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BORIS vs. GALNT14 mRNA expression correlations in TCGA data

Full description of GO categories and genes

New/enhanced CTCF binding sites associated with known genes

High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecologic cancer–related death. We have previously shown that CTCFL (also known as BORIS, Brother of the Regulator of Imprinted Sites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed BORIS in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC. BORIS-expressing cells exhibited increased motility and invasion, and BORIS expression was associated with alterations in several cancer-associated gene expression networks, including fatty acid metabolism, TNF signaling, cell migration, and ECM–receptor interactions. Importantly, GALNT14, a glycosyltransferase gene implicated in cancer cell migration and invasion, was highly induced by BORIS, and GALNT14 knockdown significantly abrogated BORIS-induced cell motility and invasion. In addition, in silico analyses provided evidence for BORIS and GALNT14 coexpression in several cancers. Finally, ChIP-seq demonstrated that expression of BORIS was associated with de novo and enhanced binding of CTCF at hundreds of loci, many of which correlated with activation of transcription at target genes, including GALNT14. Taken together, our data indicate that BORIS may promote cell motility and invasion in HGSC via upregulation of GALNT14, and suggests BORIS as a potential therapeutic target in this malignancy.Implications:These studies provide evidence that aberrant expression of BORIS may play a role in the progression to HGSC by enhancing the migratory and invasive properties of FTSEC.

Primers used for RT-qPCR

KEGG Pathways

Supplementary Figures 1-9

Figure S1. CSIOVDB Disease State Analysis. Figure S2. CSIOVDB histology and tumor grade analysis. Figure S3. Survival of ovarian cancer patients in CSIOVDB cohort with respect the ratio of BORIS/CTCF expression. Figure S4. Survival of ovarian cancer patients in TCGA cohort with respect to BORIS expression and the ratio of BORIS/CTCF expression. Figure S5. Survival of ovarian cancer patients in CSIOVDB cohort (high grade serous only) with respect to BORIS expression. Figure S6. Cellular morphology and proliferation analyses of FT282-EV and FT282-BORIS cells. Figure S7. Expression of BORIS in FT282 cells alters CTCF occupancy. Figure S8. Representative genome browser shots of CTCF and BORIS ChIP-seq tracks and RNA-seq tracks for FT282-EV and FT282-BORIS cells. Figure S9. Survival of ovarian cancer patients in CSIOVDB cohort with respect the (A) CHSY3 and (B) SERPINB2 expression.

Reactome pathways

Matching is a conceptually straightforward method to make groups of units comparable on observed characteristics. The method is, however, limited to settings where the study design is simple and the sample is moderately sized. We illustrate these limitations by asking what the causal effects would have been if a large-scale voter mobilization experiment that took place in Michigan for the 2006 election were scaled up to the full population of registered voters. Matching could help us answer this question, but no existing matching method can accommodate the six treatment arms and the 6,762,701 observations involved in the study. To offer a solution for this and similar empirical problems, we introduce a generalization of the full matching method that can be used with any number of treatment conditions and complex compositional constraints. The associated algorithm produces near-optimal matchings; the worst-case maximum within-group dissimilarity is guaranteed to be no more than four times greater than the optimal solution, and simulation results indicate that it comes considerably closer to the optimal solution on average. The algorithm’s ability to balance the treatment groups does not sacrifice speed, and it uses little memory, terminating in linearithmic time using linear space. This enables investigators to construct well-performing matchings within minutes even in complex studies with samples of several million units.

There are differential risk relationships between parity and breast cancer according to estrogen receptor (ER) status, with an increased risk of ER− disease reduced by breastfeeding. This may be particularly relevant for understanding the higher incidence of ER− tumors in Black women, who are more likely to be parous and less likely to breastfeed than other U.S. groups. Potential mechanisms for these relationships may include effects of disordered breast involution on inflammatory milieu in the breast as well as epigenetic reprogramming in the mammary gland, which can affect cell fate decisions in progenitor cell pools. In normal breast tissue, parity has been associated with hypermethylation of FOXA1, a pioneer transcription factor that promotes the luminal phenotype in luminal progenitors, while repressing the basal phenotype. In breast tumors, relationships between FOXA1 methylation and parity were strongest among women who did not breastfeed. Here, we summarize the epidemiologic literature regarding parity, breastfeeding, and breast cancer subtypes, and review potential mechanisms whereby these factors may influence breast carcinogenesis, with a focus on effects on progenitor cell pools in the mammary gland.

Among plausible causes for replicability failure, one that has not received sufficient attention is the environment in which the research is conducted. Consisting of the population, equipment, personnel, and various conditions such as location, time, and weather, the research environment can affect treatments and outcomes, and changes in the research environment that occur when an experiment is redone can affect replicability. We examine the extent to which such changes contribute to replicability failure. Our framework is that of an initial experiment that generates the data and a follow-up experiment that is done the same way except for a change in the research environment. We assume that the initial experiment satisfies the assumptions of the two-sample t-statistic and that the follow-up experiment is described by a mixed model which includes environmental parameters. We derive expressions for the effect that the research environment has on power, sample size selection, p-values, and confidence levels. We measure the size of the environmental effect with the environmental effect ratio EER which is the ratio of the standard deviations of environment by treatment interaction and error. By varying EER, it is possible to determine conditions that favor replicability and those that do not.

PURPOSE: Limited epidemiologic data are available on the expression of adipokines leptin (LEP) and adiponectin (ADIPOQ) and adipokine receptors (LEPR, ADIPOR1, ADIPOR2) in the breast tumor microenvironment (TME). The associations of gene expression of these biomarkers with tumor clinicopathology is not well understood. METHODS: NanoString multiplexed assays were used to assess the gene expression levels of LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 within tumor tissues among 162 Black and 55 White women with newly diagnosed breast cancer. Multivariate mixed effects models were used to estimate associations of gene expression with breast tumor clinicopathology (overall and separately among Blacks). RESULTS: Black race was associated with lower gene expression of LEPR (P=0.002) and ADIPOR1 (P=0.01). Lower LEP, LEPR, and ADIPOQ gene expression were associated with higher tumor grade (P=0.0007, P

Ground-level ozone is a harmful air pollutant associated with several health issues. Ozone concentrations have exceeded the National Ambient Air Quality Standards (NAAQS) in the Chicago metropolitan area on hot summer days for many years because of nitrogen oxide and volatile organic compound emissions. Annual fourth highest 8-hour ozone concentrations have been between 0.070 and 0.084 ppm at several monitoring sites in Cook county, during the 2016-2018 time period. The continuous measurement of nitrogen dioxide (NO2) and ozone (O3) was conducted in several communities in Chicago in 2017. The air pollution impacts the health of all who live in the area. The data were used to analyze correlations between the O3 distribution and its association with ambient concentrations of NO2 from transportation emissions. Higher concentrations in NO2 and O3 occurred in succession in the daytime. The diurnal variation of O3 concentration was analyzed. The daily cycle of NO2 concentration reaches a maximum in the late morning and has smaller nighttime concentrations. The daily cycle of ozone concentration reaches the maximum in the afternoon and also becomes smaller for nighttime concentrations. In addition, relationships were found between O3 and NO2. Monthly variations of ozone and NO2 are presented. Some options to reduce ozone pollution are presented.

Background: Reduced gravity treadmills have become increasingly prevalent in clinical settings. The purpose of this study was to assess the influence of manipulated levels of bodyweight during reduced gravity treadmill running on sensor-derived spatiotemporal, kinematic, and kinetic measures. Hypotheses: Reduced gravity conditions would result in significantly altered biomechanical measures compared with 100% gravity conditions, with the most pronounced effects anticipated in the 20% condition. Study Design: Cross-sectional clinic-based study. Methods: A total of 16 runners (8 male [M; age, 28.88 ± 5.69 years; body mass index [BMI], 25.08 ± 3.74 kg/m2], 8 female [F; age, 28.75 ± 5.23 years, BMI, 21.05 ± 3.46 kg/m2]) participated in this study. Participants wore commercially available sensors on their shoelaces and ran in a reduced gravity treadmill at a self-selected pace for 5 minutes each at 100%, 80%, 60%, 40%, and 20% bodyweight in a randomized order. The pace remained constant across all conditions, and rating of perceived exertion (RPE) was obtained following each condition. Step-by-step spatiotemporal, kinematic, and kinetic metrics were extracted to calculate mean outcome measures for each bodyweight condition. Repeated measures analyses of variance were conducted to assess the influence of the different bodyweight reduction levels on RPE and runners’ biomechanics. Results: Higher pressure creating lower bodyweight conditions resulted in significantly increased stride length and decreased cadence, contact time, impact g, and RPE, along with a shift toward forefoot strike types compared with higher body weight conditions ( P < 0.01). All other outcomes were comparable across conditions. Conclusion: Reduced bodyweight running significantly altered spatiotemporal measures and reduced the vertical component of loading. Clinical Relevance: Our findings offer objective information on expected biomechanical changes across pressure levels that clinicians should consider when incorporating reduced gravity treadmill running into rehabilitation plans.

Cell–material interactions play an essential role in the development of scaffold-based tissue engineering strategies. Cell therapies are still limited in treating injuries when severe damage causes irreversible loss of muscle cells. Electroactive biomaterials and, in particular, piezoelectric materials offer new opportunities for skeletal muscle tissue engineering since these materials have demonstrated suitable electroactive microenvironments for tissue development. In this study, the influence of the surface charge of piezoelectric poly(vinylidene fluoride) (PVDF) on cell adhesion was investigated. The cytoskeletal organization of C2C12 myoblast cells grown on different PVDF samples was studied by immunofluorescence staining, and the interactions between single live cells and PVDF were analyzed using an atomic force microscopy (AFM) technique termed single-cell force spectroscopy. It was demonstrated that C2C12 myoblast cells seeded on samples with net surface charge present a more elongated morphology, this effect being dependent on the surface charge but independent of the poling direction (negative or positive surface charge). It was further shown that the cell deadhesion forces of individual C2C12 cells were higher on PVDF samples with an overall negative surface charge (8.92 ± 0.45 nN) compared to those on nonpoled substrates (zero overall surface charge) (4.06 ± 0.20 nN). These findings explicitly demonstrate that the polarization/surface charge is an important parameter to determine cell fate as it affects C2C12 cell adhesion, which in turn will influence cell behavior, namely, cell proliferation and differentiation, Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2019, UID/BIA/04050/2013, UID/BIO/04469, project POCI-01-0145-FEDER-028237 and under BioTecNorte operation (NORTE-01-0145-FEDER-000004). The authors also thank the FCT for the SFRH/BD/111478/2015 (S.R.) and SFRH/BPD/90870/2012 (C.R.) grants. Funds provided by FCT in the framework of EuroNanoMed 2016 call, Project LungChek ENMed/0049/2016 are also gratefully acknowledged. The authors acknowledge funding by the Spanish Ministry of Economy and Competitiveness (MINECO) through the project MAT2016-76039-C4-3-R (AEI/FEDER, UE) and from the Basque Government Industry and Education Department under the ELKARTEK, HAZITEK and PIBA (PIBA-2018-06)

To identify if any differences exist in IFM size and quality in single leg weight bearing position between healthy and PFP participants based on foot posture.Cross-sectional, matched case-comparison study SETTING: University Laboratory Setting PARTICIPANTS: 35 PFP (age:20.46 ± 3.79yrs, mass:73.28 ± 26.58 kg, height:170.80 ± 11.91 cm) and 35 healthy (age:20.40 ± 3.16yrs, mass:64.76 ± 11.52 kg, height:169.55 ± 9.10 cm) participants METHODS: After measuring Foot Posture Index (FPI), ultrasound images (USI) of Abductor Hallucis (AH), Flexor Digitorum Brevis (FDB) and Quadratus Plantae (QP) were taken in a single limb weight bearing position. Cross-sectional area (CSA) and echogenicity were measured on the USI.FPI was not different between groups (PFP:2.34 ± 3.76, Healthy:2.34 ± 3.10, 9 pronated and 26 non-pronated in both groups). AH CSA was smaller in PFP than healthy group (PFP:0.030 ± 0.01 cm (Smith et al., 2018)/kg, Healthy:0.042 ± 0.01 cm (Smith et al., 2018)/kg, P 0.001) with a large effect (d = -1.20(-1.71, -0.69). There were no other significant group main effects or group-by-FP interactions in AH/FDB/QP CSA or echogenicity.AH CSA was smaller in PFP than healthy controls, but no difference in CSA or echogenicity of FDB/QP exist, as well as no difference in foot posture between groups. While single limb weight bearing, the PFP group presented with a smaller IFM which provides eccentric control of medial longitudinal arch, which may have implications up the chain during weight bearing functional tasks.

Within the amyloid hypothesis in Alzheimer's disease, current focus has shifted to earlier stages of amyloid beta (Aβ) peptide assembly, involving soluble oligomers and smaller aggregates, which are more toxic to cells compared to their morphological distinct fibril forms. Critical to the Aβ field is unlocking the molecular-level kinetic pathways of oligomerization, leading to the culprit subset or specific species of Aβ oligomer populations responsible for the disease etiology. Here, we apply high-speed atomic force microscopy to enable direct visualization of dynamic interactions between single Aβ42 oligomers and aggregate forms, with combined nanometre structural and millisecond temporal resolution in liquid. Analysis of dimensions revealed up to three main Aβ42 species distributions, in addition to the appearance of monomers that showed fast surface diffusion compared to the larger Aβ42 species. Significantly, we devised a new single-molecule analysis based on image contrast in high-speed atomic force microscopy movies to quantify rate determining kinetic constants for interactions between the different Aβ42 species. The findings revealed that smaller Aβ42 species show an exponential decay of lifetime distribution, indicating that all molecules undergo the same process with a single well-defined energy barrier. In contrast, larger aggregates show randomized lifetimes, indicating a distribution of interactions energies/barriers that must be overcome in order to dissociate. We interpret the latter as being due to "permissive" binding, arising from different conformation states of the aggregates, along with a variety of accessible interacting groups. Inevitably, this may lead to the formation of different complexes or alloforms, which is known to contribute to difficulties in identifying Aβ oligomer toxicity and has implications for mechanisms underlying neuronal death accompanying Alzheimer's disease.

This study used atomic force microscopy (AFM) to elucidate the interaction of fibronectin (FN) on a conducting and partially biodegradable copolymer of poly(3,4-ethylenedioxythiophene) and poly( d , l -lactic acid) (PEDOT-co-PDLLA) in three different proportions (1:05, 1:25 and 1:50). The copolymers with higher PEDOT:PDLLA content ratios (1:05 and 1:25) had higher surface roughness, water contact angle, with current and conductivity occurring at discrete large grain structures on the surface. In contrast, the lower PEDOT:PDLLA content ratio (1:50) did not show high conductivity grains but showed homogenous surface conductivity across the entire surface. Using FN-functionalized AFM probes, force measurements showed that the copolymers with higher PEDOT content (1:05 and 1:25) had significantly lower adhesion forces (~0.2–0.3 nN), while the copolymer with the lower content of PEDOT (1:50) had stronger FN interactions with significantly higher adhesion forces of 1 nN. By correlating the spatially distributed electrical surfaces with FN interactions, we observed that the synthesis of 1:50 PEDOT:PDLLA produced more uniformly doped polymer films that facilitated FN adsorption through favorable interactions with accessible sulfate dopants. Importantly, these findings are correlated with previous studies showing increased stem cell migration and differentiation on 1:50 PEDOT:PDLLA surfaces compared with surfaces with 1:05 and 1:25 PEDOT:PDLLA ratios.

Poly(vinylidene difluoride) (PVDF) has piezoelectric properties suitable for numerous applications such as flexible electronics, sensing and biomedical materials. In this study, individual fibers with diameters ranging from 17 to 55 µm were processed using melt electrowriting (MEW). Electroactive PVDF fibers can be fabricated via MEW, while the polymer can remain molten for up to 10 h without noticeable changes in the resulting fiber diameter. MEW processing parameters for PVDF were investigated, including applied voltage, pressure and temperature. A rapid fiber characterization methodology for MEW that automatically determines the fiber diameters from camera images taken of microscope slides was developed and validated. The outputs from this approach followed previous MEW processing trends already identified with different polymers, although overestimation of fiber diameters

Non-fibrillar oligomers formed via nucleation from amyloid beta (AB) peptides are currently implicated in the neurotoxicity of Alzheimer’s disease. Thus, shedding light on the molecular mechanisms underlying their formation is important for identifying targets for drug therapies. This is however an enduring challenge due to the inability to detect AB nucleation processes in the lag phase from bulk kinetic assays, while time-course analyses using a series of peptide solutions involve the discontinuous observation of dynamic nucleation processes and pathways. In this study, by adjusting the pH of AB42 peptide samples while simultaneously imaging with high-speed atomic force microscopy (HS-AFM), we show the in-situ, continuous visualization of dynamic AB42 nucleation at the molecular level. The process reveals a pH-induced saturation regime, enabling a critical monomer substrate concentration to initiate the birth of nucleation. A number of key nucleation phases are identified, including pre-nucleation, saturation regime (mass surface adsorption), nucleation and post-nucleation growth, eventually leading to the formation of predominately oligomer species. HS-AFM observations further reveal the distinct, molecular processes associated with each nucleation phase that constitute the path-dependent formation of different AB species, namely an intial monomer “diffuse-like” surface layer, followed by the emergence of nuclei and then subsequent formation and growth of new complexes and oligomers. In particular, the ability of individual nuclei to undergo surface diffusion and establish new complexes via binding interactions with other species encountered in the system was found to be a significant mechanism influencing the growth of oligomers. Herein, the study contributes to current AB nucleation theories by ascribing new molecular mechanisms. More generally, the knowledge gained from single molecule techniques can greatly assist in our current understanding of various biological processes of AB peptide such as nucleation, growth, aggregation and their related kinetic pathways.

Background: Aggressive high-grade, estrogen receptor negative (ER-) breast cancer is more common among American women of African ancestry (AA) than those of European ancestry (EA). The reasons remain largely unknown. Epigenetic mechanisms, particularly DNA methylation and altered microRNA (miRNA) expression, may contribute to racial differences in breast cancer. However, few studies have specifically characterized genome-wide DNA methylation-based modifications at the miRNA level in relation to ER+ and ER- breast cancer, and their functional role in the regulation of miRNA expression, especially among high risk AA women. Methods: In this study, genome-wide DNA methylation and miRNA expression profiling was performed using the Illumina Infinium HumanMethylation450 Bead Chip platform and miRNA sequencing (miRNA-seq) in breast tumors from both AA and EA women. Results: The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, which correspond to 2,035 unique mature miRNAs. Cluster analysis of these miRNA-associated methylation loci showed a clear pattern of ER-subtype differences. We identified differentially methylated loci (DMLs: (|delta β|)>0.10, FDRmiR-190b and miR-135b highly negatively correlated with their expression. Further target prediction and pathway analysis showed that these DNA methylation-dysregulated miRNAs are involved in multiple cancer-related pathways, including cell cycle G1-S growth factor, cytoskeleton remodeling, angiogenesis, EMT, and others such as signal transduction TGF-β, Wnt, NOTCH, and ESR1-mediated signaling pathways. Conclusions: Our results suggest that DNA methylation changes within miRNA genes are associated with altered miRNA expression, which may contribute to the network of subtype- and race-related tumor biological differences in breast cancer. These findings shed light on the epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes and to serve as potential preventative and therapeutic targets.

Nitrogen oxides and ozone impact air quality in many parts of the United States (U S ), Europe, China, and many other countries The greatest air quality challenge in Los Angeles, some other areas of California, and some parts of China is to reduce ozone levels to meet regulations Background ozone is a major factor which makes it more difficult to reduce urban concentrations in Los Angeles and some other locations Air pollution from China affects the background ozone entering California More than 50?years of history are reviewed with an emphasis on reducing concentrations of nitrogen oxides and ozone During this time period, there has been significant progress in reducing levels of these pollutants in urban air in the U S and Europe;however, ozone concentrations in China have increased since 2013 Cost and benefit analysis has shown that benefits associated with the Clean Air Act of 1970 have greatly exceeded costs to improve air quality in the U S over the past 50?years Further actions to consider to improve air quality include reducing combustion of coal and petroleum products and transitioning to renewable energy Public education is recommended to inform citizens that the benefits of reducing emissions far exceed costs This article is protected by copyright All rights reserved

Successful intracellular delivery of therapeutics requires interactions at several liquid-solid interfaces, including cell surface, endosomal membranes, and-depending on the therapeutic-the nuclear membrane. Understanding the dynamics of polymer kinetics at the liquid-solid interface is fundamental for the design of polymers for such biomedical delivery applications. However, the effect of polymer architecture and charge density on polymer kinetics is not readily investigated using routine techniques, and the role of such parameters in the context of gene delivery remains unknown. We adopted a synthetic strategy which enabled the systematic manipulation of charge density, flexibility, and molecular weight using a dendronized linear polymeric architecture. High-speed atomic force microscopy (HS-AFM) was used as a label-free method to directly observe the polymers' dynamic properties, such as velocity, displacement, and diffusion, in physiologically relevant conditions. Importantly, we found that the physical parameters measured by HS-AFM relate to the transfection potential of the individual polymers and may be a valuable tool in screening structural polymer variants.

Thin film coatings prepared from commercially available glycidoxypropyltrimethoxysilane (GPS) modified silica nanoparticles (SiNPs) (Bindzil® CC301 and Bindzil® CC302) have previously shown excellent antifouling performance against a broad range of microbes [Molino et al., “Hydration layer structure of biofouling-resistant nanoparticles,” ACS Nano 12, 11610 (2018)]. In this work, single cell force spectroscopy (SCFS) was used to measure the biological interactions between Epicoccum nigrum fungal spores and the same silica nanoparticle-based surfaces used in the aforementioned study, including a: glass coverslip, unmodified SiNP coatings, and both low (Bindzil® CC301) and high density (CC302) GPS functionalized SiNP coatings as a function of NaCl concentration. From the SCFS curves, the spore adhesion to the surface was greatest on the glass coverslip (20–80 nN) followed by the unmodified SiNP (3–5 nN) across all salt concentrations. Upon approach to both surfaces, the spores showed a long-range attraction generally with a profile characteristic of biointeractions and likely those of the outer cell wall structures or biological constituents. The attractive force allowed the spores to initially adhere to the surface and was found to be linearly proportional to the spore adhesion. In comparison, both high and low density GPS-SINP significantly reduced the spore adhesion (0.5–0.9 nN). In addition, the spore adhesion on high density GPS-SiNP occurred in only 14%–27% of SCFS curves (40%–48% for low density GPS-SiNP) compared to 83%–97% for the unmodified SiNP, indicating that in most cases the GPS functionalization completely prevented spore adhesion. The GPS-SiNP surfaces conversely showed a long-range electrostatic repulsion at low 1mM NaCl that was replaced by short-range repulsion at the higher salt concentrations. From the findings, it is proposed that the attractive force is a critical step in initial adhesion processes of the spore. The effective antifouling properties of the GPS are attributed to the ability to negate the attractive forces, either through electrostatic repulsion in low salt conditions and primarily from short-range repulsion correlating to the previously reported combined steric-hydration effect of the GPS functionalization on SiNP coatings.

The piezoelectricity of the biocompatible and biodegradable polymer polylactic acid (PLA) was investigated as a potential magnetoelectric (ME) nanocomposite for biomedical applications. A key focus was to quantify the piezoelectric properties of single PLA fibers while tuning their polymer degradability through the addition of faster degrading polymer, poly (DL-lactide-co-glycolide) (PLGA), which is not a piezoelectric polymer. Piezoresponse Force Microscopy (PFM) showed that electrospun PLA fibers gave a piezoelectric response of 186 ± 28 pm. For comparison both PLA/PLGA (75/25) and PLA/PLGA (50/50) fibers gave significantly lower piezoelectric responses of 89 ± 12 pm and 50 ± 9.1 pm, respectively. For the highest content PLGA fibers, PLA/PLGA (25/75), only very few fibers exhibited a low response of 28 pm while most showed no response. Overall, an increasing PLGA content caused a decrease in the piezoelectric response, thus an expected trade-off existed between the biodegradability (i.e. PLA to PLGA content ratio) versus piezoelectricity. The findings were considered significant due to the existence of piezoelectricity in a tuneable biodegradable material that has potential to impart piezoelectric induced effects on biointeractions with the surrounding biological environment or drug interactions with the polymer to control the rate of drug release. In such applications, there is an opportunity to magnetically control the piezoelectricity and henceforth PLA/CoFe2O4 ME nanocomposite fibers with 5% and 10% of CoFe2O4 nanoparticles were also investigated. Both 5% and 10% PLA/CoFe2O4 nanocomposites gave lower piezoelectric responses compared to the PLA presumably due to the disturbance of polymer chains and dipole moments by the magnetic nanoparticles, in addition to effects from the possible inhomogeneous distribution of CoFe2O4 nanoparticles.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a selective anticancer cytokine capable of exerting a targeted therapy approach. Disappointingly, recent research has highlighted the development of TRAIL resistance in cancer cells, thus minimising its usefulness in clinical settings. However, several recent studies have demonstrated that cancer cells can be sensitised to TRAIL through the employment of a combinatorial approach, utilizing TRAIL in conjunction with other natural or synthetic anticancer agents. In the present study, the chemo-sensitising effect of curcumin on TRAIL-induced apoptosis in renal carcinoma cells (RCC) was investigated. The results indicate that exposure of kidney cancer ACHN cells to curcumin sensitised the cells to TRAIL, with the combination treatment of TRAIL and curcumin synergistically targeting the cancer cells without affecting the normal renal proximal tubular epithelial cells (RPTEC/TERT1) cells. Furthermore, this combination treatment was shown to induce caspase-dependent apoptosis, inhibition of the proteasome, induction of ROS, upregulation of death receptor 4 (DR4), alterations in mitogen-activated protein kinase (MAPK) signalling and induction of endoplasmic reticulum stress. An in vivo zebrafish embryo study demonstrated the effectiveness of the combinatorial regime to inhibit tumour formation without affecting zebrafish embryo viability or development. Overall, the results arising from this study demonstrate that curcumin has the ability to sensitise TRAIL-resistant ACHN cells to TRAIL-induced apoptosis.

The ability to switch the physico-chemical properties of conducting polymers opens up new possibilities for a range of applications. Appropriately functionalised materials can provide routes to multi-modal switching, for example, in response to light and/or electrochemical stimuli. This capability is important in the field of bionics wherein remote and temporal control of the properties of materials is becoming attractive. The ability to actuate a film via photonic stimuli is particularly interesting as it facilitates the modulation of interactions between host binding sites and potential guest molecules. In this work, we studied two different poly-terthiophenes: one was functionalised with a spiropyran photoswitch (pTTh-SP) and the second with a non-photoswitchable methyl acetate moiety (pTTh-MA). These substrates were exposed to several cycles of illumination with light of different wavelengths and the resulting effect studied with UV-vis spectroscopy, contact angle and atomic force microscopy (AFM). The AFM tips were chemically activated with fibronectin (FN) and the adhesion force of the protein to the polymeric surface was measured. The pTTh-MA (no SP incorporated) showed a slightly higher average maximum adhesion (0.96 ± 0.14 nN) than the modified pTTh-SP surface (0.77 ± 0.08 nN), but after exposure of the pTTh-SP polymer to UV, the average maximum adhesion of the pTTh-MC (merocyanine form) was significantly smaller (0.49 ± 0.06 nN) than both the pTTh-MA and pTTh-SP. In addition, the tip-sample separation distances of the adhesive interactions are indicative of the FN interaction occurring over a distance more closely related to the average dimensions of its compact conformation. The results suggest that surface energy and hydrophobic forces are predominant in determining the protein adhesion to the films studied and that this effect can be photonically tuned. By extension, this further implies that it should be possible to obtain a degree of spatial and temporal control of the surface binding behaviour of certain proteins with these functionalised surfaces through photo-activation/deactivation, which, in principle, should facilitate patterned growth behaviour (e.g. using masks or directional illumination) or photocontrol of protein uptake and release.

This work demonstrates polymer brushes grafted from conductive polymer films which display dynamic surface switching dependent on salt, temperature and electrode potential. The electroactivity presented by the conductive polymer and the responsiveness of the grafted brushes leads to an interface with multiple control parameters. Here, we demonstrate this concept by grafting of uncharged brushes of poly(ethylene glycol)methyl ether methacrylates from conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT), and observe a temperature- and salt-induced switch of brush conformation, and their effect on the electrochemistry of the material. The switching conditions can be tailored by copolymerizing monomers with different numbers of ethylene glycol units. In addition, these surfaces exhibit antifouling properties, leading to potential applications such as electrically-addressable biointerfaces.

Flexible and wearable piezoelectric bio e-skin (PBio-e-skin) based on electrospun poly(L-lactic acid) PLLA nanofiber membrane is demonstrated for non-invasive human physiological signal monitoring and detecting dynamic tactile stimuli. The molecular orientations of the CO dipoles by electrospinning technique result in a longitudinal piezoelectric charge co-efficient (d33) value of ∼(3 ± 1) pm V−1 realized by piezoresponse force microscopy, allowing the PBio-e-skin for pressure sensing applications. The robust mechanical strength (Young's modulus ∼50 MPa) of nanofiber membrane ensures PBio-e-skin's superior operational stability over 375 000 cycles. Owing to the superior mechanosensitivity of ∼22 V N−1, PBio-e-skin has the ability to measure subtle movement of muscle in the internal organs such as esophagus, trachea, motion of joints and arterial pressure by recognition of strains on human skin. This flexible and light weight PBio-e-skin precisely detects vital signs and provides important clinical insights without using any external power source. Eventually, the low cost, environmental friendly PBio-e-skin will have a huge impact in a broad range of applications including self-powered wearable health care systems, human–machine interfacing devices, artificial intelligence and prosthetic skin.

Single Cell Force Spectroscopy was applied to measure the single cell de-adhesion between human neural stem cells (hNSC) and gelatin methacrylate (GelMA) hydrogel with varying modulus in the range equivalent to brain tissue. The cell de-adhesion force and energy were predominately generated via unbinding of complexes formed between RGD groups of the GelMA and cell surface integrin receptors and the de-adhesion force/energy were found to increase with decreasing modulus of the GelMA hydrogel. For the softer GelMA hydrogels (160 Pa and 450 Pa) it was proposed that a lower degree of cross-linking enables a greater number of polymer chains to bind and freely extend to increase the force and energy of the hNSC-GelMA de-adhesion. In this case, the multiple polymer chains are believed to act together in parallel like 'molecular tensors' to generate tensile forces on the bound receptors until the cell detaches. Counterintuitively for softer substrates, this type of interaction gave rise to higher force loading rates, including the appearance of high and low dynamic force regimes in de-adhesion rupture force versus loading rate analysis. For the stiffer GelMA hydrogel (900 Pa) it was observed that the extension and elastic restoring forces of the polymer chains contributed less to the cell de-adhesion. Due to the apparent lower extent of freely interacting chains on the stiffer GelMA hydrogel the intrinsic RGD groups are presumed to be "more fixed" to the substrate. Hence, the cell de-adhesion is suggested to be mainly governed by the discrete unbinding of integrin-RGD complexes as opposed to elastic restoring forces of polymer chains, leading to smaller piconewton rupture forces and only a single lower dynamic force regime. Intriguingly, when integrin antibodies were introduced for binding integrin α5β1, β1- and αv-subunits it was revealed that the cell modifies the de-adhesion force depending on the substrate stiffness. The antibody binding supressed the de-adhesion on the softer GelMA hydrogel while on the stiffer GelMA hydrogel caused an opposing reinforcement in the de-adhesion. STATEMENT OF SIGNIFICANCE: Conceptual models on cell mechanosensing have provided molecular-level insight to rationalize the effects of substrate stiffness. However most experimental studies evaluate the cell adhesion by analysing the bulk material properties. As such there is a discrepancy in the scale between the bulk properties versus the nano- and micro-scale cell interactions. Furthermore there is a paucity of experimental studies on directly measuring the molecular-level forces of cell-material interactions. Here we apply Single Cell Force Spectroscopy to directly measure the adhesion forces between human neural stem cells and gelatin-methacrylate hydrogel. We elucidate the mechanisms by which single cells bind and physically interact with hydrogels of varying stiffness. The study highlights the use of single cell analysis tools to probe molecular-level interactions at the cell-material interface which is of importance in designing material cues for regulating cell function.

Background The molecular mechanisms underlying the association between increased adiposity and aggressive breast cancer phenotypes remain unclear, but likely involve the adipokines, leptin (LEP) and adiponectin (ADIPOQ), and their receptors (LEPR, ADIPOR1, ADIPOR2). Methods We used immunohistochemistry (IHC) to assess LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 expression in breast tumor tissue microarrays among a sample of 720 women recently diagnosed with breast cancer (540 of whom self-identified as Black). We scored IHC expression quantitatively, using digital pathology analysis. We abstracted data on tumor grade, tumor size, tumor stage, lymph node status, Ki67, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from pathology records, and used ER, PR, and HER2 expression data to classify breast cancer subtype. We used multivariable mixed effects models to estimate associations of IHC expression with tumor clinicopathology, in the overall sample and separately among Blacks. Results Larger proportions of Black than White women were overweight or obese and had more aggressive tumor features. Older age, Black race, postmenopausal status, and higher body mass index were associated with higher LEPR IHC expression. In multivariable models, lower LEPR IHC expression was associated with ER-negative status and triple-negative subtype (P Conclusions Lower LEPR IHC expression within the breast tumor microenvironment might contribute mechanistically to inter-individual variation in aggressive breast cancer clinicopathology, particularly ER-negative status and triple-negative subtype.

Legislative redistricting is a critical element of representative democracy. A number of political scientists have used simulation methods to sample redistricting plans under various constraints to assess their impact on partisanship and other aspects of representation. However, while many optimization algorithms have been proposed, surprisingly few simulation methods exist in the published scholarship. Furthermore, the standard algorithm has no theoretical justification, scales poorly, and is unable to incorporate fundamental constraints required by redistricting processes in the real world. To fill this gap, we formulate redistricting as a graph-cut problem and for the first time in the literature propose a new automated redistricting simulator based on Markov chain Monte Carlo. The proposed algorithm can incorporate contiguity and equal population constraints at the same time. We apply simulated and parallel tempering to improve the mixing of the resulting Markov chain. Through a small-scale validation study, we show that the proposed algorithm can approximate a target distribution more accurately than the standard algorithm. We also apply the proposed methodology to data from Pennsylvania to demonstrate the applicability of our algorithm to real-world redistricting problems. The open-source software package is available so that researchers and practitioners can implement the proposed methodology. Supplementary materials for this article are available online.

A major concern in the social sciences is lack of replication of previous studies. An important methodological concern in the social sciences is the ability to determine effect sizes in add...

Breast cancer is a heterogeneous disease, characterized by molecularly and phenotypically distinct tumor subtypes, linked to disparate clinical outcomes. American women of African ancestry (AA) are more likely than those of European ancestry (EA) to be diagnosed with aggressive, estrogen receptor negative (ER−) or triple negative breast cancer, and to die of this disease. However, the underlying causes of AA predisposition to ER−/triple negative breast cancer are still largely unknown. In this study, we performed high-throughput whole-genome miRNA expression profiling in breast tissue samples from both AA and EA women. A number of differentially expressed miRNAs, i.e., DEmiRs defined as >2-fold change in expression and false discovery rate

Soft, stimulus-responsive 3D structures created from crosslinked poly(ionic liquid)s (PILs) have been fabricated at unprecedented sub-micron resolution by direct laser writing (DLW). These structures absorb considerable quantities of solvent ( e.g., water, alcohol, and acetone) to produce PIL hydrogels that exhibit stimulus-responsive behavior. Due to their flexibility and soft, responsive nature, these structures are much more akin to biological systems than the conventional, highly crosslinked, rigid structures typically produced using 2-photon polymerization (2-PP). These PIL gels expand/contract due to solvent uptake/release, and, by exploiting inherited properties of the ionic liquid monomer (ILM), thermo-responsive gels that exhibit reversible area change (30 ± 3%, n = 40) when the temperature is raised from 20 °C to 70 °C can be created. The effect is very rapid, with the response indistinguishable from the microcontroller heating rate of 7.4 °C s −1 . The presence of an endoskeleton-like framework within these structures influences movement arising from expansion/contraction and assists the retention of structural integrity during actuation cycling.

Background: Forkhead box protein A1 (FOXA1) promotes luminal differentiation, and hypermethylation of the gene can be a mechanism of developing estrogen receptor–negative (ER−) breast cancer. We examined FOXA1 in breast tumor and adjacent normal tissue in relation to reproductive factors, particularly higher parity and no breastfeeding, that are associated with ER− tumors. Methods: We performed IHC for FOXA1 in breast tumors (n = 1,329) and adjacent normal tissues (n = 298) in the Women's Circle of Health Study (949 Blacks and 380 Whites). Protein expression levels were summarized by histology (H) scores. Generalized linear models were used to assess FOXA1 protein expression in relation to reproductive factors by ER status. Results: ER-positive (ER+) versus ER− tumors had higher FOXA1 protein expression (P < 0.001). FOXA1 expression was higher in tumor versus paired adjacent normal tissue in women with ER+ or non-triple–negative cancer (both P < 0.001), but not in those with ER− or triple-negative cancer. Higher number of births (1, 2, and 3+) was associated with lower FOXA1 protein expression in ER+ tumors [differences in H score, or β = −8.5; 95% confidence interval (CI), −15.1 to −2.0], particularly among parous women who never breastfed (β = −10.4; 95% CI, −19.7 to −1.0), but not among those who breastfed (β = −7.5; 95% CI, −16.9 to 1.8). The associations for ER− tumors were similar, although they were not statistically significant. Conclusions: In this tumor-based study, higher parity was associated with lower FOXA1 expression in ER+ tumors, and breastfeeding may ameliorate the influence. Impact: These findings contribute to our understanding of FOXA1 methylation and breast cancer etiology.

The negative impacts that arise from biological fouling of surfaces have driven the development of coatings with unique physical and chemical properties that are able to prevent interactions with fouling species. Here, we report on low-fouling hydrophilic coatings presenting nanoscaled features prepared from different size silica nanoparticles (SiNPs) functionalized with zwitterionic chemistries. Zwitterionic sulfobetaine siloxane (SB) was reacted to SiNPs ranging in size from 7 to 75 nm. Particle stability and grafting density were confirmed using dynamic light scattering and thermogravimetric analysis. Thin coatings of nanoparticles were prepared by spin-coating aqueous particle suspensions. The resulting coatings were characterized using scanning electron microscopy, atomic force microscopy, and contact angle goniometry. SB functionalized particle coatings displayed increased hydrophilicity compared to unmodified particle coating controls while increasing particle size correlated with increased coating roughness and increased surface area. Coatings of zwitterated particles demonstrated a high degree of nonspecific protein resistance, as measured by quartz crystal microgravimetry. Adsorption of bovine serum albumin and hydrophobin proteins were reduced by up to 91 and 94%, respectively. Adhesion of bacteria ( Escherichia coli) to zwitterion modified particle coatings were also significantly reduced over both short and long-term assays. Maximum reductions of 97% and 94% were achieved over 2 and 24 h assay periods, respectively. For unmodified particle coatings, protein adsorption and bacterial adhesion were generally reduced with increasing particle size. Adhesion of fungal spores to SB modified SiNP coatings was also reduced, however no clear trends in relation to particle size were demonstrated.

Background: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models. Objectives: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity. Method: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8- OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3. Results: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while upregulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin. Conclusion: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3.

Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross-sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm's. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA-BRCA data were used for replication. 1,214 aDNAm's were identified; 97% with increased methylation, and all on autosomes. Sites with increased methylation were predominantly in CpG lslands and non-enhancers. aDNAm's with decreased methylation were generally located in intergenic regions, non-CpG Islands, and enhancers. Of the aDNAm's identified, 650 are known to be involved in cancer, including ESR1 and beta-estradiol responsive genes. Expression of DNMT3A was positively associated with age. Two aDNAm's showed borderline significant associations with DNMT3A expression; KRR1 (OR 6.57, 95% CI: 2.51-17.23) and DHRS12 (OR 6.08, 95% CI: 2.33-15.86). A subset of aDNAm's co-localized within vulnerable regions for somatic mutations in cancers including breast cancer. Expression of C19orf48 was inversely and significantly correlated with its methylation level. In the TCGA dataset, 84% and 64% of the previously identified aDNAm's were correlated with age in both normal-adjacent and tumor breast tissues, with differential associations by histological subtype. Given the similarity of findings in the breast tissues of healthy women and breast tumors, aDNAm's may be one pathway for increased breast cancer risk with age.

Conducting polymers are good candidates for electronic biomedical devices such as biosensors, artificial nerves, and electrodes for brain tissue. Functionalizing the conducting polymer surface with bioactive molecules can limit adverse immune reactions to the foreign body and direct tissue integration. In this work, we demonstrate a simple one-step method to attach biomolecules covalently to a conductive polymer. Electrochemically synthesized polypyrrole was activated using plasma immersion ion implantation (PIII) in nitrogen. A short treatment with relatively low ion fluence (20 s) was found to enable direct covalent immobilization of protein upon incubation in a protein solution, while the protein is easily removed from untreated polypyrrole by washing in buffer. The covalent nature of the protein immobilization was demonstrated by its resistance to elution when repeatedly washed with SDS detergent. Changes in the surface properties and their evolution with time after PIII activation were studied by a combination of attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), cyclic voltammetry, and water contact angle measurements. Notable changes in the chemistry of the modified layer in polypyrrole include the appearance of nitrile groups that gradually disappear with time and oxidation of the surface that increases over time in air. The kinetics of surface energy are consistent with the generation of radicals in the modified layer that are lost predominantly through oxidation. The conductivity of the modified surface layer (64 nm in thickness) decreases for low fluence treatments and is partially restored after high fluence treatment. This simple surface modification process opens up the possibility of creating biologically active interfaces for electro-stimulating biomedical devices and electrical sensing of neurological processes.

The growing need to develop surfaces able to effectively resist biological fouling has resulted in the widespread investigation of nanomaterials with potential antifouling properties. However, the preparation of effective antifouling coatings is limited by the availability of reactive surface functional groups and our ability to carefully control and organize chemistries at a materials' interface. Here, we present two methods of preparing hydrophilic low-fouling surface coatings through reaction of silica-nanoparticle suspensions and predeposited silica-nanoparticle films with zwitterionic sulfobetaine (SB). Silica-nanoparticle suspensions were functionalized with SB across three pH conditions and deposited as thin films via a simple spin-coating process to generate hydrophilic antifouling coatings. In addition, coatings of predeposited silica nanoparticles were surface functionalized via exposure to zwitterionic solutions. Quartz crystal microgravimetry with dissipation monitoring was employed as a high throughput technique for monitoring and optimizing reaction to the silica-nanoparticle surfaces. Functionalization of nanoparticle films was rapid and could be achieved over a wide pH range and at low zwitterion concentrations. All functionalized particle surfaces presented a high degree of wettability and resulted in large reductions in adsorption of bovine serum albumin protein. Particle coatings also showed a reduction in adhesion of fungal spores (Epicoccum nigrum) and bacteria (Escherichia coli) by up to 87 and 96%, respectively. These results indicate the potential for functionalized nanosilicas to be further developed as versatile fouling-resistant coatings for widespread coating applications.

The tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Identifying a more robust signature for LTBI is important for TB prevention and elimination. A pilot study was conducted with samples from immigrants to the United States that were screened for LTBI by the three commercially approved tests, namely, the tuberculin skin test (TST), the Quantiferon-TB Gold in-tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). QFT-GIT supernatants from 13 people with concordant positive results and 26 people with concordant negative results were analyzed via the highly multiplexed SOMAscan proteomic assay. The proteins in the stimulated supernatants that distinguished LTBI from controls included interleukin-2 (IL-2), monocyte chemotactic protein 2 (MCP-2), interferon gamma inducible protein-10 (IP-10), interferon gamma (IFN-γ), tumor necrosis factor superfamily member 14 (TNFSF14, also known as LIGHT), monokine induced by gamma interferon (MIG), and granzyme B ( P P