Maternal obesity in sheep impairs foetal hepatic mitochondrial respiratory chain capacity.

BACKGROUND: Changes in the nutritional environment in utero induced by maternal obesity (MO) lead to foetal metabolic dysfunction predisposing offspring to later-life metabolic diseases. Since mitochondria play a crucial role in hepatic metabolism and function, we hypothesized that MO prior to conception and throughout pregnancy programmes foetal sheep liver mitochondrial phenotype. MATERIAL AND METHODS: Ewes ate an obesogenic diet (150% requirements; MO), or 100% requirements (CTR), from 60 days prior to conception. Foetal livers were removed at 0.9 gestation. We measured foetal liver mitochondrial DNA copy number, activity of superoxide dismutase, cathepsins B and D and selected protein content, total phospholipids and cardiolipin and activity of mitochondrial respiratory chain complexes. RESULTS: A significant decrease in activities of mitochondrial complexes I, II-III and IV, but not aconitase, was observed in MO. In the antioxidant machinery, there was a significant increase in activity of total superoxide dismutase (SOD) and SOD2 in MO. However, no differences were found regarding autophagy-related protein content (p62, beclin-I, LC3-I, LC3-II and Lamp2A) and cathepsin B and D activities. A 21.5% decrease in total mitochondrial phospholipid was observed in MO. CONCLUSIONS: The data indicate that MO impairs foetal hepatic mitochondrial oxidative capacity and affects total mitochondrial phospholipid content. In addition, MO affects the regulation of foetal liver redox pathways, indicating metabolic adaptations to the higher foetal lipid environment. Consequences of in utero programming of foetal hepatic metabolism may persist and compromise mitochondrial bioenergetics in later life, and increase susceptibility to metabolic diseases.

Peer delivery of a brief cognitive-behavioral treatment for posttraumatic stress disorder: A hybrid effectiveness-implementation pilot study.

OBJECTIVE: Posttraumatic stress disorder (PTSD) treatment delivery by peer specialist providers could increase access to and engagement with PTSD treatment in low resource settings. The current pilot study tested the feasibility, acceptability, and initial effectiveness of a peer-delivered, brief cognitive-behavioral therapy for PTSD. METHOD: Four certified peer specialists delivered the intervention to 18 participants with probable PTSD. We assessed PTSD symptoms weekly and administered surveys and interviews at baseline and posttreatment. RESULTS: Our mixed-methods approach suggests that the intervention was feasible and acceptable, demonstrating high client satisfaction. We also found significant improvements in PTSD, depressive, anxiety, and general stress symptoms. CONCLUSIONS: Peer-delivered interventions may be a good fit for addressing posttraumatic stress symptoms for people accessing care in low resource settings. Future research should evaluate peer-delivered PTSD treatment as a strategy for both reducing symptoms and improving access and engagement in professional care.

Understanding of evidence-based mental health care and the perceived importance of scientific information in a sample of U.S. adults.

OBJECTIVES: This online survey sought to qualitatively ascertain the extent to which a sample of U.S. adults understood the concept of evidence-based mental health care (EBMHC). Additional goals included assessing the perceived importance of scientific information in EBMHC, and examining whether understanding EBMHC and science values varied as a function of participant factors. METHOD: Participants (N = 221) defined EBMHC and rated the importance of scientific information. Open-ended EBMHC definitions were content-coded, and binomial logistic and linear regressions examined predictors of accurately defining EBMHC and of the perceived importance of scientific information. RESULTS: Participants endorsed seven definitions of EBMHC, and only 20% defined it accurately. Having greater knowledge about mental health conditions was associated with understanding EBMHC and with the higher perceived importance of scientific information. Greater help-seeking efficacy also predicted higher perceived importance of scientific information. CONCLUSIONS: Results support customized strategies to promote basic EBMHC education among U.S. adults.

Preaching to the Choir? Predictors of Engagement in a Community-Based Learning Collaborative.

This study examined predictors of engagement among 283 professionals from 34 agencies participating in three community-based learning collaboratives (CBLCs) on trauma-focused cognitive-behavioral therapy (TF-CBT). Only 50.2% of participants completed the CBLC, primarily due to not attending consultation calls or completing training cases. While higher engagement was associated with being trauma-informed and using more of the TF-CBT components prior to the CBLC, most predictors were not significant, perhaps due to ceiling effects. Positive attitudes and high organizational support were not sufficient to ensure engagement. Future research using longitudinal measurement of a wider range of predictors is needed.

Ligand-Mediated Deposition of Noble Metals at Nanoparticle Plasmonic Hotspots.

We report the use of gold nanoparticle surface chemistry as a tool for site-selective noble metal deposition onto colloidal gold nanoparticle substrates. Specifically, we demonstrate that partial passivation of the gold nanoparticle surface using thiolated ligands can induce a transition from linear palladium island deposition to growth of palladium selectively at plasmonic hotspots on the edges or vertices of the underlying particle substrate. Further, we demonstrate the broader applicability of this approach with respect to substrate morphology (e.g., prismatic and rod-shaped nanoparticles), secondary metal (e.g., palladium, gold, and platinum), and surface ligand (e.g., surfactant molecules and n-alkanethiols). Taken together, these results demonstrate the important role of metal-ligand surface chemistry and ligand packing density on the resulting modes of multimetallic nanoparticle growth, and in particular, the ability to direct that growth to particle regions of impact such as plasmonic hotspots.

Outcome Measure Scores Predict Discharge Destination in Patients With Acute and Subacute Stroke: A Systematic Review and Series of Meta-analyses.

BACKGROUND AND PURPOSE: To identify the association between outcome measure score and discharge destination in adults following acute or subacute stroke in the United States. METHODS: A systematic literature search was performed in 3 databases using the PRISMA guidelines. Cohort studies were selected that included patients with acute or subacute stroke, which explored the relationship between scores on outcome measures and discharge destination. Four meta-analyses were performed. RESULTS: Nine articles met the inclusion criteria for systematic review and 5 for the series of meta-analyses. For every 1-point increase on the Functional Independence Measure (FIM), a patient is approximately 1.08 times more likely to be discharged home than to institutionalized care (odds ratio [OR] = 1.079; 95% confidence interval [CI], 1.056- 1.102). Patients with stroke who performed above-average (FIM ≥80; NIH Stroke Scale [NIHSS] score ≤5; etc) are 12 times (OR = 12.08; 95% CI, 3.550-41.07) more likely to discharge home. Patients who perform poorly (FIM ≤39; NIHSS score ≥14), experience discharge to institutionalized care 3.4 times (OR = 3.385; 95% CI, 2.591-4.422) more likely than home, with skilled nursing facility admission more likely than inpatient rehabilitation facility. Patients who perform average (FIM = 40-79; NIHSS score = 6-13) are 1.9 times (OR = 1.879; 95% CI, 1.227-2.877) more likely to be discharged to institutionalized care. DISCUSSION AND CONCLUSION: Outcome measure scores are strong predictors of discharge destination among patients with stroke and provide an objective means of early discharge planning. Discharge decisions should be made with consideration for patient-specific biopsychosocial factors that may supersede isolated results of the outcome measures, and further research needs to assess the success of the location that a patient is referred at discharge.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A194).

Monitoring Treatment Progress and Providing Feedback is Viewed Favorably but Rarely Used in Practice.

Numerous trials demonstrate that monitoring client progress and using feedback for clinical decision-making enhances treatment outcomes, but available data suggest these practices are rare in clinical settings and no psychometrically validated measures exist for assessing attitudinal barriers to these practices. This national survey of 504 clinicians collected data on attitudes toward and use of monitoring and feedback. Two new measures were developed and subjected to factor analysis: The monitoring and feedback attitudes scale (MFA), measuring general attitudes toward monitoring and feedback, and the attitudes toward standardized assessment scales-monitoring and feedback (ASA-MF), measuring attitudes toward standardized progress tools. Both measures showed good fit to their final factor solutions, with excellent internal consistency for all subscales. Scores on the MFA subscales (Benefit, Harm) indicated that clinicians hold generally positive attitudes toward monitoring and feedback, but scores on the ASA-MF subscales (Clinical Utility, Treatment Planning, Practicality) were relatively neutral. Providers with cognitive-behavioral theoretical orientations held more positive attitudes. Only 13.9 % of clinicians reported using standardized progress measures at least monthly and 61.5 % never used them. Providers with more positive attitudes reported higher use, providing initial support for the predictive validity of the ASA-MF and MFA. Thus, while clinicians report generally positive attitudes toward monitoring and feedback, routine collection of standardized progress measures remains uncommon. Implications for the dissemination and implementation of monitoring and feedback systems are discussed.

Individualized Progress Measures Are More Acceptable to Clinicians Than Standardized Measures: Results of a National Survey.

Despite research supporting measurement-based care grounded in standardized progress measures, such measures are underutilized by clinicians. Individualized measures of client-specific targets present an alternative, but little is known about their acceptability or use. We compared attitudes toward and use of standardized and individualized progress measures in a national sample of 504 clinicians. Clinicians reported neutral to positive attitudes toward both types of measures, but strongly preferred and were more likely to use individualized measures. Clinician attitudes, theoretical orientation, and work setting predicted assessment preferences and practices. Implications for dissemination and implementation of measurement-based care are discussed.

Efficient Energy Transfer from Near-Infrared Emitting Gold Nanoparticles to Pendant Ytterbium(III).

Here, we demonstrate efficient energy transfer from near-infrared-emitting ortho-mercaptobenzoic acid-capped gold nanoparticles (AuNPs) to pendant ytterbium(III) cations. These functional materials combine the high molar absorptivity (1.21 × 106 M-1 cm-1) and broad excitation features (throughout the UV and visible regions) of AuNPs with the narrow emissive properties of lanthanides. Interaction between the AuNP ligand shell and ytterbium is determined using both nuclear magnetic resonance and electron microscopy measurements. In order to identify the mechanism of this energy transfer process, the distance of the ytterbium(III) from the surface of the AuNPs is systematically modulated by changing the size of the ligand appended to the AuNP. By studying the energy transfer efficiency from the various AuNP conjugates to pendant ytterbium(III) cations, a Dexter-type energy transfer mechanism is suggested, which is an important consideration for applications ranging from catalysis to energy harvesting. Taken together, these experiments lay a foundation for the incorporation of emissive AuNPs in energy transfer systems.

Pseudoalteromonas piratica sp. nov., a budding, prosthecate bacterium from diseased Montipora capitata, and emended description of the genus Pseudoalteromonas.

A Gram-stain-negative, motile, rod-shaped bacterium designated OCN003T was cultivated from mucus taken from a diseased colony of the coral Montipora capitata in Kane'ohe Bay, O'ahu, Hawai'i. Colonies of OCN003T were pale yellow, 1-3 mm in diameter, convex, smooth and entire. The strain was heterotrophic, strictly aerobic and strictly halophilic. Cells of OCN003T produced buds on peritrichous prosthecae. Growth occurred within the pH range of 5.5 to 10, and the temperature range of 14 to 39 °C. Major fatty acids were 16 : 1ω7c, 16 : 0, 18 : 1ω7c, 17 : 1ω8c, 12 : 0 3-OH and 17 : 0. Phylogenetic analysis of 1399 nucleotides of the 16S rRNA gene nucleotide sequence and a multi-locus sequence analysis of three genes placed OCN003T in the genus Pseudoalteromonas and indicated that the nearest relatives described are Pseudoalteromonas spongiae, P. luteoviolacea, P. ruthenica and P. phenolica(97-99 % sequence identity). The DNA G+C content of the strain's genome was 40.0 mol%. Based on in silico DNA-DNA hybridization and phenotypic differences from related type strains, we propose that OCN003T represents the type strain of a novel species in the genus Pseudoalteromonas, proposed as Pseudoalteromonas piratica sp. nov. OCN003T (=CCOS1042T=CIP 111189T). An emended description of the genus Pseudoalteromonas is presented.

Impact of As-Synthesized Ligands and Low-Oxygen Conditions on Silver Nanoparticle Surface Functionalization.

Here, we compare the ligand exchange behaviors of silver nanoparticles synthesized in the presence of two different surface capping agents: poly(vinylpyrrolidone) (MW = 10 or 40 kDa) or trisodium citrate, and under either ambient or low-oxygen conditions. In all cases, we find that the polymer capping agent exhibits features of a weakly bound ligand, producing better ligand exchange efficiencies with an incoming thiolated ligand compared to citrate. The polymer capping agent also generates nanoparticles that are more susceptible to reactions with oxygen during both synthesis and ligand exchange. The influence of the original ligand on the outcome of ligand exchange reactions with an incoming thiolated ligand highlights important aspects of silver nanoparticle surface chemistry, crucial for applications ranging from photocatalysis to antimicrobials.

Ligand density quantification on colloidal inorganic nanoparticles.

Colloidal inorganic nanoparticles are being used in an increasingly large number of applications ranging from biological imaging to television displays. In all cases, nanoparticle surface chemistry can significantly impact particle physical properties, processing, and performance. The first step in leveraging this tunability is to develop analytical approaches to describe surface chemical features. Some of the most basic descriptors of particle surface chemistry include the quantity, identity, and arrangement of ligands appended to the particle core. Here, we review approaches to quantify molecular ligand densities on nanoparticle surfaces and consider fundamental barriers to the accuracy of this analysis including parameters such as dispersity in colloidal nanoparticle samples, particle-ligand interactions, and currently available analytical techniques. Techniques reviewed include widely studied methods such as optical, atomic, vibrational, and nuclear magnetic resonance spectroscopies as well as emerging or niche approaches including electrospray-differential mobility analysis, pH-based methods, and X-ray photoelectron spectroscopy. Collectively, these studies elucidate surface chemistry architectures that accelerate both fundamental understanding of nanoscale physical phenomena and the implementation of these materials in a wide range of technologies.

Ligand-Mediated "Turn On," High Quantum Yield Near-Infrared Emission in Small Gold Nanoparticles.

Small gold nanoparticles (∼1.4-2.2 nm core diameters) exist at an exciting interface between molecular and metallic electronic structures. These particles have the potential to elucidate fundamental physical principles driving nanoscale phenomena and to be useful in a wide range of applications. Here, we study the optoelectronic properties of aqueous, phosphine-terminated gold nanoparticles (core diameter = 1.7 ± 0.4 nm) after ligand exchange with a variety of sulfur-containing molecules. No emission is observed from these particles prior to ligand exchange, however the introduction of sulfur-containing ligands initiates photoluminescence. Further, small changes in sulfur substituents produce significant changes in nanoparticle photoluminescence features including quantum yield, which ranges from 0.13 to 3.65% depending on substituent. Interestingly, smaller ligands produce the most intense, highest energy, narrowest, and longest-lived emissions. Radiative lifetime measurements for these gold nanoparticle conjugates range from 59 to 2590 µs, indicating that even minor changes to the ligand substituent fundamentally alter the electronic properties of the luminophore itself. These results isolate the critical role of surface chemistry in the photoluminescence of small metal nanoparticles and largely rule out other mechanisms such as discrete (Au(I)-S-R)n impurities, differences in ligand densities, and/or core diameters. Taken together, these experiments provide important mechanistic insight into the relationship between gold nanoparticle near-infrared emission and pendant ligand architectures, as well as demonstrate the pivotal role of metal nanoparticle surface chemistry in tuning and optimizing emergent optoelectronic features from these nanostructures.

Description and Role of Bimetallic Prenucleation Species in the Formation of Small Nanoparticle Alloys.

We report the identification, description, and role of multinuclear metal-thiolate complexes in aqueous Au-Cu nanoparticle syntheses. The structure of these species was characterized by nuclear magnetic resonance spectroscopy, mass spectrometry, X-ray photoelectron spectroscopy, and X-ray absorption spectroscopy techniques. The observed structures were found to be in good agreement with thermodynamic growth trends predicted by first-principles calculations. The presence of metal-thiolate complexes is then shown to be critical for the formation of alloyed Au-Cu architectures in the small nanoparticle regime (diameter ∼2 nm). In the absence of mixed metal-thiolate precursors, nanoparticles form with a Cu-S shell and a Au-rich interior. Taken together, these results demonstrate that prenucleation species, which are discrete molecular precursors distinct from both initial reagents and final particle products, may provide an important new synthetic route to control final metal nanoparticle composition and composition architectures.

Quantitative analysis of thiolated ligand exchange on gold nanoparticles monitored by 1H NMR spectroscopy.

We use nuclear magnetic resonance spectroscopy methods to quantify the extent of ligand exchange between different types of thiolated molecules on the surface of gold nanoparticles. Specifically, we determine ligand density values for single-moiety ligand shells and then use these data to describe ligand exchange behavior with a second, thiolated molecule. Using these techniques, we identify trends in gold nanoparticle functionalization efficiency with respect to ligand type, concentration, and reaction time as well as distinguish between functionalization pathways where the new ligand may either replace the existing ligand shell (exchange) or add to it ("backfilling"). Specifically, we find that gold nanoparticles functionalized with thiolated macromolecules, such as poly(ethylene glycol) (1 kDa), exhibit ligand exchange efficiencies ranging from 70% to 95% depending on the structure of the incoming ligand. Conversely, gold nanoparticles functionalized with small-molecule thiolated ligands exhibit exchange efficiencies as low as 2% when exposed to thiolated molecules under identical exchange conditions. Taken together, the reported results provide advances in the fundamental understanding of mixed ligand shell formation and will be important for the preparation of gold nanoparticles in a variety of biomedical, optoelectronic, and catalytic applications.

Photoluminescent gold-copper nanoparticle alloys with composition-tunable near-infrared emission.

Discrete gold nanoparticles with diameters between 2 and 3 nm show remarkable properties including enhanced catalytic behavior and photoluminescence. However, tunability of these properties is limited by the tight size range within which they are observed. Here, we report the synthesis of discrete, bimetallic gold-copper nanoparticle alloys (diameter ≅ 2-3 nm) which display photoluminescent properties that can be tuned by changing the alloy composition. Electron microscopy, X-ray photoelectron spectroscopy, inductively coupled plasma mass spectrometry, and pulsed-field gradient stimulated echo (1)H NMR measurements show that the nanoparticles are homogeneous, discrete, and crystalline. Upon varying the composition of the nanoparticles from 0% to 100% molar ratio copper, the photoluminescence maxima shift from 947 to 1067 nm, with excitation at 360 nm. The resulting particles exhibit brightness values (molar extinction coefficient (ε) × quantum yield (Φ)) that are more than an order of magnitude larger than the brightest near-infrared-emitting lanthanide complexes and small-molecule probes evaluated under similar conditions.

Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.

Retraction Notice to: Modulation of TNFα Activity by the microRNA Let-7 Coordinates Zebrafish Heart Regeneration.

[This retracts the article DOI: 10.1016/j.isci.2019.06.017.].

Retraction Notice to: Modulation of TNFa Activity by the microRNA Let-7 Coordinates Zebrafish Heart Regeneration.

[This retracts the article DOI: 10.1016/j.isci.2019.04.009.].