The cellular interactions of PEGylated gold nanoparticles : effect of PEGylation on cellular uptake and cytotoxicity

Poly(ethylene glycol) (PEG) is frequently used to coat various medical nanoparticles (NPs). As PEG is known to minimize NP interactions with biological specimens, the question remains whether PEGylated NPs are intrinsically less toxic or whether this is caused by reduced NP uptake. In the present work, the effect of gold NP PEGylation on uptake by three cell types is compared and evaluated the effect on cell viability, oxidative stress, cell morphology, and functionality using a multiparametric methodology. The data reveal that PEGylation affects cellular NP uptake in a cell-type-dependent manner and influences toxicity by different mechanisms. At similar intracellular NP numbers, PEGylated NPs are found to yield higher levels of cell death, mostly by induction of oxidative stress. These findings reveal that PEGylation significantly reduces NP uptake, but that at similar functional (= cell-associated) NP levels, non-PEGylated NPs are better tolerated by the cells

Reconstruction of source location in a network of gravitational wave interferometric detectors

This paper deals with the reconstruction of the direction of a gravitational wave source using the detection made by a network of interferometric detectors, mainly the LIGO and Virgo detectors. We suppose that an event has been seen in coincidence using a filter applied on the three detector data streams. Using the arrival time (and its associated error) of the gravitational signal in each detector, the direction of the source in the sky is computed using a chi^2 minimization technique. For reasonably large signals (SNR>4.5 in all detectors), the mean angular error between the real location and the reconstructed one is about 1 degree. We also investigate the effect of the network geometry assuming the same angular response for all interferometric detectors. It appears that the reconstruction quality is not uniform over the sky and is degraded when the source approaches the plane defined by the three detectors. Adding at least one other detector to the LIGO-Virgo network reduces the blind regions and in the case of 6 detectors, a precision less than 1 degree on the source direction can be reached for 99% of the sky.Comment: Accepted in Phys. Rev.

Pea aphid winged and wingless males exhibit reproductive, gene expression, and lipid metabolism differences

Alternative, intraspecific phenotypes offer an opportunity to identify the mechanistic basis of differences asso- ciated with distinctive life history strategies. Wing dimorphic insects, in which both flight-capable and flight- incapable individuals occur in the same population, are particularly well-studied in terms of why and how the morphs trade offflight for reproduction. Yet despite a wealth of studies examining the differences between fe- male morphs, little is known about male differences, which could arise from different causes than those acting on females. Here we examined reproductive, gene expression, and biochemical differences between pea aphid ( Acyrthosiphon pisum ) winged and wingless males. We find that winged males are competitively superior in one- on-one mating circumstances, but wingless males reach reproductive maturity faster and have larger testes. We suggest that males tradeoffincreased local matings with concurrent possible inbreeding for outbreeding and in- creased ability to find mates. At the mechanistic level, differential gene expression between the morphs revealed a possible role for activin and insulin signaling in morph differences; it also highlighted genes not previously identified as being functionally important in wing polymorphism, such as genes likely involved in sperm produc- tion. Further, we find that winged males have higher lipid levels, consistent with their use as flight fuel, but we find no consistent patterns of different levels of activity among five enzymes associated with lipid biosynthesis. Overall, our analyses provide evidence that winged versus wingless males exhibit differences at the reproductive, gene expression, and biochemical levels, expanding the field’s understanding of the functional aspects of morph differences

Comparison Between Wolfe, Boyd, BI-RADS and Tabár Based Mammographic Risk Assessment

Abstract. Mammographic risk assessment provides an indication of the likelihood of women developing breast cancer. Anumber ofmammographic image based classification methods have been developed, such as Wolfe, Boyd, BI-RADS and Tabár based assessment. We provide a comparative study of these four approaches. Results on the full MIAS database are presented, which indicate strong correlation (Spearman’s> 0.9) between Wolfe, Boyd andBI-RADSbased classification, whilst the correlation with Tabár based classification is less straight forward (Spearman’s < 0.5, but low correlations mainly caused by one of the classes).

Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair

Eukaryotic cells possess a universal repair machinery that ensures rapid resealing of plasma membrane disruptions. Before resealing, the torn membrane is submitted to considerable tension, which functions to expand the disruption. Here we show that annexin-A5 (AnxA5), a protein that self-assembles into two-dimensional (2D) arrays on membranes upon Ca2+ activation, promotes membrane repair. Compared with wild-type mouse perivascular cells, AnxA5-null cells exhibit a severe membrane repair defect. Membrane repair in AnxA5-null cells is rescued by addition of AnxA5, which binds exclusively to disrupted membrane areas. In contrast, an AnxA5 mutant that lacks the ability of forming 2D arrays is unable to promote membrane repair. We propose that AnxA5 participates in a previously unrecognized step of the membrane repair process: triggered by the local influx of Ca2+, AnxA5 proteins bind to torn membrane edges and form a 2D array, which prevents wound expansion and promotes membrane resealing

Greatly increased occurrence of breast cancers in areas of mammographically dense tissue

INTRODUCTION: Mammographic density is a strong, independent risk factor for breast cancer. A critical unanswered question is whether cancers tend to arise in mammographically dense tissue (i.e. are densities directly related to risk or are they simply a marker of risk). This question cannot be addressed by studying invasive tumors because they manifest as densities and cannot be confidently differentiated from the densities representing fibrous and glandular tissue. We addressed this question by studying ductal carcinoma in situ (DCIS), as revealed by microcalcifications. METHOD: We studied the cranio-caudal and the mediolateral-oblique mammograms of 28 breasts with a solitary DCIS lesion. Two experienced radiologists independently judged whether the DCIS occurred in a mammographically dense area, and determined the density of different areas of the mammograms. RESULTS: It was not possible to determine whether the DCIS was or was not in a dense area for six of the tumors. Of the remaining 22 lesions, 21 occurred in dense tissue (test for difference from expected taken as the percentage of density of the 'mammographic quadrant' containing DCIS; P < 0.0001). A preponderance of DCIS (17 out of 28) occurred in the mammographic quadrant with the highest percentage density. CONCLUSION: DCIS occurs overwhelmingly in the mammographically dense areas of the breast, and pre-DCIS mammograms showed that this relationship was not brought about by the presence of the DCIS. This strongly suggests that some aspect of stromal tissue comprising the mammographically dense tissue directly influences the carcinogenic process in the local breast glandular tissue

Brainstem Respiratory Oscillators Develop Independently of Neuronal Migration Defects in the Wnt/PCP Mouse Mutant looptail

The proper development and maturation of neuronal circuits require precise migration of component neurons from their birthplace (germinal zone) to their final positions. Little is known about the effects of aberrant neuronal position on the functioning of organized neuronal groups, especially in mammals. Here, we investigated the formation and properties of brainstem respiratory neurons in looptail (Lp) mutant mice in which facial motor neurons closely apposed to some respiratory neurons fail to migrate due to loss of function of the Wnt/Planar Cell Polarity (PCP) protein Vangl2. Using calcium imaging and immunostaining on embryonic hindbrain preparations, we found that respiratory neurons constituting the embryonic parafacial oscillator (e-pF) settled at the ventral surface of the medulla in Vangl2Lp/+ and Vangl2Lp/Lp embryos despite the failure of tangential migration of its normally adjacent facial motor nucleus. Anatomically, the e-pF neurons were displaced medially in Lp/+ embryos and rostro-medially Lp/Lp embryos. Pharmacological treatments showed that the e-pF oscillator exhibited characteristic network properties in both Lp/+ and Lp/Lp embryos. Furthermore, using hindbrain slices, we found that the other respiratory oscillator, the preBötzinger complex, was also anatomically and functionally established in Lp mutants. Importantly, the displaced e-pF oscillator established functional connections with the preBötC oscillator in Lp/+ mutants. Our data highlight the robustness of the developmental processes that assemble the neuronal networks mediating an essential physiological function

Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy

Impact of herpes zoster and post-herpetic neuralgia on patients’ quality of life: a patient-reported outcomes survey

Background: The impact of herpes zoster (HZ) and post-herpetic neuralgia (PHN) on patients’ quality of life (QoL) is currently poorly documented. Subjects and methods: Telephone interviews in Germany identified patients ≥50 years old with painful HZ diagnosed during the previous 5 years. Bespoke questions evaluated previous HZ episodes. Results: Of 11,009 respondents, 280 met the screening criteria, and 32 (11%) developed PHN. PHN was associated with significantly worse outcomes than HZ (all P < 0.05). Mean pain scores associated with PHN and HZ, respectively, were 7.1 and 6.2 (average) and 8.2 and 7.0 (worst). Many patients with PHN (91%) and HZ (73%) experienced problems with daily activities, including work, studies, housework, family and leisure activities. Mean pain interference scores in patients with PHN versus HZ were highest for sleep (6.5 versus 4.9), normal work (6.1 versus 4.4) and mood (5.9 versus 4.4). Most employed interviewees with PHN (70%) and HZ (64%) stopped work during the disease. Pain and QoL outcomes were not significantly different between all patients versus those diagnosed during the previous 12 months or between patients aged 50–59 years versus ≥60 years. Conclusions: HZ causes substantial pain, which seriously interferes with many aspects of daily life, particularly in patients with PHN

Uncertainty in Simulating Wheat Yields Under Climate Change

Projections of climate change impacts on crop yields are inherently uncertain1. Uncertainty is often quantified when projecting future greenhouse gas emissions and their influence on climate2. However, multi-model uncertainty analysis of crop responses to climate change is rare because systematic and objective comparisons among process-based crop simulation models1,3 are difficult4. Here we present the largest standardized model intercomparison for climate change impacts so far. We found that individual crop models are able to simulate measured wheat grain yields accurately under a range of environments, particularly if the input information is sufficient. However, simulated climate change impacts vary across models owing to differences in model structures and parameter values. A greater proportion of the uncertainty in climate change impact projections was due to variations among crop models than to variations among downscaled general circulation models. Uncertainties in simulated impacts increased with CO2 concentrations and associated warming. These impact uncertainties can be reduced by improving temperature and CO2 relationships in models and better quantified through use of multi-model ensembles. Less uncertainty in describing how climate change may affect agricultural productivity will aid adaptation strategy development and policymaking