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Abstract Understanding the interplay between individual magnetic impurities and superconductivity is crucial for bottom-up construction of novel phases of matter. Sub-gap bound states that are used in this endeavor are typically considered as independent entities that each result from the exchange scattering between the respective impurity orbitals and electrons of the superconducting condensate. Here we present experimental evidence of individual multi-spin impurities where the sub-gap states are not independent. Specifically, we find that by tuning the energy of the state closest to zero through zero, all other sub-gap states change particle-hole asymmetry as well. We show that this can be understood by including Hund’s coupling, which favors high-spin configurations, into a multi-orbital Anderson model. Unlike for the case of independent spins, the transition we observe signals the simultaneous departure of more than one quasiparticle from the impurity, while the parity of the ground state may remain unchanged. Our results show that Hund’s coupling is not only crucial in generating high-spin impurities, but also to understand the transition between two distinct ground states, and should therefore be taken into account for e.g. impurity-based band-structure engineering.

Abstract Pathological fibrosis is a significant complication of surgical procedures resulting from the accumulation of excess collagen at the site of repair which can compromise the tissue architecture and severely impede the function of the affected tissue. Few prophylactic treatments exist to counteract this process; however, the use of amniotic membrane allografts has demonstrated promising clinical outcomes. This study aimed to identify the underlying mechanism of action by utilizing relevant models that accurately represent the pathophysiology of the disease state. This study employed a pro-fibrotic in vitro system using TGFβ1 stimulation and macromolecular crowding techniques to evaluate the mechanism by which amniotic membrane allografts regulate collagen biosynthesis and deposition. Following treatment with dehydrated human amnion chorion membrane (DHACM), subsequent RNA sequencing and functional enrichment with Reactome pathway analysis indicated that amniotic membranes are indeed capable of regulating genes associated with the composition and function of the extracellular matrix. Furthermore, macromolecular crowding was used in vitro to expand the evaluation to include both the effects of DHACM and a lyophilized human amnion/chorion membrane (LHACM). DHACM and LHACM regulate the TGFβ pathway and myofibroblast differentiation. Additionally, both DHACM and LHACM modulate the production, secretion, and deposition of collagen type I, a primary target for pathological fibrosis. These observations support the hypothesis that amniotic membranes may interrupt pathological fibrosis by regulating collagen biosynthesis and associated pathways.

Abstract Structural distortions and imperfections are a crucial aspect of materials science, on the macroscopic scale providing strength, but also enhancing corrosion and reducing electrical and thermal conductivity. At the nanometre scale, multi-atom imperfections, such as atomic chains and crystalline domain walls have conversely been proposed as a route to topological superconductivity, whose most prominent characteristic is the emergence of Majorana Fermions that can be used for error-free quantum computing. Here, we shed more light on the nature of purported domain walls in Fe(Se,Te) that may host 1D dispersing Majorana modes. We show that the displacement shift of the atomic lattice at these line-defects results from sub-surface impurities that warp the topmost layer(s). Using the electric field between the tip and sample, we manage to reposition the sub-surface impurities, directly visualizing the displacement shift and the underlying defect-free lattice. These results, combined with observations of a completely different type of 1D defect where superconductivity remains fully gapped, highlight the topologically trivial nature of 1D defects in Fe(Se,Te).

Abstract Visualizing atomic-orbital degrees of freedom is a frontier challenge in scanned microscopy. Some types of orbital order are virtually imperceptible to normal scattering techniques because they do not reduce the overall crystal lattice symmetry. A good example is d xz /d yz (π,π) orbital order in tetragonal lattices. For enhanced detectability, here we consider the quasiparticle scattering interference (QPI) signature of such (π,π) orbital order in both normal and superconducting phases. The theory reveals that sublattice-specific QPI signatures generated by the orbital order should emerge strongly in the superconducting phase. Sublattice-resolved QPI visualization in superconducting CeCoIn5 then reveals two orthogonal QPI patterns at lattice-substitutional impurity atoms. We analyze the energy dependence of these two orthogonal QPI patterns and find the intensity peaked near E = 0, as predicted when such (π,π) orbital order is intertwined with d-wave superconductivity. Sublattice-resolved superconductive QPI techniques thus represent a new approach for study of hidden orbital order.

Category: Basic Sciences/Biologics; Other Introduction/Purpose: Placental tissue allografts have long been used as effective wound dressings for hard to heal wounds and are demonstrating increasing utility in the field of foot and ankle surgeries. Previous observations of the PURION-processed dehydrated amnion/chorion membrane (dHACM) demonstrated retention of regulatory proteins inherent to amniotic tissues and preservation of the bioactivity to stimulate cellular activities. Novel and patent-pending processing techniques have been developed to introduce a thicker and more robust allograft, as compared to dHACM. Lyophilized human amnion chorion membrane (LHACM) will confer versatility to clinicians with improved handling while maintaining the natural tissue composition and intrinsic biological activities. This study characterizes the biological properties of LHACM which may support the healing cascade. Methods: LHACM was processed using a modified PURION process which incorporates an optimized cleansing process, enabling retention of the intermediate layer, and lyophilization. Tissue architecture was visualized with hematoxylin and eosin staining. The hygroscopic contribution of the intermediate layer was appraised with absorbency measurements. Cleansing efficiency was determined through quantification of residual hemin remaining in the tissue. Regulatory proteins were quantified using a multiplex ELISA. The cellular response to LHACM treatment was assessed using multiple in vitro assays targeting cellular proliferation and analysis of signaling pathways. Adult dermal fibroblasts (HDFs) cultured over a 3-day period in LHACM eluates were assessed for cellular proliferation. In vitro models were developed to assess the regulation of relevant signaling pathways, including TGF-β1 and Wnt/β-catenin for fibrotic and proliferative processes, respectively. Cellular responses were evaluated through quantitative PCR and cell reporter lines. Results: Histological evaluation showed that processing maintains the tissue structure. Absorption testing demonstrated LHACM is more hygroscopic than dHACM. Hemin analysis demonstrated low levels of residual hemin which were comparable for LHACM and dHACM allografts. Screening for regulatory proteins indicate that LHACM contains a diverse array of regulatory proteins, inherent to amniotic membranes. In vitro treatment of primary cells with LHACM eluates promoted dermal fibroblast proliferation as well as regulation of elevated TGFβ- and Wnt/β-catenin signaling. Conclusion: The processing method of LHACM maintains the intrinsic properties of amniotic membranes with similar levels of biological activity as compared to dHACM, while providing an option for a thicker allograft with alternative handling characteristics. LHACM represents a novel product concept which increases versatility of amniotic membrane application in varied outpatient and surgical uses.

Objective: Inflammation, catabolism, and hypertrophy in chondrocytes play a central role in osteoarthritis (OA). The Wnt/β-catenin and NF-κβ pathways contribute to these degradative processes. This in vitro study evaluates the inhibitory effect of a novel therapeutic, micronized dehydrated human amnion/chorion membrane (μdHACM), as a potential treatment to offset elevated Wnt/β-catenin and NF-κβ signaling. Design: Three-dimensional human articular chondrocyte pellets were stimulated with an inflammatory cocktail to induce a degenerative phenotype. Treatments included varying doses of μdHACM. Protein and gene expression were analyzed using qRT-PCR, immunoblotting, and immunofluorescence to assess changes in the major constituents of Wnt/β-catenin and NF-κβ signaling. Regulation of catabolic activity was evaluated using enzymatic assays that detect MMP-13 and aggrecanase-mediated degradation products in conditioned media. Results: Confirmation of the model was established through the expression of specific markers and extracellular matrix genes, verifying a chondrogenic phenotype was maintained. Inflammatory stimulation elicited a change in the chondrocyte proteome and secretome, elevating Wnt/β-catenin and NF-κβ signaling and downstream expression of inflammatory, proteolytic, and hypertrophic markers, while decreasing primary cartilage matrix components, ACAN and COL2A1. μdHACM reversed these inflammatory-induced changes, suppressing phospho-GSK-3β, β-catenin expression/nuclear localization of the Wnt signaling axis and inhibiting IKKβ, phospho-IκBα, and phospho-p65 in the NF-κβ signaling cascade. Additionally, μdHACM altered expression of direct downstream targets, namely MCP1, MMP3, MMP13, ADAMTS4, ADAMTS5, RUNX2 and COL10A1. Moreover, μdHACM reduced MMP-13 and aggrecanase-mediated substrate degradation. Conclusion: μdHACM ameloriated the effects of inflammatory-induced degeneration in chondrocytes through Wnt/β-catenin and NF-κβ inhibition, subsequently downregulating key inflammatory, hypertrophic and catabolic mediators in vitro.

Excessive fibrosis affects more than 100 million patients yearly, leading to the accumulation of extracellular matrix that compromises tissue architecture and impedes its function. Intrinsic properties of the amniotic membrane have alluded to its potential to inhibit excessive fibrosis; therefore, this study aimed to investigate the effects of dehydrated human amnion/chorion membrane (dHACM) on dermal fibroblasts and their role in fibrotic pathways. Human dermal fibroblasts were stimulated with TGFβ1, triggering myofibroblast-like characteristics in vitro. Subsequent addition of dHACM in the continued presence of TGFβ1 inhibited downstream signaling, leading to a reduction in the expression of known fibrotic and extracellular matrix genes. In addition, dHACM decreased alpha-smooth muscle actin, a stress filament responsible for contractile activity in scarring. The functional outcome of these effects was observed in an ex vivo model for cellular contraction. Hyperactivation of TGFβ signaling increased the contractile capacity of myofibroblasts embedded within a collagen substrate. Simultaneous addition of dHACM treatment prevented the marked contraction, which is likely a direct result of the inhibition of TGFβ signaling mentioned earlier. These observations may support the use of dHACM in the regulation of fibroblast activity as it relates to tissue fibrosis.

Canonical Wnt signaling is a major pathway known to regulate diverse physiological processes in multicellular organisms. Signaling is tightly regulated by feedback mechanisms; however, persistent dysregulation of this pathway is implicated in the progression of multiple disease states. In this study, proteomic analysis identified endogenous Wnt antagonists in micronized dehydrated human amnion/chorion membrane (μdHACM); thereby, prompting a study to further characterize the intrinsic properties of μdHACM as it relates to Wnt activity, in vitro. A TCF/LEF reporter cell line demonstrated the general ability of μdHACM to inhibit β-catenin induced transcription activity. Furthermore, in vitro systems, modeling elevated Wnt signaling, were developed in relevant cell types including tenocytes, synoviocytes, and human dermal fibroblasts (HDFs). Stimulation of these cells with Wnt3A resulted in translocation of β-catenin to the nucleus and increased expression of Wnt related genes. The subsequent addition of μdHACM, in the continued presence of Wnt-stimulus, mitigated the downstream effects of Wnt3A in tenocytes, synoviocytes, and HDFs. Nuclear localization of β-catenin was abated with corresponding reduction of Wnt related gene expression. These data demonstrate the in vitro regulation of canonical Wnt signaling as an inherent property of μdHACM and a novel mechanism of action.

The effects of dopants in high-temperature superconductors on the surrounding electronic structure give insights into their unconventional microscopic behaviour. Here the authors find a new class of defects that they identify as oxygen dopants whose ionization and local environment induce unusual atomic-scale charge dynamics.

Background: Inequalities in health represent a major problem in many countries, including Indonesia. Addressing health inequality is a central component of the Sustainable Development Goals and a priority of the World Health Organization (WHO). WHO provides technical support for health inequality monitoring among its member states. Following a capacity-building workshop in the WHO South-East Asia Region in 2014, Indonesia expressed interest in incorporating health-inequality monitoring into its national health information system. Objectives: This article details the capacity-building process for national health inequality monitoring in Indonesia, discusses successes and challenges, and how this process may be adapted and implemented in other countries/settings. Methods: We outline key capacity-building activities undertaken between April 2016 and December 2017 in Indonesia and present the four key outcomes of this process. Results: The capacity-building process entailed a series of workshops, meetings, activities, and processes undertaken between April 2016 and December 2017. At each stage, a range of stakeholders with access to the relevant data and capacity for data analysis, interpretation and reporting was engaged with, under the stewardship of state agencies. Key steps to strengthening health inequality monitoring included capacity building in (1) identification of the health topics/areas of interest, (2) mapping data sources and identifying gaps, (3) conducting equity analyses using raw datasets, and (4) interpreting and reporting inequality results. As a result, Indonesia developed its first national report on the state of health inequality. A number of peer-reviewed manuscripts on various aspects of health inequality in Indonesia have also been developed. Conclusions: The capacity-building process undertaken in Indonesia is designed to be adaptable to other contexts. Capacity building for health inequality monitoring among countries is a critical step for strengthening equity-oriented national health information systems and eventually tackling health inequities.

BACKGROUND:Indonesia's national health information systems collect data on maternal deaths but the completeness of reporting is questionable, making it difficult to design appropriate interventions. This study examines the completeness of maternal death reporting by the district health office (DHO) system in Banten Province. METHOD:We used a nested-control study design to compare data on maternal deaths in 2016 from the DHO reporting system and the MADE-IN/MADE-FOR method in two districts and one municipality in Banten Province, with the aim of identifying and characterizing missed deaths in the DHO reporting system. The capture-recapture method was used to assess the magnitude of underreporting of maternal deaths by both systems. RESULTS:A total of 169 maternal deaths were reported in the MADE-IN/MADE-FOR study for calendar year 2016 in the three study areas. The DHO system reported 105 maternal deaths for the same period, of which 90 cases were found in both data sources. Capture-recapture analyses suggest that the MADE-IN/MADE-FOR approach identified 92% (95% CI: 87%-95%) of all maternal deaths, while the DHO system captured 57% (95% CI: 50%-64%) of all maternal deaths. Deaths of women who resided in urban areas had four times higher odds (OR 4.3, 95% CI: 1.52-12.3) of being missed by the DHO system compared to deaths among women who lived in rural or remote areas after adjusting for other covariates. CONCLUSION:The DHO reporting system missed approximately half of the maternal deaths in the 3 study areas, suggesting that the DHO system is likely to grossly underestimate the maternal mortality ratio. The DHO reporting system needs to be improved to capture and characterize all maternal deaths.

Ideal tunnel junctions require high-quality, defect-free insulating barriers. Here, the authors demonstrate that van der Waals tunnel barriers atop bulk and ultrathin superconducting NbSe2 sustain a stable tunneling current and allow mapping of the spectral evolution of layered superconductors.

Sablefish (Anoplopoma fimbria) is a marine groundfish that supports valuable fisheries in the North Pacific Ocean and holds promise for marine aquaculture. Limited information is available, however, about its reproductive biology. This study aimed to characterize the complete reproductive cycle, including seasonal changes in gonadal development (macroscopic and histological), plasma sex steroid levels (17β-estradiol -E2-, and 11-ketotestosterone -11KT-), gonadosomatic and hepatosomatic indices (GSI, and HSI), and condition factor (K) of female and male sablefish captured off the Washington coast. Adult fish (209 females, 159 males) were caught by longline monthly from August 2012 to August 2013. Early signs of recruitment of ovarian follicles into secondary growth, indicated by oocytes containing small yolk granules and cortical alveoli, were first observed in March. Oogenesis progressed during spring and summer, and fully vitellogenic follicles were first observed in July. Vitellogenic growth was correlated with increases in plasma E2, GSI, HSI and K. Periovulatory females, indicated by fully-grown oocytes with migrating germinal vesicles and hydrated oocytes, were found from November to February. At this stage, plasma E2 and GSI reached maximal levels. In males, proliferating cysts containing spermatocytes were first observed in April. Testicular development proceeded during spring and summer, a period during which all types of male germ cells were found. The first clusters of spermatozoa appeared in July, concomitant with a 5.2-fold increase in GSI. Spermiating males were observed from November to April; at this time, spermatids were absent or greatly reduced, and testis lobules were filled with spermatozoa. The highest levels of plasma 11KT were found in males at this stage. Postspawning ovaries and testes, and basal steroids levels were found in fish captured from February to April. These results suggest that sablefish in coastal Washington initiate their reproductive cycle in March/April and spawn primarily in January/February.

The original version of this Article contained an error in the right-hand y-axis of Fig. 2c, which incorrectly read ‘S/2e (pA)’. The correct version states ‘nA’ in place of ‘pA’. This has been corrected in both the PDF and HTML versions of the Article.

Cocoa supplementation has been associated with benefits to cardiovascular health. However, cocoa’s effects on cognition are less clear. A randomized, placebo-controlled, double-blind clinical trial (n=40, age M= 24.13 years, SD = 4.47 years) was conducted to investigate the effects of both acute (same-day) and sub-chronic (daily for four-weeks) 250mg cocoa supplementation on mood and mental fatigue, cognitive performance and cardiovascular functioning in young, healthy adults. Assessment involved repeated 10-minute cycles of the Cognitive Demand Battery (CDB) encompassing two serial subtraction tasks (Serial Threes and Sevens), a Rapid Visual Information Processing task, and a mental fatigue scale over the course of half an hour. The Swinburne University Computerised Cognitive Assessment Battery (SUCCAB) was also completed to evaluate cognition. Cardiovascular function included measuring both peripheral and central blood pressure and cerebral blood flow. At the acute time point, consumption of cocoa significantly improved self-reported mental fatigue and performance on the Serial Sevens task in cycle one of the CDB. No other significant effects were found. This trial was registered with the Australian and New Zealand Clinical Trial Registry (Trial ID: ACTRN12613000626763). Accessible via http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN126130006 26763&ddlSearch=Registered