The series of complexes Os(bpy)3–n (pytz) n PF62 (bpy = 2,2′-bipyridyl, pytz = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, 1 n = 0, 2 n = 1, 3 n = 2, 4 n = 3) were prepared and characterized and are ...rare examples of luminescent 1,2,3-triazole-based osmium(II) complexes. For 3 we present an attractive and particularly mild preparative route via an osmium(II) η6-arene precursor circumventing the harsh conditions that are usually required. Because of the high spin–orbit coupling constant associated with the Os(II) center the absorption spectra of the complexes all display absorption bands of appreciable intensity in the range of 500–700 nm corresponding to spin-forbidden ground-state-to-3MLCT transitions (MLCT = metal-to-ligand charge transfer), which occur at significantly lower energies than the corresponding spin-allowed 1MLCT transitions. The homoleptic complex 4 is a bright emitter (λmax em = 614 nm) with a relatively high quantum yield of emission of ∼40% in deoxygenated acetonitrile solutions at room temperature. Water-soluble chloride salts of 1–4 were also prepared, all of which remain emissive in aerated aqueous solutions at room temperature. The complexes were investigated for their potential as phosphorescent cellular imaging agents, whereby efficient excitation into the 3MLCT absorption bands at the red side of the visible range circumvents autofluorescence from biological specimens, which do not absorb in this region of the spectrum. Confocal microscopy reveals 4 to be readily taken up by cancer cell lines (HeLa and EJ) with apparent lysosomal and endosomal localization, while toxicity assays reveal that the compounds have low dark and light toxicity. These complexes therefore provide an excellent platform for the development of efficient luminescent cellular imaging agents with advantageous photophysical properties that enable excitation and emission in the biologically transparent region of the optical spectrum.
WHO core components for infection prevention and control (IPC) are important building blocks for effective IPC programmes. To our knowledge, we did the first WHO global survey to assess ...implementation of these programmes in health-care facilities.
In this cross-sectional survey, IPC professionals were invited through global outreach and national coordinated efforts to complete the online WHO IPC assessment framework (IPCAF). The survey was created in English and was then translated into ten languages: Arabic, Chinese, English, French, German, Italian, Japanese, Russian, Spanish, and Thai. Post-stratification weighting was applied and countries with low response rates were excluded to improve representativeness. Weighted median scores and IQRs as well as weighted proportions (Nw) meeting defined IPCAF minimum requirements were reported. Indicators associated with the IPCAF score were assessed using a generalised estimating equation.
From Jan 16 to Dec 31, 2019, 4440 responses were received from 81 countries. The overall weighted IPCAF median score indicated an advanced level of implementation (605, IQR 450·4–705·0), but significantly lower scores were found in low-income (385, 279·7–442·9) and lower-middle-income countries (500·4, 345·0–657·5), and public facilities (515, 385–637·8). Core component 8 (built environment; 90·0, IQR 75·0–100·0) and core component 2 (guidelines; 87·5, 70·0–97·5) scored the highest, and core component 7 (workload, staffing, and bed occupancy; 70·0, 50–90) and core component 3 (education and training; 70 ·0, 50·0–85·0) scored the lowest. Overall, only 15·2% (Nw: 588 of 3873) of facilities met all IPCAF minimum requirements, ranging from 0% (0 of 417) in low-income countries to 25·6% (278 of 1087) in primary facilities, 9% (24 of 268) in secondary facilities, and 19% (18 of 95) in tertiary facilities in high-income countries.
Despite an overall high IPCAF score globally, important gaps in IPC facility implementation and core components across income levels hinder IPC progress. Increased support for more effective and sustainable IPC programmes is crucial to reduce risks posed by outbreaks to global health security and to ensure patient and health worker safety.
WHO and the Infection Control Programme, University of Geneva Hospitals and Faculty of Medicine.
For the French and Spanish translations of the abstract see Supplementary Materials section.
Active plasma lensing is a compact technology for strong focusing of charged particle beams, which has gained considerable interest for use in novel accelerator schemes. While providing kT/m focusing ...gradients, active plasma lenses can have aberrations caused by a radially nonuniform plasma temperature profile, leading to degradation of the beam quality. We present the first direct measurement of this aberration, consistent with theory, and show that it can be fully suppressed by changing from a light gas species (helium) to a heavier gas species (argon). Based on this result, we demonstrate emittance preservation for an electron beam focused by an argon-filled active plasma lens.
Investigating Variation in Replicability Klein, Richard A.; Ratliff, Kate A.; Vianello, Michelangelo ...
Social psychology (Göttingen, Germany),
01/2014, Letnik:
45, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Although replication is a central tenet of science, direct replications are rare
in psychology. This research tested variation in the replicability of 13 classic and
contemporary effects across 36 ...independent samples totaling 6,344 participants. In the
aggregate, 10 effects replicated consistently. One effect - imagined contact reducing
prejudice - showed weak support for replicability. And two effects - flag priming
influencing conservatism and currency priming influencing system justification - did not
replicate. We compared whether the conditions such as lab versus online or US versus
international sample predicted effect magnitudes. By and large they did not. The results of
this small sample of effects suggest that replicability is more dependent on the effect itself
than on the sample and setting used to investigate the effect.
•First simultaneous measurement of GABA+, Glx and GSH in the neonatal human brain.•Robust metabolic estimation in neonates requires a specific quantification strategy.•GABA+ has a doublet peak in ...neonates indicating lower macromolecular contributions.•Future application can inform about pathophysiology in neurodevelopment.
Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder.
Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T.
The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GABA+ and Glx levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites.
Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.
Abstract
Background
Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with ...small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of
TP53
-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with
TP53
mutations, has not been definitively evaluated.
Methods
Anti-leukemic effects of adavosertib were investigated using a relapsed
TP53
isogenic cell model system, primary patient, and patient-derived ALL samples (
n
= 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively.
Results
Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (
n
= 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of
TP53
mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL.
Conclusions
Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.
In this paper, we present the results of an observational search for gas phase urea (NH2)2CO observed toward the Sgr B2(N-LMH) region. We show data covering urea transitions from ∼100 GHz to 250 GHz ...from five different observational facilities: the Berkeley-Illinois-Maryland-Association (BIMA) Array, the Combined Array for Research in Millimeter-wave Astronomy (CARMA), the NRAO 12 m telescope, the IRAM 30 m telescope, and the Swedish-ESO Submillimeter Telescope (SEST). The results show that the features ascribed to urea can be reproduced across the entire observed bandwidth and all facilities by best-fit column density, temperature, and source size parameters which vary by less than a factor of two between observations merely by adjusting for telescope-specific parameters. Interferometric observations show that the emission arising from these transitions is cospatial and compact, consistent with the derived source sizes and emission from a single species. Despite this evidence, the spectral complexity of both (NH2)2CO and of Sgr B2(N) makes the definitive identification of this molecule challenging. We present observational spectra, laboratory data, and models, and discuss our results in the context of a possible molecular detection of urea.
Little is known about the fractionation of Li isotopes during formation of biogenic carbonates, which form the most promising geological archives of past seawater composition. Here we investigated ...the Li isotope composition (δ7Li) and Li/Ca ratios of organisms that are abundant in the Phanerozoic record: mollusks (mostly bivalves), echinoderms, and brachiopods. The measured samples include (i) modern calcite and aragonite shells from various species and natural environments (13 mollusk samples, 5 brachiopods and 3 echinoderms), and (ii) shells from mollusks grown under controlled conditions at various temperatures. When possible, the mollusk shell ultrastructure was micro-sampled in order to assess intra-shell heterogeneity. In this paper, we systematically characterize the influence of mineralogy, temperature, and biological processes on the δ7Li and Li/Ca of these shells and compare with published data for other taxa (foraminifera and corals).
Aragonitic mollusks have the lowest δ7Li, ranging from +16 to +22‰, echinoderms have constant δ7Li of about +24‰, brachiopods have δ7Li of +25 to +28‰, and finally calcitic mollusks have the largest range and highest δ7Li values, ranging from +25‰ to +40‰. Measured brachiopods have similar δ7Li compared to inorganic calcite precipitated from seawater (δ7Li of +27 to +29‰), indicating minimum influence of vital effects, as also observed for other isotope systems and making them a potentially viable proxy of past seawater composition. Calcitic mollusks, on the contrary, are not a good archive for seawater paleo–δ7Li because many samples have significantly higher δ7Li values than inorganic calcite and display large inter-species variability, which suggests large vital effects. In addition, we observe very large intra-shell variability, in particular for mixed calcite-aragonite shells (over 20‰ variability), but also in mono-mineralic shells (up to 12‰ variability). Aragonitic bivalves have less variable δ7Li (7‰ variability) compared to calcitic mollusks, but with significantly lower δ7Li compared to inorganic aragonite, indicating the existence of vital effects. Bivalves grown at various temperatures show that temperature has only a minor influence on fractionation of Li isotopes during shell precipitation. Interestingly, we observe a strong correlation (R2 = 0.83) between the Li/Mg ratio in bivalve Mytilus edulis and temperature, with potential implications for paleo-temperature reconstructions.
Finally, we observe a negative correlation between the δ7Li and both the Li/Ca and Mg/Ca ratio of calcite mollusks, which we relate to biomineralization processes. To explain this correlation, we propose preferential removal of 6Li from the calcification site of calcite mollusks by physiological processes corresponding to the regulation of the amount of Mg in the calcifying medium. We calculate that up to 80% of the initial Li within the calcification site is removed by this process, leading to high δ7Li and low Li/Ca in some calcite mollusk specimens. Collectively, these results suggest that Mg (and thus Li) is strongly biologically controlled within the calcifying medium of calcite mollusks.
Overall, the results of this study show that brachiopods are likely to be suitable targets for future work on the determination of paleo-seawater Li isotope composition—an emerging proxy for past weathering and hydrothermal processes.
In vitro production (IVP) of equine embryos is increasingly popular in clinical practice but suffers from higher incidences of early embryonic loss and monozygotic twin development than transfer of ...in vivo derived (IVD) embryos. Early embryo development is classically characterized by two cell fate decisions: (1) first, trophectoderm (TE) cells differentiate from inner cell mass (ICM); (2) second, the ICM segregates into epiblast (EPI) and primitive endoderm (PE). This study examined the influence of embryo type (IVD versus IVP), developmental stage or speed, and culture environment (in vitro versus in vivo) on the expression of the cell lineage markers, CDX-2 (TE), SOX-2 (EPI) and GATA-6 (PE). The numbers and distribution of cells expressing the three lineage markers were evaluated in day 7 IVD early blastocysts (
= 3) and blastocysts (
= 3), and in IVP embryos first identified as blastocysts after 7 (fast development,
= 5) or 9 (slow development,
= 9) days. Furthermore, day 7 IVP blastocysts were examined after additional culture for 2 days either in vitro (
= 5) or in vivo (after transfer into recipient mares,
= 3). In IVD early blastocysts, SOX-2 positive cells were encircled by GATA-6 positive cells in the ICM, with SOX-2 co-expression in some presumed PE cells. In IVD blastocysts, SOX-2 expression was exclusive to the compacted presumptive EPI, while GATA-6 and CDX-2 expression were consistent with PE and TE specification, respectively. In IVP blastocysts, SOX-2 and GATA-6 positive cells were intermingled and relatively dispersed, and co-expression of SOX-2 or GATA-6 was evident in some CDX-2 positive TE cells. IVP blastocysts had lower TE and total cell numbers than IVD blastocysts and displayed larger mean inter-EPI cell distances; these features were more pronounced in slower-developing IVP blastocysts. Transferring IVP blastocysts into recipient mares led to the compaction of SOX-2 positive cells into a presumptive EPI, whereas extended in vitro culture did not. In conclusion, IVP equine embryos have a poorly compacted ICM with intermingled EPI and PE cells; features accentuated in slowly developing embryos but remedied by transfer to a recipient mare.
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