bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting high culture
Authors: Morgan Kenneth
Published: June 2020

This article analyses the musical work of the Brisbane Musical Union (BMU) between its founding in 1872 and the consolidation of its position by 1898. During this period, the BMU benefited from the dedicated leadership of its main conductor, R. T. Jefferies, who drew upon his high standing as a violinist, ensemble player and conductor in Brisbane to present regular choral concerts, mainly comprising oratorios, with an amateur choir. Despite financial challenges, difficulties over rehearsal and concert venues, periodic problems concerning the choice of repertoire, an insufficient number of available professional musicians and competition from rival local musical societies, Jefferies’ work with the BMU promoted an important aspect of high musical culture to the public and laid the foundations for further development of classical musical performance in Brisbane.
'We are nearer the East than the other states'
Authors: Cotton James
Published: June 2020

Frederic Jones became the Queensland Commercial Agent in the Far East in 1904. He worked assiduously to extend Queensland’s trade with Asia, often pursuing a vigorously competitive approach in his dealings with the other states. Based in Shanghai from 1906, he became the first official from Australia to serve in China. He persuaded the Commonwealth government to authorise him to provide visiting Chinese merchants and travellers with documentation that would allow them to enter without undergoing the dictation test. Foreseeing the potential for trade complementarity between Queensland and China, after his appointment concluded in December 1907 he remained in business in Shanghai.
COVID-19 and Health-Related Authority Allocation Puzzles
Authors: DA SILVA MICHAEL
Published: June 2020

COVID-19-related controversies concerning the allocation of scarce resources, travel restrictions, and physical distancing norms each raise a foundational question: How should authority, and thus responsibility, over healthcare and public health law and policy be allocated? Each controversy raises principles that support claims by traditional wielders of authority in “federal” countries, like federal and state governments, and less traditional entities, like cities and sub-state nations. No existing principle divides “healthcare and public law and policy” into units that can be allocated in intuitively compelling ways. This leads to puzzles concerning (a) the principles for justifiably allocating “powers” in these domains and (b) whether and how they change during “emergencies.” This work motivates the puzzles, explains why resolving them should be part of long-term responses to COVID-19, and outlines some initial COVID-19-related findings that shed light on justifiable authority allocation, emergencies, emergency powers, and the relationships between them.
Anomalous origin of a single coronary artery from the pulmonary artery associated with patent ductus arteriosus
Authors: Hugues Nicolas , Dommerc Carine , Pretre René
Published: June 2020

We report an unusual case of a 12-month-old boy diagnosed with anomalous origin of a single coronary artery from the pulmonary artery associated with patent ductus arteriosus. The patient survival was attributed to left-to-right shunt (patent ductus arteriosus) allowing for appropriate myocardial perfusion. Successful surgical correction involved patent ductus arteriosus closure, mitral annuloplasty and reimplantation of the coronary artery into the aortic root.
1968: Towards a General Secularism
Authors: During Simon
Published: June 2020

The numerous interpretations and evaluations of 1968 that have been developed over the past half-century can arguably be divided into two. On one side, there are those accounts that regard 1968 as the threshold across which an older form of modernity passed to become what student revolutionaries of the period began to call late capitalism; and although late capitalism itself quickly became a fissured thing, this view has become orthodox. On the other side, there are those who insist that ’68 was a Badiousian event, an outbreak of liberatory possibilities to which we not only have a responsibility to remain faithful, but which provided a template for later more or less insurrectionary movements; undoubtedly the strongest argument for ’68’s enduring radical meaning and potential has been made by Kristin Ross in her 2002 book, May ’68 and its Afterlives. This article is partly committed to arguing for a middle way between these two views. I accept that the processes leading to and following the events of 1968 triggered the development of a new kind of capitalist society as well as formed the template for the radicalisms we now have. This mediation might seem to involve a contradiction, but in the end it is more accurate not to see these two views as they see themselves, namely as enemies, but rather as dialectically and functionally united. Without the kind of capitalism that the 1960s triggered, no radical movement politics; without radical, post-communist movement politics, no such late capitalism. To see that, we need to think about ’68 in larger contexts and terms than is usual. I will call the context I wish to bring to bear general secularization.
Low Molecular Weight Dissolved Organic Carbon: Aging, Compositional Changes, and Selective Utilization During Global Ocean Circulation
Authors: Broek Taylor A. B. , Walker Brett D. , Guilderson Thomas P. , Vaughn John S. , Mason Harris E. , McCarthy Matthew D.
Published: June 2020

The composition and cycling dynamics of marine dissolved organic carbon (DOC) have received increased interest in recent years; however, little research has focused on the refractory, low molecular weight (LMW) component that makes up the majority of this massive C pool. We measured stable isotopic (δ13C), radioisotopic (Δ14C), and compositional (C/N, 13C solid‐state NMR) properties of separately isolated high molecular weight (HMW) and LMW DOC fractions collected using a coupled ultrafiltration and solid phase extraction approach from throughout the water column in the North Central Pacific and Central North Atlantic. The selective isolation of LMW DOC material allowed the first investigation of the composition and cycling of a previously elusive fraction of the DOC pool. The structural composition of the LMW DOC material was homogeneous throughout the water column and closely matched carboxylic‐rich alicyclic material that has been proposed as a major component of the marine refractory DOC pool. Examination of offsets in the measured parameters between the deep waters of the two basins provides the first direct assessment of changes in the properties of this material with aging and utilization during ocean circulation. While our direct measurements largely confirm hypotheses regarding the relative recalcitrance of HMW and LMW DOC, we also demonstrate a number of novel observations regarding the removal and addition of DOC during global ocean circulation, including additions of fresh carbohydrate‐like HMW DOC to the deep ocean and large‐scale removal of both semilabile HMW and recalcitrant LMW DOC.
Impact of the 2018 Ambae Eruption on the Global Stratospheric Aerosol Layer and Climate
Authors: Kloss Corinna , Sellitto Pasquale , Legras Bernard , Vernier Jean‐Paul , Jégou Fabrice , Venkat Ratnam M. , Suneel Kumar B. , Lakshmi Madhavan B. , Berthet Gwenaël
Published: June 2020

During an extended volcanic unrest starting in 2017, two main moderate stratospheric eruptions occurred at the Ambae volcano (15°S and 167°E), Vanuatu, in April and July 2018. Observations from a geostationary orbit show that the April and July eruptions injected a volcanic plume into the lower stratosphere. While aerosol enhancements from the April eruption have only had an impact on the Southern Hemisphere, the plume from the July eruption was distributed within the lower branch of the Brewer–Dobson circulation to both hemispheres. Satellite, ground‐based and in situ observations show that the background aerosol is enhanced throughout the year after the July eruption on a global scale. A volcanic‐induced perturbation of the global stratospheric aerosol optical depth up to 0.011 is found, in the ultraviolet/visible spectral range. This perturbation is comparable to that of recent moderate stratospheric eruptions like from Kasatochi, Sarychev, and Nabro. Top of the atmosphere radiative forcing values are estimated between −0.45 and −0.6 W/m2 for this event, showing that the Ambae eruption had the strongest climatic impact of the year 2018. Thus, the Ambae eruption in 2018 has to be taken into account when studying the decadal lower stratospheric aerosol budget and in climate studies.
Including the Temporal Dimension in the SECS Technique
Authors: Marsal S. , Torta J. M. , Pavón‐Carrasco F. J. , Blake S. P. , Piersanti M.
Published: June 2020

The equivalent source method of Spherical Elementary Current Systems (SECS) has contributed valuable results for spatial magnetic interpolation purposes where no observations are available, as well as for modeling equivalent currents both in the ionosphere and in the subsurface, thus providing a separation between external and internal sources. It has been successfully applied to numerous Space Weather (SW) events, whereas some advantages have been reported over other techniques such as Fourier or Spherical (Cap) Harmonic Analysis. Although different modalities of SECS exist (either 1‐D, 2‐D, or 3‐D) depending on the number of space dimensions involved, the method provides a sequence of instantaneous pictures of the source current. We present an extension of SECS consisting in the introduction of a temporal dependence in the formulation based on a cubic B‐splines expansion. The technique thus adds one dimension, becoming 4‐D in general (e.g., 3‐D + t), and its application is envisaged for, though not restricted to, the analysis of past events including heterogeneous geomagnetic data sets, such as those containing gaps, different sampling rates or diverse data sources. A synthetic model based on the SW Modeling Framework is used to show the efficacy of the extended scheme. We apply this method to characterize the current systems of past and significant SW events producing geomagnetically induced currents, which we exemplify with an outstanding geomagnetic sudden commencement occurred on 24 March 1991.
Streamflow Recession Analysis Using Water Height
Authors: Jachens E. R. , Roques C. , Rupp D. E. , Selker J. S.
Published: June 2020

Recession analysis is widely used for characterizing aquifer and basin properties based on the falling limb of the hydrograph. However, recession analysis using streamflow discharge requires a relationship (the rating curve) between simultaneous measurements of water height, h, and discharge, Q, across a wide range of flows, which is expensive to obtain, and changes in time. We leverage the relationship between h and Q (typical power law) to perform recession analysis using h directly, thus permitting identification of transient flow regimes, where only h is available. Recession analysis evaluates the rate of change in discharge, −dQ/dt, as a function of discharge, Q, in a bilogarithmic plot where the slope, b, contains information about aquifer characteristics. While values of b are not conserved when replacing Q with h, we find that the variability in values of b within and between events is captured in recession analysis for both Q and h. For example, when considering individual recessions from a large number of watersheds, a change from a smaller b at high discharge/stage to a larger b at lower discharge/stage occurs in most watersheds and suggests a transition to a more long‐lasting, and less drought‐sensitive, baseflow regime. With the advent of low‐cost reliable pressure loggers, as well as satellites that provide global reporting of river stage, recession analysis using water height expands the number of river systems where recession analysis can be conducted and provides the potential for insights into the variability of watershed drainage characteristics without the need for a discharge record.
Measuring Aquifer Specific Yields With Absolute Gravimetry: Result in the Choushui River Alluvial Fan and Mingchu Basin, Central Taiwan
Authors: Chen Kuan‐Hung , Hwang Cheinway , Chang Liang‐Cheng , Tsai Jui‐Pin , Yeh Tian‐Chyi Jim , Cheng Ching‐Chung , Ke Chien‐Chung , Feng Wei
Published: June 2020

Accurate and densely covered specific yields (Sy) are essential for estimating the storage capacity of a groundwater reservoir. A cross‐well pumping test can determine Sy, but its high cost often makes it unsuitable for sampling high‐resolution Sy. The gravity‐based method (GBM) based on gravity changes near existing groundwater wells may outperform cross‐well pumping tests in estimating Sy. We established 10 gravity sites close to groundwater wells in the aquifer‐rich Choushui River Alluvial Fan and Mingchu Basin in central Taiwan and measured gravity changes with two FG5 gravimeters from 2012 to 2017. Thirty‐nine Sy values with formal errors are determined by natural rises and falls in gravity and groundwater level. The representative Sy values (0.04 to 0.29) from GBM are in general consistent with those from cross‐well pumping tests (0.03 to 0.24). Repeated groundwater level changes over similar depth range at different times serve as revisit tests, showing that GBM can reproduce a reliable Sy value at a given site and depth. Soil moisture and compaction data show that the effects of gravity changes originating from unsaturated zones and deep aquifer layers are minor. Using the cylinder model for aquifers with limited lateral extents, we assess the validity of the Bouguer model by quantifying gravity differences and relative Sy differences originating from the model assumption. Improvements in environmental resilience and transportability achieved by recent atomic gravimeters may increase the potential of GBM to replace or supplement cross‐well pumping tests in densifying Sy point densities for an improved groundwater resource management.
Ghost spintronic THz-emitter-array microscope
Authors: Chen Si-Chao , Feng Zheng , Li Jiang , Tan Wei , Du Liang-Hui , Cai Jianwang , Ma Yuncan , He Kang , Ding Haifeng , Zhai Zhao-Hui , Li Ze-Ren , Qiu Cheng-Wei , Zhang Xi-Cheng , Zhu Li-Guo
Published: June 2020

Terahertz (THz) waves show great potential in nondestructive testing, biodetection and cancer imaging. Despite recent progress in THz wave near-field probes/apertures enabling raster scanning of an object’s surface, an efficient, nonscanning, noninvasive, deep subdiffraction imaging technique remains challenging. Here, we demonstrate THz near-field microscopy using a reconfigurable spintronic THz emitter array (STEA) based on the computational ghost imaging principle. By illuminating an object with the reconfigurable STEA followed by computing the correlation, we can reconstruct an image of the object with deep subdiffraction resolution. By applying an external magnetic field, in-line polarization rotation of the THz wave is realized, making the fused image contrast polarization-free. Time-of-flight (TOF) measurements of coherent THz pulses further enable objects at different distances or depths to be resolved. The demonstrated ghost spintronic THz-emitter-array microscope (GHOSTEAM) is a radically novel imaging tool for THz near-field imaging, opening paradigm-shifting opportunities for nonintrusive label-free bioimaging in a broadband frequency range from 0.1 to 30 THz (namely, 3.3–1000 cm−1).
Diagnosing metabolic syndrome in a multi-ethnic country: is an ethnic-specific cut-off point of waist circumference needed?
Authors: Tahapary Dicky L. , Harbuwono Dante S. , Yunir Em , Soewondo Pradana
Published: June 2020

The definition of Metabolic Syndrome (MS) required an ethnic-specific cut-off point for waist circumference (WC). We aim to assess the optimal ethnic-specific WC cut-off point for MS in Indonesia, a multi-ethnic country. Three population-based studies in Indonesia were included for analysis [Flores (n = 1227, Floresian), Depok (n = 904, Sundanese), and Jakarta (n = 1574, Javanese)]. All subjects were 25–65 years old. The receiver operator characteristic curve analysis and Youden index method was used to determine the optimal cut-offs of WC to predict two or more risk factors of MS. In Flores, the cut-offs were 80 cm (Sensitivity and Specificity, AUC, 84% and 73%, 0.86) and 77 cm (86% and 68%, 0.85), for men and women, respectively. While in Depok, the values were 87 cm (87% and 67%, 0.85) and 79 cm (94% and 54%, 0.79), for men and women, respectively. While in Jakarta, the values were 83 cm (92% and 60%, 0.85) and 81 cm (84% and 60%, 0.77), for men and women, respectively. The optimal WC cut-off values for MS were different in those three ethnicities, and in general were lower than the currently used cut-off points for Asian population.
Melatonin-induced ApoE expression in mouse astrocytes protects endothelial cells from OGD-R induced injuries
Authors: Xiang Jun , Zhu Wen , Yang Feng , Yu Zhong-Hai , Cai Min , Li Xiang-Ting , Zhang Jing-Si , Zhang Wen , Cai Ding-Fang
Published: June 2020

Stroke is a leading reason of death and long-term disability, and most studies mainly focus on efforts to protect neurons. However, failed clinical trials suggest that therapies against single target in neurons may not be sufficient and the involvement of endothelial cells and glial cells have been underestimated. Astrocytes are the major source of ApoE in the brain and endothelial cells express high level of ApoE receptors. Thus, ApoE may mediate the interaction between astrocytes and endothelial cells. To address whether and how ApoE-mediated astrocytes–endothelial cells interaction contributes to the pathogenesis of stroke, we used oxygen and glucose deprivation-reoxygenation (OGD-R) as a stroke model and investigated the effects of OGD-R on astrocytes-endothelial cell co-cultures in the current study. We find that OGD-R leads to various damages to endothelial cells, including compromised cell viability, increased ROS level, enhanced caspase activity, and higher apoptotic rate. Meanwhile, mouse astrocytes could secrete ApoE to activate PI3K/eNOS signaling in endothelial cells to prevent OGD-R induced injuries. In addition, OGD-R induces down-regulation of ApoE in astrocyte–endothelial cell co-cultures while melatonin restores astrocytic ApoE expression via pCREB pathway and protects endothelial cell in OGD-R treated co-cultures. Our study provides evidence that astrocytes could protect endothelial cells via ApoE in OGD-R condition and Melatonin could induce ApoE expression to protect endothelial cells.
Investigating resting brain perfusion abnormalities and disease target-engagement by intranasal oxytocin in women with bulimia nervosa and binge-eating disorder and healthy controls
Authors: Martins Daniel , Leslie Monica , Rodan Sarah , Zelaya Fernando , Treasure Janet , Paloyelis Yannis
Published: June 2020

Advances in the treatment of bulimia nervosa and binge-eating disorder (BN/BED) have been marred by our limited understanding of the underpinning neurobiology. Here we measured regional cerebral blood flow (rCBF) to map resting perfusion abnormalities in women with BN/BED compared with healthy controls and investigate whether intranasal oxytocin (OT), proposed as a potential treatment, can restore perfusion in disorder-related brain circuits. Twenty-four women with BN/BED and 23 healthy women participated in a randomized, double-blind, crossover, placebo-controlled study. We used arterial spin labelling MRI to measure rCBF and the effects of an acute dose of intranasal OT (40 IU) or placebo over 18–26 min post dosing, as we have previously shown robust OT-induced changes in resting rCBF in men in a similar time-window (15–36 min post dosing). We tested for effects of treatment, diagnosis and their interaction on extracted rCBF values in anatomical regions-of-interest previously implicated in BN/BED by other neuroimaging modalities, and conducted exploratory whole-brain analyses to investigate previously unidentified brain regions. We demonstrated that women with BN/BED presented increased resting rCBF in the medial prefrontal and orbitofrontal cortices, anterior cingulate gyrus, posterior insula and middle/inferior temporal gyri bilaterally. Hyperperfusion in these areas specifically correlated with eating symptoms severity in patients. Our data did not support a normalizing effect of intranasal OT on perfusion abnormalities in these patients, at least for the specific dose (40 IU) and post-dosing interval (18–26 min) examined. Our findings enhance our understanding of resting brain abnormalities in BN/BED and identify resting rCBF as a non-invasive potential biomarker for disease-related changes and treatment monitoring. They also highlight the need for a comprehensive investigation of intranasal OT pharmacodynamics in women before we can fully ascertain its therapeutic value in disorders affecting predominantly this gender, such as BN/BED.
COVID-19 infection: the China and Italy perspectives
Authors: Chen Jun , Lu Hongzhou , Melino Gerry , Boccia Stefania , Piacentini Mauro , Ricciardi Walter , Wang Ying , Shi Yufang , Zhu Tongyu
Published: June 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Since its first report in December 2019, despite great efforts made in almost every country worldwide, this disease continues to spread globally, especially in most parts of Europe, Iran, and the United States. Here, we update the recent understanding in clinical characteristics, diagnosis strategies, as well as clinical management of COVID-19 in China as compared to Italy, with the purpose to integrate the China experience with the global efforts to outline references for prevention, basic research, treatment as well as final control of the disease. Being the first two countries we feel appropriate to evaluate the evolution of the disease as well as the early result of the treatment, in order to offer a different baseline to other countries. It is also interesting to compare two countries, with a very significant difference in population, where the morbidity and mortality has been so different, and unrelated to the size of the country.
Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice
Authors: He Zitian , Yang Yunjie , Xing Zhiwei , Zuo Zejie , Wang Rui , Gu Huaiyu , Qi Fangfang , Yao Zhibin
Published: June 2020

Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer’s disease (AD) and directly regulates amyloid-β (Aβ) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in Aβ degradation in AD mouse models remains to be elucidated. Here, we found that 9 days of the intraperitoneal administration of IFN-γ significantly increased the LC3II/I ratio and decreased the level of p62 in APP/PS1 mice, an AD mouse model. In vitro, IFN-γ protected BV2 cells from Aβ toxicity by upregulating the expressions of Atg7 and Atg5 and the LC3II/I ratio, whereas these protective effects were ablated by interference with Atg5 expression. Moreover, IFN-γ enhanced autophagic flux, probably through suppressing the AKT/mTOR pathway both in vivo and in vitro. Importantly, using intravital two-photon microscopy and fluorescence staining, we found that microglia interacted with exogenous IFN-γ and Aβ, and surrounded Aβ in APP/PS1;CX3CR1-GFP+/− mice. In addition, IFN-γ treatment decreased the Aβ plaque load in the cortex and hippocampus and rescued cognitive deficits in APP/PS1 mice. Our data suggest a possible mechanism by which the peripheral injection of IFN-γ restores microglial autophagy to induce the phagocytosis of cerebral Aβ, which represents a potential therapeutic approach for the use of exogenous IFN-γ in AD.
Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration
Authors: Chauhan Monika , Modi Prashant Kumar , Sharma Pushkar
Published: June 2020

It is critical for the neuronal cell cycle to remain suppressed in terminally differentiated neurons as its activation results in aberrant cell cycle re-entry that causes neuronal apoptosis (CRNA), which has been observed in several neurodegenerative disorders like Alzheimer’s disease (AD). In the present study, we report that E3 ubiquitin ligase Itch is a major regulator of CRNA and elucidated the mechanism via which it is regulated in this process. Neurotoxic amyloid peptide Aβ42-treated neurons or neurons from an AD transgenic mouse model (TgAD) exhibited aberrant activation of the JNK pathway which resulted in the hyperphosphorylation of Itch. The phosphorylation of Itch primes it for autoubiquitination, which is necessary for its activation. These post-translational modifications of Itch facilitate its interaction with TAp73 resulting in its degradation. These series of events are critical for Itch-mediated CRNA and its phosphorylation and autoubiquitination site mutants reversed this process and were neuroprotective. These studies unravel a novel pathway via which neurodegeneration in AD and possibly other related disorders may be regulated by aberrant regulation of the neuronal cell cycle.
Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease
Authors: Parackova Zuzana , Milota Tomas , Vrabcova Petra , Smetanova Jitka , Svaton Michael , Freiberger Tomas , Kanderova Veronika , Sediva Anna
Published: June 2020

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.
Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions
Authors: Obergasteiger Julia , Frapporti Giulia , Lamonaca Giulia , Pizzi Sara , Picard Anne , Lavdas Alexandros A. , Pischedda Francesca , Piccoli Giovanni , Hilfiker Sabine , Lobbestael Evy , Baekelandt Veerle , Hicks Andrew A. , Corti Corrado , Pramstaller Peter P. , Volta Mattia
Published: June 2020

The Parkinson’s disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a crucial modulator of the autophagy-lysosome pathway, but unclarity exists on the precise mechanics of its role and the direction of this modulation. In particular, LRRK2 is involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and a significant proportion of LRRK2 patients presenting Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to obtain a comprehensive knowledge on LRRK2-associated pathology. Here, we investigated a G2019S-LRRK2 recombinant cell line exhibiting accumulation of endogenous, phosphorylated alpha-synuclein. We found that G2019S-LRRK2 leads to accumulation of LC3 and abnormalities in lysosome morphology and proteolytic activity in a kinase-dependent fashion, but independent from constitutively active Rab10. Notably, LRRK2 inhibition was ineffective upon upstream blockade of autophagosome-lysosome fusion events, highlighting this step as critical for alpha-synuclein clearance.
Inflammasome activation and regulation: toward a better understanding of complex mechanisms
Authors: Zheng Danping , Liwinski Timur , Elinav Eran
Published: June 2020

Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.
Unusual context of CENPJ variants and primary microcephaly: compound heterozygosity and nonconsanguinity in an Argentinian patient
Authors: Cueto-González Anna M. , Fernández-Cancio Mónica , Fernández-Alvarez Paula , García-Arumí Elena , Tizzano Eduardo F.
Published: June 2020

Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual disability, with normal brain structure in most patients, or with a small brain and gyri without visceral malformations. We present the case of an adult patient born from Argentinian nonconsanguineous healthy parents. He had a head circumference >5 SD below the mean, cerebral neuroimaging showing hypoplasia of the corpus callosum, bilateral migration disorder with heterotopia of the sylvian fissure and colpocephaly. The patient was compound heterozygous for pathogenic variants in the CENPJ gene (c.289dupA inherited from his mother and c.1132 C > T inherited from his father). Our patient represents an uncommon situation for the usual known context of CENPJ and MCPH, including family origin (Argentinian), pedigree (nonconsanguineous), and genotype (a compound heterozygous case with two variants predicting a truncated protein). Next-generation sequencing studies applied in a broader spectrum of clinical presentations of MCPH syndromes may discover additional similar patients and families.
Victoria continental microplate dynamics controlled by the lithospheric strength distribution of the East African Rift
Authors: Glerum Anne , Brune Sascha , Stamps D. Sarah , Strecker Manfred R.
Published: June 2020

The Victoria microplate between the Eastern and Western Branches of the East African Rift System is one of the largest continental microplates on Earth. In striking contrast to its neighboring plates, Victoria rotates counterclockwise with respect to Nubia. The underlying cause of this distinctive rotation has remained elusive so far. Using 3D numerical models, we investigate the role of pre-existing lithospheric heterogeneities in continental microplate rotation. We find that Victoria’s rotation is primarily controlled by the distribution of rheologically stronger zones that transmit the drag of the major plates to the microplate and of the mechanically weaker mobile belts surrounding Victoria that facilitate rotation. Our models reproduce Victoria’s GPS-derived counterclockwise rotation as well as key complexities of the regional tectonic stress field. These results reconcile competing ideas on the opening of the rift system by highlighting differences in orientation of the far-field divergence, local extension, and the minimum horizontal stress.
Animal biosynthesis of complex polyketides in a photosynthetic partnership
Authors: Torres Joshua P. , Lin Zhenjian , Winter Jaclyn M. , Krug Patrick J. , Schmidt Eric W.
Published: June 2020

Complex polyketides are typically associated with microbial metabolism. Here, we report that animals also make complex, microbe-like polyketides. We show there is a widespread branch of fatty acid synthase- (FAS)-like polyketide synthase (PKS) proteins, which sacoglossan animals use to synthesize complex products. The purified sacogolassan protein EcPKS1 uses only methylmalonyl-CoA as a substrate, otherwise unknown in animal lipid metabolism. Sacoglossans are sea slugs, some of which eat algae, digesting the cells but maintaining functional chloroplasts. Here, we provide evidence that polyketides support this unusual photosynthetic partnership. The FAS-like PKS family represents an uncharacterized branch of polyketide and fatty acid metabolism, encoding a large diversity of biomedically relevant animal enzymes and chemicals awaiting discovery. The biochemical characterization of an intact animal polyketide biosynthetic enzyme opens the door to understanding the immense untapped metabolic potential of metazoans.
Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
Authors: Martinez-Corral Ines , Zhang Yan , Petkova Milena , Ortsäter Henrik , Sjöberg Sofie , Castillo Sandra D. , Brouillard Pascal , Libbrecht Louis , Saur Dieter , Graupera Mariona , Alitalo Kari , Boon Laurence , Vikkula Miikka , Mäkinen Taija
Published: June 2020

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.
Marriage of black phosphorus and Cu2+ as effective photothermal agents for PET-guided combination cancer therapy
Authors: Hu Kuan , Xie Lin , Zhang Yiding , Hanyu Masayuki , Yang Zhimin , Nagatsu Kotaro , Suzuki Hisashi , Ouyang Jiang , Ji Xiaoyuan , Wei Junjie , Xu Hao , Farokhzad Omid C. , Liang Steven H. , Wang Lu , Tao Wei , Zhang Ming-Rong
Published: June 2020

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu2+-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu2+into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing64Cu2+, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an “ideal” PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
Shape adaptable and highly resilient 3D braided triboelectric nanogenerators as e-textiles for power and sensing
Authors: Dong Kai , Peng Xiao , An Jie , Wang Aurelia Chi , Luo Jianjun , Sun Baozhong , Wang Jie , Wang Zhong Lin
Published: June 2020

Combining traditional textiles with triboelectric nanogenerators (TENGs) gives birth to self-powered electronic textiles (e-textiles). However, there are two bottlenecks in their widespread application, low power output and poor sensing capability. Herein, by means of the three-dimensional five-directional braided (3DB) structure, a TENG-based e-textile with the features of high flexibility, shape adaptability, structural integrity, cyclic washability, and superior mechanical stability, is designed for power and sensing. Due to the spatial frame-column structure formed between the outer braided yarn and inner axial yarn, the 3DB-TENG is also endowed with high compression resilience, enhanced power output, improved pressure sensitivity, and vibrational energy harvesting ability, which can power miniature wearable electronics and respond to tiny weight variations. Furthermore, an intelligent shoe and an identity recognition carpet are demonstrated to verify its performance. This study hopes to provide a new design concept for high-performance textile-based TENGs and expand their application scope in human-machine interfacing.
Synergistic gene editing in human iPS cells via cell cycle and DNA repair modulation
Authors: Maurissen Thomas L. , Woltjen Knut
Published: June 2020

Precise gene editing aims at generating single-nucleotide modifications to correct or model human disease. However, precision editing with nucleases such as CRIPSR-Cas9 has seen limited success due to poor efficiency and limited practicality. Here, we establish a fluorescent DNA repair assay in human induced pluripotent stem (iPS) cells to visualize and quantify the frequency of DNA repair outcomes during monoallelic and biallelic targeting. We found that modulating both DNA repair and cell cycle phase via defined culture conditions and small molecules synergistically enhanced the frequency of homology-directed repair (HDR). Notably, targeting in homozygous reporter cells results in high levels of editing with a vast majority of biallelic HDR outcomes. We then leverage efficient biallelic HDR with mixed ssODN repair templates to generate heterozygous mutations. Synergistic gene editing represents an effective strategy to generate precise genetic modifications in human iPS cells.
Sequential modification of bacterial chemoreceptors is key for achieving both accurate adaptation and high gain
Authors: Mello Bernardo A. , Beserra Anderson B. , Tu Yuhai
Published: June 2020

Many regulatory and signaling proteins have multiple modification sites. In bacterial chemotaxis, each chemoreceptor has multiple methylation sites that are responsible for adaptation. However, whether the ordering of the multisite methylation process affects adaptation remains unclear. Furthermore, the benefit of having multiple modification sites is also unclear. Here, we show that sequentially ordered methylation/demethylation is critical for perfect adaptation; adaptation accuracy decreases as randomness in the multisite methylation process increases. A tradeoff between adaptation accuracy and response gain is discovered. We find that this accuracy-gain tradeoff is lifted significantly by having more methylation sites, but only when the multisite modification process is sequential. Our study suggests that having multiple modification sites and a sequential modification process constitute a general strategy to achieve both accurate adaptation and high response gain simultaneously. Our theory agrees with existing data and predictions are made to help identify the molecular mechanism underlying ordered covalent modifications.
Adaptive reduction of male gamete number in the selfing plant Arabidopsis thaliana
Authors: Tsuchimatsu Takashi , Kakui Hiroyuki , Yamazaki Misako , Marona Cindy , Tsutsui Hiroki , Hedhly Afif , Meng Dazhe , Sato Yutaka , Städler Thomas , Grossniklaus Ueli , Kanaoka Masahiro M. , Lenhard Michael , Nordborg Magnus , Shimizu Kentaro K.
Published: June 2020

The number of male gametes is critical for reproductive success and varies between and within species. The evolutionary reduction of the number of pollen grains encompassing the male gametes is widespread in selfing plants. Here, we employ genome-wide association study (GWAS) to identify underlying loci and to assess the molecular signatures of selection on pollen number-associated loci in the predominantly selfing plant Arabidopsis thaliana. Regions of strong association with pollen number are enriched for signatures of selection, indicating polygenic selection. We isolate the gene REDUCED POLLEN NUMBER1 (RDP1) at the locus with the strongest association. We validate its effect using a quantitative complementation test with CRISPR/Cas9-generated null mutants in nonstandard wild accessions. In contrast to pleiotropic null mutants, only pollen numbers are significantly affected by natural allelic variants. These data support theoretical predictions that reduced investment in male gametes is advantageous in predominantly selfing species.
NAP1-RELATED PROTEIN1 and 2 negatively regulate H2A.Z abundance in chromatin in Arabidopsis
Authors: Wang Yafei , Zhong Zhenhui , Zhang Yaxin , Xu Linhao , Feng Suhua , Rayatpisheh Shima , Wohlschlegel James A. , Wang Zonghua , Jacobsen Steven E. , Ausin Israel
Published: June 2020

In eukaryotes, DNA wraps around histones to form nucleosomes, which are compacted into chromatin. DNA-templated processes, including transcription, require chromatin disassembly and reassembly mediated by histone chaperones. Additionally, distinct histone variants can replace core histones to regulate chromatin structure and function. Although replacement of H2A with the evolutionarily conserved H2A.Z via the SWR1 histone chaperone complex has been extensively studied, in plants little is known about how a reduction of H2A.Z levels can be achieved. Here, we show that NRP proteins cause a decrease of H2A.Z-containing nucleosomes in Arabidopsis under standard growing conditions. nrp1-1 nrp2-2 double mutants show an over-accumulation of H2A.Z genome-wide, especially at heterochromatic regions normally H2A.Z-depleted in wild-type plants. Our work suggests that NRP proteins regulate gene expression by counteracting SWR1, thereby preventing excessive accumulation of H2A.Z.
Devil's staircase transition of the electronic structures in CeSb
Authors: Kuroda Kenta , Arai Y. , Rezaei N. , Kunisada S. , Sakuragi S. , Alaei M. , Kinoshita Y. , Bareille C. , Noguchi R. , Nakayama M. , Akebi S. , Sakano M. , Kawaguchi K. , Arita M. , Ideta S. , Tanaka K. , Kitazawa H. , Okazaki K. , Tokunaga M. , Haga Y. , Shin S. , Suzuki H. S. , Arita R. , Kondo Takeshi
Published: June 2020

Solids with competing interactions often undergo complex phase transitions with a variety of long-periodic modulations. Among such transition, devil’s staircase is the most complex phenomenon, and for it, CeSb is the most famous material, where a number of the distinct phases with long-periodic magnetostructures sequentially appear below the Néel temperature. An evolution of the low-energy electronic structure going through the devil’s staircase is of special interest, which has, however, been elusive so far despite 40 years of intense research. Here, we use bulk-sensitive angle-resolved photoemission spectroscopy and reveal the devil’s staircase transition of the electronic structures. The magnetic reconstruction dramatically alters the band dispersions at each transition. Moreover, we find that the well-defined band picture largely collapses around the Fermi energy under the long-periodic modulation of the transitional phase, while it recovers at the transition into the lowest-temperature ground state. Our data provide the first direct evidence for a significant reorganization of the electronic structures and spectral functions occurring during the devil’s staircase.
Transcriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk
Authors: Anderson Kevin M. , Collins Meghan A. , Chin Rowena , Ge Tian , Rosenberg Monica D. , Holmes Avram J.
Published: June 2020

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk.