Highly Efficient and Scalable p-i-n Perovskite Solar Cells Enabled by Poly-metallocene Interfaces.

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

Magnetic Sensor Angle Adjustment to Improve Corrosion under Insulation Detection.

A large portion of the pipe infrastructure used in the chemical processing industry is susceptible to corrosion under insulation (CUI). Eddy current-based magnetic sensing is one of the methods that can be used as an early detector of this corrosion. However, the large sensor-to-pipe distances used in this method, due to the presence of insulation, limits the sensitivity to corrosion. This paper will describe the development of instrumentation and methods based on eddy current sensing with thin-film magnetic sensors. In particular, it focuses on the influence of the sensor angle relative to the radial magnetic field. The influence of this parameter on the amplitude of the measured signal was investigated by both finite element simulations and experimental observations. The measured magnetic field was found to be highly sensitive to small changes in sensor angle, with the estimated depth of a defect changing at a rate of 11.2 mm/degree of sensor rotation for small angles. It is also shown that a sensor aligned with the radial direction should be avoided, with an optimal sensor angle between 0.5 and 4 degrees. With the sensor in this angle range, the simulations have shown it should be possible to resolve the depth of corrosion to a resolution of 0.1 mm.

Site-Specific 68Ga Radiolabeling of Trastuzumab Fab via Methionine for ImmunoPET Imaging.

Bioconjugates of antibodies and their derivatives radiolabeled with ß+-emitting radionuclides can be utilized for diagnostic PET imaging. Site-specific attachment of radioactive cargo to antibody delivery vectors provides homogeneous, well-defined immunoconjugates. Recent studies have demonstrated the utility of oxaziridine chemistry for site-specific labeling of methionine residues. Herein, we applied this approach to site-specifically radiolabel trastuzumab-derived Fab immunoconjugates with 68Ga, which can be used for in vivo PET imaging of HER2-positive breast cancer tumors. Initially, a reactive azide was introduced to a single solvent-accessible methionine residue in both the wild-type Fab and an engineered derivative containing methionine residue M74, utilizing the principles of oxaziridine chemistry. Subsequently, these conjugates were functionalized with a modified DFO chelator incorporating dibenzocyclooctyne. The resulting DFO-WT and DFO-M74 conjugates were radiolabeled with generator-produced [68Ga]Ga3+, to yield the novel PET radiotracers, [68Ga]Ga-DFO-WT and [68Ga]Ga-DFO-M74. In vitro and in vivo studies demonstrated that [68Ga]Ga-DFO-M74 exhibited a higher affinity for HER2 receptors. Biodistribution studies in mice bearing orthotopic HER2-positive breast tumors revealed a higher uptake of [68Ga]Ga-DFO-M74 in the tumor tissue, accompanied by rapid renal clearance, enabling clear delineation of tumors using PET imaging. Conversely, [68Ga]Ga-DFO-WT exhibited lower uptake and inferior image contrast compared to [68Ga]Ga-DFO-M74. Overall, the results demonstrate that the highly facile methionine-oxaziridine modification approach can be simply applied to the synthesis of stable and site-specifically modified radiolabeled antibody-chelator conjugates with favorable pharmacokinetics for PET imaging.

Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1.

RATIONALE: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an AMPK (AMP-activated protein kinase)/ATF1 (activating transcription factor-1) pathway that directs Mhem macrophages through coregulation of HO-1 (heme oxygenase-1; HMOX1) and lipid homeostasis genes. OBJECTIVE: We asked whether this pathway had an in vivo role in mice. METHODS AND RESULTS: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow-derived macrophages, heme induced HO-1, lipid regulatory genes including LXR (lipid X receptor), the growth factor IGF1 (insulin-like growth factor-1), and the splenic red pulp macrophage gene Spic. This response was lost in bone marrow-derived macrophages from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between days 8 and 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-; n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent. CONCLUSIONS: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution. Graphic Abstract: An online graphic abstract is available for this article.

N-Centered Tripodal Phosphine Re(V) and Tc(V) Oxo Complexes: Revisiting a [3 + 2] Mixed-Ligand Approach.

N-Triphos derivatives (NP3R, R = alkyl, aryl) and asymmetric variants (NP2RXR', R' = alkyl, aryl, X = OH, NR2, NRR') are an underexplored class of tuneable, tripodal ligands in relation to the coordination chemistry of Re and Tc for biomedical applications. Mixed-ligand approaches are a flexible synthetic route to obtain Tc complexes of differing core structures and physicochemical properties. Reaction of the NP3Ph ligand with the Re(V) oxo precursor [ReOCl3(PPh3)2] generated the bidentate complex [ReOCl3(κ2-NP2PhOHAr)], which possesses an unusual AA'BB'XX' spin system with a characteristic second-order NMR lineshape that is sensitive to the bi- or tridentate nature of the coordinating diphosphine unit. The use of the asymmetric NP2PhOHAr ligand resulted in the formation of both bidentate and tridentate products depending on the presence of base. The tridentate Re(V) complex [ReOCl2(κ3-NP2PhOAr)] has provided the basis of a new reactive "metal-fragment" for further functionalization in [3 + 2] mixed-ligand complexes. The synthesis of [3 + 2] complexes with catechol-based π-donors could also be achieved under one-pot, single-step conditions from Re(V) oxo precursors. Analogous complexes can also be synthesized from suitable 99Tc(V) precursors, and these complexes have been shown to exhibit highly similar structural properties through spectroscopic and chromatographic analysis. However, a tendency for the {MVO}3+ core to undergo hydrolysis to the {MVO2}+ core has been observed both in the case of M = Re and markedly for M = 99Tc complexes. It is likely that controlling this pathway will be critical to the generation of further stable Tc(V) derivatives.

Bioinspired artificial exosomes based on lipid nanoparticles carrying let-7b-5p promote angiogenesis in vitro and in vivo.

MicroRNAs (miRNAs) regulate gene expression by post-transcriptional inhibition of target genes. Proangiogenic small extracellular vesicles (sEVs; popularly identified with the name "exosomes") with a composite cargo of miRNAs are secreted by cultured stem cells and present in human biological fluids. Lipid nanoparticles (LNPs) represent an advanced platform for clinically approved delivery of RNA therapeutics. In this study, we aimed to (1) identify the miRNAs responsible for sEV-induced angiogenesis; (2) develop the prototype of bioinspired "artificial exosomes" (AEs) combining LNPs with a proangiogenic miRNA, and (3) validate the angiogenic potential of the bioinspired AEs. We previously reported that human sEVs from bone marrow (BM)-CD34+ cells and pericardial fluid (PF) are proangiogenic. Here, we have shown that sEVs secreted from saphenous vein pericytes and BM mesenchymal stem cells also promote angiogenesis. Analysis of miRNA datasets available in-house or datamined from GEO identified the let-7 family as common miRNA signature of the proangiogenic sEVs. LNPs with either hsa-let-7b-5p or cyanine 5 (Cy5)-conjugated Caenorhabditis elegans miR-39 (Cy5-cel-miR-39; control miRNA) were prepared using microfluidic micromixing. let-7b-5p-AEs did not cause toxicity and transferred functionally active let-7b-5p to recipient endothelial cells (ECs). let-7b-AEs also improved EC survival under hypoxia and angiogenesis in vitro and in vivo. Bioinspired proangiogenic AEs could be further developed into innovative nanomedicine products targeting ischemic diseases.

Pathways and obstacles to social recovery following the elimination of SARS-CoV-2 from Aotearoa New Zealand: a qualitative cross-sectional study.

BACKGROUND: Many public health experts have claimed that elimination strategies of pandemic response allow 'normal social life' to resume. Recognizing that social connections and feelings of normality are important for public health, this study examines whether, and for whom, that goal is realized, and identifies obstacles that may inhibit its achievement. METHODS: Thematic analysis of narratives obtained via a qualitative cross-sectional survey of a community cohort in Aotearoa | New Zealand. RESULTS: A majority of participants reported that life after elimination was 'more or less the same' as before the pandemic. Some became more social. Nevertheless, a sizeable minority reported being less social, even many months after elimination. Key obstacles to social recovery included fears that the virus was circulating undetected and the enduring impact of lockdowns upon social relationships, personal habits and mental health. Within our sample, old age and underlying health conditions were both associated with a propensity to become less social. CONCLUSIONS: Elimination strategies can successfully allow 'normal social life' to resume. However, this outcome is not guaranteed. People may encounter difficulties with re-establishing social connections in Zero-COVID settings. Measures designed to overcome such obstacles should be an integral part of elimination strategies.

Behavioral Parent Training for Preschool ADHD: Family-Centered Profiles Predict Changes in Parenting and Child Outcomes.

OBJECTIVE: Behavioral parent training (BPT) is the first line of treatment for preschool-aged children with attention-deficit hyperactivity disorder (ADHD); however, clinically significant improvements are not universal. In the current study, we employ a person-centered approach to create subgroups of families based on the intersection of multiple parent, child, and family pre-treatment factors. Further, we explore the utility of pre-treatment family profiles in predicting post-treatment differences in observed parenting behavior (i.e., behavioral control, parental warmth) and clinically significant change in child ADHD and oppositional symptoms. METHOD: Longitudinal data were collected using observational and parent-, teacher- and clinician-reported assessments from 130 parent-child dyads (Mage= 3.57, range = 3.0- 4.11, 73.8% male, 69.2% White, 25.6% Hispanic) participating in BPT. RESULTS: Findings from the current study suggest three distinct family profiles, which consisted of one profile with high family stress (HFS) as evidenced by elevated symptomatology across parent, child, and family-level domains, a second profile with elevated parental anxiety (PA), and a final profile with elevated parental depression (PD). These family-centered profiles were differentially associated with changes in observed parenting practices. Specifically, the PD profile (39%) demonstrated minimal improvements in behavioral control and warmth following treatment. In contrast, the HFS profile (30%) only improved in behavioral control and the PA profile (31%) improved in both parenting domains following treatment. In addition, marginally significant differences in child oppositional and ADHD symptoms were observed across profiles. CONCLUSIONS: Family-centered approaches may be useful for selecting and implementing interventions.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV protein-specific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

A Coumarin-Porphyrin FRET Break-Apart Probe for Heme Oxygenase-1.

Heme oxygenase-1 (HO-1) is a vital enzyme in humans that primarily regulates free heme concentrations. The overexpression of HO-1 is commonly associated with cardiovascular and neurodegenerative diseases including atherosclerosis and ischemic stroke. Currently, there are no known chemical probes to detect HO-1 activity, limiting its potential as an early diagnostic/prognostic marker in these serious diseases. Reported here are the design, synthesis, and photophysical and biological characterization of a coumarin-porphyrin FRET break-apart probe to detect HO-1 activity, Fe-L1. We designed Fe-L1 to "break-apart" upon HO-1-catalyzed porphyrin degradation, perturbing the efficient FRET mechanism from a coumarin donor to a porphyrin acceptor fluorophore. Analysis of HO-1 activity using Escherichia coli lysates overexpressing hHO-1 found that a 6-fold increase in emission intensity at 383 nm was observed following incubation with NADPH. The identities of the degradation products following catabolism were confirmed by MALDI-MS and LC-MS, showing that porphyrin catabolism was regioselective at the α-position. Finally, through the analysis of Fe-L2, we have shown that close structural analogues of heme are required to maintain HO-1 activity. It is anticipated that this work will act as a foundation to design and develop new probes for HO-1 activity in the future, moving toward applications of live fluorescent imaging.

New Bifunctional Chelators Incorporating Dibromomaleimide Groups for Radiolabeling of Antibodies with Positron Emission Tomography Imaging Radioisotopes.

Positron Emission Tomography (PET) imaging with antibody-based contrast agents frequently uses the radioisotopes [64Cu]Cu2+ and [89Zr]Zr4+. The macrobicyclic chelator commonly known as sarcophagine (sar) is ideal for labeling receptor-targeted biomolecules with [64Cu]Cu2+. The siderophore chelator, desferrioxamine-B (dfo), has been widely used to incorporate [89Zr]Zr4+ into antibodies. Here, we describe new bifunctional chelators of sar and dfo: these chelators have been functionalized with dibromomaleimides (dbm), that enable site-specific and highly stable attachment of molecular cargoes to reduced, solvent-accessible, interstrand native disulfide groups. The new sar-dbm and dfo-dbm derivatives can be easily conjugated with the IgG antibody trastuzumab via reaction with reduced interstrand disulfide groups to give site-specifically modified dithiomaleamic acid (dtm) conjugates, sar-dtm-trastuzumab and dfo-dtm-trastuzumab, in which interstrand disulfides are rebridged covalently with a small molecule linker. Both sar- and dfo-dtm-trastuzumab conjugates have been radiolabeled with [64Cu]Cu2+ and [89Zr]Zr4+, respectively, in near quantitative radiochemical yield (>99%). Serum stability studies, in vivo PET imaging, and biodistribution analyses using these radiolabeled immunoconjugates demonstrate that both [64Cu]Cu-sar-dtm-trastuzumab and [89Zr]Zr-dfo-dtm-trastuzumab possess high stability in biological milieu. Dibromomaleimide technology can be easily applied to enable stable, site-specific attachment of radiolabeled chelators, such as sar and dfo, to native interstrand disulfide regions of antibodies, enabling tracking of antibodies with PET imaging.

Discharge Behaviour and Modelling of a 1.5T REBCO Magnet With Quench Tolerant Coils Impregnated with Conductive Epoxy.

We have designed and built a small, conduction cooled, 1.5 T high-temperature superconductor (HTS) magnet. The magnet coils have been wet-wound with a novel conductive epoxy resin system to achieve a derivative of the no-insulation coil winding method. The epoxy is filled with copper powder to reliably set the turn-to-turn contact resistivity and diamond powder to accurately space the coil turns apart, as well as match the filled epoxy thermal contraction rate to that of the HTS. The magnet is designed to act as a test bed to measure sudden discharge rates and hence validate models of coil behaviour using the filled epoxy system we have developed. A lumped-element electrical model was used to predict the coil contact resistivity needed to bring the magnetic field of the 1.5 T magnet down to a near-zero level within 0.5 s. The conductive epoxy blend was tuned to give a contact resistivity of 1 × 10-6 Ω m2, based on previous measurements of coil contact resistivity at 77 K. Once the magnet was wound and tested at 40 K, we found the magnet's sudden discharge time constant was 500 ms rather than 69 ms as was predicted from the 77 K measurements. The discrepancy was traced to the temperature dependence of the contact resistivity. With further testing of the individual coils this was accounted for and the model adjusted. The predicted discharge time was 2 s, in good agreement with the measured sudden discharge time of the magnet.

Solid-Phase Peptide Macrocyclization and Multifunctionalization via Dipyrrin Construction.

We introduce a new and highly efficient synthetic protocol towards multifunctional fluorescent cyclopeptides by solid-phase peptide macrocyclization via dipyrrin construction, with full scope of proteinogenic amino acids and different ring sizes. Various bicyclic peptides can be created by dipyrrin-based crosslinking and double dipyrrin-ring formation. The embedded dipyrrin can be either transformed to fluorescent BODIPY and then utilized as cancer-selective targeted protein imaging probe in vitro, or directly employed as a selective metal sensor in aqueous media. This work provides a valuable addition to the peptide macrocyclization toolbox, and a blueprint for the development of multifunctional dipyrrin linkers in cyclopeptides for a wide range of potential bioapplications.

Scale-Up of Room-Temperature Constructive Quantum Interference from Single Molecules to Self-Assembled Molecular-Electronic Films.

The realization of self-assembled molecular-electronic films, whose room-temperature transport properties are controlled by quantum interference (QI), is an essential step in the scale-up of QI effects from single molecules to parallel arrays of molecules. Recently, the effect of destructive QI (DQI) on the electrical conductance of self-assembled monolayers (SAMs) has been investigated. Here, through a combined experimental and theoretical investigation, we demonstrate chemical control of different forms of constructive QI (CQI) in cross-plane transport through SAMs and assess its influence on cross-plane thermoelectricity in SAMs. It is known that the electrical conductance of single molecules can be controlled in a deterministic manner, by chemically varying their connectivity to external electrodes. Here, by employing synthetic methodologies to vary the connectivity of terminal anchor groups around aromatic anthracene cores, and by forming SAMs of the resulting molecules, we clearly demonstrate that this signature of CQI can be translated into SAM-on-gold molecular films. We show that the conductance of vertical molecular junctions formed from anthracene-based molecules with two different connectivities differ by a factor of approximately 16, in agreement with theoretical predictions for their conductance ratio based on CQI effects within the core. We also demonstrate that for molecules with thioether anchor groups, the Seebeck coefficient of such films is connectivity dependent and with an appropriate choice of connectivity can be boosted by ∼50%. This demonstration of QI and its influence on thermoelectricity in SAMs represents a critical step toward functional ultra-thin-film devices for future thermoelectric and molecular-scale electronics applications.

Sensory neuronal sensitisation occurs through HMGB-1-RAGE and TRPV1 in high-glucose conditions.

Many potential causes for painful diabetic neuropathy have been proposed including actions of cytokines and growth factors. High mobility group protein B1 (HMGB1) is a RAGE (also known as AGER) agonist whose levels are increased in diabetes and that contributes to pain by modulating peripheral inflammatory responses. HMGB1 enhances nociceptive behaviour in naïve animals through an unknown mechanism. We tested the hypothesis that HMGB1 causes pain through direct neuronal activation of RAGE and alteration of nociceptive neuronal responsiveness. HMGB1 and RAGE expression were increased in skin and primary sensory (dorsal root ganglion, DRG) neurons of diabetic rats at times when pain behaviour was enhanced. Agonist-evoked TRPV1-mediated Ca2+ responses increased in cultured DRG neurons from diabetic rats and in neurons from naïve rats exposed to high glucose concentrations. HMGB1-mediated increases in TRPV1-evoked Ca2+ responses in DRG neurons were RAGE- and PKC-dependent, and this was blocked by co-administration of the growth factor splice variant VEGF-A165b. Pain behaviour and the DRG RAGE expression increases were blocked by VEGF-A165b treatment of diabetic rats in vivo Hence, we conclude that HMGB1-RAGE activation sensitises DRG neurons in vitro, and that VEGF-A165b blocks HMGB-1-RAGE DRG activation, which may contribute to its analgesic properties in vivo.

Linker engineering in anti-TAG-72 antibody fragments optimizes biophysical properties, serum half-life, and high-specificity tumor imaging.

Antibody (Ab) fragments have great clinical potential as cancer therapeutics and diagnostics. Their small size allows for fast clearance from blood, low immunoreactivity, better tumor penetration, and simpler engineering and production. The smallest fragment derived from a full-length IgG that retains binding to its antigen, the single-chain variable fragment (scFV), is engineered by fusing the variable light and variable heavy domains with a peptide linker. Along with switching the domain orientation, altering the length and amino acid sequence of the linker can significantly affect scFV binding, stability, quaternary structure, and other biophysical properties. Comprehensive studies of these attributes in a single scaffold have not been reported, making design and optimization of Ab fragments challenging. Here, we constructed libraries of 3E8, an Ab specific to tumor-associated glycoprotein 72 (TAG-72), a mucinous glycoprotein overexpressed in 80% of adenocarcinomas. We cloned, expressed, and characterized scFVs, diabodies, and higher-order multimer constructs with varying linker compositions, linker lengths, and domain orientations. These constructs dramatically differed in their oligomeric states and stabilities, not only because of linker and orientation but also related to the purification method. For example, protein L-purified constructs tended to have broader distributions and higher oligomeric states than has been reported previously. From this library, we selected an optimal construct, 3E8.G4S, for biodistribution and pharmacokinetic studies and in vivo xenograft mouse PET imaging. These studies revealed significant tumor targeting of 3E8.G4S with a tumor-to-background ratio of 29:1. These analyses validated 3E8.G4S as a fast, accurate, and specific tumor-imaging agent.

Rapid Short-pulse Ultrasound Delivers Drugs Uniformly across the Murine Blood-Brain Barrier with Negligible Disruption.

Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally disruptive and efficient drug delivery method that could improve the treatment, diagnosis, and study of neurologic diseases. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Klibanov and McDannold in this issue.

Enormous gill chambers of deep-sea coffinfishes (Lophiiformes: Chaunacidae) support unique ventilatory specialisations such as breath holding and extreme inflation.

Deep sea habitats tend to favor species with low energetic demands, and therefore we predict that deep sea fishes will have behavioral and morphological specializations of the gill ventilatory system to reduce the energetic cost of pumping water across the gills. However, it is difficult to study functional morphology of deep sea fishes due the lack of ability to conduct laboratory experiments with living fishes. For this study, we combined analysis of publicly available video recorded by remote-operated vehicles (ROV) with detailed anatomical study of museum specimens to document the functional morphology of the massive gill chambers that are observed in coffinfishes (Lophiiformes: Chaunacidae). Chaunacids, like other lophiiforms, exhibit highly specialised ventilatory anatomy such as an enlarged branchiostegal apparatus and restricted gill openings, but videos show them using this anatomy in a new and unusual way. We observed eight individuals ventilating extremely slowly at rates of 0.03-0.004 Hz, during which the gill chambers were full yet we saw no inhalation or exhalation for periods of 26 to 245 s. This holding breath behaviour has not been observed in any other fishes and is probably highly energetically efficient. This inflation of the gill chambers also increases body volume by up to 30%, making them more globose and difficult to be taken as prey, much like stomach inflation in pufferfishes (Tetraodontidae). We also used micro computed-tomography (CT) scans to document the enormous branchiostegal rays and associated muscles that support this unique behaviour.

"Accept and Utilize": Alternative Medicine, Minimality, and Ethics in an Indonesian Healing Collective.

Cosmopolitan forms of alternative medicine have become very popular in contemporary Indonesia. Many healers have trained in an eclectic range of techniques, predicated on ontological claims so diverse that they call each other's legitimacy into question. This article explores how a collective of alternative healers in central Java navigated the quandaries presented by such therapeutic eclecticism over a six-year period. Healers' engagement with, or indifference toward, the principles underpinning therapeutic efficacy fluctuated in ways that allowed them to surmount the dilemmas of Islamization, the changing demographic of their collective's membership, and the threat of commercialization, thereby maintaining a medical landscape in which alternative healing was widely available and accessible. Transformations in their understanding, experience, and practice of healing should thus be understood in terms of how enduring ethical commitments are refracted through ongoing engagements with a changing social world.

VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis.

Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation. Using pharmacological interventions targeting VEGFR2 in arthritic rats, to inhibit endothelial cell activation, the number of dorsal horn ICAM-1+ blood vessels, CD11b+ microglia and the development of secondary mechanical allodynia, an indicator of central sensitization, were all prevented. Targeting endothelial VEGFR2 by inducible Tie2-specific VEGFR2 knock-out also prevented secondary allodynia in mice and glio-vascular activation in the dorsal horn in response to inflammatory arthritis. Inhibition of VEGFR2 in vitro significantly blocked ICAM-1-dependent monocyte adhesion to brain microvascular endothelial cells, when stimulated with inflammatory mediators TNF-α and VEGF-A165a. Taken together our findings suggest that a novel VEGFR2-mediated spinal cord glio-vascular mechanism may promote peripheral CD11b+ circulating cell transmigration into the CNS parenchyma and contribute to the development of chronic pain in inflammatory arthritis. We hypothesise that preventing this glio-vascular activation and circulating cell translocation into the spinal cord could be a new therapeutic strategy for pain caused by rheumatoid arthritis.