One-Pot 3D Printing of Robust Multimaterial Devices

Polymer 3D printing is a broad set of manufacturing methods that permit the fabrication of complex architectures, and, as a result, numerous efforts focus on formulating processible chemistries that produce desirable material behavior in printed parts. However, current resin chemistries typically result in a single fixed set of properties once fully polymerized, a fact that poses significant engineering challenges to obtaining multimaterial devices. As an alternative to single-property materials, we introduce a ternary sequential reaction scheme that exhibits diverse multimaterial properties by profoundly altering the polymer microstructure from within a single resin composition. In this system, the photodosage during 3D printing sets both the shape and extent of conversion for each subsequent reaction. This different polymerization mechanisms of the subsequent stages yield disparate crosslink densities and viscoelastic properties. As a result, our materials possess Young's Moduli spanning over three orders of magnitude (400 kPa < E < 1.6 GPa) with smooth transitions between soft and stiff regions. We successfully pattern a 500x change in modulus in under a millimeter while the sequential assembly of our polymer networks ensures robust interfaces and enhances toughness by 10x compared to the single property materials. Most importantly, the final objects remain stable to UV and thermal aging, a key limitation to applications of previous multimaterial chemistries. We demonstrate the ability to 3D print intricate multimaterial architectures by fabricating a soft, wearable braille display.Comment: 54 pages including supplemental information, 5 main text figure

Associations between endogenous sex hormone levels and mammographic and bone densities in premenopausal women

PURPOSE: Mammographic breast and bone mineral densities (BMD) have been associated with luteal phase hormone concentrations in premenopausal women. We assessed the associations of breast and bone densities with follicular phase hormones and sex hormone binding globulin (SHBG) in premenopausal women given that follicular phase hormones have been shown to be positively associated with premenopausal breast cancer risk. METHODS: One hundred and ninety two 40-45 year old women provided a spot urine and/or blood sample during the follicular phase. Hormone and SHBG concentrations and bone density were measured and routine mammograms were accessed and digitized to obtain breast density measures. Regression models were fit to assess the associations between hormones and SHBG and breast and bone densities. RESULTS: Positive associations were observed between percent breast density and SHBG (p trend = 0.02), as well as estradiol (p trend = 0.08), after controlling for body mass index (BMI), number of pregnancies, and breast feeding history. In addition, a statistically significant inverse association was observed between total testosterone and head BMD (p trend = 0.01), after controlling for BMI. CONCLUSIONS: Associations were observed between breast and bone densities and serum hormone concentrations during the follicular phase of the menstrual cycle

'It's Reducing a Human Being to a Percentage'; Perceptions of Justice in Algorithmic Decisions

Data-driven decision-making consequential to individuals raises important questions of accountability and justice. Indeed, European law provides individuals limited rights to 'meaningful information about the logic' behind significant, autonomous decisions such as loan approvals, insurance quotes, and CV filtering. We undertake three experimental studies examining people's perceptions of justice in algorithmic decision-making under different scenarios and explanation styles. Dimensions of justice previously observed in response to human decision-making appear similarly engaged in response to algorithmic decisions. Qualitative analysis identified several concerns and heuristics involved in justice perceptions including arbitrariness, generalisation, and (in)dignity. Quantitative analysis indicates that explanation styles primarily matter to justice perceptions only when subjects are exposed to multiple different styles---under repeated exposure of one style, scenario effects obscure any explanation effects. Our results suggests there may be no 'best' approach to explaining algorithmic decisions, and that reflection on their automated nature both implicates and mitigates justice dimensions.Comment: 14 pages, 3 figures, ACM Conference on Human Factors in Computing Systems (CHI'18), April 21--26, Montreal, Canad

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis

Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF. This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF

Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy

The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program

Background:Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. Methods: The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12 months.Results: Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow-up of 25 months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p &lt; 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1–13, p = 0.03). Conclusions: In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.</p

Structures of the Signal Recognition Particle Receptor from the Archaeon Pyrococcus furiosus: Implications for the Targeting Step at the Membrane

In all organisms, a ribonucleoprotein called the signal recognition particle (SRP) and its receptor (SR) target nascent proteins from the ribosome to the translocon for secretion or membrane insertion. We present the first X-ray structures of an archeal FtsY, the receptor from the hyper-thermophile Pyrococcus furiosus (Pfu), in its free and GDP•magnesium-bound forms. The highly charged N-terminal domain of Pfu-FtsY is distinguished by a long N-terminal helix. The basic charges on the surface of this helix are likely to regulate interactions at the membrane. A peripheral GDP bound near a regulatory motif could indicate a site of interaction between the receptor and ribosomal or SRP RNAs. Small angle X-ray scattering and analytical ultracentrifugation indicate that the crystal structure of Pfu-FtsY correlates well with the average conformation in solution. Based on previous structures of two sub-complexes, we propose a model of the core of archeal and eukaryotic SRP•SR targeting complexes

Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance

<p>Abstract</p> <p>Background</p> <p>Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>OCT1 (<it>SLC22A1</it>) and OCT3 (<it>SLC22A3</it>) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.</p> <p>Results</p> <p>Real time PCR showed a downregulation of <it>SLC22A1 </it>and <it>SLC22A3 </it>in HCC compared to TST (p ≤ 0.001). A low <it>SLC22A1 </it>expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, <it>SLC22A1 </it>was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low <it>SLC22A1 </it>expression (< median) showed a higher <it>SLC22A3 </it>expression compared to HCC with high <it>SLC22A1 </it>expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the <it>SLC22A3 </it>expression.</p> <p>In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.</p> <p>Conclusion</p> <p>The downregulation of OCT1 is associated with tumor progression and a worse patient survival.</p

Interplay between cell adhesion and growth factor receptors: from the plasma membrane to the endosomes

The emergence of multicellular animals could only take place once evolution had produced molecular mechanisms for cell adhesion and communication. Today, all metazoans express integrin-type adhesion receptors and receptors for growth factors. Integrins recognize extracellular matrix proteins and respective receptors on other cells and, following ligand binding, can activate the same cellular signaling pathways that are regulated by growth factor receptors. Recent reports have indicated that the two receptor systems also collaborate in many other ways. Here, we review the present information concerning the role of integrins as assisting growth factor receptors and the interplay between the receptors in cell signaling and in the orchestration of receptor recycling