bluuebunny/crossref_metadata_2025 huggingface dataset:
Watershed Merging: A Simple and Effective Algorithm for Channel Network Identification and Extraction
Authors: Zhang Yaoxin , Jia Yafei
Published: September 2020

Channel network identification is an important practice in not only hydrologic analysis but also hydraulic computation. In this paper, a new algorithm, watershed merging, is proposed to automatically identify and extract channel networks. In the water‐merging algorithm, based on the fact that the sink cell of a dendritic watershed is either a depression cell or a flat cell, a macroscale approach is proposed to treat the depression and flat areas (DAFA) and determine the flow direction within those areas, where the conventional D8 slope calculation fails. The separated neighboring watersheds are merged together using information of neighboring watersheds instead of the D8 cells. This progressive merging process starts from small neighboring watershed to larger ones. The example and applications demonstrated that the proposed watershed‐merging algorithm is effective in resolving the DAFA problems and identifying channel networks.
Ross Receives 2019 Keiiti Aki Early Career Award
Authors:   AGU
Published: September 2020

Zachary E. Ross received the 2019 Keiiti Aki Early Career Award at AGU’s Fall Meeting 2019, held 9–13 December in San Francisco, Calif. The award recognizes “scientific accomplishments in the field of seismology.”
Fast Climate Responses to Aerosol Emission Reductions During the COVID‐19 Pandemic
Authors: Yang Yang , Ren Lili , Li Huimin , Wang Hailong , Wang Pinya , Chen Lei , Yue Xu , Liao Hong
Published: September 2020

The reduced human activities and associated decreases in aerosol emissions during the COVID‐19 pandemic are expected to affect climate. Assuming emission changes during lockdown, back‐to‐work and post‐lockdown stages of COVID‐19, climate model simulations show a surface warming over continental regions of the Northern Hemisphere. In January–March, there was an anomalous warming of 0.05–0.15 K in eastern China, and the surface temperature increase was 0.04–0.07 K in Europe, eastern United States, and South Asia in March–May. The longer the emission reductions undergo, the warmer the climate would become. The emission reductions explain the observed temperature increases of 10–40% over eastern China relative to 2019. A southward shift of the ITCZ is also seen in the simulations. This study provides an insight into the impact of COVID‐19 pandemic on global and regional climate and implications for immediate actions to mitigate fast global warming.
Reconciling the Relationship Between the AMOC and Labrador Sea in OSNAP Observations and Climate Models
Authors: Menary Matthew B. , Jackson Laura C. , Lozier M. Susan
Published: September 2020

The AMOC (Atlantic Meridional Overturning Circulation) is a key driver of climate variability. Our understanding, based largely on climate models, is that the Labrador Sea has an important role in shaping the evolution of the AMOC. However, a recent high‐profile observational campaign (Overturning in the Subpolar North Atlantic, OSNAP) has called into question the importance of the Labrador Sea, and hence the credibility of the AMOC representation in climate models. Here, we attempt to reconcile these viewpoints by making the first direct comparison between OSNAP and a coupled climate model. The model compares well to the observations, demonstrating a more prominent role for overturning in the eastern than western subpolar gyre. Density anomalies generated by surface forcing in the Irminger Sea propagate into the Labrador Sea, where they dominate the density variability. Thus, the Labrador Sea may not be the origin of AMOC variability despite correlations with densities there.
Local and Remote Drivers of Southeast Australian Drought
Authors: Holgate C. M. , Van Dijk A. I. J. M. , Evans J. P. , Pitman A. J.
Published: September 2020

Droughts are associated with large‐scale modes of variability, synoptic‐scale systems, and terrestrial processes. Quantifying their relative roles in influencing drought guides process understanding, helps identify weaknesses in climate models, and focuses model improvements. Using a Lagrangian back‐trajectory approach we provide the first quantification of the change in moisture supply during major droughts in southeast Australia, including the causes of the changes. Drought onset and intensification were driven by reduced moisture supply from the ocean, as moisture was circulated away from the region, combined with an absence of precipitation‐generating mechanisms over land. During termination, strengthened moist easterly flows from the Tasman and Coral Seas promoted anomalously high rainfall. Our approach reveals terrestrial moisture sources played a secondary role, amplifying rainfall anomalies by less than 6%. Simulating droughts therefore requires deeper understanding of the relationship between moisture advection and synoptic‐scale circulation and how large‐scale climate variability and terrestrial processes modify these relationships.
Ultrafast Kelvin Wave Variations in the Surface Magnetic Field
Authors: Forbes Jeffrey M. , He Maosheng , Maute Astrid , Zhang Xiaoli
Published: September 2020

A suite of general circulation models is used to investigate the surface magnetic perturbations due to the ionospheric currents driven by an eastward‐propagating ultrafast Kelvin wave (UFKW) packet with periods between 2 and 4 days and zonal wave number
. The simulated daytime UFKW‐driven meridional magnetic perturbations dBn (∼±5 nT) (or zonal currents) between about 5° and 20° magnetic latitude in each hemisphere are opposite in sign to those equatorward of ±5° and produced by the equatorial electrojet (EEJ), with the directions on any given day determined by the phase of the UFKW as it propagates eastward with respect to the sunlit ionosphere. Since the nominal daytime Sq zonal current between ∼±30° is uniformly eastward flowing, the present results are consistent with the hypothesis that the EEJ is part of a local current vortex with oppositely directed currents near the equator versus those between 5° and 20° at low latitudes. UFKWs are a special wave type wherein meridional winds are relatively small, which leads to our finding that the EEJ dBn constitutes a simple quantitative proxy for E‐region UFKW neutral winds near the 107‐km peak height of the Hall conductivity, including the variable wave period of the UFKW packet. Numerical experiments are also performed to understand the longitude distribution of actual ground magnetometer measurements that are needed to reliably extract the UFKW dBn signal and hence the neutral winds, both of which are closely linked to plasma drifts and electron densities in the equatorial F region. Using actual magnetometer data it is moreover shown that the UFKW dBn signal is easily measurable. Therefore measurements of EEJ dBn can potentially be used to infer UFKW activity for scientific investigations focusing on coupling between the tropical troposphere and the ionosphere‐thermosphere.
Detachment of Low‐Salinity Water From the Yellow River Plume in Summer
Authors: Yu Xiaojie , Guo Xinyu , Gao Huiwang
Published: September 2020

Historical hydrographic data reveal that low‐salinity water can detach from the Yellow River plume in summer. In this study, the mechanism of this detachment is examined using a three‐dimensional numerical model that reproduced the observed detachment, including the position and size of the detached low‐salinity water patch. Sensitivity experiments showed that tide‐induced residual currents and tidal mixing around the Yellow River mouth played key roles in the detachment during spring tide. During the transition from neap tide to spring tide, the intensification of the northward tide‐induced residual current and the weakening of the southward density‐driven current lead to a net northward residual current (0.03 m/s), transporting high‐salinity water to the southern area of low‐salinity water. Meanwhile, the gradually strengthened tidal mixing also increased surface salinity, which was apparent in the central area of low‐salinity water. With the combination of these two effects, the low‐salinity water was separated into two parts during spring tide; that is, detachment of low‐salinity water occurred. The above scenario works with a condition of no wind. With the prevailing southeasterly winds during summer, the northeastward wind‐induced surface current promoted detachment by moving the detached low‐salinity water northeastward and enlarging its size. In contrast, the northerly wind that prevails in the other seasons drove low‐salinity water southward, which then flowed along the coast and hindered detachment. Consequently, the detachment of low‐salinity water from the Yellow River plume occurs only in summer.
Atlantic Water Modification North of Svalbard in the Mercator Physical System From 2007 to 2020
Authors: Athanase Marylou , Provost Christine , Pérez‐Hernández M. Dolores , Sennéchael Nathalie , Bertosio Cécilia , Artana Camila , Garric Gilles , Lellouche Jean‐Michel
Published: September 2020

The Atlantic Water (AW) inflow through Fram Strait, largest oceanic heat source to the Arctic Ocean, undergoes substantial modifications in the Western Nansen Basin (WNB). Evaluation of the Mercator system in the WNB, using 1,500 independent temperature‐salinity profiles and five years of mooring data, highlighted its performance in representing realistic AW inflow and hydrographic properties. In particular, favorable comparisons with mooring time‐series documenting deep winter mixed layers and changes in AW properties led us to examine winter conditions in the WNB over the 2007–2020 period. The model helped describe the interannual variations of winter mixed layers and documented several processes at stake in modifying AW beyond winter convection: trough outflows and lateral exchange through vigorous eddies. Recently modified AW, either via local convection or trough outflows, were identified as homogeneous layers of low buoyancy frequency. Over the 2007–2020 period, two winters stood out with extreme deep mixed layers in areas that used to be ice‐covered: 2017/18 over the northern Yermak Plateau‐Sofia Deep; 2012/13 on the continental slope northeast of Svalbard with the coldest and freshest modified AW of the 12‐year time series. The northern Yermak Plateau‐Sofia Deep and continental slope areas became “Marginal Convection Zones” in 2011 with, from then on, occasionally ice‐free conditions, 50‐m‐ocean temperatures always above 0 °C and highly variable mixed layer depths and ocean‐to‐atmosphere heat fluxes. In the WNB where observations require considerable efforts and resources, the Mercator system proved to be a good tool to assess Atlantic Water modifications in winter.
Herbivore Assemblage as an Important Factor Modulating Grazing Effects on Ecosystem Carbon Fluxes in a Meadow Steppe in Northeast China
Authors: Chang Qing , Xu Tongtong , Ding Shiwen , Wang Ling , Liu Jushan , Wang Deli , Wang Ying , Li Zhiqiang , Zhao Xuan , Song Xuxin , Pan Duofeng
Published: September 2020

A better understanding of how grazing by large herbivores, as the major land use worldwide, affects grassland carbon fluxes is critical for predicting future uptake of CO2 in terrestrial ecosystem. Previous studies have focused on individual herbivore species; it remains poorly understood as to if and how herbivore assemblage (single vs. mixed species) would alter the impact of grazers on grassland carbon fluxes. Here we examined the effects of moderate grazing by different herbivore assemblages on net ecosystem CO2 exchange (NEE), gross ecosystem productivity (GEP), and ecosystem respiration (ER) over the growing season in two types of grassland communities in a meadow steppe. We found that herbivore assemblages significantly affected NEE, and the effects varied in the two types of grassland communities. Compared to ungrazed grassland, mixed grazing of sheep and cattle increased NEE (i.e., increased CO2 uptake) over the growing season regardless of community type, while sheep‐ or cattle‐only grazing increased NEE in the low‐diversity community and decreased it in the high‐diversity community. Herbivore assemblages altered the NEE primarily via changing GEP. The different effects of herbivore assemblages on GEP may be attributed mainly to grazing‐induced changes in soil water availability and canopy light availability. Our study indicates that mixed grazing of sheep and cattle might be an important grazing management practice to improve plant aboveground productivity and help mitigate CO2 emissions during the growing season. It should be particularly used in diverse plant communities, where it might increase grassland carbon sequestration.
δ15N of Nitric Oxide Produced Under Aerobic or Anaerobic Conditions From Seven Soils and Their Associated N Isotope Fractionations
Authors: Su Chenxia , Kang Ronghua , Zhu Weixing , Huang Wentao , Song Linlin , Wang Ang , Liu Dongwei , Quan Zhi , Zhu Feifei , Fu Pingqing , Fang Yunting
Published: September 2020

Measuring the nitrogen isotope compositions (δ15N) of nitric oxide (NO) from different sources helps to quantify the relative contributions of atmospheric NOx. Soil is one of the most important sources of atmospheric NOx, but only limited measurements on the δ15N of soil‐emitted NO exist, hampering our ability to partition sources to air pollution. Here we conducted soil incubations to measure the δ15N‐NO under defined aerobic or anaerobic conditions, favoring either nitrification or denitrification. Soils were collected from seven sites spanning three ecosystems in northern China (two agricultural, two forest, and three grassland sites). We found that the δ15N‐NO and their associated N isotope fractionations were significantly different between anaerobic and aerobic conditions in seven soils. Under aerobic condition, the δ15N‐NO ranged from −62‰ to −50‰ (averaged −56 ± 4‰), being significantly more negative (by 23‰) than those under anaerobic condition (−45‰ to −23‰, averaged −33 ± 7‰). The apparent N isotope fractionation for NO production under aerobic condition (15εaerobic = 61 ± 3‰) was significantly higher (by 26‰) than under anaerobic condition (15εanaerobic = 35 ± 6‰), with a small variability among ecosystem types. Our study demonstrates that the δ15N‐NO from different soils are very different from fuel combustions (mainly from 0‰ to +20‰), supporting that measuring 15N is a useful tool to partition the contributions of soil NO to atmospheric NOx. Our results also imply δ15N‐NO produced by nitrification and denitrification distinctly different, as these two processes are dominant processes producing NO under aerobic and anaerobic conditions, respectively.
Attribution of Land‐Use/Land‐Cover Change Induced Surface Temperature Anomaly: How Accurate Is the First‐Order Taylor Series Expansion?
Authors: Chen Chi , Wang Liang , Myneni Ranga B. , Li Dan
Published: September 2020

Land surface temperature (LST) responds to land‐use/land‐cover change (LULCC), which modifies surface properties that control the surface energy balance (SEB). Quantifying changes in LST due to individual perturbations caused by LULCC is an attribution problem. Most attribution methods are based on the first‐order Taylor series expansion (FOTSE) of a linearized SEB equation. The accuracy of these methods is affected by the use of FOTSE at two places. The first is to linearize the SEB equation and to obtain an analytical solution for LST (the LST model), and the second is to obtain LST changes as the linear sum of concurrent changes in multiple factors (the attribution model). In this study, we systematically assess the importance of non‐linear effects lost in these linearization processes using the second‐order Taylor series expansion (SOTSE). Results show that while the SOTSE LST model outperforms the FOTSE LST model, the order of Taylor series expansion in the LST model does not significantly influence the attribution of LST changes. However, the SOTSE attribution model is considerably more accurate than the FOTSE attribution model, especially when the magnitude of perturbations is large. Results suggest that contributions from higher‐order and cross‐order terms in the attribution model can be as large as 50%. Sensitivity analysis further shows that non‐linear effects associated with changing surface resistance for LULCC scenarios with large perturbations (e.g., deforestation and urbanization) are particularly strong. In conclusion, we recommend using the FOTSE LST model and the SOTSE attribution model.
Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer
Authors: Wang Zhen , Yang Chenghui , Li Lili , Jin Xiaoyan , Zhang Zhigang , Zheng Haiyan , Pan Jun , Shi Liyun , Jiang Zhou , Su Ke , Li Baizhou , Shao Xuan , Qiu Fuming , Yan Jun , Huang Jian
Published: September 2020

Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62Ldim neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62Ldim neutrophils in 86 breast cancer patients. We demonstrated that CD62Ldim neutrophils accelerated lung metastasis and that interventions targeting the “HMGB1-CD62Ldim neutrophil-NETs” axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62Ldim neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.
Breast cancer survival in Nordic BRCA2 mutation carriers—unconventional association with oestrogen receptor status
Authors: Olafsdottir Elinborg J. , Borg Ake , Jensen Maj-Britt , Gerdes Anne-Marie , Johansson Anna L. V. , Barkardottir Rosa B. , Johannsson Oskar T. , Ejlertsen Bent , Sønderstrup Ida Marie Heeholm , Hovig Eivind , Lænkholm Anne-Vibeke , Hansen Thomas van Overeem , Olafsdottir Gudridur H. , Rossing Maria , Jonasson Jon G. , Sigurdsson Stefan , Loman Niklas , Nilsson Martin P. , Narod Steven A. , Tryggvadottir Laufey
Published: September 2020

Background

The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers.

Methods

We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression.

Results

About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26–0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07–3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26–4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11–3.59, P = 0.02).

Conclusions

The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models
Authors: Vervloessem Tamara , Sasi Binu K. , Xerxa Elena , Karamanou Spyridoula , Kale Justin , La Rovere Rita M. , Chakraborty Supriya , Sneyers Flore , Vogler Meike , Economou Anastassios , Laurenti Luca , Andrews David W. , Efremov Dimitar G. , Bultynck Geert
Published: September 2020

Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2’s hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366’s cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation.
Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis
Authors: O’Neill John S. , Hoyle Nathaniel P. , Robertson J. Brian , Edgar Rachel S. , Beale Andrew D. , Peak-Chew Sew Y. , Day Jason , Costa Ana S. H. , Frezza Christian , Causton Helen C.
Published: September 2020

Yeast physiology is temporally regulated, this becomes apparent under nutrient-limited conditions and results in respiratory oscillations (YROs). YROs share features with circadian rhythms and interact with, but are independent of, the cell division cycle. Here, we show that YROs minimise energy expenditure by restricting protein synthesis until sufficient resources are stored, while maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells sequester and store metabolic resources via increased transport, autophagy and biomolecular condensation. Replete stores trigger increased H+ export which stimulates TORC1 and liberates proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates translational bursting, liquidation of storage carbohydrates, increased ATP turnover, and the export of osmolytes. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints selected for temporal organisation that promotes oscillatory behaviour.
Multiple capsid protein binding sites mediate selective packaging of the alphavirus genomic RNA
Authors: Brown Rebecca S. , Anastasakis Dimitrios G. , Hafner Markus , Kielian Margaret
Published: September 2020

The alphavirus capsid protein (Cp) selectively packages genomic RNA (gRNA) into the viral nucleocapsid to produce infectious virus. Using photoactivatable ribonucleoside crosslinking and an innovative biotinylated Cp retrieval method, here we comprehensively define binding sites for Semliki Forest virus (SFV) Cp on the gRNA. While data in infected cells demonstrate Cp binding to the proposed genome packaging signal (PS), mutagenesis experiments show that PS is not required for production of infectious SFV or Chikungunya virus. Instead, we identify multiple Cp binding sites that are enriched on gRNA-specific regions and promote infectious SFV production and gRNA packaging. Comparisons of binding sites in cytoplasmic vs. viral nucleocapsids demonstrate that budding causes discrete changes in Cp-gRNA interactions. Notably, Cp’s top binding site is maintained throughout virus assembly, and specifically binds and assembles with Cp into core-like particles in vitro. Together our data suggest a model for selective alphavirus genome recognition and assembly.
SARS-CoV-2 seroprevalence and neutralizing activity in donor and patient blood
Authors: Ng Dianna L. , Goldgof Gregory M. , Shy Brian R. , Levine Andrew G. , Balcerek Joanna , Bapat Sagar P. , Prostko John , Rodgers Mary , Coller Kelly , Pearce Sandra , Franz Sergej , Du Li , Stone Mars , Pillai Satish K. , Sotomayor-Gonzalez Alicia , Servellita Venice , Martin Claudia Sanchez San , Granados Andrea , Glasner Dustin R. , Han Lucy M. , Truong Kent , Akagi Naomi , Nguyen David N. , Neumann Neil M. , Qazi Daniel , Hsu Elaine , Gu Wei , Santos Yale A. , Custer Brian , Green Valerie , Williamson Phillip , Hills Nancy K. , Lu Chuanyi M. , Whitman Jeffrey D. , Stramer Susan L. , Wang Candace , Reyes Kevin , Hakim Jill M. C. , Sujishi Kirk , Alazzeh Fariba , Pham Lori , Thornborrow Edward , Oon Ching-Ying , Miller Steve , Kurtz Theodore , Simmons Graham , Hackett John , Busch Michael P. , Chiu Charles Y.
Published: September 2020

Given the limited availability of serological testing to date, the seroprevalence of SARS-CoV-2-specific antibodies in different populations has remained unclear. Here, we report very low SARS-CoV-2 seroprevalence in two San Francisco Bay Area populations. Seroreactivity was 0.26% in 387 hospitalized patients admitted for non-respiratory indications and 0.1% in 1,000 blood donors in early April 2020. We additionally describe the longitudinal dynamics of immunoglobulin-G (IgG), immunoglobulin-M (IgM), and in vitro neutralizing antibody titers in COVID-19 patients. The median time to seroconversion ranged from 10.3–11.0 days for these 3 assays. Neutralizing antibodies rose in tandem with immunoglobulin titers following symptom onset, and positive percent agreement between detection of IgG and neutralizing titers was >93%. These findings emphasize the importance of using highly accurate tests for surveillance studies in low-prevalence populations, and provide evidence that seroreactivity using SARS-CoV-2 anti-nucleocapsid protein IgG and anti-spike IgM assays are generally predictive of in vitro neutralizing capacity.
mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability
Authors: Gremke Niklas , Polo Pierfrancesco , Dort Aaron , Schneikert Jean , Elmshäuser Sabrina , Brehm Corinna , Klingmüller Ursula , Schmitt Anna , Reinhardt Hans Christian , Timofeev Oleg , Wanzel Michael , Stiewe Thorsten
Published: September 2020

Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.
A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease
Authors: Ikenoue Tatsuya , Aprile Francesco A. , Sormanni Pietro , Ruggeri Francesco S. , Perni Michele , Heller Gabriella T. , Haas Christian P. , Middel Christoph , Limbocker Ryan , Mannini Benedetta , Michaels Thomas C. T. , Knowles Tuomas P. J. , Dobson Christopher M. , Vendruscolo Michele
Published: September 2020

Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.
Scavenging by threatened turtles regulates freshwater ecosystem health during fish kills
Authors: Santori Claudia , Spencer Ricky-John , Thompson Michael B. , Whittington Camilla M. , Burd Thomas H. , Currie Samantha B. , Finter Timothy J. , Van Dyke James U.
Published: September 2020

Humans are increasing the frequency of fish kills by degrading freshwater ecosystems. Simultaneously, scavengers like freshwater turtles are declining globally, including in the Australian Murray–Darling Basin. Reduced scavenging may cause water quality problems impacting both ecosystems and humans. We used field and mesocosm experiments to test whether scavenging by turtles regulates water quality during simulated fish kills. In the field, we found that turtles were important scavengers of fish carrion. In mesocosms, turtles rapidly consumed carrion, and water quality in mesocosms with turtles returned to pre-fish kill levels faster than in turtle-free controls. Our experiments have important ecological implications, as they suggest that turtles are critical scavengers that regulate water quality in freshwater ecosystems. Recovery of turtle populations may be necessary to avoid the worsening of ecosystem health, particularly after fish kills, which would have devastating consequences for many freshwater species.
Efficacy of microbicides for inactivation of Ebola–Makona virus on a non-porous surface: a targeted hygiene intervention for reducing virus spread
Authors: Cutts Todd A. , Robertson Catherine , Theriault Steven S. , Nims Raymond W. , Kasloff Samantha B. , Rubino Joseph R. , Ijaz M. Khalid
Published: September 2020

Microbicides play critical roles in infection prevention and control of Ebola virus by decontaminating high-touch environmental surfaces (HITES), interrupting the virus-HITES-hands nexus. We evaluated the efficacy of formulations containing different microbicidal actives for inactivating Ebola virus–Makona strain (EBOV/Mak) on stainless-steel carriers per ASTM E2197-11. Formulations of sodium hypochlorite (NaOCl) (0.05–1%), ethanol (70%), chloroxylenol (PCMX) (0.12–0.48% by weight) in hard water, and a ready-to-use disinfectant spray with 58% ethanol (EDS), were tested at contact times of 0, or 0.5 to 10 min at ambient temperature. EBOV/Mak was inactivated (> 6 log10) by 70% ethanol after contact times ≥ 2.5 min, by 0.5% and 1% NaOCl or EDS (> 4 log10) at contact times ≥ 5 min, and by 0.12–0.48% PCMX (> 4.2 log10) at contact times ≥ 5 min. Residual infectious virus in neutralized samples was assessed by passage on cells and evaluation for viral cytopathic effect. No infectious virus was detected in cells inoculated with EBOV/Mak exposed to NaOCl (0.5% or 1%), PCMX (0.12% to 0.48%), or EDS for ≥ 5 min. These results demonstrate ≥ 6 log10 inactivation of EBOV/Mak dried on prototypic surfaces by EDS or formulations of NaOCl (≥ 0.5%), PCMX (≥ 0.12%), or 70% ethanol at contact times ≥ 5 min.
Whole transcriptome approach to evaluate the effect of aluminium hydroxide in ovine encephalon
Authors: Varela-Martínez Endika , Bilbao-Arribas Martin , Abendaño Naiara , Asín Javier , Pérez Marta , de Andrés Damián , Luján Lluís , Jugo Begoña M.
Published: September 2020

Aluminium hydroxide adjuvants are crucial for livestock and human vaccines. Few studies have analysed their effect on the central nervous system in vivo. In this work, lambs received three different treatments of parallel subcutaneous inoculations during 16 months with aluminium-containing commercial vaccines, an equivalent dose of aluminium hydroxide or mock injections. Brain samples were sequenced by RNA-seq and miRNA-seq for the expression analysis of mRNAs, long non-coding RNAs and microRNAs and three expression comparisons were made. Although few differentially expressed genes were identified, some dysregulated genes by aluminium hydroxide alone were linked to neurological functions, the lncRNA TUNA among them, or were enriched in mitochondrial energy metabolism related functions. In the same way, the miRNA expression was mainly disrupted by the adjuvant alone treatment. Some differentially expressed miRNAs had been previously linked to neurological diseases, oxidative stress and apoptosis. In brief, in this study aluminium hydroxide alone altered the transcriptome of the encephalon to a higher degree than commercial vaccines that present a milder effect. The expression changes in the animals inoculated with aluminium hydroxide suggest mitochondrial disfunction. Further research is needed to elucidate to which extent these changes could have pathological consequences.
Harmonic motion imaging of human breast masses: an in vivo clinical feasibility
Authors: Saharkhiz Niloufar , Ha Richard , Taback Bret , Li Xiaoyue Judy , Weber Rachel , Nabavizadeh Alireza , Lee Stephen A. , Hibshoosh Hanina , Gatti Vittorio , Kamimura Hermes A. S. , Konofagou Elisa E.
Published: September 2020

Non-invasive diagnosis of breast cancer is still challenging due to the low specificity of the imaging modalities that calls for unnecessary biopsies. The diagnostic accuracy can be improved by assessing the breast tissue mechanical properties associated with pathological changes. Harmonic motion imaging (HMI) is an elasticity imaging technique that uses acoustic radiation force to evaluate the localized mechanical properties of the underlying tissue. Herein, we studied the in vivo feasibility of a clinical HMI system to differentiate breast tumors based on their relative HMI displacements, in human subjects. We performed HMI scans in 10 female subjects with breast masses: five benign and five malignant masses. Results revealed that both benign and malignant masses were stiffer than the surrounding tissues. However, malignant tumors underwent lower mean HMI displacement (1.1 ± 0.5 µm) compared to benign tumors (3.6 ± 1.5 µm) and the adjacent non-cancerous tissue (6.4 ± 2.5 µm), which allowed to differentiate between tumor types. Additionally, the excised breast specimens of the same patients (n = 5) were imaged post-surgically, where there was an excellent agreement between the in vivo and ex vivo findings, confirmed with histology. Higher displacement contrast between cancerous and non-cancerous tissue was found ex vivo, potentially due to the lower nonlinearity in the elastic properties of ex vivo tissue. This preliminary study lays the foundation for the potential complementary application of HMI in clinical practice in conjunction with the B-mode to classify suspicious breast masses.
Monitoring PSA levels as chemical state-variables in metal-oxide memristors
Authors: Tzouvadaki Ioulia , Stathopoulos Spyros , Abbey Tom , Michalas Loukas , Prodromakis Themis
Published: September 2020

Medical interventions increasingly rely on biosensors that can provide reliable quantitative information. A longstanding bottleneck in realizing this, is various non-idealities that generate offsets and variable responses across sensors. Current mitigation strategies involve the calibration of sensors, performed in software or via auxiliary compensation circuitry thus constraining real-time operation and integration efforts. Here, we show that bio-functionalized metal-oxide memristors can be utilized for directly transducing biomarker concentration levels to discrete memory states. The introduced chemical state-variable is found to be dependent on the devices’ initial resistance, with its response to chemical stimuli being more pronounced for higher resistive states. We leverage this attribute along with memristors’ inherent state programmability for calibrating a biosensing array to render a homogeneous response across all cells. Finally, we demonstrate the application of this technology in detecting Prostate Specific Antigen in clinically relevant levels (ng/ml), paving the way towards applications in large multi-panel assays.
Single-institution case series of pituitary biopsy for suspected germinoma in the pediatric population: diagnostic utility, operative risks, and biopsy approaches
Authors: Day Emily L. , Smith Edward R. , Fehnel Katie P.
Published: September 2020

Little has been reported on the safety and efficacy of pituitary biopsy in the pediatric population for suspected germinoma. An updated review is needed. Patients who underwent biopsy (endoscopic endonasal vs. open craniotomy) for isolated pituitary stalk thickening were identified. Age, pre- and post-operative endocrine status, surgical approach, length of surgery, estimated blood loss, surgical morbidity, length of ICU stay, total length of stay, and pathology reports were reviewed. Nine patients met inclusion criteria. Germinoma diagnosis was rendered in 7 of 9 patients; 1 patient required two biopsy attempts. Two-patients had histology consistent with inflammation and a subsequently self-limited disease course. Average operative time, blood loss, ICU stay and overall length of stay was just over 2 h, 28 mL, 1.6 days and 3.7 days respectively. There were no intraoperative complications and all patients were discharged home. One patient developed new diabetes insipidus post-operatively. Patients who underwent endoscopic biopsy had decreased operative times and shorter hospitalizations. Biopsy for isolated pituitary stalk thickening for suspected germinoma is generally safe with high diagnostic utility. Importantly, 22% of presumed germinomas on imaging yielded alternative diagnoses on biopsy, adding support for pathology-proven data to guide treatment in relevant cases.
First report of an Onchocercidae worm infecting Psychodopygus carrerai carrerai sandfly, a putative vector of Leishmania braziliensis in the Amazon
Authors: Brilhante Andreia Fernandes , de Albuquerque Alessandra Lima , Rocha Abraham Cézar de Brito , Ayres Constância Flávia Junqueira , Paiva Marcelo Henrique Santos , de Ávila Márcia Moreira , Cardoso Cristiane de Oliveira , Mauricio Isabel L. , Galati Eunice Aparecida Bianchi
Published: September 2020

Sandflies are insects of public health interest due to their role as vectors of parasites of the genusLeishmania, as well as other pathogens.Psychodopygus carrerai carreraiis considered an important sylvatic vector ofLeishmania(Viannia)braziliensisin Amazonia. In this study, sandflies were collected in a forested area in the Xapuri municipality, in the State of Acre (Northern Brazil). TwoPs. carrerai carreraifemales were found parasitized with a larval form of a filarial worm, one in the labium of the proboscis, the other after the head was squashed, suggesting they were infective larvae. Sandflies were identified through morphological characters as well as amplification and sequencing of the cytochrome oxidase gene (COI). This was the first sequence obtained forPs. carrerai carreraifor this marker. The obtained nematodes were also characterized through direct sequencing of a fragment of COI and 12S genes, both mitochondrial, and ITS1, a nuclear marker. Phylogenetic analyses revealed that the filarial nematodes belong to a species without sequences for these markers in the database, part of family Onchocercidade and closely related to genusOnchocerca(12S tree). Although sandfly infection with nematodes including members of the Onchocercidae has been reported in the Old World, this is the first report of sandfly infection by a member of the Onchocercidae family in the New World, to the best of our knowledge. Considering that the phylogenetic relationships and location in the insect, it can be expected that this is a parasite of mammals and the transmission cycle should be clarified.
Causes and consequences of the opioid epidemic in the Netherlands: a population-based cohort study
Authors: Bedene Ajda , van Dorp Eveline L. A. , Faquih Tariq , Cannegieter Suzanna C. , Mook-Kanamori Dennis O. , Niesters Marieke , van Velzen Monique , Gademan Maaike G. J. , Rosendaal Frits R. , Bouvy Marcel L. , Dahan Albert , Lijfering Willem M.
Published: September 2020

Over the past decade opioid use has risen globally. The causes and consequences of this increase, especially in Europe, are poorly understood. We conducted a population-based cohort study using national statistics on analgesics prescriptions, opioid poisoning hospital admissions and deaths in the Netherlands from 2013 to 2017. Pain prevalence and severity was determined by using results of 2014–2017 Health Interview Surveys. Between 2013 and 2017 the proportion of residents receiving opioid prescription rose from 4.9% to 6.0%, and the proportion of those receiving NSAIDs decreased from 15.5% to 13.7%. Self-reported pain prevalence and severity remained constant, as 44.7% of 5,119 respondents reported no pain-impeded activities-of-daily-living in 2014 (aRR, 1.00 [95% CI, 0.95–1.06] in 2017 vs 2014). Over the observation period, the incidence of opioid poisoning hospitalization and death increased from 8.6 to 12.9 per 100,000 inhabitants. The incidence of severe outcomes related to opioid use increased, as 3.9% of 1,343 hospitalized for opioid poisoning died in 2013 and 4.6% of 2,055 in 2017. We demonstrated that NSAIDs prescription decreased and opioid prescription increased in the Netherlands since 2013, without an increase in pain prevalence and severity. Consequently, the incidence of severe outcomes related to opioids increased.
Traceable stimulus-dependent rapid molecular changes in dendritic spines in the brain
Authors: Kuboyama Kazuya , Inoue Takafumi , Hashimotodani Yuki , Itoh Takuya , Suzuki Tohsuke , Tetsuzawa Aya , Ohtsuka Yosuke , Kinoshita Ryo , Takara Ren , Miyazawa Tohru , Gusain Pooja , Kano Masanobu , Yamada Maki K.
Published: September 2020

Dendritic spines function as microcompartments that can modify the efficiency of their associated synapses. Here, we analyzed stimulus-dependent molecular changes in spines. The F-actin capping protein CapZ accumulates in parts of dendritic spines within regions where long-term potentiation has been induced. We produced a transgenic mouse line, AiCE-Tg, in which CapZ tagged with enhanced green fluorescence protein (EGFP-CapZ) is expressed. Twenty minutes after unilateral visual or somatosensory stimulation in AiCE-Tg mice, relative EGFP-CapZ signal intensification was seen in a subset of dendritic spines selectively in stimulated-side cortices; this right-left difference was abolished by NMDA receptor blockade. Immunolabeling of α-actinin, a PSD-95 binding protein that can recruit AMPA receptors, showed that the α-actinin signals colocalized more frequently in spines with the brightest EGFP-CapZ signals (top 100) than in spines with more typical EGFP-CapZ signal strength (top 1,000). This stimulus-dependent in vivo redistribution of EGFP-CapZ represents a novel molecular event with plasticity-like characteristics, and bright EGFP-CapZ in AiCE-Tg mice make high-CapZ spines traceable in vivo and ex vivo. This mouse line has the potential to be used to reveal sequential molecular events, including synaptic tagging, and to relate multiple types of plasticity in these spines, extending knowledge related to memory mechanisms.
Diagnosis of thyroid nodules on ultrasonography by a deep convolutional neural network
Authors: Koh Jieun , Lee Eunjung , Han Kyunghwa , Kim Eun-Kyung , Son Eun Ju , Sohn Yu-Mee , Seo Mirinae , Kwon Mi-ri , Yoon Jung Hyun , Lee Jin Hwa , Park Young Mi , Kim Sungwon , Shin Jung Hee , Kwak Jin Young
Published: September 2020

The purpose of this study was to evaluate and compare the diagnostic performances of the deep convolutional neural network (CNN) and expert radiologists for differentiating thyroid nodules on ultrasonography (US), and to validate the results in multicenter data sets. This multicenter retrospective study collected 15,375 US images of thyroid nodules for algorithm development (n = 13,560, Severance Hospital, SH training set), the internal test (n = 634, SH test set), and the external test (n = 781, Samsung Medical Center, SMC set; n = 200, CHA Bundang Medical Center, CBMC set; n = 200, Kyung Hee University Hospital, KUH set). Two individual CNNs and two classification ensembles (CNNE1 and CNNE2) were tested to differentiate malignant and benign thyroid nodules. CNNs demonstrated high area under the curves (AUCs) to diagnose malignant thyroid nodules (0.898–0.937 for the internal test set and 0.821–0.885 for the external test sets). AUC was significantly higher for CNNE2 than radiologists in the SH test set (0.932 vs. 0.840, P < 0.001). AUC was not significantly different between CNNE2 and radiologists in the external test sets (P = 0.113, 0.126, and 0.690). CNN showed diagnostic performances comparable to expert radiologists for differentiating thyroid nodules on US in both the internal and external test sets.
The use of commercial computerised cognitive games in older adults: a meta-analysis
Authors: Bonnechère Bruno , Langley Christelle , Sahakian Barbara Jacquelyn
Published: September 2020

Brain training programs are currently one effective solution to prevent cognitive decline in healthy aging. We conducted a meta-analysis of randomized controlled trials assessing the use of commercially available computerised cognitive games to improve cognitive function in people aged above 60 years old without cognitive impairment. 1,543 participants from sixteen studies were included in the meta-analysis. Statistically significant improvements were observed for processing speed (SMD increased 0.40 [95% CI 0.20–0.60], p < 0.001), working memory (0.21 [95% CI 0.08–0.34], p = 0.001), executive function (0.21 [95% CI 0.06–0.35], p = 0.006), and for verbal memory (0.12 [95% CI 0.01–0.24, p = 0.031), but not for attention or visuospatial abilities. No relationship between the age of the participants and the amount of training was found. Commercially available computerised cognitive games are effective in improving cognitive function in participants without cognitive impairment aged over 60 years.