Encoding Reversible Hierarchical Structures with Supramolecular Peptide-DNA Materials.

Creating soft materials with the tunable hierarchical structures observed in nature remains an enormous challenge. Synthetic hierarchical systems have been reported, yet strategies to reversibly modulate their structure and function are scarce. We report on the programmable self-assembly of peptide-DNA brush copolymers into supramolecular architectures that can be tuned with changes in temperature, pH, or addition of a soluble trigger. A fiber to bundle transition occurs upon mixing peptides bearing complementary oligonucleotides. These hierarchical structures can be reversed using the programmable nature of DNA-DNA interactions. The ability to encode the final assemblies in the composition of both amino acid and DNA building blocks provides a strategy for constructing a unique class of reconfigurable supramolecular materials.

Participants' Views About the Survivor Contact Element of IPV Perpetrator Programs: A Preliminary Study.

Advocacy services, for victims and survivors, are at the core of our response to Intimate Partner Violence (IPV). The survivor contact element of IPV perpetrator programs is recognized as a necessary safety measure for their operation. Within the context of equivocal evaluations of these programs, and the impetus to find opportunities to enhance their effectiveness, this study report explores the service user perspective on survivor contact work. In-depth semi-structured interviews were completed with 18 perpetrators and 18 survivors involved in three Irish-based programs, and findings were analyzed using grounded theory principles. Almost without exception, survivors were positive about their engagement with an outreach service. There was evidence to suggest that perpetrator program outreach services do reach survivors who may not ordinarily make contact with an advocacy service. In general terms, survivors felt validated as survivors, they felt supported, they learned about abusive behaviors and some saw the service as a monitor of what their partner was saying during group work. However, some survivors described their fear that any reports of ongoing abuse, which they offered, would attract reprisals from their partner or the attentions of child protection services. More determined application of criminal justice measures, and enhanced resourcing of the survivor contact element of these programs, should be considered.

Luminescent Difluoroboron ß-Diketonate PLA-PEG Nanoparticle.

Luminescent difluoroboron ß-diketonate poly(lactic acid) (BF2bdkPLA) materials serve as biological imaging agents. In this study, dye structures were modified to achieve emission colors that span the visible region with potential for multiplexing applications. Four dyes with varying π-conjugation (phenyl, naphthyl) and donor groups (-OMe, -NMe2) were coupled to PLLA-PEG block copolymers (∼11 kDa) by a postpolymerization Mitsunobu reaction. The resulting dye-polymer conjugates were fabricated as nanoparticles (∼55 nm diameter) to produce nanomaterials with a range of emission colors (420-640 nm). For increased stability, dye-PLLA-PEG conjugates were also blended with dye-free PDLA-PEG to form stereocomplex nanoparticles of smaller size (∼45 nm diameter). The decreased dye loading in the stereoblocks blue-shifted the emission, generating a broader range of fluorescence colors (410-620 nm). Tumor accumulation was confirmed in a murine model through biodistribution studies with a red emitting dimethyl amino-substituted dye-polymer analogue. The synthesis, optical properties, oxygen-sensing capabilities, and stability of these block copolymer nanoparticles are presented.

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study.

BACKGROUND: Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. OBJECTIVE: To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). METHODS: Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. RESULTS: 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes. CONCLUSIONS: The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice.

Designer peptide-DNA cytoskeletons regulate the function of synthetic cells.

The bottom-up engineering of artificial cells requires a reconfigurable cytoskeleton that can organize at distinct locations and dynamically modulate its structural and mechanical properties. Here, inspired by the vast array of actin-binding proteins and their ability to reversibly crosslink or bundle filaments, we have designed a library of peptide-DNA crosslinkers varying in length, valency and geometry. Peptide filaments conjoint through DNA hybridization give rise to tactoid-shaped bundles with tunable aspect ratios and mechanics. When confined in cell-sized water-in-oil droplets, the DNA crosslinker design guides the localization of cytoskeletal structures at the cortex or within the lumen of the synthetic cells. The tunable spatial arrangement regulates the passive diffusion of payloads within the droplets and complementary DNA handles allow for the reversible recruitment and release of payloads on and off the cytoskeleton. Heat-induced reconfiguration of peptide-DNA architectures triggers shape deformations of droplets, regulated by DNA melting temperatures. Altogether, the modular design of peptide-DNA architectures is a powerful strategy towards the bottom-up assembly of synthetic cells.

Uncovering supramolecular chirality codes for the design of tunable biomaterials.

In neurodegenerative diseases, polymorphism and supramolecular assembly of ß-sheet amyloids are implicated in many different etiologies and may adopt either a left- or right-handed supramolecular chirality. Yet, the underlying principles of how sequence regulates supramolecular chirality remains unknown. Here, we characterize the sequence specificity of the central core of amyloid-ß 42 and design derivatives which enable chirality inversion at biologically relevant temperatures. We further find that C-terminal modifications can tune the energy barrier of a left-to-right chiral inversion. Leveraging this design principle, we demonstrate how temperature-triggered chiral inversion of peptides hosting therapeutic payloads modulates the dosed release of an anticancer drug. These results suggest a generalizable approach for fine-tuning supramolecular chirality that can be applied in developing treatments to regulate amyloid morphology in neurodegeneration as well as in other disease states.

Influence of kelp forests on flow around headlands.

Kelp forests affect coastal circulation but their influence on upwelling around headlands is poorly understood. Tidal-cycle surveys off two headlands with contrasting kelp coverage illustrated the influence of kelp forests on headland upwelling. Underway acoustic Doppler current and backscatter profiles were collected simultaneously to surface water temperature. Surveys occurred along three off-headland transects in July 25-29, 2018, off Isla Natividad, located midway on the western coast of the Baja California peninsula. Flows and water temperature distributions off the headland with no kelp coverage were consistent with headland upwelling. In contrast, the kelp around the headland with dense coverage: 1) attenuated the ambient flow; 2) favored an increase in effective radius of flow curvature; 3) promoted flow ducting, which consists of enhancing flow through channels unobstructed by kelp; and 4) suppressed headland upwelling. Kelp suppressed upwelling by channeling the flow away from the headland, keeping nearshore waters warmer than offshore. PLAIN LANGUAGE ABSTRACT: This study documents a way in which biology can affect physics in coastal ocean environments. In particular, the study describes how a kelp forest suppresses the upward pumping of cool subsurface waters that is typically found around headlands. Such suppression of subsurface waters injection occurs via a process that we refer to as 'flow ducting.' In flow ducting, coastal flows are channelized through kelp gaps, concentrated in bands <30 m wide, and kept away from the morphological influences of a headland. This ducting is analogous to the tortuous flow through porous media.

A Programmable Toolkit to Dynamically Signal Cells Using Peptide Strand Displacement.

The native extracellular matrix communicates and interacts with cells by dynamically displaying signals to control their behavior. Mimicking this dynamic environment in vitro is essential in order to unravel how cell-matrix interactions guide cell fate. Here, we present a synthetic platform for the temporal display of cell-adhesive signals using coiled-coil peptides. By designing an integrin-engaging coiled-coil pair to have a toehold (unpaired domain), we were able to use a peptide strand displacement reaction to remove the cell cue from the surface. This allowed us to test how the user-defined display of RGDS ligands at variable duration and periodicity of ligand exposure influence cell spreading degree and kinetics. Transient display of αVß3-selective ligands instructed fibroblast cells to reversibly spread and contract in response to changes in ligand exposure over multiple cycles, exhibiting a universal kinetic response. Also, cells that were triggered to spread and contract repeatedly exhibited greater enrichment of integrins in focal adhesions versus cells cultured on persistent RGDS-displaying surfaces. This dynamic platform will allow us to uncover the molecular code by which cells sense and respond to changes in their environment and will provide insights into ways to program cellular behavior.

Profiles of Irish survivors of institutional abuse with different adult attachment styles.

Two hundred and forty seven survivors of institutional abuse in Ireland were classified with the Experiences in Close Relationships Inventory as having fearful (44%), preoccupied (13%), dismissive (27%), or secure (17%) adult attachment styles. The group with the secure adult attachment style had the most positive profile, while the most negative profile occurred for the fearful group in terms of DSM IV diagnoses and scores on the Trauma Symptom Inventory, the Global Assessment of Functioning Scale, the World Health Organization Quality of Life 100 scale, and the Kansas Marital Satisfaction Scale. The profile of the preoccupied group was more similar to that of the fearful group. The profile of the dismissive group was more similar to that of the secure group.

Meta-Alkoxy-Substituted Difluoroboron Dibenzoylmethane Complexes as Environment-Sensitive Materials.

The optical properties of meta-alkoxy-substituted difluoroboron dibenzoylmethane dyes were investigated in solution and in the solid state. Meta-alkoxy substitution induced strong intramolecular charge transfer (ICT) from the oxygen-donating substituent to the halide and boron acceptors in the excited state, as compared to the π-π* transition that is observed with para-alkoxy substitution. The optical properties of para- and meta-substituted alkoxy boron dyes were evaluated by calculations, in dilute solution, and in solid-state films. When embedded in amorphous matrixes (e.g., PLA, PMMA, PS, cholesterol), all dyes showed fluorescence (F) and phosphorescence (P) emission. In this report, we show that meta-substitution resulted in enhanced solvatochromism and an increased phosphorescence-to-fluorescence ratio in solid-state films compared to analogous para-substituted samples. With enhanced phosphorescence intensity via the heavy-atom effect, iodo-substituted dyes were further studied in PLA-PEG nanoparticles. Oxygen calibrations revealed stronger phosphorescence and a greater oxygen-sensing range for the meta- versus para-alkoxy-substituted dyes, features that are important for oxygen-sensing materials design.

Multi-stimuli responsive luminescent azepane-substituted ß-diketones and difluoroboron complexes.

Difluoroboron ß-diketonate (BF2bdk) compounds show environment-sensitive optical properties in solution, aggregation-induced emission (AIE) and multi-stimuli responsive fluorescence switching in the solid state. Here, a series of 4-azepane-substituted ß-diketone (bdk) ligands (L-H, L-OMe, L-Br) and their corresponding difluoroboron dyes (D-H, D-OMe, D-Br) were synthesized, and various responsive fluorescence properties of the compounds were studied, including solvatochromism, viscochromism, AIE, mechanochromic luminescence (ML) and halochromism. Compared to the ß-diketones, the boron complexes exhibited higher extinction coefficients but lower quantum yields, and red-shifted absorption and emission in CH2Cl2. Computational studies showed that intramolecular charge transfer (ICT) dominated rather than π-π* transitions in all the compounds regardless of boron coordination. In solution, all the bdk ligands and boron dyes showed red-shifted emission in more polar solvents and increased fluorescence intensity in more viscous media. Upon aggregation, the emission of the ß-diketones was quenched, however, the boronated dyes showed increased emission, indicative of AIE. Solid-state emission properties, ML and halochromism, were investigated on spin cast films. For ML, smearing caused a bathochromic emission shift for L-Br, and powder X-ray diffraction (XRD) patterns showed that the "as spun" and thermally annealed states were more crystalline and the smeared state was amorphous. No obvious ML emission shift was observed for L-H or L-OMe, and the boronated dyes were not mechano-active. Trifluoroacetic acid (TFA) and triethylamine (TEA) vapors were used to study halochromism. Large hypsochromic emission shifts were observed for all the compounds after TFA vapor was applied, and reversible fluorescence switching was achieved using the acid/base pair.

Oxygen-Sensing Difluoroboron Thienyl Phenyl ß-Diketonate Polylactides.

Difluoroboron ß-diketonate-polylactides are versatile oxygen-sensing materials. These materials have both fluorescence (F) and oxygen-sensitive, room-temperature phosphorescence (RTP). The fluorescence, being insensitive to oxygen, can act as an internal standard to the changing phosphorescence, and ratiometric sensing of oxygen can be achieved with these simple, single-component materials. To expand the range of colors for this family of fluorophores, a series of thienyl-phenyl-substituted dyes were synthesized with initiator sites for the ring-opening polymerization of lactide. Heavy atoms (Br and I) were added to the dye to modulate the phosphorescence intensity. These halide-substituted thiophene dyes readily aggregated in the poly(lactic acid) (PLA) matrix, generating two fluorescence peaks in air, one for monomer emission and another for aggregate emission. When the dye was dilute in PLA, as a blend, the iodo-thienyl derivative showed impressive singlet-triplet splitting, with blue fluorescence (440 nm) and orange phosphorescence (585 nm), the largest gap recorded for a boron ß-diketonate dye. Nanoparticles fabricated from a mixture of PLA and dye-PLA conjugated polymer benefited from the large singlet-triplet splitting to yield oxygen sensitivity at levels between 0 and 21 %, which can be utilized in biological oxygen-sensing applications.

Blue Thermally Activated Delayed Fluorescence from a Biphenyl Difluoroboron ß-Diketonate.

Optical properties of biphenyl difluoroboron ß-diketonates were studied in poly(lactic acid) (PLA) blends. Increased conjugation lowered the emission energy, decreased the singlet-triplet energy gap and yielded blue thermally activated delayed fluorescence (TADF). The properties of these biphenyl dyes may inform organic light emitting diode (OLED) and bioimaging agent design.

Does androgen excess contribute to the cardiovascular risk profile in postmenopausal women with type 2 diabetes?

The purpose of this study was to determine if postmenopausal women with type 2 diabetes have clinical and biochemical evidence of androgen excess as a potential contributor to an increase in risk for coronary heart disease when compared with women without diabetes. Fasting glucose, insulin, lipids, sex hormone-binding globulin (SHBG), and sex steroids (from pooled samples) (total testosterone and free testosterone [non-SHBG-T], androstenedione [A-dione], total estrogens) were measured at baseline in 16 postmenopausal women with type 2 diabetes treated with diet or a sulfonylurea and 17 age-matched controls. Measurements of glucose, insulin, and sex steroids were repeated at hourly intervals for 3 hours after oral glucose administration. Hirsutism scores and insulin sensitivity (homeotasis model assessment [HOMA] insulin [SI]) were obtained. Women with type 2 diabetes were more hyperglycemic, hyperinsulinemic, and insulin-resistant (HOMA SI, 46.7 +/- 7.0 vs 12.9 +/- 2.0, P < .001), and had higher total to high-density lipoprotein cholesterol (TC/HDL) ratios, lower SHBG (20.8 +/- 3.5 vs 59.3 +/- 14.4 nmol/L, P < .05), higher non-SHBG-T (0.225 +/- 0.025 vs 0.135 +/- 0.021 nmol/L, P < .05), and higher hirsutism scores (1.1 +/- 0.3 vs 0.3 +/- 0.2, P = .004) than those without diabetes. No changes in sex steroids occurred after the oral glucose challenge. HOMA SI and area under the curve for glucose correlated significantly with SHBG (r = -0.42), non-SHBG-T (r = 0.40), and TC/HDL (r = 0.41) (all P < .05) in the combined groups. Postmenopausal women with type 2 diabetes have both clinical and biochemical evidence of androgen excess that may contribute to more adverse cardiovascular risk profiles.

Comparative study of electronic vs. paper VAS ratings: a randomized, crossover trial using healthy volunteers.

The visual analogue scale (VAS) is an established, validated, self-report measure usually consisting of a 10 cm line on paper with verbal anchors labeling the ends. Palmtop computers (PTCs also known as personal digital appliances) have incorporated VAS entry by use of a touch screen. However, the validity and psychophysical properties of the electronic VAS have never been formally compared with the conventional paper VAS. The aim of this study is to determine the agreement between the electronic (eVAS) and paper (pVAS) modes. Twenty-four healthy volunteers were recruited for this study. Each study participant provided input using both measurement methods by marking the eVAS and pVAS in response to two kinds of stimuli, cognitive and sensory. A verbal rating scale of seven descriptors of intensity represented the cognitive stimuli. Participants were asked to mark the location that best corresponded to the pain intensity described by each word on scales from 'no pain' to 'worst possible pain'. The sensory stimuli used were a set of test weights consisting of plastic containers ranging from 7 to 129 g. The VAS for sensory stimuli ranged from 0 (no weight) to 'reference weight' (the heaviest weight outside the range of test weights). There were two types of input stimuli and two modes for recording responses for a total of four experimental conditions. Two evaluators independently measured and recorded all the pVAS forms to the nearest millimeter. A total of 2016 stimuli were rated. The overall correlation for ratings of both sensory and cognitive stimuli on eVAS and pVAS was r = 0.91. For paired verbal stimuli the correlation was r = 0.97. For paired sensory stimuli the correlation was r = 0.86. The correlation between group eVAS and pVAS ratings to common verbal stimuli was r = 0.99. For common sensory stimuli the group correlation was r = 0.99. The median of correlations comparing eVAS and pVAS ratings was 0.99 for verbal stimuli and 0.98 for sensory stimuli. Multivariate analyses showed equivalent stimuli to be rated much the same whether entered on paper VAS or PTC touch screen VAS (P < 0.0001). Support was found for the validity of the computer version of the VAS scale.

Adult adjustment of survivors of institutional child abuse in Ireland.

OBJECTIVE: To document the adult adjustment of survivors of childhood institutional abuse. METHOD: Two hundred and forty-seven adult survivors of institutional abuse with a mean age of 60 were interviewed with a protocol that included the Childhood Trauma Questionnaire, modules from the Structured Clinical Interview for Axis I Disorders of DSM IV and the Structured Clinical Interview for DSM IV Personality Disorders, the Trauma Symptom Inventory, and the Experiences in Close Relationships Inventory. RESULTS: The prevalence of psychological disorders among adult survivors of institutional abuse was over 80% and far higher than in the normal population, with anxiety, mood and substance use disorders being the most prevalent diagnoses. Survivors also had high rates of trauma symptoms and insecure adult attachment styles, and these were higher for those who had experienced both institutional and intrafamilial abuse. CONCLUSIONS: There was an association between the experience of institutional abuse in childhood and the prevalence of adult mental health problems, particularly anxiety, mood and substance use disorders. PRACTICE IMPLICATIONS: Policies, practices and procedures should be regularly reviewed and revised to maximize protection of young people in institutional care. Evidence-based psychological treatment should be made available to adult survivors of institutional abuse.

Development and initial validation of the institutional child abuse processes and coping inventory among a sample of Irish adult survivors of institutional abuse.

OBJECTIVE: To develop a psychometric instrument to evaluate psychological processes associated with institutional abuse and coping strategies used to deal with such abuse. METHODS: As part of a comprehensive assessment protocol, an inventory containing theoretically derived multi-item rational scales which assessed institutional abuse-related psychological processes and coping strategies were administered to 247 Irish adult survivors of institutional child abuse. Exploratory and confirmatory factor analyses were used to derive 6-factor scales, the reliability and validity of which were assessed. RESULTS: Factor scales to assess the following constructs were developed (1) traumatization, (2) re-enactment, (3) spiritual disengagement, (4) positive coping, (5) coping by complying, and (6) avoidant coping. There were varying degrees of support for the validity of the scales with most support for the traumatization and re-enactment scales. CONCLUSIONS: The Institutional Child Abuse Processes and Coping Inventory (ICAPCI), particularly its traumatization and re-enactment scales, may be used in future research on adult survivors of institutional child abuse because they are currently the only scales that have been developed with this population to provide reliable and valid assessments of these constructs. PRACTICE IMPLICATIONS: The ICAPCI may be used, cautiously, to assess adult survivors of institutional child abuse.