion criteria. Quantitative data on brain structure were available in three studies.The cerebellum, occipital and temporal lobes were significantly smaller in the cleft group compared to controls (MD: -12.46, 95% CI: -18.26, -6.67, n=3 studies; MD:-7.39, 95% CI: -12.80, -1.99, n=2 studies; MD: -10.53, 95% CI: -18.23, -2.82, n=2 studies, respectively). Conclusions There may be structural brain differences between individuals with nonsyndromic oral clefts and their controls based on the available evidence. Disclosure No significant relationships.

Introduction Following the mentalization of interpersonal relations can be improved through reading for which the influence of literary fiction can also serve as a model. Schizophrenia is characterized by extensive deficits in mentalization, and the amelioration of these impairments is a major focus in psychosocial treatment research. Reading literature can be a potential tool in improving mentalizing skills. Objectives We aimed to examine and compare healthy participants with patients living with schizophrenia, focusing on measuring mentalizing skills and the impact of reading literary fiction on their mentalization skills. Methods 47 persons with schizophrenia in remission and 48 healthy controls were assessed and compared with Short Story Task (SST) a new measurement of ToM. SST proved to be a sensitive tool, to individual differences. After reading the short story “The End of Something” (Hemingway) a structured interview was done with 14 questions. Results We found that patients with schizophrenia performed significantly worse in their ToM scores compared to healthy controls (ANOVA test, p Conclusions We found that mentalization skills could be improved by regular reading. Our results could also be influenced by several other factors such as empathy skills, identification with the characters etc. Our results and conclusions are in line with the results of international research on this topic. Disclosure No significant relationships.

Superfluid $^4$He is a promising material for optomechanical and electromechanical applications due to its low acoustic loss. Some of the more intriguing aspects of superfluidity -- the macroscopic coherence, topological nature of vorticity, and capability of supporting non-classical flows -- remain, however, poorly explored resources in opto- and electro-mechanical systems. Here, we present an electromechanical coupling to pure superflow inside a nanofluidic Helmholtz resonator with viscously clamped normal fluid. The system is capable of simultaneous measurement of displacement and velocity of the Helmholtz mechanical mode weakly driven by incoherent environmental noise. Additionally, we implement feedback capable of inducing self-oscillation of the non-classical acoustic mode, damping the motion below the ambient level, and tuning of the mode frequency., Comment: 12 pages, 5 figures

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an adjunct in the management of critically ill patients with non-compressible torso hemorrhage. REBOA is a less invasive alternative to resuscitative thoracotomy, designed to sustain central circulation until hemostasis can be achieved. This chapter outlines the brief history of REBOA and the steps required when placing the device as well as potential complications.

Optical resolution is still the dominant route to obtaining enantiopure active ingredients. The traditional methods require large organic solvent quantities and long processing times. Antisolvent fractionation with supercritical carbon dioxide offers intensified processing by drastically reducing the time requirement of the diastereomeric salt precipitation. A novel optical resolution of ibuprofen was developed and optimized with phenylglycinol as a resolving agent and gas antisolvent fractionation as the separation method. Above the critical values of certain operational parameters (carbon dioxide to methanol ratio, apparent diastereomeric salt concentration, equilibration time, the relative volume of the extracting fluid) the selectivity was roughly constant, the optical resolution is robust. The scalemic mixtures were purified by repeated resolution and enantiomeric purities above 99% were reached in three consecutive steps.

BACKGROUND Afamin is a plasma vitamin E-binding glycoprotein partially associated with ApoA1-containing high-density lipoprotein (HDL) subfractions. In a previous study, the serum vitamin E decreased after low-density lipoprotein (LDL) apheresis, while vitamin E/cholesterol ratio increased. We aimed to study the effect of LDL apheresis on serum afamin level. METHODS The serum level of afamin and oxidized LDL were measured by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments and in seven healthy controls. We also investigated the changes in total cholesterol, LDL-C, HDL-C, ApoB, ApoA1, HDL subfractions, and α- and γ-tocopherol levels during the treatment. HDL subfractions were detected by an electrophoretic method on polyacrylamide gel (Lipoprint). Serum α- and γ-tocopherol levels were detected by gas chromatography-mass spectrometry. RESULTS The first treatment sessions decreased serum afamin levels by an average of 9.4%. Total cholesterol, LDL-C, HDL-C and ApoA1 levels decreased by 52.6; 61.8; 10.5; and 14.1%, respectively. We found that α- and γ-tocopherol levels markedly decreased (by 34.1 and 32.9%, respectively), while α- tocopherol/cholesterol and γ-tocopherol/cholesterol ratios significantly increased (by 41.4 and 40.3%, respectively). Oxidized LDL levels significantly decreased. There was a shift toward the larger HDL subfractions. CONCLUSION LDL apheresis moderately decreases the circulating levels of afamin parallel to lowering HDL-C and ApoA1 levels. Tocopherol levels decreases markedly compared to afamin levels, however, beneficial changes in vitamin E/cholesterol ratios, oxidized LDL levels and HDL subfraction distribution were detected. These additional effects of LDL apheresis may result in further cardiovascular risk reduction in FH patients.

Full author list: E. Szegedi-Elek, P. Ábrahám, Ł. Wyrzykowski, M. Kun, Á. Kóspál, L. Chen, G. Marton, A. Moór, C. Kiss, A. Pál, L. Szabados, J. Varga, E. Varga-Verebélyi, C. Andreas, E. Bachelet, R. Bischoff, A. Bódi, E. Breedt, U. Burgaz, T. Butterley, J. M. Carrasco, V. Čepas, G. Damljanovic, I. Gezer, V. Godunova, M. Gromadzki, A. Gurgul, L. Hardy, F. Hildebrandt, S. Hoffmann, M. Hundertmark, N. Ihanec, R. Janulis, Cs. Kalup, Z. Kaczmarek, R. Könyves-Tóth, M. Krezinger, K. Kruszyńska, S. Littlefair, M. Maskoliūnas, L. Mészáros, P. Mikołajczyk, M. Mugrauer, H. Netzel, A. Ordasi, E. Pakštienė, K. A. Rybicki, K. Sárneczky, B. Seli, A. Simon, K. Šiškauskaitė, Á. Sódor, K. V. Sokolovsky2, W. Stenglein, R. Street, R. Szakáts, L. Tomasella, Y. Tsapras, K. Vida, J. Zdanavičius, M. Zieliński, P. Zieliński, and O. Ziółkowska, We present optical-infrared photometric and spectroscopic observations of Gaia 18dvy, located in the Cygnus OB3 association at a distance of 1.88 kpc. Gaia 18dvy was noted by the Gaia alerts system when its light curve exhibited a ⪆4 mag rise in 2018-2019. The brightening was also observable at mid-infared wavelengths. The infrared colors of Gaia 18dvy became bluer as the outburst progressed. Its optical and near-infrared spectroscopic characteristics in the outburst phase are consistent with those of bona fide FU Orionis-type young eruptive stars. The progenitor of the outburst is probably a low-mass K-type star with an optical extinction of ∼3 mag. A radiative transfer modeling of the circumstellar structure, based on the quiescent spectral energy distribution, indicates a disk with a mass of 4 10-3 M o˙. Our simple accretion disk modeling implies that the accretion rate had been exponentially increasing for more than 3 yr until mid-2019, when it reached a peak value of 6.9 10-6 M o˙ yr-1. In many respects, Gaia 18dvy is similar to the FU Ori-type object HBC 722., We thank the anonymous referee, whose questions and comments significantly improved the paper. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement No. 716155 (SACCRED), Lendület LP2018-7/2019 and KEP-7/2018 of the Hungarian Academy of Sciences, GINOP 2.3.2-15-2016-00003 and PD-128360 of the Hungarian National Research, Development and Innovation Office, Polish NCN DAINA grant 2017/27/ L/ST9/03221, European Commission’s Horizon 2020 OPTICON grant 730890, Polish MNiSW grant DIR/WK/2018/12, grant No. S-LL-19-2 of the Research Council of Lithuania, Project No. 176011 “Dynamics and kinematics of celestial bodies and systems” of the Ministry of Education, Science and Technological Development of the Republic of Serbia, DFG priority program SPP 1992 “Exploring the Diversity of Extrasolar Planets” (WA 1047/11-1), the MINECO (Spanish Ministry of Economy) through grant RTI2018-095076-B-C21 (MINECO/FEDER, UE). The Joan Oró Telescope (TJO) of the Montsec Astronomical Observatory (OAdM) is owned by the Catalan Government and is operated by the Institute for Space Studies of Catalonia (IEEC). MG is supported by the Polish NCN MAESTRO grant 2014/14/ A/ST9/00121. We acknowledge ESA Gaia, DPAC, and the Photometric Science Alerts Team. We thank Christina Conner, Megan Davis, Alessandro Dellarovere, Hannah Gallamore, Mira Ghazali, Aaron Kruskie, Dylan Mankel, Jesse Leahy–McGregor, Brandon McIntyre, Barrett Ross, Courtney Wicklund, and Evan Zobel for observing Gaia 18dvy at the Michigan State University Observatory. Based on observations made with the Nordic Optical Telescope, operated by the Nordic Optical Telescope Scientific Association at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofísica de Canarias. Based on observations obtained with telescopes of the University Observatory Jena, which is operated by the Astrophysical Institute of the Friedrich-Schiller-University.

All authors: Ortiz, J. L.; Santos-Sanz, P.; Sicardy, B.; Benedetti-Rossi, G.; Duffard, R.; Morales, N.; Braga-Ribas, F.; Fernández-Valenzuela, E.; Nascimbeni, V.; Nardiello, D.; Carbognani, A.; Buzzi, L.; Aletti, A.; Bacci, P.; Maestripieri, M.; Mazzei, L.; Mikuz, H.; Skvarc, J.; Ciabattari, F.; Lavalade, F. Scarfi, G.; Mari, J. M.; Conjat, M.; Sposetti, S.; Bachini, M.; Succi, G.; Mancini, F.; Alighieri, M.; Dal Canto, E.; Masucci, M.; Vara-Lubiano, M.; Gutiérrez, P. J.; Desmars, J.; Lecacheux, J.; Vieira-Martins, R.; Camargo, J. I. B.; Assafin, M.; Colas, F.; Beisker, W.; Behrend, R.; Mueller, T. G.; Meza, E.; Gomes-Junior, A. R.; Roques, F.; Vachier, F.; Mottola, S.; Hellmich, S.; Campo Bagatin, A.; Alvarez-Candal, A.; Cikota, S.; Cikota, A.; Christille, J. M.; Pál, A.; Kiss, C.; Pribulla, T.; Komžík, R.; Madiedo, J. M.; Charmandaris, V.; Alikakos, J.; Szakáts, R.; Farkas-Takács, A.; Varga-Verebélyi, E.; Marton, G.; Marciniak, A.; Bartczak, P.; Butkiewicz-Baķ, M.; Dudziński, G.; Alí-Lagoa, V.; Gazeas, K.; Paschalis, N.; Tsamis, V.; Guirado, J. C.; Peris, V.; Iglesias-Marzoa, R.; Schnabel, C.; Manzano, F.; Navarro, A.; Perelló, C.; Vecchione, A.; Noschese, A.; Morrone, L., Context. Deriving physical properties of trans-Neptunian objects is important for the understanding of our Solar System. This requires observational efforts and the development of techniques suitable for these studies. Aims. Our aim is to characterize the large trans-Neptunian object (TNO) 2002 TC302. Methods. Stellar occultations offer unique opportunities to determine key physical properties of TNOs. On 28 January 2018, 2002 TC302 occulted a mv ∼ 15.3 star with designation 593-005847 in the UCAC4 stellar catalog, corresponding to Gaia source 130957813463146112. Twelve positive occultation chords were obtained from Italy, France, Slovenia, and Switzerland. Also, four negative detections were obtained near the north and south limbs. This represents the best observed stellar occultation by a TNO other than Pluto in terms of the number of chords published thus far. From the 12 chords, an accurate elliptical fit to the instantaneous projection of the body can be obtained that is compatible with the near misses. Results. The resulting ellipse has major and minor axes of 543 ± 18 km and 460 ± 11 km, respectively, with a position angle of 3 ± 1 degrees for the minor axis. This information, combined with rotational light curves obtained with the 1.5 m telescope at Sierra Nevada Observatory and the 1.23 m telescope at Calar Alto observatory, allows us to derive possible three-dimensional shapes and density estimations for the body based on hydrostatic equilibrium assumptions. The effective diameter in equivalent area is around 84 km smaller than the radiometrically derived diameter using thermal data from Herschel and Spitzer Space Telescopes. This might indicate the existence of an unresolved satellite of up to ∼300 km in diameter, which is required to account for all the thermal flux, although the occultation and thermal diameters are compatible within their error bars given the considerable uncertainty of the thermal results. The existence of a potential satellite also appears to be consistent with other ground-based data presented here. From the effective occultation diameter combined with absolute magnitude measurements we derive a geometric albedo of 0.147 ± 0.005, which would be somewhat smaller if 2002 TC302 has a satellite. The best occultation light curves do not show any signs of ring features or any signatures of a global atmosphere. © ESO 2020., This research was partially based on data taken at the Sierra Nevada Observatory, which is operated by the Instituto de Astrofisica de Andalucia (CSIC). This research is also partially based on data taken at the German-Spanish Calar Alto observatory, which is jointly operated by the Max Planck Institute fur Astronomie and the Instituto de Astrofisica de Andalucia (CSIC). Part of the results were also based on observations taken at the 1.6m telescope on Pico dos Dias Observatory. This research was partially based on observations collected at the Schmidt telescope 67/92 cm (Asiago, Italy) of the INAF - Osservatorio Astronomico di Padova. Funding from Spanish projects AYA2014-56637-C2-1-P, AYA2017-89637-R, from FEDER, and Proyecto de Excelencia de la Junta de Andalucia 2012-FQM1776 is acknowledged. We would like to acknowledge financial support by the Spanish grant AYA-RTI2018-098657-JI00 "LEO-SBNAF" (MCIU/AEI/FEDER, UE) and the financial support from the State Agency for Research of the Spanish MCIU through the "Center of Excellence Severo Ochoa" award for the Instituto de Astrofisica de Andalucia (SEV- 2017-0709). Part of the research received funding from the European Union's Horizon 2020 Research and Innovation Programme, under grant agreement no. 687378 and from the ERC programme under Grant Agreement no. 669416 Lucky Star. The following authors acknowledge the respective CNPq grants: FB-R 309578/2017-5; RV-M 304544/2017-5, 401903/2016-8; J.I.B.C. 308150/2016-3; MA 427700/2018-3, 310683/2017-3, 473002/2013-2. This study was financed in part by the CoordenacAo de Aperfeiacoamento de Pessoal de Nivel Superior - Brasil (CAPES) - Finance Code 001 and the National Institute of Science and Technology of the e-Universe project (INCT do e-Universo, CNPq grant 465376/2014-2). GBR acknowledges CAPES-FAPERJ/PAPDRJ grant E26/203.173/2016, MA FAPERJ grant E-26/111.488/2013 and ARGJr FAPESP grant 2018/11239-8. E.F.-V. acknowledges support from the 2017 Preeminent Postdoctoral Program (P3) at UCF. C.K., R.S., A.F-T., and G.M. have been supported by the K-125015 and GINOP-2.3.2-15-2016-00003 grants of the Hungarian National Research, Development and Innovation Office (NKFIH), Hungary. G.M. was also supported by the Hungarian National Research, Development and Innovation Office (NKFIH) grant PD-128 360. R.K. and T.P. were supported by the VEGA 2/0031/18 grant. We acknowledge the use of Occult software by D. Herald.

We report measurements of longitudinal temperature gradient in thermal counterflow of superfluid $^{4}\mathrm{He}$ performed directly in the 17.5 cm long channel of a square cross section of 7 mm side using static temperature sensors placed on its wall and one small sensor movable along its axis. For various temperatures and heat inputs, we verify linear temperature gradient in the bulk and detect a ``boundary layer''---a region with increased temperature gradient---adjacent to the planar heater. We verify this result using three different heater geometries, all of which display similar thickness of this region but differ in exact details of the temperature profile. We propose that the observed temperature gradient enhancement is at least partly due to an increase of the density of the vortex tangle induced by the inhomogeneity of areal heat input distribution and support this claim by numerical simulations.

We report preliminary results of a systematic study of the flow of normal fluid component in steady-state quantum turbulence in thermal counterflow of superfluid \(^{4}\hbox {He}\) using a high-precision flow visualisation technique based on the tracking of thin lines of \(\hbox {He}_2^{*}\) molecular tracers. Non-trivial profiles of mean velocity and turbulent fluctuation across the channel are observed with complicated temperature- and heat flux-dependencies. Mean turbulence intensity, however, depends on velocity only very weakly and is controlled primarily by the temperature.

We summarize recent experiments on thermal counterflow turbulence in superfluid 4He, emphasizing the observation of turbulence in the normal fluid and its effect on the decay process when the heat flux is turned off. We argue that what is observed as turbulence in the normal fluid is a novel form of coupled turbulence in the superfluid and normal components, with injection of energy on the scales of both the (large) channel width and the (small) spacing between quantized vortices. Although an understanding of this coupled turbulence remains challenging, a theory of its decay is developed which accounts for the experimental observations.

Detailed target-selectivity information and experiment-based efficacy prediction tools are primarily available for Streptococcus pyogenes Cas9 (SpCas9). One obstacle to develop such tools is the rarity of accurate data. Here, we report a method termed ‘Self-targeting sgRNA Library Screen’ (SLS) for assaying the activity of Cas9 nucleases in bacteria using random target/sgRNA libraries of self-targeting sgRNAs. Exploiting more than a million different sequences, we demonstrate the use of the method with the SpCas9-HF1 variant to analyse its activity and reveal motifs that influence its target-selectivity. We have also developed an algorithm for predicting the activity of SpCas9-HF1 with an accuracy matching those of existing tools. SLS is a facile alternative to the much more expensive and laborious approaches used currently and has the capability of delivering sufficient amount of data for most of the orthologs and variants of SpCas9.

Montenegro plans to enhance and modernize the curricula and programs in public health fields in line with EU standards and hence the Erasmus-Phelim project developed a framework to develop, implement, and evaluate the education process. A stepwise approach consisting of three dimensions per step was implemented for workshop development.. For the evaluation, a train-the-trainer approach was developed and a self-regulation concept consisting of three phases was applied.. Semi-structured interviews with the workshop participants were conducted and results suggested that self-regulation is an understandable concept and can be applied as a training and knowledge transfer method. © 2019 International Medical Informatics Association (IMIA) and IOS Press.

Rationale & Objective Clinical practice guidelines for dietary intake in hemodialysis focus on individual nutrients. Little is known about associations of dietary patterns with survival. We evaluated the associations of dietary patterns with cardiovascular and all-cause mortality among adults treated by hemodialysis. Study Design Prospective cohort study. Setting & Participants 8,110 of 9,757 consecutive adults on hemodialysis (January 2014 to June 2017) treated in a multinational private dialysis network and with analyzable dietary data. Exposures Data-driven dietary patterns based on the GA2LEN food frequency questionnaire. Participants received a score for each identified pattern, with higher scores indicating closer resemblance of their diet to the identified pattern. Quartiles of standardized pattern scores were used as primary exposures. Outcomes Cardiovascular and all-cause mortality. Analytical Approach Principal components analysis with varimax rotation to identify common dietary patterns. Adjusted proportional hazards regression analyses with country as a random effect to estimate the associations between dietary pattern scores and mortality. Associations were expressed as adjusted HRs with 95% CIs, using the lowest quartile score as reference. Results During a median follow-up of 2.7 years (18,666 person-years), there were 2,087 deaths (958 cardiovascular). 2 dietary patterns, “fruit and vegetable” and “Western,” were identified. For the fruit and vegetable dietary pattern score, adjusted HRs, in ascending quartiles, were 0.94 (95% CI, 0.76-1.15), 0.83 (95% CI, 0.66-1.06), and 0.91 (95% CI, 0.69-1.21) for cardiovascular mortality and 0.95 (95% CI, 0.83-1.09), 0.84 (95% CI, 0.71-0.99), and 0.87 (95% CI, 0.72-1.05) for all-cause mortality. For the Western dietary pattern score, the corresponding estimates were 1.10 (95% CI, 0.90-1.35), 1.11 (95% CI, 0.87-1.41), and 1.09 (95% CI, 0.80-1.49) for cardiovascular mortality and 1.01 (95% CI, 0.88-1.16), 1.00 (95% CI, 0.85-1.18), and 1.14 (95% CI, 0.93-1.41) for all-cause mortality. Limitations Self-reported food frequency questionnaire, data-driven approach. Conclusions These findings did not confirm an association between mortality among patients receiving long-term hemodialysis and the extent to which dietary patterns were either high in fruit and vegetables or consistent with a Western diet.

In June 2015, an outbreak of cryptosporidiosis with 35 cases (23 probable and 12 laboratory-confirmed) occurred among 191 attendees of a residential rehabilitation holiday for paediatric organ transplant patients (n= 49) and their families at a hotel in Somogy county, Hungary. The overall attack rate was 18%. Most of the cases were transplanted children who experienced severe acute disease and required adjustment to their tacrolimus immunosuppression. A retrospective case-control study suggested an association between recreational water exposures and illness: cases were seven times more likely than controls to have swum in the children's pool (odds ratio 7.17; 95% confidence interval 2.9–17.2;P< 0.0001) and five times more likely to have used the jetted whirlpool (odds ratio 5.25; 95% confidence interval 2.1–13.1;P< 0.0001). This was the first outbreak of cryptosporidiosis in Hungary and it is especially unfortunate that it affected vulnerable children who experienced severe symptoms.Cryptosporidiumpresents specific infection control difficulties in treated recreational water venues; the link to a whirlpool is unusual and highlights the importance of the age-appropriate use of these facilities and reminding users not to immerse their heads or swallow the water. Cryptosporidiosis is more commonly linked to children’ pools where improved bather hygiene and promoting exclusion of diarrhoea cases could help to avoid similar outbreaks.

Lipedema is a disproportional obesity featuring spontaneous or light pressure-induce pain and frequent hematoma formation due to even minor traumatic injuries. It is generally distinguished from general obesity primarily based on clinical hallmarks; however, this becomes difficult when appearing in a concomitant form (combination of obesity and lipedema). Our study group has recently demonstrated that lipedema-associated bruising is correlated with increased capillary fragility (CF) and also that CF could be significantly improved by complex decongestive physiotherapy (CDP). In this study, we measured CF in female subjects with lipedema (15) or non-complicated obesity (15) who were body mass index (BMI) and waist-to-hip ratio (WHR) matched. CF was evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer in both groups. Application of VSM resulted in a significantly higher number of petechiae in subjects with lipedema. Capillary fragility measurement appears to be a useful differential diagnostic tool between lipedema and obesity under these trial parameters.

Cpf1s, the RNA-guided nucleases of the class II clustered regularly interspaced short palindromic repeats system require a short motive called protospacer adjacent motif (PAM) to be present next to the targeted sequence for their activity. The TTTV PAM sequence of As- and LbCpf1 nucleases is relatively rare in the genome of higher eukaryotic organisms. Here, we show that two other Cpf1 nucleases, Fn- and MbCpf1, which have been reported to utilize a shorter, more frequently occurring PAM sequence (TTN) when tested in vitro, carry out efficient genome modification in mammalian cells. We found that all four Cpf1 nucleases showed similar activities and TTTV PAM preferences. Our approach also revealed that besides their activities their PAM preferences are also target dependent. To increase the number of the available targets for Fn- and MbCpf1 we generated their RVR and RR mutants with altered PAM specificity and compared them to the wild-type and analogous As- and LbCpf1 variants. The mutants gained new PAM specificities but retained their activity on targets with TTTV PAMs, redefining RR-Cpf1’s PAM-specificities as TTYV/TCCV, respectively. These variants may become versatile substitutes for wild-type Cpf1s by providing an expanded range of targets for genome engineering applications.

Intermittency of quasiclassical quantum turbulence in superfluid ${}^{4}$He is experimentally found to be temperature dependent and enhanced for a range of temperatures compared to classical turbulence, in contrast with nearly flow-independent intermittency of turbulence in classical fluids.

Prunus spinosa L. (blackthorn, sloe) is a com- mon species in the wild flora of Europe. Marmalade, syrup, and alcoholic beverages have been prepared from fruits. In folk medicine they'are used due to the astringent effect. However there are few studies on these indigenous fruits. According to the literature they contain tannins, anthocyanins, sugars, vitamin C etc.Our objective is to determine the antioxidant activity as related to their phenolic composition. For this purpose we prepared extracts using methanol, methanol-water (1: 1) and water. The antioxidant activity was determined by DPPH method and by photochemiluminescens (PCL) method. The total polyphenols, total anthocyanins and flavonoids were determined by colorimetric methods. Individual polyphenols were identified by a RP-HPLC-UVIVIS method.The antioxidant activity decreased in the extracts as follows: methanolmethanol-waterwater (IC₅₀= 1.33 mg/ml for DPPH; 11.94 μmol AAEIml for PCLIC₅₀ = 1.87 mg/ml for DPPH; 10.35 μmol AAElml for PCLIC₅₀ = 15.29 mg/ml for DPPH, 1.89 μmol AAElml for PCL) which is cor- related with the total polyphenol content (369 mg/100g244 mg1100g101 mg1100g) and total anthocyanin content (37.11 mg/100 g16.33 mg/100g7.76 mg/100g). The fla- vonoid content is similar in the three extracts (between 35.82 - 37.32 mg1100 g). The HPLC analysis shows high chloro- genic and neochlorogenic acid levels, followed by glycosides of quercetin.Our results demonstrated that blackthorn fruits are a rich source of phenolic compounds, with anti- oxidant activity, which are best extracted with methanol or methanol-water.

Recently the interest in thermal counterflow of superfluid $^{4}\mathrm{He}$, the most extensively studied form of quantum turbulence, has been renewed. Particularly, an intense theoretical debate has arisen about what form, if any, of the so-called Vinen equation accurately captures the dynamics of vortex line density, $L$. We address this problem experimentally, in a 21 cm long channel of square $7\ifmmode\times\else\texttimes\fi{}7\phantom{\rule{4pt}{0ex}}{\mathrm{mm}}^{2}$ cross section. Based on large statistics of second-sound data measured in nonequilibrium square-wave modulated thermally induced counterflow we investigate the phase portrait of the general form of the governing dynamical equation and conclude that for sparse tangles $(L\ensuremath{\lesssim}{10}^{5}\phantom{\rule{4pt}{0ex}}{\mathrm{cm}}^{\ensuremath{-}2})$ all proposed forms of this equation based on the concept of a homogeneous random tangle of quantized vortices provide equally adequate descriptions of the growth of $L$, while for dense tangles $(Lg{10}^{5}\phantom{\rule{4pt}{0ex}}{\mathrm{cm}}^{\ensuremath{-}2})$ none of them is satisfactory or able to account for the significant slow-down in tangle growth rate as the steady state is approached. We claim, however, that agreement with theory is recovered if the geometrical parameter ${c}_{2}$ introduced in numerical studies by K. W. Schwarz [Phys. Rev. B 38, 2398 (1988)] is allowed to vary with vortex line density which also greatly improves the prediction of the observed early decay rate.

Background Immune checkpoint inhibitors have shown limited clinical benefits in MSS-CRC; dual targeting of non-redundant pathways may enhance antitumor immune response. In a phase I/II, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was combined with monalizumab (M), an IgG4 mAb that blocks NKG2A binding to HLA-E to reduce inhibition of NK and CD8+ T cells. The combination (D+M) was well tolerated and showed encouraging activity in heavily pretreated pts with advanced MSS-CRC. In a dose-exploration cohort, D+M was assessed in combination with standard of care (SOC) chemotherapy and bevacizumab, an anti-VEGF agent, as first-line therapy for advanced/metastatic MSS-CRC. Methods Eligible pts had histologically defined MSS-CRC, regardless of RAS/RAF mutational status, ECOG 0–1 and no prior systemic therapy. They received durvalumab 1500mg Q4W, monalizumab 750mg Q2W, modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) Q2W and bevacizumab 5mg/kg Q2W until end of treatment; dose modifications were allowed according to SOC practice except during the DLT evaluation period. The primary endpoint was safety and tolerability of D+M with FOLFOX6 and bevacizumab; secondary endpoints included antitumor activity. Results As of Mar 25, 2019, 18 pts were enrolled with median follow-up of 6.2 months. Monalizumab-related adverse events (AEs) occurred in 13 (72%), serious in 1 (6%; embolism). Durvalumab-related AEs occurred in 14 (78%; none serious). All pts had chemotherapy-related AEs, serious in 1 (6%; febrile neutropenia) and 10 (56%) had bevacizumab-related AEs, serious in 2 (11%; embolism and febrile neutropenia). There were no grade 5 or dose-limiting toxicities. At 16 weeks, 17 pts were evaluable for response; 9 (53%) had partial responses (7 confirmed, 2 unconfirmed), 6 (35%) had stable disease and 2 (12%) had progressive disease; there were no complete responses. Median time to response for the 7 confirmed responders was 15.4 weeks; median duration of response was not yet reached. Conclusions First-line D+M combined with SOC showed manageable safety and preliminary activity in pts with advanced/metastatic MSS-CRC. Accrual is complete. Clinical trial identification NCT02671435. Editorial acknowledgement Medical writing support was provided by Hashem Dbouk, PhD, of Cirrus Communications (Lyndhurst, NJ), an Ashfield company, and was funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J.C. Bendell: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Gilead; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Taiho; Advisory / Consultancy, Research grant / Funding (institution): MacroGenics; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: OncoMed; Advisory / Consultancy, Research grant / Funding (institution): LEAP; Advisory / Consultancy, Research grant / Funding (institution): TG Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BI; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): Koltan; Research grant / Funding (institution): SynDevRex; Research grant / Funding (institution): Forty Seven; Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Array; Research grant / Funding (institution): Onyx; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Celldex; Advisory / Consultancy, Research grant / Funding (institution): Agios; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Nektar; Research grant / Funding (institution), Travel / Accommodation / Expenses: ARMO; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Tyrogenex; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Oncogenex; Research grant / Funding (institution): Marshall Edwards; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Evelo; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Forma; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Effector; Research grant / Funding (institution): Novocare; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Sierra; Advisory / Consultancy, Research grant / Funding (institution): Innate; Advisory / Consultancy, Research grant / Funding (institution): Arch Oncology; Advisory / Consultancy, Research grant / Funding (institution): Prelude Oncology; Research grant / Funding (institution): Unum Therapeutics; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Harpoon; Research grant / Funding (institution): ADC; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Imclone; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Rgenix; Research grant / Funding (institution): Bellicum; Advisory / Consultancy: Phoenix Bio; Advisory / Consultancy: Cyteir; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Innate; Advisory / Consultancy: Torque; Advisory / Consultancy: Tizona; Advisory / Consultancy: Janssen; Advisory / Consultancy: Tolero; Advisory / Consultancy: TD2 (Translational Drug Development); Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Moderna Therapeutics; Advisory / Consultancy: Tanabe Research Laboratories; Advisory / Consultancy: Beigene; Advisory / Consultancy: Continuum Clinical; Advisory / Consultancy: Kyn. J. Naidoo: Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: BMS. X. Li: Full / Part-time employment: AstraZeneca. P. Kourtesis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.E. Abdullah: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S. Patel: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Illumina; Advisory / Consultancy: Nektar; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Fate; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Fate Therapeutics; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Iovance. All other authors have declared no conflicts of interest.