bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Visualisation, Sizing and Counting of Virus and Phage Particles in Liquids
Authors: Carr Bob , Griffiths Duncan
Published: May 2018

A laser-based, single nano-particle tracking analysis system was described in the March issue of Microscopy Today. The LM series of analyzers from NanoSight allows nanoscale particles such as viruses to be directly and individually visualised in liquids in real time, from which high-resolution particle size distribution profiles can be obtained, figure 1. The technique is fast, robust, accurate, and low cost representing an attractive alternative or complement to expensive and more complex methods of nano-particle analysis such as dynamic light scattering (photon correlation spectroscopy) or electron microscopy.

By simultaneously and directly measuring the diffusion coefficient of each and every particle, the dedicated Nanoparticle Tracking Analysis (NTA) software suite allows the user to automatically count and size the viruses in a sample. Results are displayed as graphs of size against count of individual particles (or size versus relative brightness), thus overcoming the limitations inherent in other particle analysis systems that generate only mean particle size distribution data with resolution.
Single-Molecule DNA Stretching Using Optical Tweezers
Authors: van Mameren Joost , Wozniak Anna , Ragona Sid
Published: May 2018

The advent of techniques to mechanically manipulate single (bio)molecules has sparked large efforts to precisely study the mechanical and elastic properties of proteins, protein fibers, DNA, RNA, etc. Two widely used techniques in this area are atomic force microscopy (AFM) and optical tweezers. Optical tweezers complement AFM at the lower end of the force regime: forces of typically a few hundred picoNewtons down to fractions of a picoNewton can be assessed using optical tweezers. This has allowed for, among other things, the precise measurement of forces and displacements exerted by individual motor proteins. In this report, we focus on the use of optical tweezers for force spectroscopy on single DNA molecules, and on the range of applications that this technique offers to learn not only about DNA itself, but also about the mechanics and thermodynamics of protein-DNA interaction.
Preventing the Sale of Fraudulent Gemstones using Non-Destructive X-Ray Fluoresence Spectroscopy
Authors: Goldman Mary S , Davis Dan L , Clifford Robert H
Published: May 2018

As the old adage goes, beauty is in the eye of the beholder. Ultimately, in the world of jewelry, the unwitting buyer uses his or her naked eye to decide which baubles are the most beautiful and worthy of wear. The expert jeweler and gemologist, however, know that each gem is subjected to rigorous scientific examinations and standards to determine its value and authenticity.

As the number of methods for altering gems grows with technology, methods to counteract counterfeiters, who can take a worthless stone and alter it to make it appear like a more expensive gem, are essential to gem buyers and traders. They must be able to detect artificial stones.

Gemologists assess gemstones based on several standards such as chemical composition and purity. Chemical composition plays a significant role in evaluating gems, as two of the same gemstone can differ chemically. One of the most well known methods of non-destructive testing for detecting gem quality is X-ray fluorescence (XRF) spectroscopy. Increasingly in demand, XRF spectroscopy is an ideal technique for fighting the battle against fraud.
Addressing the protection and assistance needs of migrants: The ICRC approach to migration
Authors: Le Bihan Stéphanie
Published: May 2018

The vulnerability of migrants and the threats to which they are exposed during their journey, on land, at sea, or in countries where they have settled, raise serious humanitarian concerns that cannot be ignored. In view of the transregional nature of migration, the International Committee of the Red Cross (ICRC) and other components of the International Red Cross and Red Crescent Movement (the Movement) draw on their presence all along migration routes to contribute to the humanitarian response and alleviate the suffering of vulnerable migrants. The Movement's proximity to vulnerable migrants through its solid and experienced network of responders along migratory routes is one of its specific advantages. The aim of this article is to explain the ICRC's view on and approach to migration. It underlines that the ICRC's response is dictated by humanitarian needs, and stresses that these needs can be greatly reduced when States abide by their commitments under international law and adopt and implement policies that take into account the protection and assistance needs of migrants. It acknowledges the diverse and complex human realities behind migration and outlines the main protection and assistance concerns of migrants in countries and regions where the ICRC operates.
Mobilising the Movement: Australian Red Cross, migration, and the role of the Red Cross and Red Crescent Movement around humanitarian response
Authors: Mau Vicki
Published: May 2018

Established in war, embedded in communities and operational in every major natural and man-made disaster, the International Red Cross and Red Crescent Movement (the Movement) – including 191 National Societies – is uniquely positioned to address the humanitarian needs of migrants at all points of their journey. With migration on the rise and an area of intense debate, this article examines the work of Australian Red Cross and the collective efforts of the International Federation of Red Cross Red and Red Crescent Societies, the International Committee of the Red Cross and the Asia Pacific Migration Network, particularly across 2015-17, to support the Movement in the region in providing assistance and protection to those who are most vulnerable. It considers the progress made so far, and the potential of the Movement to engage more effectively and collaboratively on opportunities and challenges into the future.
Assistance for and protection of migrants: Experience of the Honduran Red Cross
Authors: Ponce Arnaldo , Archila Norma
Published: May 2018

The Honduran Red Cross began working in the area of migration in July 2012, when it set up the Migrant Assistance Module in Corinto for Honduran migrants returning over land at the Honduran–Guatemalan border. The Honduran Red Cross has helped hundreds of returning and irregular migrants, thanks to agreements with the Ministry of Foreign Affairs and the National Migration Institute. It has also worked with other National Red Cross Societies in the region, the International Federation of Red Cross and Red Crescent Societies and the International Committee of the Red Cross, which have helped it to strengthen its capacity and build a comprehensive vision for the protection and assistance of migrants. This article summarizes the action that the Honduran Red Cross has undertaken with respect to migration and explores the services provided at the Corinto module, the Honduran Red Cross's subsequent management of the Returning Migrant Assistance Centre in Omoa and other care centres for migrants returning because of their irregular status, and the development and implementation of projects on migration and related topics.
Impact of Land‐Sea Thermal Contrast on the Inland Penetration of Sea Fog Over the Coastal Area Around the Korean Peninsula
Authors: Lee Ho‐Yeon , Chang Eun‐Chul
Published: May 2018

Based on the difference between sea surface temperature (SST) and sea air temperature (SAT), sea fog can be classified as cold sea fog (SST < SAT) or warm sea fog (SST > SAT). First, two sea fog events over the Yellow Sea are selected and simulated using Weather Research and Forecasting model. The two sea fogs are designated as cold and warm types, and cooling and moistening rates of each case are calculated to understand the contributions of major factors to the sea fog formation. Turbulence plays a role in the cooling (warming) of the sea air, while advection is responsible for sea air warming (cooling) during the cold (warm) sea fog event. Thus, these two effects cancel each other out. However, the longwave radiative cooling effect is as stronger as or stronger than the other effects in both cases. We conducted sensitivity tests of SST and land skin temperature, which induced obvious changes in turbulent heat flux and land‐sea thermal contrast, respectively. In the increased (decreased) SST experiments, sea fog evaporates (expands) because of more (less) heat transfer from sea to air. The land skin temperature experiments show that increases (decreases) in land‐sea air temperature differences hinder (favor) sea fog penetration.
Temporal Characteristics of Actual Evapotranspiration Over China Under Global Warming
Authors: Feng Taichen , Su Tao , Ji Fei , Zhi Rong , Han Zixuan
Published: May 2018

In this study, an assessment is made of the trends of actual evapotranspiration (AE) over China under global warming from an ensemble of the following data sets: National Centers for Environmental Prediction‐National Center for Atmospheric Research reanalysis I, National Centers for Environmental Prediction‐Department of Energy reanalysis II, Modern‐Era Retrospective Analysis for Research and Applications (MERRA), MERRA Version 2, European Centre for Medium‐Range Weather Forecasts Interim Re‐Analysis, and Japanese 55‐year Reanalysis. For China as a whole, annual AE exhibited a significant increasing trend from 1979 to 2015, and the rate of increase was highest in autumn and lowest in summer. By subdividing China into six climatic regions using the aridity index, significant increasing trends in AE are found over the hyperarid, arid, and humid regions, but slightly decrease over the dry subhumid and subhumid regions. For the hyperarid and arid regions, the increases in potential evapotranspiration and the water supply from melting glaciers due to both climate warming and human activities might be the main contributors to the AE increases. An increase in potential evapotranspiration driven by global warming is the main cause of the increased AE over the humid region. On a seasonal basis, most AE over China occurs in summer. However, increasing AE trends have been observed mainly in autumn and winter, and the increase is statistically significant over all of China's six climatic regions in winter. In view of data availability, reanalyses are compared with the results from Mezentsev‐Choudhury‐Yang equation (AE_Budyko). The correlations between individual reanalyses and AE_Budyko tend to be higher over the arid region.
Global Extent of Early Eocene Hyperthermal Events: A New Pacific Benthic Foraminiferal Isotope Record From Shatsky Rise (ODP Site 1209)
Authors: Westerhold T. , Röhl U. , Donner B. , Zachos J. C.
Published: May 2018

Studying the dynamics of past global warming events during the late Paleocene to middle Eocene informs our understanding of Earth's carbon cycle behavior under elevated atmospheric pCO2 conditions. Due to sparse data coverage, the spatial character of numerous hyperthermal events during this period is still poorly constrained. Here we present a high‐resolution, benthic foraminiferal stable isotope record for northwest Pacific ODP Site 1209 (Leg 198) spanning 44 to 56 Ma with 5 kyr resolution. An existing Paleocene section was extended into the middle Eocene creating an unprecedented 22 Myr single‐site record. Several identified carbon isotope excursions correspond in timing and magnitude to hyperthermal layers previously described elsewhere. Maxima in scanning X‐ray fluorescence Fe intensities and pronounced minima in the wt% coarse fraction characterize carbonate dissolution for all of the hyperthermal events. The new astronomically calibrated stable oxygen isotope record assists in defining the onset, duration, and demise of the Early Eocene Climate Optimum (EECO, 49.14 to 53.26 Ma) and the onset of global cooling after the EECO (49.14 Ma). The cooling trend was interrupted by two warming episodes at 47.2 and 46.7 Ma. A major positive shift in the benthic foraminiferal carbon isotope record occurring from 51.2 to 51.0 Ma is now confirmed to be global. Benthic foraminiferal δ13C records from Atlantic and Pacific Oceans converge from 52.0 to 47.5 Ma pointing to a closer connection of deepwater convection initiating well in advance of the final connection ~40 Ma ago or an increase in bottom water formation around Antarctica.
Fresh Take on a Gold Treasure’s Origins Using Geochemistry
Authors: Cartier Kimberly
Published: May 2018

Blending geoscience and archaeology, researchers apply a new technique to pinpoint where ancient and unique gold artifacts were crafted.
Mantle Transition Zone Thickness Beneath the Middle East: Evidence for Segmented Tethyan Slabs, Delaminated Lithosphere, and Lower Mantle Upwelling
Authors: Kaviani Ayoub , Sandvol Eric , Moradi Ali , Rümpker Georg , Tang Zheng , Mai Paul Martin
Published: May 2018

We use a very large seismic data set to provide a comprehensive image of the mantle transition zone (MTZ) beneath the Middle East. We utilized the technique of Common Conversion Point stacking of P wave receiver functions to investigate the topography on the 410‐ and 660‐km discontinuities defining the upper and lower boundaries of the MTZ. Our results show significant topography on the 410‐ and 660‐km discontinuities and corresponding variations in the MTZ thickness. The MTZ topography is broadly consistent with the results of seismic tomography studies, implying the presence of both cold thermal anomalies imparted by detached Tethyan slabs and lithospheric segments and hot thermal anomalies induced by upwelling of lower mantle material. The MTZ topography in the northern Middle East is dominated by the presence of patches of cold material that are intermittently separated by regions of hot to normal MTZ. Our results suggest that instead of a continuous slab, the Tethyan slab in the Middle East is strongly segmented along the strike of the subduction boundary. Furthermore, we find evidence for a significant gap in subduction extending from the eastern edge of the Cyprean arc to NW Iran. The southern Middle East is dominated by the processes related to the mantle upwelling beneath the Afar depression. Our results imply that buoyant lower mantle material enters the MTZ beneath the Afar depression and then spreads laterally to the northeast beneath the western Arabia, flowing within the MTZ and in the upper mantle.
The Density of the Medusae Fossae Formation: Implications for its Composition, Origin, and Importance in Martian History
Authors: Ojha Lujendra , Lewis Kevin
Published: May 2018

The Medusae Fossae Formation (MFF) is one of the largest sedimentary deposits on Mars. The origin of the MFF is uncertain, though several processes including volcanic, eolian, and ice‐related mechanisms have been proposed in its formation. Here we localize the gravity and topography signature of the MFF and place the first direct constraint on its density. We find that the MFF is a relatively porous unit with a bulk density of 1,765 ± 105 kg m−3. When combined with previous radar measurements, our density constraint rules out the presence of ice as the cause of unusual radar permittivity. Rather, we find the joint radar and gravity constraints imply a dry and highly porous rock unit. Based on the relatively low density, lack of ice, and the previously known enrichment of volatile elements associated with volcanic emissions (Cl and S), we propose that the MFF was deposited by pyroclastic eruptions. Using our density estimate, the mass of the MFF is found to be 2 orders of magnitude greater than the largest terrestrial pyroclastic deposit, making it the largest known pyroclastic deposit in the solar system. Outgassing of volatiles such as CO2 and H2O from the MFF would have substantially contributed to the Martian atmosphere and hydrosphere.
Geology and Scientific Significance of the Rümker Region in Northern Oceanus Procellarum: China's Chang'E‐5 Landing Region
Authors: Qian Y. Q. , Xiao L. , Zhao S. Y. , Zhao J. N. , Huang J. , Flahaut J. , Martinot M. , Head J. W. , Hiesinger H. , Wang G. X.
Published: May 2018

The Rümker region (41–45°N, 49–69°W) is located in northern Oceanus Procellarum of the Moon. Mons Rümker is the most distinctive geological feature in the area. The region is characterized by prolonged lunar volcanism (Late Imbrian Period to Eratosthenian Period), forming multiple geologic units in the area, including very low‐Ti to low‐Ti mare basalts, high‐Ti mare basalts, and volcanic complexes. Each geologic unit has distinct element composition and mineral assemblages. The Rümker region, overlying the Procellarum KREEP Terrain, was selected as the landing region for China's Chang'E‐5 lunar sample return mission. Prelanding analyses of the geologic context and scientific potential are reported in this contribution. We conducted detailed geological mapping using image, spectral, and altimetry data. Fourteen geological units were defined, a geologic map was constructed, and the geologic history was outlined. The western mare units (Im1, Im2, and Im3) are Imbrian‐aged (~3.4–3.5 Ga) representing the major stage of lunar mare eruptive volcanism. The eastern young mare units (Em3 and Em4; <2 Ga) are among the youngest mare basalts on the Moon. They have never been explored in situ or studied in the laboratory. We suggest that samples returned from the eastern mare unit (Em4) could answer many fundamental questions and that this unit should be listed as the top priority landing site for Chang'E‐5 sample return mission.
Affinity kinetics of leptin-reactive immunoglobulins are associated with plasma leptin and markers of obesity and diabetes
Authors: Bouhajja Houda , Bougacha-Elleuch Noura , Lucas Nicolas , Legrand Romain , Marrakchi Rim , Kaveri Srini V. , Jamoussi Kamel , Ayadi Hammadi , Abid Mohamed , Mnif-Feki Mouna , Fetissov Sergueï O.
Published: May 2018

Obese subjects display elevated plasma levels of leptin reflecting the phenomenon of leptin resistance. Here, we aimed to determine whether leptin-reactive immunoglobulins (Ig) are present in obese and type 2 diabetes (T2D) patients and whether their plasma levels and affinity kinetics may correlate with obesity and diabetes markers. We show that leptin levels are increased in obese patients with and without T2D. Although mean plasma levels of leptin-reactive IgG were similar between study groups, IgG in obese non-diabetic patients had increased dissociation rate and lower affinity (increased dissociation equilibrium constant value; KD). In controls and diabetic patients, the association rates of leptin IgG correlated negatively with obesity and diabetes markers, respectively. In contrast, KD values correlated positively with plasma leptin levels and obesity traits in our cohort, and with diabetes markers in both the total cohort and in the obese T2D group. Taken together, our data reveal that leptin-reactive IgG are present in healthy subjects, obese, and diabetic patients but display altered affinity kinetics in obesity. Increased IgG binding to leptin in healthy subjects associated with lower body mass index (BMI) suggests an enhancing role of IgG in leptin signaling. Accordingly, a decreased affinity of IgG for leptin, found in obese patients, can be relevant to leptin resistance.
Ferroptosis-inducing agents compromise in vitro human islet viability and function
Authors: Bruni Antonio , Pepper Andrew R. , Pawlick Rena L. , Gala-Lopez Boris , Gamble Anissa F. , Kin Tatsuya , Seeberger Karen , Korbutt Gregory S. , Bornstein Stefan R. , Linkermann Andreas , Shapiro A. M. James
Published: May 2018

Human islet transplantation has been hampered by donor cell death associated with the islet preparation procedure before transplantation. Regulated necrosis pathways are biochemically and morphologically distinct from apoptosis. Recently, ferroptosis was identified as a non-apoptotic form of iron-dependent regulated necrosis implicated in various pathological conditions. Mediators of islet oxidative stress, including glutathione peroxidase-4 (GPX4), have been identified as inhibitors of ferroptosis, and mechanisms that affect GPX4 function can impact islet function and viability. Ferroptosis has not been investigated directly in human islets, and its relevance in islet transplantation remains unknown. Herein, we sought to determine whether in vitro human islet viability and function is compromised in the presence of two distinct ferroptosis-inducing agents (FIA), erastin or RSL3, and whether these effects could be rescued with ferroptosis inhibitors, ferrostatin-1 (Fer-1), or desferrioxamine (DFO). Viability, as assessed by lactate dehydrogenase (LDH) release, revealed significant death in erastin- and RSL3-treated islets, 20.3% ± 3.8 and 24.4% ± 2.5, 24 h post culture, respectively. These effects were ameliorated in islets pre-treated with Fer-1 or the iron chelator, desferrioxamine (DFO). Stimulation index, a marker of islet function revealed a significant reduction in function in erastin-treated islets (control 1.97 ± 0.13 vs. 50 μM erastin 1.32 ± 0.1) (p < 0.05). Fer-1 and DFO pre-treatment alone did not augment islet viability or function. Pre-treatment of islets with erastin or Fer-1 did not impact in vivo engraftment in an immunodeficient mouse transplant model. Our data reveal that islets are indeed susceptible to ferroptosis in vitro, and induction of this novel cell death modality leads to compromised islet function, which can be recoverable in the presence of the ferroptosis inhibitors. The in vivo impact of this pathway in islet transplantation remains elusive given the constraints of our study, but warrants continued investigation.
Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells
Authors: Qiao Lijun , Zheng Jingyi , Tian Yonghao , Zhang Qishu , Wang Xiao , Chen Jason J. , Zhang Weifang
Published: May 2018

Regulator of chromatin condensation 1 (RCC1) is a major guanine-nucleotide exchange factor for Ran GTPase and plays key roles in nucleo-cytoplasmic transport, mitosis, and nuclear envelope assembly. RCC1 is known to be a critical cell cycle regulator whose loss causes G1 phase arrest, but the molecular basis for this regulation is poorly understood. Furthermore, little is known about the relationship between RCC1 and carcinomas. Human papillomavirus (HPV) infection is highly associated with the development of cervical cancer. The expression and function of RCC1 in HPV-related cervical cancer and cell cycle regulation have not yet been explored. In this study, we first observed that RCC1 immunostaining was mildly increased in cervical cancer tissues and significantly upregulated in HPV E7-expressing cells; this localization was primarily nuclear. We showed that the transcription factor c-Jun transcriptionally upregulates RCC1 via a direct interaction with the RCC1 promoter. Moreover, siRNA-mediated knockdown of RCC1 inhibited G1/S cell cycle progression and DNA synthesis, while overexpression of RCC1 abrogated the G1 checkpoint. RCC1 knockdown downregulated the protein levels of the transcription factor E2F1, especially nuclear E2F1, by promoting its degradation in HPV E7-expressing cells. Overexpression of E2F1 rescued RCC1 knockdown-mediated inhibition of G1/S progression. Additionally, we showed that cyclin-dependent kinase 1 (Cdk1), a known target of E2F1, is involved in G1 checkpoint regulation, as Cdk1 knockdown hindered G1/S progression, while Cdk1 overexpression rescued RCC1 knockdown-mediated effect on G1 cell cycle progression. Furthermore, RCC1 knockdown reduced HPV E7 protein levels, which may in turn downregulate E2F1. Our study explores the function of RCC1 in G1/S cell cycle progression and suggests that RCC1 may be involved in HPV E7-mediated genomic instability.
Hirsutine induces mPTP-dependent apoptosis through ROCK1/PTEN/PI3K/GSK3β pathway in human lung cancer cells
Authors: Zhang Rong , Li Guobing , Zhang Qian , Tang Qin , Huang Jingbin , Hu Changpeng , Liu Yali , Wang Qing , Liu Wuyi , Gao Ning , Zhou Shiwen
Published: May 2018

Hirsutine extracted from Uncaria rhynchophylla has been shown to exhibit anti-cancer activity. However, the molecular mechanism by which hirsutine exhibits anti-lung cancer activity remains unclear. In the present study, we showed that hirsutine induces apoptosis in human lung cancer cells via loss of mitochondrial membrane potential (∆ψm), adenosine triphosphate (ATP) depletion, ROS production, as well as cytochrome c release. Dephosphorylation of GSK3β is involved in hirsutine-mediated mitochondrial permeability transition pore (mPTP) opening through ANT1/CypD interaction. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K/Akt signaling pathway plays a critical role in hirsutine-mediated GSK3β dephosphorylation and mitochondrial apoptosis. Our in vivo study also showed that hirsutine effectively inhibits tumor growth in a A549 xenograft mouse model through ROCK1/PTEN/PI3K/Akt signaling-mediated GSK3β dephosphorylation and apoptosis. Collectively, these findings suggest a hierarchical model in which induction of apoptosis by hirsutine stems primarily from activation of ROCK1 and PTEN, inactivation of PI3K/Akt, leading in turn to GSK3β dephosphorylation and mPTP opening, and culminating in caspase-3 activation and apoptosis. These findings could provide a novel mechanistic basis for the application of hirsutine in the treatment of human lung cancer.
RNF25 promotes gefitinib resistance in EGFR-mutant NSCLC cells by inducing NF-κB-mediated ERK reactivation
Authors: Cho Jung Hee , You Yeon-Mi , Yeom Y I , Lee Dong Chul , Kim Bo-Kyung , Won Misun , Cho Byoung Chul , Kang Minho , Park Seulki , Yang Suk-Jin , Kim Jang Seong , Kim Jung-Ae , Park Kyung Chan
Published: May 2018

Non-small cell lung cancer (NSCLC) patients with EGFR mutations initially respond well to EGFR tyrosine kinase inhibitors (TKIs) but eventually exhibit acquired or innate resistance to the therapies typically due to gene mutations, such as EGFR T790M mutation or a second mutation in the downstream pathways of EGFR. Importantly, a significant portion of NSCLC patients shows TKI resistance without any known mechanisms, calling more comprehensive studies to reveal the underlying mechanisms. Here, we investigated a synthetic lethality with gefitinib using a genome-wide RNAi screen in TKI-resistant EGFR-mutant NSCLC cells, and identified RNF25 as a novel factor related to gefitinib resistance. Depletion of RNF25 expression substantially sensitized NSCLC cells to gefitinib treatment, while forced expression of RNF25 augmented gefitinib resistance in sensitive cells. We demonstrated that RNF25 mediates NF-κB activation in gefitinib-treated cells, which, in turn, induces reactivation of ERK signal to cause the drug resistance. We identified that the ERK reactivation occurs via the function of cytokines, such as IL-6, whose expression is transcriptionally induced in a gefitinib-dependent manner by RNF25-mediated NF-κB signals. These results suggest that RNF25 plays an essential role in gefitinib resistance of NSCLC by mediating cross-talk between NF-κB and ERK pathways, and provide a novel target for the combination therapy to overcome TKI resistance of NSCLC.
IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner
Authors: Zhao Mingsheng , Li Yulan , Guo Chun , Wang Liyang , Chu Hongxia , Zhu Faliang , Li Yan , Wang Xiaoyan , Wang Qun , Zhao Wei , Shi Yongyu , Chen WanJun , Zhang Lining
Published: May 2018

IL-37 is a new member of IL-1 family and possesses five different isoforms (named as IL-37 a–e). IL-37b has been demonstrated as a physiological suppressor of immune responses. However, the function of other isoforms remains unknown. Here, we show that IL-37d possesses anti-inflammatory roles both in vitro and in vivo. Firstly, IL-37d is expressed in peripheral blood mononuclear cells (PBMCs) and umbilical cords-derived mesenchymal stem cells (UCMSCs). Secondly, IL-37d overexpression markedly inhibits IL-1β-induced IL-6 production in A549 cells. Consistently, bone marrow-derived macrophages (BMDMs) from IL-37d transgenic mice express low levels of pro-inflammatory cytokines (such as IL-6 and TNF-α) following LPS stimulation, compared with those from wild-type mice. Furthermore, IL-37d transgenic mice produce less pro-inflammatory cytokines, and show much less degree of LPS-induced endotoxemia in vivo. Mechanistically, IL-37d interacts with Smad3 and promotes nuclear translocation of pSmad3. SIS3 (a specific Smad3 inhibitor) treatment completely blocks the inhibitory effects of IL-37d. Thus, our data indicate that IL-37d is a functional cytokine that negatively regulates pro-inflammatory cytokines expression in a Smad3-dependent manner.
Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting ANO5 mutations
Authors: Sui Tingting , Xu Li , Lau Yeh Siang , Liu Di , Liu Tingjun , Gao Yandi , Lai Liangxue , Han Renzhi , Li Zhanjun
Published: May 2018

Limb girdle muscular dystrophy type 2L (LGMD2L) and Miyoshi myopathy type 3 (MMD3) are autosomal recessive muscular dystrophy caused by mutations in the gene encoding anoctamin-5 (ANO5), which belongs to the anoctamin protein family. Two independent lines of mice with complete disruption of ANO5 transcripts did not exhibit overt muscular dystrophy phenotypes; instead, one of these mice was observed to present with some abnormality in sperm motility. In contrast, a third line of ANO5-knockout (KO) mice with residual expression of truncated ANO5 expression was reported to display defective membrane repair and very mild muscle pathology. Many of the ANO5-related patients carry point mutations or small insertions/deletions (indels) in the ANO5 gene. To more closely mimic the human ANO5 mutations, we engineered mutant ANO5 rabbits via co-injection of Cas9 mRNA and sgRNA into the zygotes. CRISPR-mediated small indels in the exon 12 and/or 13 in the mutant rabbits lead to the development of typical signs of muscular dystrophy with increased serum creatine kinase (CK), muscle necrosis, regeneration, fatty replacement and fibrosis. This novel ANO5 mutant rabbit model would be useful in studying the disease pathogenesis and therapeutic treatments for ANO5-deficient muscular dystrophy.
Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition
Authors: Jing Bo , Jin Jin , Xiang Rufang , Liu Meng , Yang Li , Tong Yin , Xiao Xinhua , Lei Hu , Liu Wei , Xu Hanzhang , Deng Jiong , Zhou Li , Wu Yingli
Published: May 2018

Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.
mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis
Authors: Chapman Nicole M. , Zeng Hu , Nguyen Thanh-Long M. , Wang Yanyan , Vogel Peter , Dhungana Yogesh , Liu Xiaojing , Neale Geoffrey , Locasale Jason W. , Chi Hongbo
Published: May 2018

Regulatory T (Treg) cells derived from the thymus (tTreg) and periphery (pTreg) have central and distinct functions in immunosuppression, but mechanisms for the generation and activation of Treg subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tTreg and pTreg cells. mTOR signaling is crucial for programming activated Treg-cell function to protect immune tolerance and tissue homeostasis. Treg-specific deletion of mTOR drives spontaneous effector T-cell activation and inflammation in barrier tissues and is associated with reduction in both thymic-derived effector Treg (eTreg) and pTreg cells. Mechanistically, mTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, deletion of mitochondrial transcription factor A (Tfam) severely impairs Treg-cell suppressive function and eTreg-cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis.
Author Correction: Atomic-resolution three-dimensional hydration structures on a heterogeneously charged surface
Authors: Umeda Kenichi , Zivanovic Lidija , Kobayashi Kei , Ritala Juha , Kominami Hiroaki , Spijker Peter , Foster Adam S. , Yamada Hirofumi
Published: May 2018

The original version of the Supplementary Information associated with this Article contained an error in Supplementary Figure 9e,f in which the y-axes were incorrectly labelled from ‘−40’ to ‘40’, rather than the correct ‘-400’ to ‘400’. The HTML has been updated to include a corrected version of the Supplementary Information.
Male germ cells support long-term propagation of Zika virus
Authors: Robinson Christopher L. , Chong Angie C. N. , Ashbrook Alison W. , Jeng Ginnie , Jin Julia , Chen Haiqi , Tang Elizabeth I. , Martin Laura A. , Kim Rosa S. , Kenyon Reyn M. , Do Eileen , Luna Joseph M. , Saeed Mohsan , Zeltser Lori , Ralph Harold , Dudley Vanessa L. , Goldstein Marc , Rice Charles M. , Cheng C. Yan , Seandel Marco , Chen Shuibing
Published: May 2018

Evidence of male-to-female sexual transmission of Zika virus (ZIKV) and viral RNA in semen and sperm months after infection supports a potential role for testicular cells in ZIKV propagation. Here, we demonstrate that germ cells (GCs) are most susceptible to ZIKV. We found that only GCs infected by ZIKV, but not those infected by dengue virus and yellow fever virus, produce high levels of infectious virus. This observation coincides with decreased expression of interferon-stimulated gene Ifi44l in ZIKV-infected GCs, and overexpression of Ifi44l results in reduced ZIKV production. Using primary human testicular tissue, we demonstrate that human GCs are also permissive for ZIKV infection and production. Finally, we identified berberine chloride as a potent inhibitor of ZIKV infection in both murine and human testes. Together, these studies identify a potential cellular source for propagation of ZIKV in testes and a candidate drug for preventing sexual transmission of ZIKV.
The hepcidin-ferroportin axis controls the iron content of Salmonella-containing vacuoles in macrophages
Authors: Lim Daejin , Kim Kwang Soo , Jeong Jae-Ho , Marques Oriana , kim Hyun-Ju , Song Miryoung , Lee Tae-Hoon , Kim Jae Il , Choi Hueng-Sik , Min Jung-Joon , Bumann Dirk , Muckenthaler Martina U. , Choy Hyon E.
Published: May 2018

Macrophages release iron into the bloodstream via a membrane-bound iron export protein, ferroportin (FPN). The hepatic iron-regulatory hormone hepcidin controls FPN internalization and degradation in response to bacterial infection. Salmonella typhimurium can invade macrophages and proliferate in the Salmonella-containing vacuole (SCV). Hepcidin is reported to increase the mortality of Salmonella-infected animals by increasing the bacterial load in macrophages. Here we assess the iron levels and find that hepcidin increases iron content in the cytosol but decreases it in the SCV through FPN on the SCV membrane. Loss-of-FPN from the SCV via the action of hepcidin impairs the generation of bactericidal reactive oxygen species (ROS) as the iron content decreases. We conclude that FPN is required to provide sufficient iron to the SCV, where iron serves as a cofactor for the generation of antimicrobial ROS rather than as a nutrient for Salmonella.
Overpumping leads to California groundwater arsenic threat
Authors: Smith Ryan , Knight Rosemary , Fendorf Scott
Published: May 2018

Water resources are being challenged to meet domestic, agricultural, and industrial needs. To complement finite surface water supplies that are being stressed by changes in precipitation and increased demand, groundwater is increasingly being used. Sustaining groundwater use requires considering both water quantity and quality. A unique challenge for groundwater use, as compared with surface water, is the presence of naturally occurring contaminants within aquifer sediments, which can enter the water supply. Here we find that recent groundwater pumping, observed through land subsidence, results in an increase in aquifer arsenic concentrations in the San Joaquin Valley of California. By comparison, historic groundwater pumping shows no link to current groundwater arsenic concentrations. Our results support the premise that arsenic can reside within pore water of clay strata within aquifers and is released due to overpumping. We provide a quantitative model for using subsidence as an indicator of arsenic concentrations correlated with groundwater pumping.
Observation of different reactivities of para and ortho-water towards trapped diazenylium ions
Authors: Kilaj Ardita , Gao Hong , Rösch Daniel , Rivero Uxia , Küpper Jochen , Willitsch Stefan
Published: May 2018

Water is one of the most fundamental molecules in chemistry, biology and astrophysics. It exists as two distinct nuclear-spin isomers, para- and ortho-water, which do not interconvert in isolated molecules. The experimental challenges in preparing pure samples of the two isomers have thus far precluded a characterization of their individual chemical behavior. Capitalizing on recent advances in the electrostatic deflection of polar molecules, we separate the ground states of para- and ortho-water in a molecular beam to show that the two isomers exhibit different reactivities in a prototypical reaction with trapped diazenylium ions. Based on ab initio calculations and a modelling of the reaction kinetics using rotationally adiabatic capture theory, we rationalize this finding in terms of different rotational averaging of ion-dipole interactions during the reaction.
Signal and noise extraction from analog memory elements for neuromorphic computing
Authors: Gong N. , Idé T. , Kim S. , Boybat I. , Sebastian A. , Narayanan V. , Ando T.
Published: May 2018

Dense crossbar arrays of non-volatile memory (NVM) can potentially enable massively parallel and highly energy-efficient neuromorphic computing systems. The key requirements for the NVM elements are continuous (analog-like) conductance tuning capability and switching symmetry with acceptable noise levels. However, most NVM devices show non-linear and asymmetric switching behaviors. Such non-linear behaviors render separation of signal and noise extremely difficult with conventional characterization techniques. In this study, we establish a practical methodology based on Gaussian process regression to address this issue. The methodology is agnostic to switching mechanisms and applicable to various NVM devices. We show tradeoff between switching symmetry and signal-to-noise ratio for HfO2-based resistive random access memory. Then, we characterize 1000 phase-change memory devices based on Ge2Sb2Te5 and separate total variability into device-to-device variability and inherent randomness from individual devices. These results highlight the usefulness of our methodology to realize ideal NVM devices for neuromorphic computing.
Regulation of cortical activity and arousal by the matrix cells of the ventromedial thalamic nucleus
Authors: Honjoh Sakiko , Sasai Shuntaro , Schiereck Shannon S , Nagai Hirotaka , Tononi Giulio , Cirelli Chiara
Published: May 2018

The “non-specific” ventromedial thalamic nucleus (VM) has long been considered a candidate for mediating cortical arousal due to its diffuse, superficial projections, but direct evidence was lacking. Here, we show in mice that the activity of VM calbindin1-positive matrix cells is high in wake and REM sleep and low in NREM sleep, and increases before cortical activity at the sleep-to-wake transition. Optogenetic stimulation of VM cells rapidly awoke all mice from NREM sleep and consistently caused EEG activation during slow wave anesthesia, while arousal did not occur from REM sleep. Conversely, chemogenetic inhibition of VM decreased wake duration. Optogenetic activation of the “specific” ventral posteromedial nucleus (VPM) did not cause arousal from either NREM or REM sleep. Thus, matrix cells in VM produce arousal and broad cortical activation during NREM sleep and slow wave anesthesia in a way that accounts for the effects classically attributed to “non-specific” thalamic nuclei.
Trapping an octahedral Ag6 kernel in a seven-fold symmetric Ag56 nanowheel
Authors: Wang Zhi , Su Hai-Feng , Kurmoo Mohamedally , Tung Chen-Ho , Sun Di , Zheng Lan-Sun
Published: May 2018

High-nuclearity silver clusters are appealing synthetic targets for their remarkable structures, but most are isolated serendipitously. We report here six giant silver-thiolate clusters mediated by solvents, which not only dictate the formation of an octahedral Ag64+ kernel, but also influence the in situ-generated Mo-based anion templates. The typical sevenfold symmetric silver nanowheels show a hierarchical cluster-in-cluster structure that comprises an outermost Ag56 shell and an inner Ag64+ kernel in the centre with seven MoO42− anion templates around it. Electrospray ionization mass spectrometry analyses reveal the underlying rule for the formation of such unique silver nanowheels. This work establishes a solvent–intervention approach to construct high-nuclearity silver clusters in which both the formation of octahedral Ag64+ kernel and in situ generation of various Mo-based anion templates can be simultaneously controlled.
Interfacial photochemistry at the ocean surface is a global source of organic vapors and aerosols
Authors: Brüggemann Martin , Hayeck Nathalie , George Christian
Published: May 2018

The surface of the oceans acts as a global sink and source for trace gases and aerosol particles. Recent studies suggest that photochemical reactions at this air/water interface produce organic vapors, enhancing particle formation in the atmosphere. However, current model calculations neglect this abiotic source of reactive compounds and account only for biological emissions. Here we show that interfacial photochemistry serves as a major abiotic source of volatile organic compounds (VOCs) on a global scale, capable to compete with emissions from marine biology. Our results indicate global emissions of 23.2–91.9 TgC yr–1 of organic vapors from the oceans into the marine atmosphere and a potential contribution to organic aerosol mass of more than 60% over the remote ocean. Moreover, we provide global distributions of VOC formation potentials, which can be used as simple tools for field studies to estimate photochemical VOC emissions depending on location and season.
Amorphous topological superconductivity in a Shiba glass
Authors: Pöyhönen Kim , Sahlberg Isac , Westström Alex , Ojanen Teemu
Published: May 2018

Topological states of matter support quantised nondissipative responses and exotic quantum particles that cannot be accessed in common materials. The exceptional properties and application potential of topological materials have triggered a large-scale search for new realisations. Breaking away from the popular trend focusing almost exclusively on crystalline symmetries, we introduce the Shiba glass as a platform for amorphous topological quantum matter. This system consists of an ensemble of randomly distributed magnetic atoms on a superconducting surface. We show that subgap Yu–Shiba–Rusinov states on the magnetic moments form a topological superconducting phase at critical density despite a complete absence of spatial order. Experimental signatures of the amorphous topological state can be obtained by scanning tunnelling microscopy measurements probing the topological edge mode. Our discovery demonstrates the physical feasibility of amorphous topological quantum matter, presenting a concrete route to fabricating new topological systems from nontopological materials with random dopants.
Superfluid motion and drag-force cancellation in a fluid of light
Authors: Michel Claire , Boughdad Omar , Albert Mathias , Larré Pierre-Élie , Bellec Matthieu
Published: May 2018

Quantum fluids of light merge many-body physics and nonlinear optics, revealing quantum hydrodynamic features of light when it propagates in nonlinear media. One of the most outstanding evidence of light behaving as an interacting fluid is its ability to carry itself as a superfluid. Here, we report a direct experimental detection of the transition to superfluidity in the flow of a fluid of light past an obstacle in a bulk nonlinear crystal. In this cavityless all-optical system, we extract a direct optical analog of the drag force exerted by the fluid of light and measure the associated displacement of the obstacle. Both quantities drop to zero in the superfluid regime characterized by a suppression of long-range radiation from the obstacle. The experimental capability to shape both the flow and the potential landscape paves the way for simulation of quantum transport in complex systems.
A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin
Authors: Menchon Grégory , Prota Andrea E. , Lucena-Agell Daniel , Bucher Pascal , Jansen Rolf , Irschik Herbert , Müller Rolf , Paterson Ian , Díaz J. Fernando , Altmann Karl-Heinz , Steinmetz Michel O.
Published: May 2018

Microtubule-targeting agents (MTAs) like taxol and vinblastine are among the most successful chemotherapeutic drugs against cancer. Here, we describe a fluorescence anisotropy-based assay that specifically probes for ligands targeting the recently discovered maytansine site of tubulin. Using this assay, we have determined the dissociation constants of known maytansine site ligands, including the pharmacologically active degradation product of the clinical antibody-drug conjugate trastuzumab emtansine. In addition, we discovered that the two natural products spongistatin-1 and disorazole Z with established cellular potency bind to the maytansine site on β-tubulin. The high-resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of an additional sub-site adjacent to the pocket shared by all maytansine-site ligands, which could be exploitable as a distinct, separate target site for small molecules. Our study provides a basis for the discovery and development of next-generation MTAs for the treatment of cancer.