bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Governance, Sustainability and the Earth System: Critical Reflections on the Role of Global Law
Authors: Cardesa-Salzmann Antonio , Cocciolo Endrius
Published: May 2019

This article begins by questioning the capacity of the concept of sustainable development to stabilize social reproduction and foster global justice. Based on interdisciplinary perspectives on global governance, it discusses the way in which global law fails to cope with the resonance of advanced capitalism in the world society and ecological systems. Our analysis focuses on the regulatory and institutional features of three interwoven functional regulatory regimes (global finance, energy, and environmental protection), which demonstrate structural governance dysfunction at the expense of ecological integrity and justice in the global realm. The article further examines the capacity of global law to foster a ‘compositive’ and ‘compensatory’ contribution to global justice and the stability of the Earth system through global constitutionalism. In this context, it concludes that Neil Walker's global law approach provides a fertile analytical framework for describing the patterns of interaction between different species of global law but proves to be particularly ‘slippery’ in its normative propositions regarding the gap between global law and justice. Drawing from the Earth system approach, we argue in favour of a global material constitutionalism, recognizant of ecosystemic boundaries and socio-environmental impacts of the global socio-economic metabolism. We consider that the gap between global law and global justice is best addressed by devising more deliberative patterns of transnational governance, as well as ecosystem and human rights approaches, in order to accommodate the fair and equitable internalization of material limits across global regulatory regimes that act as functionally differentiated economic constitutions of advanced capitalism.
North Atlantic Sub‐Polar Gyre Climate Index: A New Approach
Authors: Biri Stavroula , Klein Birgit
Published: May 2019

As decadal predictions become operational, the need to use, understand, and extract information from them becomes essential. A climate index is a simple diagnostic quantity that can be used to characterize integral aspects of a geophysical system such as circulation patterns, and thus can be used to evaluate decadal forecasts. One of the most studied and well documented regions of the World Ocean is the North Atlantic. The North Atlantic subpolar gyre is an important region for the modulation of European climate and where skillful predictions of up to a decade can be obtained. Ocean re‐analysis (ORA‐S4) data from 1959 to 2017 are used to introduce a new methodology to compute a climate index of the North Atlantic subpolar gyre that captures both the variability in its strength and shape, the latter was to our knowledge never investigated previously as part of the variability of the gyre on interannual to decadal time scales. The methodology reveals two states of the gyre (before and after 2000), the former is mainly driven by temperature and the latter by a combination of mechanisms that interact to sustain a relatively stable subpolar gyre in terms of strength.
Vapor‐Deposited Minerals Contributed to the Martian Surface During Magmatic Degassing
Authors: Nekvasil H. , DiFrancesco N. J. , Rogers A. D. , Coraor A. E. , King P. L.
Published: May 2019

Martian magmas were likely enriched in S and Cl with respect to H2O. Exsolution of a vapor phase from these magmas and ascent of the gas bubbles through the magma plumbing system would have given rise to shallow magmas that were gas‐charged. Release and cooling of this gas from lava flows during eruption may have resulted in the addition of a significant amount of vapor‐deposited phases to the fines of the surface. Experiments were conducted to simulate degassing of gas‐charged lava flows and shallow intrusions in order to determine the nature of vapor‐deposited phases that may form through this process. The results indicate that magmatic gas may have contributed a large amount of Fe, S, and Cl to the Martian surface through the deposition of iron oxides (magnetite, maghemite, and hematite), chlorides (molysite, halite, and sylvite), sulfur, and sulfides (pyrrhotite and pyrite). Primary magmatic vapor‐deposited minerals may react during cooling to form a variety of secondary products, including iron oxychloride (FeOCl), akaganéite (Fe3+O (OH,Cl)), and jarosite (KFe3+3(OH)6(SO4)2). Vapor‐deposition does not transport significant amounts of Ca, Al, or Mg from the magma and hence, this process does not directly deposit Ca‐ or Mg‐sulfates.
Climate Change Feedbacks in Aquaplanet Experiments With Explicit and Parametrized Convection for Horizontal Resolutions of 2,525 Up to 5 km
Authors: Retsch M. H. , Mauritsen T. , Hohenegger C.
Published: May 2019

Earth's equilibrium climate sensitivity (ECS) is the long‐term response to doubled atmospheric CO2 and likely between 1.5 and 4.5 K. Conventional general circulation models do not convincingly narrow down this range, and newly developed nonhydrostatic models with relatively fine horizontal resolutions of a few kilometers have thus far delivered diverse results. Here we use the nonhydrostatic ICON model with the physics package normally used for climate simulations at resolutions as fine as 5 km to study the response to a uniform surface warming in an aquaplanet configuration. We apply the model in two setups: one with convection parametrization employed and one with explicit convection. ICON exhibits a negative total feedback independent of convective representation, thus providing a stable climate with an ECS comparable to other general circulation models, though three interesting new results are found. First, ECS varies little across resolution for both setups but runs with explicit convection have systematically lower ECS than the parametrized case, mainly due to more negative tropical clear‐sky longwave feedbacks. These are a consequence of a drier mean state of about 6% relative humidity for explicit convection and less midtropospheric moistening with global warming. Second, shortwave feedbacks switch from positive to negative with increasing resolution, originating foremost in the tropics and high latitudes. Third, the model shows no discernible high cloud area feedback (iris effect) in any configuration. It is possible that ICON's climate model parametrizations applied here are less appropriate for cloud resolving scales, and therefore, ongoing developments aim at implementing a more advanced prognostic cloud microphysics scheme.
ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children’s Oncology Group AAML0531 Trial
Authors: Rafiee Roya , Chauhan Lata , Alonzo Todd A. , Wang Yi-Cheng , Elmasry Ahlam , Loken Michael R. , Pollard Jessica , Aplenc Richard , Raimondi Susana , Hirsch Betsy A. , Bernstein Irwin D. , Gamis Alan S. , Meshinchi Soheil , Lamba Jatinder K.
Published: May 2019

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.
Dendritic cell-associated B7-H3 suppresses the production of autoantibodies and renal inflammation in a mouse model of systemic lupus erythematosus
Authors: Zheng Xu , Xiao Ze Xiu , Hu Li , Fang Xuan , Luo Liqun , Chen Lieping
Published: May 2019

B7-H3 immune modulatory molecule has been implicated in the generation and pathogenesis of autoimmune diseases, the mechanism of action is less known. We explored the role of B7-H3 in the induction of autoantibodies and organ-directed inflammation in a murine systemic lupus erythematosus (SLE) model in which the immunization with DNA extracted from activated T cells induced the production of anti-DNA autoantibodies and subsequent glomerulonephritis, two hallmarks of human SLE. Mice deficient of B7-H3 or treated with a B7-H3 specific antibody produced significantly higher levels of anti-DNA autoantibodies and more severe glomerulonephritis than wild-type mice, indicating an inhibitory function of B7-H3 in this model. Interestingly, immunization of mice with DNA-pulsed dendritic cells induced severe SLE symptoms while B7-H3 on dendritic cells is required in this process. Importantly, treatment of mice with recombinant B7-H3Ig fusion protein effectively ameliorated progression of murine SLE, accompanied with decreased level of anti-DNA autoantibodies and alleviated glomerulonephritis, decreased autoantibody deposition and complement deposition in kidney. Our findings implicate a potential role of B7-H3 on dendritic cells in the induction of SLE and as a potential target for the treatment of autoimmune diseases.
A novel UCHL3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair
Authors: Song Zhiwang , Tu Xinyi , Zhou Qin , Huang Jinzhou , Chen Yuping , Liu Jiaqi , Lee SeungBaek , Kim Wootae , Nowsheen Somaira , Luo Kuntian , Yuan Jian , Lou Zhenkun
Published: May 2019

Triple-negative breast cancer (TNBC) treatment remains a great challenge for clinical practice and novel therapeutic strategies are urgently needed. UCHL3 is a deubiquitinase that is overexpressed in TNBC and correlates with poor prognosis. UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair. Therefore, UCHL3 overexpression can render cancer cells resistant to DNA damage inducing chemo and radiotherapy, and targeting UCHL3 can sensitize TNBC to radiation and chemotherapy. However, small molecule inhibitors of UCHL3 are yet to be identified. Here we report that perifosine, a previously reported Akt inhibitor, can inhibit UCHL3 in vitro and in vivo. We found low dose (50 nM) perifosine inhibited UCHL3 deubiquitination activity without affecting Akt activity. Furthermore, perifosine enhanced Olaparib-induced growth inhibition in TNBC cells. Mechanistically, perifosine induced RAD51 ubiquitination and blocked the RAD51-BRCA2 interaction, which in turn decreased ionizing radiation-induced foci (IRIF) of Rad51 and, thereby, homologous recombination (HR)-mediated DNA double strand break repair. In addition, combination of perifosine and Olaparib showed synergistic antitumor activity in vivo in TNBC xenograft model. Thus, our present study provides a novel therapeutic approach to optimize PARP inhibitor treatment efficiency.
Coordinated representational reinstatement in the human hippocampus and lateral temporal cortex during episodic memory retrieval
Authors: Pacheco Estefan D. , Sánchez-Fibla M. , Duff A. , Principe A. , Rocamora R. , Zhang H. , Axmacher N. , Verschure P. F. M. J.
Published: May 2019

Theoretical models of episodic memory have proposed that retrieval depends on interactions between the hippocampus and neocortex, where hippocampal reinstatement of item-context associations drives neocortical reinstatement of item information. Here, we simultaneously recorded intracranial EEG from hippocampus and lateral temporal cortex (LTC) of epilepsy patients who performed a virtual reality spatial navigation task. We extracted stimulus-specific representations of both item and item-context associations from the time-frequency patterns of activity in hippocampus and LTC. Our results revealed a double dissociation of representational reinstatement across time and space: an early reinstatement of item-context associations in hippocampus preceded a later reinstatement of item information in LTC. Importantly, reinstatement levels in hippocampus and LTC were correlated across trials, and the quality of LTC reinstatement was predicted by the magnitude of phase synchronization between hippocampus and LTC. These findings confirm that episodic memory retrieval in humans relies on coordinated representational interactions within a hippocampal-neocortical network.
Seismic evidence for a mantle suture and implications for the origin of the Canadian Cordillera
Authors: Chen Yunfeng , Gu Yu Jeffrey , Currie Claire A. , Johnston Stephen T. , Hung Shu-Huei , Schaeffer Andrew J. , Audet Pascal
Published: May 2019

The origin of the North American Cordillera and its affinity with the bounding craton are subjects of contentious debate. The mechanisms of orogenesis are rooted in two competing hypotheses known as the accretionary and collisional models. The former model attributes the Cordillera to an archetypal accretionary orogen comprising a collage of exotic terranes. The latter, less popular view argues that the Cordillera is a collisional product between an allochthonous ribbon microcontinent and cratonic North America. Here we present new seismic evidence of a sharp and structurally complex Cordillera–craton boundary in the uppermost mantle beneath the southern Canadian Cordillera, which can be interpreted as either a reshaped craton margin or a Late Cretaceous collisional boundary based on the respective hypotheses. This boundary dips steeply westward underneath a proposed (cryptic) suture in the foreland, consisent with the predicted location and geometry of the mantle suture, thus favoring a collisional origin.
The extracellular gate shapes the energy profile of an ABC exporter
Authors: Hutter Cedric A. J. , Timachi M. Hadi , Hürlimann Lea M. , Zimmermann Iwan , Egloff Pascal , Göddeke Hendrik , Kucher Svetlana , Štefanić Saša , Karttunen Mikko , Schäfer Lars V. , Bordignon Enrica , Seeger Markus A.
Published: May 2019

ABC exporters harness the energy of ATP to pump substrates across membranes. Extracellular gate opening and closure are key steps of the transport cycle, but the underlying mechanism is poorly understood. Here, we generated a synthetic single domain antibody (sybody) that recognizes the heterodimeric ABC exporter TM287/288 exclusively in the presence of ATP, which was essential to solve a 3.2 Å crystal structure of the outward-facing transporter. The sybody binds to an extracellular wing and strongly inhibits ATPase activity by shifting the transporter’s conformational equilibrium towards the outward-facing state, as shown by double electron-electron resonance (DEER). Mutations that facilitate extracellular gate opening result in a comparable equilibrium shift and strongly reduce ATPase activity and drug transport. Using the sybody as conformational probe, we demonstrate that efficient extracellular gate closure is required to dissociate the NBD dimer after ATP hydrolysis to reset the transporter back to its inward-facing state.
Impaired cerebellar Purkinje cell potentiation generates unstable spatial map orientation and inaccurate navigation
Authors: Lefort Julie Marie , Vincent Jean , Tallot Lucille , Jarlier Frédéric , De Zeeuw Chris Innocentius , Rondi-Reig Laure , Rochefort Christelle
Published: May 2019

Cerebellar activity supported by PKC-dependent long-term depression in Purkinje cells (PCs) is involved in the stabilization of self-motion based hippocampal representation, but the existence of cerebellar processes underlying integration of allocentric cues remains unclear. Using mutant-mice lacking PP2B in PCs (L7-PP2B mice) we here assess the role of PP2B-dependent PC potentiation in hippocampal representation and spatial navigation. L7-PP2B mice display higher susceptibility to spatial map instability relative to the allocentric cue and impaired allocentric as well as self-motion goal-directed navigation. These results indicate that PP2B-dependent potentiation in PCs contributes to maintain a stable hippocampal representation of a familiar environment in an allocentric reference frame as well as to support optimal trajectory toward a goal during navigation.
ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes
Authors: Fang Caodi , Manes Thomas D. , Liu Lufang , Liu Kevin , Qin Lingfeng , Li Guangxin , Tobiasova Zuzana , Kirkiles-Smith Nancy C. , Patel Manal , Merola Jonathan , Fu Whitney , Liu Rebecca , Xie Catherine , Tietjen Gregory T. , Nigrovic Peter A. , Tellides George , Pober Jordan S. , Jane-wit Dan
Published: May 2019

Complement promotes vascular inflammation in transplant organ rejection and connective tissue diseases. Here we identify ZFYVE21 as a complement-induced Rab5 effector that induces non-canonical NF-κB in endothelial cells (EC). In response to membrane attack complexes (MAC), ZFYVE21 is post-translationally stabilized on MAC+Rab5+ endosomes in a Rab5- and PI(3)P-dependent manner. ZFYVE21 promotes SMURF2-mediated polyubiquitinylation and proteasome-dependent degradation of endosome-associated PTEN to induce vesicular enrichment of PI(3,4,5)P3 and sequential recruitment of activated Akt and NF-κB-inducing kinase (NIK). Pharmacologic alteration of cellular phosphoinositide content with miltefosine reduces ZFYVE21 induction, EC activation, and allograft vasculopathy in a humanized mouse model. ZFYVE21 induction distinctly occurs in response to MAC and is detected in human renal and synovial tissues. Our data identifies ZFYVE21 as a Rab5 effector, defines a Rab5-ZFYVE21-SMURF2-pAkt axis by which it mediates EC activation, and demonstrates a role for this pathway in complement-mediated conditions.
The Kibble-Zurek mechanism at exceptional points
Authors: Dóra Balázs , Heyl Markus , Moessner Roderich
Published: May 2019

Exceptional points (EPs) are ubiquitous in non-Hermitian systems, and represent the complex counterpart of critical points. By driving a system through a critical point at finite rate induces defects, described by the Kibble-Zurek mechanism, which finds applications in diverse fields of physics. Here we generalize this to a ramp across an EP. We find that adiabatic time evolution brings the system into an eigenstate of the final non-Hermitian Hamiltonian and demonstrate that for a variety of drives through an EP, the defect density scales as τ−(d + z)ν/(zν + 1) in terms of the usual critical exponents and 1/τ the speed of the drive. Defect production is suppressed compared to the conventional Hermitian case as the defect state can decay back to the ground state close to the EP. We provide a physical picture for the studied dynamics through a mapping onto a Lindblad master equation with an additionally imposed continuous measurement.
Artisanal fish fences pose broad and unexpected threats to the tropical coastal seascape
Authors: Exton Dan A. , Ahmadia Gabby N. , Cullen-Unsworth Leanne C. , Jompa Jamaluddin , May Duncan , Rice Joel , Simonin Paul W. , Unsworth Richard K. F. , Smith David J.
Published: May 2019

Gear restrictions are an important management tool in small-scale tropical fisheries, improving sustainability and building resilience to climate change. Yet to identify the management challenges and complete footprint of individual gears, a broader systems approach is required that integrates ecological, economic and social sciences. Here we apply this approach to artisanal fish fences, intensively used across three oceans, to identify a previously underrecognized gear requiring urgent management attention. A longitudinal case study shows increased effort matched with large declines in catch success and corresponding reef fish abundance. We find fish fences to disrupt vital ecological connectivity, exploit > 500 species with high juvenile removal, and directly damage seagrass ecosystems with cascading impacts on connected coral reefs and mangroves. As semi-permanent structures in otherwise open-access fisheries, they create social conflict by assuming unofficial and unregulated property rights, while their unique high-investment-low-effort nature removes traditional economic and social barriers to overfishing.
Pheomelanin pigment remnants mapped in fossils of an extinct mammal
Authors: Manning Phillip L. , Edwards Nicholas P. , Bergmann Uwe , Anné Jennifer , Sellers William I. , van Veelen Arjen , Sokaras Dimosthenis , Egerton Victoria M. , Alonso-Mori Roberto , Ignatyev Konstantin , van Dongen Bart E. , Wakamatsu Kazumasa , Ito Shosuke , Knoll Fabien , Wogelius Roy A.
Published: May 2019

Recent progress has been made in paleontology with respect to resolving pigmentation in fossil material. Morphological identification of fossilized melanosomes has been one approach, while a second methodology using chemical imaging and spectroscopy has also provided critical information particularly concerning eumelanin (black pigment) residue. In this work we develop the chemical imaging methodology to show that organosulfur-Zn complexes are indicators of pheomelanin (red pigment) in extant and fossil soft tissue and that the mapping of these residual biochemical compounds can be used to restore melanin pigment distribution in a 3 million year old extinct mammal species (Apodemus atavus). Synchotron Rapid Scanning X-ray Fluorescence imaging showed that the distributions of Zn and organic S are correlated within this fossil fur just as in pheomelanin-rich modern integument. Furthermore, Zn coordination chemistry within this fossil fur is closely comparable to that determined from pheomelanin-rich fur and hair standards. The non-destructive methods presented here provide a protocol for detecting residual pheomelanin in precious specimens.
The composition of British bird communities is associated with long-term garden bird feeding
Authors: Plummer Kate E. , Risely Kate , Toms Mike P. , Siriwardena Gavin M.
Published: May 2019

There is a multi-billion dollar global industry dedicated to feeding wild birds in residential gardens. This extraordinary boost to food resources is almost certainly reshaping entire bird communities, yet the large-scale, long-term impacts on community ecology remain unknown. Here we reveal a 40-year transformation of the bird communities using garden bird feeders in Britain, and provide evidence to suggest how this may have contributed to national-scale population changes. We find that increases in bird diversity at feeders are associated with increasing community evenness, as species previously rarely observed in gardens have increasingly exploited the growing variety of foods on offer over time. Urban areas of Britain are consequently nurturing growing populations of feeder-using bird species, while the populations of species that do not use feeders remain unchanged. Our findings illustrate the on-going, gross impact people can have on bird community structure across large spatial scales.
Ubiquitylome study identifies increased histone 2A ubiquitylation as an evolutionarily conserved aging biomarker
Authors: Yang Lu , Ma Zaijun , Wang Han , Niu Kongyan , Cao Ye , Sun Le , Geng Yang , Yang Bo , Gao Feng , Chen Zuolong , Wu Zhen , Li Qingqing , Shen Yong , Zhang Xumin , Jiang Hong , Chen Yelin , Liu Rui , Liu Nan , Zhang Yaoyang
Published: May 2019

The long-lived proteome constitutes a pool of exceptionally stable proteins with limited turnover. Previous studies on ubiquitin-mediated protein degradation primarily focused on relatively short-lived proteins; how ubiquitylation modifies the long-lived proteome and its regulatory effect on adult lifespan is unclear. Here we profile the age-dependent dynamics of long-lived proteomes in Drosophila by mass spectrometry using stable isotope switching coupled with antibody-enriched ubiquitylome analysis. Our data describe landscapes of long-lived proteins in somatic and reproductive tissues of Drosophila during adult lifespan, and reveal a preferential ubiquitylation of older long-lived proteins. We identify an age-modulated increase of ubiquitylation on long-lived histone 2A protein in Drosophila, which is evolutionarily conserved in mouse, monkey, and human. A reduction of ubiquitylated histone 2A in mutant flies is associated with longevity and healthy lifespan. Together, our data reveal an evolutionarily conserved biomarker of aging that links epigenetic modulation of the long-lived histone protein to lifespan.
Relict subduction initiation along a passive margin in the northwest Indian Ocean
Authors: Pandey Dhananjai K. , Pandey Anju , Whattam Scott A.
Published: May 2019

The tectonic evolution of Laxmi basin, presently located along western Indian passive margin, remains debated. Prevailing geodynamic models of Laxmi basin include two mutually competing hypotheses, culminating in either a hyper-stretched continental crust or an oceanic crust overlying an extinct spreading centre. The longstanding conundrum surrounding its precise crustal affinity precludes a complete understanding of the early opening of the Indian Ocean. Here, we present distinct geochemical and geophysical imprints from the igneous crust in Laxmi basin obtained through International Ocean Discovery Program Expedition 355. The geochemical and isotopic signatures of the Laxmi basin crust exhibit uncanny similarities with forearc tectonic settings. Our observations imply a relict subduction initiation event occurred in the Laxmi basin in the Late Cretaceous-Early Cenozoic that marks a significant Cenozoic plate reorganisation record in the northwest Indian Ocean. New findings therefore warrant re-evaluation of the Gondwana breakup to account for the nascent subduction in the northwest Indian Ocean.
Publisher Correction: Scaling of domain cascades in stripe and skyrmion phases
Authors: Singh A. , Lee J. C. T. , Avila K. E. , Chen Y. , Montoya S. A. , Fullerton E. E. , Fischer P. , Dahmen K. A. , Kevan S. D. , Sanyal M. K. , Roy S.
Published: May 2019

The original version of this Article contained an error in Fig. 4d, in which the label of the region to the left of the white dashed lines incorrectly read ‘Order stripes’. The correct version states ‘Disorder stripes’. This has been corrected in both the PDF and HTML versions of the Article.
Implantable hyaluronic acid-deferoxamine conjugate prevents nonunions through stimulation of neovascularization
Authors: Donneys Alexis , Yang Qiuhong , Forrest Marcus Laird , Nelson Noah S. , Zhang Ti , Ettinger Russell , Ranganathan Kavitha , Snider Alicia , Deshpande Sagar S. , Cohen Mark S. , Buchman Steven R.
Published: May 2019

Approximately 6.3 million fractures occur in the U.S. annually, with 5–10% resulting in debilitating nonunions. A major limitation to achieving successful bony union is impaired neovascularization. To augment fracture healing, we designed an implantable drug delivery technology containing the angiogenic stimulant, deferoxamine (DFO). DFO activates new blood vessel formation through iron chelation and upregulation of the HIF-1α pathway. However, due to its short half-life and rapid clearance, maintaining DFO at the callus site during peak fracture angiogenesis has remained challenging. To overcome these limitations, we composed an implantable formulation of DFO conjugated to hyaluronic acid (HA). This compound immobilizes DFO within the fracture callus throughout the angiogenic window, making it a high-capacity iron sponge that amplifies blood vessel formation and prevents nonunions. We investigated implanted HA-DFO’s capacity to facilitate fracture healing in the irradiated rat mandible, a model whereby nonunions routinely develop secondary to obliteration of vascularity. HA-DFO implantation significantly improved radiomorphometrics and metrics of biomechanical strength. In addition, HA-DFO treated mandibles exhibited a remarkable 91% bone union rate, representing a 3.5-fold improvement over non-treated/irradiated controls (20% bone union rate). Collectively, our work proposes a unique methodology for the targeted delivery of DFO to fracture sites in order to facilitate neovascularization. If these findings are successfully translated into clinical practice, millions of patients will benefit from the prevention of nonunions.
Characterization of different bubble formulations for blood-brain barrier opening using a focused ultrasound system with acoustic feedback control
Authors: Bing Chenchen , Hong Yu , Hernandez Christopher , Rich Megan , Cheng Bingbing , Munaweera Imalka , Szczepanski Debra , Xi Yin , Bolding Mark , Exner Agata , Chopra Rajiv
Published: May 2019

Focused ultrasound combined with bubble-based agents serves as a non-invasive way to open the blood-brain barrier (BBB). Passive acoustic detection was well studied recently to monitor the acoustic emissions induced by the bubbles under ultrasound energy, but the ability to perform reliable BBB opening with a real-time feedback control algorithm has not been fully evaluated. This study focuses on characterizing the acoustic emissions of different types of bubbles: Optison, Definity, and a custom-made nanobubble. Their performance on reliable BBB opening under real-time feedback control based on acoustic detection was evaluated bothin-vitroandin-vivo. The experiments were conducted using a 0.5 MHz focused ultrasound transducer within-vivofocal pressure ranges from 0.1–0.7 MPa. Successful feedback control was achieved with all three agents when combining with infusion injection. Localized opening was confirmed with Evans blue dye leakage. Microscopic images were acquired to review the opening effects. Under similar total gas volume, nanobubble showed a more reliable opening effect compared to Optison and Definity (p < 0.05). The conclusions obtained from this study confirm the possibilities of performing stable opening using a feedback control algorithm combined with infusion injection. It also opens another potential research area of BBB opening using sub-micron bubbles.
Analytical Validation of Multiplex Biomarker Assay to Stratify Colorectal Cancer into Molecular Subtypes
Authors: Ragulan Chanthirika , Eason Katherine , Fontana Elisa , Nyamundanda Gift , Tarazona Noelia , Patil Yatish , Poudel Pawan , Lawlor Rita T. , Del Rio Maguy , Koo Si-Lin , Tan Wah-Siew , Sclafani Francesco , Begum Ruwaida , Teixeira Mendes Larissa S. , Martineau Pierre , Scarpa Aldo , Cervantes Andrés , Tan Iain Beehuat , Cunningham David , Sadanandam Anguraj
Published: May 2019

Previously, we classified colorectal cancers (CRCs) into five CRCAssigner (CRCA) subtypes with different prognoses and potential treatment responses, later consolidated into four consensus molecular subtypes (CMS). Here we demonstrate the analytical development and validation of a custom NanoString nCounter platform-based biomarker assay (NanoCRCA) to stratify CRCs into subtypes. To reduce costs, we switched from the standard nCounter protocol to a custom modified protocol. The assay included a reduced 38-gene panel that was selected using an in-house machine-learning pipeline. We applied NanoCRCA to 413 samples from 355 CRC patients. From the fresh frozen samples (n = 237), a subset had matched microarray/RNAseq profiles (n = 47) or formalin-fixed paraffin-embedded (FFPE) samples (n = 58). We also analyzed a further 118 FFPE samples. We compared the assay results with the CMS classifier, different platforms (microarrays/RNAseq) and gene-set classifiers (38 and the original 786 genes). The standard and modified protocols showed high correlation (> 0.88) for gene expression. Technical replicates were highly correlated (> 0.96). NanoCRCA classified fresh frozen and FFPE samples into all five CRCA subtypes with consistent classification of selected matched fresh frozen/FFPE samples. We demonstrate high and significant subtype concordance across protocols (100%), gene sets (95%), platforms (87%) and with CMS subtypes (75%) when evaluated across multiple datasets. Overall, our NanoCRCA assay with further validation may facilitate prospective validation of CRC subtypes in clinical trials and beyond.
Methyl-β-cyclodextrin, an actin depolymerizer augments the antiproliferative potential of microtubule-targeting agents
Authors: Mundhara Nikita , Majumder Abhijit , Panda Dulal
Published: May 2019

Methyl-β-cyclodextrin (MCD), an established pharmacological excipient, depolymerizes the actin cytoskeleton. In this work, we investigated the effect of MCD-mediated actin depolymerization on various cellular phenotypes including traction force, cell stiffness, focal adhesions, and intracellular drug accumulation. In addition to a reduction in the contractile cellular traction, MCD acutely inhibits the maturation of focal adhesions. Alteration of contractile forces and focal adhesions affects the trypsin-mediated detachment kinetics of cells. Moreover, MCD-mediated actin depolymerization increases the intracellular accumulation of microtubule-targeting agents (MTAs) by ~50% with respect to the untreated cells. As MCD treatment enhances the intracellular concentration of drugs, we hypothesized that the MCD-sensitized cancer cells could be effectively killed by low doses of MTAs. Our results in cervical, breast, hepatocellular, prostate cancer and multidrug-resistant breast cancer cells confirmed the above hypothesis. Further, the combined use of MCD and MTAs synergistically inhibits the proliferation of tumor cells. These results indicate the potential use of MCD in combination with MTAs for cancer chemotherapy and suggest that targeting both actin and microtubules simultaneously may be useful for cancer therapy. Importantly, the results provide significant insight into the crosstalk between actin and microtubules in regulating the traction force and dynamics of cell deadhesion.
Restoration of correct βIVS2-654-globin mRNA splicing and HbA production by engineered U7 snRNA in β-thalassaemia/HbE erythroid cells
Authors: Nualkaew Tiwaporn , Jearawiriyapaisarn Natee , Hongeng Suradej , Fucharoen Suthat , Kole Ryszard , Svasti Saovaros
Published: May 2019

A cytosine to thymine mutation at nucleotide 654 of human β-globin intron 2 (βIVS2-654) is one of the most common mutations causing β-thalassaemia in Chinese and Southeast Asians. This mutation results in aberrant β-globin pre-mRNA splicing and prevents synthesis of β-globin protein. Splicing correction using synthetic splice-switching oligonucleotides (SSOs) has been shown to restore expression of the β-globin protein, but to maintain therapeutically relevant levels of β-globin it would require lifelong administration. Here, we demonstrate long-term splicing correction using U7 snRNA lentiviral vectors engineered to target several pre-mRNA splicing elements on the βIVS2-654-globin pre-mRNA such as cryptic 3′ splice site, aberrant 5′ splice site, cryptic branch point and an exonic splicing enhancer. A double-target engineered U7 snRNAs targeted to the cryptic branch point and an exonic splicing enhancer, U7.BP + 623, was the most effective in a model cell line, HeLa IVS2-654. Moreover, the therapeutic potential of the vector was demonstrated in erythroid progenitor cells derived from βIVS2-654-thalassaemia/HbE patients, which showed restoration of correctly spliced β-globin mRNA and led to haemoglobin A synthesis, and consequently improved thalassaemic erythroid cell pathology. These results demonstrate proof of concept of using the engineered U7 snRNA lentiviral vector for treatment of β-thalassaemia.
Gender and Child Behavior Problems in Rural Nepal: Differential Expectations and Responses
Authors: Langer Julia A. , Ramos Julia V. , Ghimire Lajina , Rai Sauharda , Kohrt Brandon A. , Burkey Matthew D.
Published: May 2019

Whereas epidemiologic studies consistently identify different rates and types of problematic behavior in boys and girls, there has been little research examining the ecocultural context in which these gender differences in child behavior problems develop, especially in non-Western settings. This qualitative study in rural Nepal explored how behavioral expectations differed based on gender role, gender discrimination, inequity, and treatment of children based on their gender identity. We conducted semi-structured interviews with a total of 14 parents, school workers, and community leaders from a village in rural Nepal. Interview transcripts were coded by two authors using predetermined and emergent codes to identify expectations, behavior problems, and responses to behavior problems, stratified by gender. Authors then arranged codes into categories based on emergent themes. Four major themes in the interviews were identified: (1) self-reported gender non-bias; (2) differentiated role expectations; (3) gender, “goodness”, and differential thresholds for problem behaviors; and (4) boys and girls require different responses for misbehavior. Results from our study in Nepal reflect nearly universal models of gender differences in behavior. Of particular importance in South Asia, patrilocal marital practices were used to frame gender differences in expectations. To protect girls’ future potential to marry, local cultural practices provide girls with lesser opportunities and less cultural space to conduct themselves in a disruptive manner than boys. Greater understanding of differential expectations and responses to disruptive behaviors by gender will be important for culturally-appropriate equitable programming in child development.
Long-term drift of Si-MOS quantum dots with intentional donor implants
Authors: Rudolph M. , Sarabi B. , Murray R. , Carroll M. S. , Zimmerman Neil M.
Published: May 2019

Charge noise can be detrimental to the operation of quantum dot (QD) based semiconductor qubits. We study the low-frequency charge noise by charge offset drift measurements for Si-MOS devices with intentionally implanted donors near the QDs. We show that the MOS system exhibits non-equilibrium drift characteristics, in the form of transients and discrete jumps, that are not dependent on the properties of the donor implants. The equilibrium charge noise indicates a 1/f noise dependence, and a noise strength as low as $$1\,\mu {\rm{eV}}/\sqrt{{\rm{Hz}}}$$
1

μ
eV
/

Hz

, comparable to that reported in more model GaAs and Si/SiGe systems (which have also not been implanted). We demonstrate that implanted qubits, therefore, can be fabricated without detrimental effects on long-term drift or 1/f noise for devices with less than 50 implanted donors near the qubit.
Ring roads and urban biodiversity: distribution of butterflies in urban parks in Beijing city and correlations with other indicator species
Authors: Sing Kong-Wah , Luo Jiashan , Wang Wenzhi , Jaturas Narong , Soga Masashi , Yang Xianzhe , Dong Hui , Wilson John-James
Published: May 2019

The capital of China, Beijing, has a history of more than 800 years of urbanization, representing a unique site for studies of urban ecology. Urbanization can severely impact butterfly communities, yet there have been no reports of the species richness and distribution of butterflies in urban parks in Beijing. Here, we conducted the first butterfly survey in ten urban parks in Beijing and estimated butterfly species richness. Subsequently, we examined the distribution pattern of butterfly species and analyzed correlations between butterfly species richness with park variables (age, area and distance to city center), and richness of other bioindicator groups (birds and plants). We collected 587 individual butterflies belonging to 31 species from five families; 74% of the species were considered cosmopolitan. The highest butterfly species richness and abundance was recorded at parks located at the edge of city and species richness was significantly positively correlated with distance from city center (p < 0.05). No significant correlations were detected between the species richness and park age, park area and other bioindicator groups (p > 0.05). Our study provides the first data of butterfly species in urban Beijing, and serves as a baseline for further surveys and conservation efforts.
Characterization of Mechanical Stability and Immunological Compatibility for Functionalized Modification Interfaces
Authors: Hsu Yao-Tsung , Wu Chih-Yu , Guan Zhen-Yu , Sun Ho-Yi , Mei Chieh , Chen Wen-Chien , Cheng Nai-Chen , Yu Jiashing , Chen Hsien-Yeh
Published: May 2019

Surface modification layers are performed on the surfaces of biomaterials and have exhibited promise for decoupling original surface properties from bulk materials and enabling customized and advanced functional properties. The physical stability and the biological compatibility of these modified layers are equally important to ensure minimized delamination, debris, leaching of molecules, and other problems that are related to the failure of the modification layers and thus can provide a long-term success for the uses of these modified layers. A proven surface modification tool of the functionalized poly-para-xylylene (PPX) system was used as an example, and in addition to the demonstration of their chemical conjugation capabilities and the functional properties that have been well-documented, in the present report, we additionally devised the characterization protocols to examine stability properties, including thermostability and adhesive strength, as well as the biocompatibility, including cell viability and the immunological responses, for the modified PPX layers. The results suggested a durable coating stability for PPXs and firmly attached biomolecules under these stability and compatibility tests. The durable and stable modification layers accompanied by the native properties of the PPXs showed high cell viability against fibroblast cells and macrophages (MΦs), and the resulting immunological activities created by the MΦs exhibited excellent compatibility with non-activated immunological responses and no indication of inflammation.
Meibum Expressibility Improvement as a Therapeutic Target of Intense Pulsed Light Treatment in Meibomian Gland Dysfunction and Its Association with Tear Inflammatory Cytokines
Authors: Choi Moonjung , Han Soo Jung , Ji Yong Woo , Choi Young Joon , Jun Ikhyun , Alotaibi Mutlaq Hamad , Ko Byung Yi , Kim Eung Kweon , Kim Tae-im , Nam Sang Min , Seo Kyoung Yul
Published: May 2019

Many recent studies have demonstrated the efficacy of intense pulsed light (IPL) for the treatment of meibomian gland dysfunction (MGD); however, its effective treatment targets have not yet been elucidated. This study aimed to investigate the baseline characteristics associated with an improvement in symptoms after IPL treatment; to examine the course of change in inflammatory tear cytokines, meibomian gland function, and tear stability; and to investigate the correlation between cytokines and ocular surface parameters. Thirty participants underwent three sessions of IPL treatment. During each examination, tear film lipid layer interferometry, meibography, tear meniscus height measurement, tear sampling, and slit-lamp examination were performed, and the Ocular Surface Disease Index (OSDI) questionnaire was administered. Meibum quality, meibum expressibility, lid margin abnormality, tear film break-up time (TBUT), ocular surface staining, and the OSDI significantly improved after treatment. Poor meibum expressibility and short TBUT were associated with greater recovery in the OSDI after IPL. Tear levels of IL-4, IL-6, IL-10, IL-17A, and TNF-α decreased after IPL, and IL-6, and TNF-α were correlated with the improvement in meibum expressibility. Therefore, IPL treatment improved meibomian gland function, stabilized the tear film, and decreased ocular surface inflammation. Patients with obstructive MGD and tear instability were more likely to experience an improvement in ocular discomfort after IPL treatment.
Hair Proteome Variation at Different Body Locations on Genetically Variant Peptide Detection for Protein-Based Human Identification
Authors: Chu Fanny , Mason Katelyn E. , Anex Deon S. , Jones A. Daniel , Hart Bradley R.
Published: May 2019

Human hair contains minimal intact nuclear DNA for human identification in forensic and archaeological applications. In contrast, proteins offer a pathway to exploit hair evidence for human identification owing to their persistence, abundance, and derivation from DNA. Individualizing single nucleotide polymorphisms (SNPs) are often conserved as single amino acid polymorphisms in genetically variant peptides (GVPs). Detection of GVP markers in the hair proteome via high-resolution tandem mass spectrometry permits inference of SNPs with known statistical probabilities. To adopt this approach for forensic investigations, hair proteomic variation and its effects on GVP identification must first be characterized. This research aimed to assess variation in single-inch head, arm, and pubic hair, and discover body location-invariant GVP markers to distinguish individuals. Comparison of protein profiles revealed greater body location-specific variation in keratin-associated proteins and intracellular proteins, allowing body location differentiation. However, robust GVP markers derive primarily from keratins that do not exhibit body location-specific differential expression, supporting GVP identification independence from hair proteomic variation at the various body locations. Further, pairwise comparisons of GVP profiles with 8 SNPs demonstrated greatest interindividual variation and high intraindividual consistency, enabling similar differentiative potential of individuals using single hairs irrespective of body location origin.
Rat liver folate metabolism can provide an independent functioning of associated metabolic pathways
Authors: Zaitsev Aleksandr V. , Martinov Michael V. , Vitvitsky Victor M. , Ataullakhanov Fazoil I.
Published: May 2019

Folate metabolism in mammalian cells is essential for multiple vital processes, including purine and pyrimidine synthesis, histidine catabolism, methionine recycling, and utilization of formic acid. It remains unknown, however, whether these processes affect each other via folate metabolism or can function independently based on cellular needs. We addressed this question using a quantitative mathematical model of folate metabolism in rat liver cytoplasm. Variation in the rates of metabolic processes associated with folate metabolism (i.e., purine and pyrimidine synthesis, histidine catabolism, and influxes of formate and methionine) in the model revealed that folate metabolism is organized in a striking manner that enables activation or inhibition of each individual process independently of the metabolic fluxes in others. In mechanistic terms, this independence is based on the high activities of a group of enzymes involved in folate metabolism, which efficiently maintain close-to-equilibrium ratios between substrates and products of enzymatic reactions.