His Story: “I would be better off dead”

A physician shares the story of his brother’s experience in an ICU, how the hospital caring for him failed him as a human being, and how the pain of not being properly cared for and not being treated with dignity and respect left the patient feeling he would be better off dead. In the back of his mind the patient wondered if it was because he is Black. The story prompts the author to reflect on patient rights as a reminder that healthcare is called to serve, to love, to be empathetic, to be respectful, to be humble, to listen, and to be trustworthy. Re-establishing trust with the people and communities that healthcare serves is the hill that all in healthcare must climb together to ensure his brother’s story is never repeated. Experience Framework This article is associated with the Patient, Family & Community Engagement lens of The Beryl Institute Experience Framework (https://www.theberylinstitute.org/ExperienceFramework). Access other PXJ articles related to this lens. Access other resources related to this lens

Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion

Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([125I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted. © 2012 PLoS On

Low-temperature annealing of 2D Ti3C2Tx MXene films using electron wind force in ambient conditions

Two-dimensional transition metal carbides and nitrides, known as MXenes, are layered materials with unique functionalities which make them suitable for applications such as energy storage devices, supercapacitors, electromagnetic interference shielding, and wireless communications. Since they are wet-processed, MXenes need annealing to improve their electrical conductivity. The extent of annealing highly depends on temperature; however, higher temperatures can also impact the resulting phases and structure. In this study, we present a non-thermal annealing process utilizing an electron wind force (EWF) method in ambient conditions. This process is demonstrated on freestanding Ti3C2Tx films, where we show up to 70% decrease in resistivity at temperatures below 120 °C compared to conventional thermal annealing methods. MXene structures before and after annealing are analyzed using Raman spectroscopy and ex situ and in situ X-ray diffraction. Surface terminations and intra-flake defects modification in Ti3C2Tx layers after EWF annealing impart better electrical conductivity to MXene film than the non-annealed films

Evidence for alterations in fixational eye movements in glaucoma

BACKGROUND: Fixation changes in glaucoma are generally overlooked, as they are not strikingly evident as in macular diseases. Fundus perimetry might give additional insights into this aspect, along with traditional perimetric measures. In this work we propose a novel method to quantify glaucomatous changes in fixation features as detected by fundus perimetry and relate them to the extent of glaucomatous damage. METHODS: We retrospectively analysed fixation data from 320 people (200 normal subjects and 120 with glaucoma) from the Preferred Retinal Locus (PRL) detection of a Compass perimeter. Fixation stability was measured as Bivariate Contour Ellipse Area (BCEA), and using two novel metrics: (1) Mean Euclidean Distance (MED) from the Preferred Retinal Locus, and (2) Sequential Euclidean Distance (SED) of sequential fixation locations. These measures were designed to capture the spread of fixation points, and the frequency of position changes during fixation, respectively. RESULTS: In the age corrected analysis, SED was significantly greater in glaucomatous subjects than controls (P = 0.002), but there was no difference in BCEA (P = 0.15) or MED (P = 0.054). Similarly, SED showed a significant association with Mean Deviation (P  0.14 for both). CONCLUSION: Changes in the scanning pattern detected by SED are better than traditional measures of fixation spread (BCEA) for describing the changes in fixation stability observed in glaucoma

A small-changes approach reduces energy intake in free-living humans

Abstract Objective-America On the Move (AOM) is a national weight gain prevention initiative that promotes small lifestyle changes by increasing walking by 2000 steps/day and reducing energy intake by about 100 kcal/day. The study's intent was to determine the impact of these small changes recommendations on steps/day and energy intake. Methods-In this cross-sectional study, food and fluid intake and physical activity in 116 healthy overweight adults (BMI: 25-36 kg/m 2 ; age: 18-60y) was compared between a non-intervention and an intervention week using diet diaries and pedometers. The major outcomes were steps/day, daily caloric intake, macronutrient intake and meal size. Within subject ANOVAs were conducted to compare results between intervention and non-intervention weeks. Results-Total energy intake was lower during intervention week than non-intervention week (P < .01), including macronutrient contents (all P's < .01), meal size (P < .01), consumption of sugar (P < .01), sugared sodas (P < .01) and sodium (P < .01). Steps/day were higher during intervention week than non-intervention week (P < .01). Conclusions- The results support previous research showing that the message to increase steps/ day results in an increase in physical activity. The results demonstrate for the first time that the message to reduce intake by 100 kcal/day does actually result in a lower intake in the short term. People seem to be able to make positive changes in diet and physical activity in response to these messages. If these small changes can be sustained, this approach could be effective in preventing further weight gain in the population

Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion

Background Stromal fibroblasts can contribute to tumor invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion. Methods Primary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided. Results Tumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04). Conclusion This study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively

Identification and Characterization of Inhibitors of Human Apurinic/apyrimidinic Endonuclease APE1

APE1 is the major nuclease for excising abasic (AP) sites and particular 3′-obstructive termini from DNA, and is an integral participant in the base excision repair (BER) pathway. BER capacity plays a prominent role in dictating responsiveness to agents that generate oxidative or alkylation DNA damage, as well as certain chain-terminating nucleoside analogs and 5-fluorouracil. We describe within the development of a robust, 1536-well automated screening assay that employs a deoxyoligonucleotide substrate operating in the red-shifted fluorescence spectral region to identify APE1 endonuclease inhibitors. This AP site incision assay was used in a titration-based high-throughput screen of the Library of Pharmacologically Active Compounds (LOPAC1280), a collection of well-characterized, drug-like molecules representing all major target classes. Prioritized hits were authenticated and characterized via two high-throughput screening assays – a Thiazole Orange fluorophore-DNA displacement test and an E. coli endonuclease IV counterscreen – and a conventional, gel-based radiotracer incision assay. The top, validated compounds, i.e. 6-hydroxy-DL-DOPA, Reactive Blue 2 and myricetin, were shown to inhibit AP site cleavage activity of whole cell protein extracts from HEK 293T and HeLa cell lines, and to enhance the cytotoxic and genotoxic potency of the alkylating agent methylmethane sulfonate. The studies herein report on the identification of novel, small molecule APE1-targeted bioactive inhibitor probes, which represent initial chemotypes towards the development of potential pharmaceuticals

5-Formylcytosine alters the structure of the DNA double helix.

The modified base 5-formylcytosine (5fC) was recently identified in mammalian DNA and might be considered to be the 'seventh' base of the genome. This nucleotide has been implicated in active demethylation mediated by the base excision repair enzyme thymine DNA glycosylase. Genomics and proteomics studies have suggested an additional role for 5fC in transcription regulation through chromatin remodeling. Here we propose that 5fC might affect these processes through its effect on DNA conformation. Biophysical and structural analysis revealed that 5fC alters the structure of the DNA double helix and leads to a conformation unique among known DNA structures including those comprising other cytosine modifications. The 1.4-Å-resolution X-ray crystal structure of a DNA dodecamer comprising three 5fCpG sites shows how 5fC changes the geometry of the grooves and base pairs associated with the modified base, leading to helical underwinding.E.-A.R. is supported as a Herchel Smith Fellow. The Balasubramanian laboratory is supported by a Senior Investigator Award from the Wellcome Trust (099232/Z/12/Z to S.B.), and it also receives core funding from Cancer Research UK (C9681/A11961 to S.B.). D.Y.C. is supported by the Crystallographic X-ray Facility (CXF) at the Department of Biochemistry, University of Cambridge, and B.F.L. is supported by the Wellcome Trust (076846/Z/05/A to B.F.L.). We thank the staff of Soleil and Diamond Light Source for use of facilities. We thank C. Calladine for stimulating discussions.This is the accepted manuscript for a paper published in Nature Structural & Molecular Biology 22, 44–49 (2015) doi: 10.1038/nsmb.293

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal

A dearth of small particles in the transiting material around the white dwarfWD 1145+017

White dwarf WD 1145+017 is orbited by several clouds of dust, possibly emanating from actively disintegrating bodies. These dust clouds reveal themselves through deep, broad, and evolving transits in the star's light curve. Here, we report two epochs of multi-wavelength photometric observations of WD 1145+017, including several filters in the optical, K$_\mathrm{s}$ and 4.5 $\mu$m bands in 2016 and 2017. The observed transit depths are different at these wavelengths. However, after correcting for excess dust emission at K$_\mathrm{s}$ and 4.5 $\mu$m, we find the transit depths for the white dwarf itself are the same at all wavelengths, at least to within the observational uncertainties of $\sim$5%-10%. From this surprising result, and under the assumption of low optical depth dust clouds, we conclude that there is a deficit of small particles (with radii $s \lesssim$ 1.5 $\mu$m) in the transiting material. We propose a model wherein only large particles can survive the high equilibrium temperature environment corresponding to 4.5 hr orbital periods around WD 1145+017, while small particles sublimate rapidly. In addition, we evaluate dust models that are permitted by our measurements of infrared emission