bluuebunny/crossref_metadata_2025 huggingface dataset:
From Russia to Palestine via Poland: The Shifting Centre of Interwar Labour Zionism
Authors: Yona Rona
Published: July 2021

Under British rule Palestine gradually emerged as the new centre of Zionism. The Zionist centre shifted from Eastern and Central Europe to Mandatory Palestine through a combined process of mass migration and the creation of transnational institutions. By exploring the building of transnational institutions in the 1920's, this article shows how the Labour Zionist leadership in Palestine turned its communities of origin in Eastern Europe into their supporters. With the rapid decline of the former Russian centre under the communist dictatorship, independent Poland emerged as a new centre of Zionism and the labour movement outside Palestine. The two new centres were connected by a dual structure, with Poland as the demographic centre and Palestine the political-cultural one. The dual-centre structure was unique to Labour Zionism, building a mass movement between Eastern Europe and Palestine in the 1930s, and leading ultimately to the transition of power from liberal Zionism to a Labour hegemony.
Effects of credit restrictions in the Netherlands on credit growth and inflation
Authors: Galati Gabriele , Kakes Jan , Moessner Richhild
Published: July 2021

Credit restrictions were used as a monetary policy instrument in the Netherlands from the 1960s to the early 1990s. Since these restrictions were aimed at containing money rather than credit growth, their focus was on net credit creation by the financial sector. We document the rationale of these credit restrictions and how their implementation evolved in line with the evolution of the financial system. We study the impact on the balance sheet structure of banks and other financial institutions. We find that banks mainly responded to credit restrictions by making adjustments to the liability side of their balance sheets, particularly by increasing the proportion of long-term funding. Responses on the asset side were limited, while part of the banking sector even increased lending after the adoption of a restriction. These results suggest that banks and financial institutions responded by switching to long-term funding to meet the restriction and shield their lending business. Arguably, the credit restrictions were therefore still effective in reaching their main goal. Indeed, we do find evidence of a significant effect of credit restrictions on inflation.
A captorhinid-dominated assemblage from the palaeoequatorial Permian of Menorca (Balearic Islands, western Mediterranean)
Authors: MATAMALES-ANDREU Rafel , ROIG-MUNAR Francesc X. , OMS Oriol , GALOBART Àngel , FORTUNY Josep
Published: July 2021

Moradisaurine captorhinid eureptiles were a successful group of high-fibre herbivores that lived in the arid low latitudes of Pangaea during the Permian. Here we describe a palaeoassemblage from the Permian of Menorca (Balearic Islands, western Mediterranean), consisting of ichnites of small captorhinomorph eureptiles, probably moradisaurines (Hyloidichnus), and parareptiles (cf.Erpetopus), and bones of two different taxa of moradisaurines. The smallest of the two is not diagnostic beyond Moradisaurinaeincertae sedis. The largest one, on the other hand, shows characters that are not present in any other known species of moradisaurine (densely ornamented maxillar teeth), and it is therefore described asBalearosaurus bombardensisgen. et sp. nov. Other remains found in the same outcrop are identified as cf.Balearosaurus bombardensisgen. et sp. nov., as they could also belong to the newly described taxon. This species is sister to the moradisaurine from the lower Permian of the neighbouring island of Mallorca, and is also closely related to the North American genusRothianiscus. This makes it possible to suggest the hypothesis that the Variscan mountains, which separated North America from southern Europe during the Permian, were not a very important palaeobiogeographical barrier to the dispersion of moradisaurines. In fact, mapping all moradisaurine occurrences known so far, it is shown that their distribution area encompassed both sides of the Variscan mountains, essentially being restricted to the arid belt of palaeoequatorial Pangaea, where they probably outcompeted other herbivorous clades until they died out in the late Permian.
Die intrazerebrale Hirnblutung: Akutes Ereignis und chronische Erkrankung
Authors: Göldlin Martina , Radojewski Piotr , Siepen Bernhard , Müller Madlaine , Wiest Roland , Mordasini Pasquale , Polymeris Alexandros , Engelter Stefan T. , Lyrer Philippe , Z’Graggen Werner , Fischer Urs , Seiffge David
Published: July 2021

Zusammenfassung. Die intrazerebrale Hirnblutung ist für ca. 10–15% aller Hirnschläge verantwortlich und betrifft in der Schweiz ca. 1’500–2’000 Patienten pro Jahr. Bei der Akutbehandlung ist eine interdisziplinäre Behandlung durch spezialisierte Experten in einer zertifizierten Stroke Unit oder einem Stroke Center von entscheidender Bedeutung. Ein simples ABC-care bundle (Antikoagulation revertieren, Blutdruck kontrollieren, Neurochirurgen informieren) kann das Outcome signifikant verbessern. Trotz einer hohen Mortalität sind ca. ein Drittel aller Patienten nach einer Hirnblutung funktionell unabhängig und der weitverbreitete Pessimismus ist unangebracht. Über 80% aller Hirnblutungen werden durch verschiedene Formen cerebraler Mikroangiopathien verursacht und die Risiken für eine erneute Hirnblutung oder einen ischämischen Hirnschlag unterscheiden sich deutlich. Hirnblutungspatienten sind vaskuläre Hochrisikopatienten mit einer chronischen, cerebrovaskulären Erkrankung. Sie sollten langfristig und regelmässig von neurovaskulären Spezialisten behandelt werden, um wichtige Fragen (Blutdruckmanagement, antithrombotische Therapie/Antikoagulation, spezialisierte Neurorehabilitation zur Verbesserung insbesondere neurokognitiver Defizite, Therapie zusätzlicher Komplikationen, z. B. Epilepsie) individuell zu klären und die optimale Behandlung für die Patienten zu gewährleisten. Viele aktuelle Studien werden in den nächsten Jahren wichtige Ergebnisse liefern, um die Behandlung der Hirnblutung weiter zu verbessern.
ICESat‐2 Atmospheric Channel Description, Data Processing and First Results
Authors: Palm Stephen P. , Yang Yuekui , Herzfeld Ute , Hancock David , Hayes Adam , Selmer Patrick , Hart William , Hlavka Dennis
Published: July 2021

The Advanced Topographic Laser Altimeter System (ATLAS) was launched aboard the Ice Cloud and land‐Elevation Satellite‐2 (ICESat‐2) satellite in September 2018. ATLAS is a single wavelength (532 nm) lidar system designed to acquire high resolution measurements of the earth's surface while also obtaining atmospheric backscatter from molecules, clouds, and aerosols. Because ATLAS is optimized for altimetry, the atmospheric data acquired is unique in many respects and requires non‐standard analysis techniques. For example, the high repetition rate laser limits the vertical extent of the profiles to just 14 km and causes atmospheric scattering from above 15 km to be added to the scattering in the lower 0–14 km profile. In addition, the limited vertical range of the acquired profiles renders it difficult to compute the magnitude of the solar background and hinders the application of standard calibration techniques. Despite these limitations, methods have been developed to successfully produce data products that have value to the atmospheric community for cloud and aerosol research and are currently available at the National Snow and Ice Data Center (NSIDC). In this paper we describe the ICESat‐2 atmospheric channel and the methods used to process the ATLAS raw photon count data to obtain calibrated backscatter and higher level products such as layer heights and type, blowing snow, column optical depth and apparent surface reflectance.
A Comparison of Radial Diffusion Coefficients in 1‐D and 3‐D Long‐Term Radiation Belt Simulations
Authors: Drozdov A. Y. , Allison H. J. , Shprits Y. Y. , Elkington S. R. , Aseev N. A.
Published: July 2021

Radial diffusion is one of the dominant physical mechanisms driving acceleration and loss of radiation belt electrons. A number of parameterizations for radial diffusion coefficients have been developed, each differing in the data set used. Here, we investigate the performance of different parameterizations by Brautigam and Albert (2000), https://doi.org/10.1029/1999ja900344, Brautigam et al. (2005), https://doi.org/10.1029/2004ja010612, Ozeke et al. (2014), https://doi.org/10.1002/2013ja019204, Ali et al. (2015), https://doi.org/10.1002/2014ja020419; Ali et al. (2016), https://doi.org/10.1002/2016ja023002; Ali (2016), and Liu et al. (2016), https://doi.org/10.1002/2015gl067398 on long‐term radiation belt modeling using the Versatile Electron Radiation Belt (VERB) code, and compare the results to Van Allen Probes observations. First, 1‐D radial diffusion simulations are performed, isolating the contribution of solely radial diffusion. We then take into account effects of local acceleration and loss showing additional 3‐D simulations, including diffusion across pitch‐angle, energy, and mixed diffusion. For the L* range studied, the difference between simulations with Brautigam and Albert (2000), https://doi.org/10.1029/1999ja900344, Ozeke et al. (2014), https://doi.org/10.1002/2013ja019204, and Liu et al. (2016), https://doi.org/10.1002/2015gl067398 parameterizations is shown to be small, with Brautigam and Albert (2000), https://doi.org/10.1029/1999ja900344 offering the smallest averaged (across multiple energies) absolute normalized difference with observations. Using the Ali et al. (2016), https://doi.org/10.1002/2016ja023002 parameterization tended to result in a lower flux than both the observations and the VERB simulations using the other coefficients. We find that the 3‐D simulations are less sensitive to the radial diffusion coefficient chosen than the 1‐D simulations, suggesting that for 3‐D radiation belt models, a similar result is likely to be achieved, regardless of whether Brautigam and Albert (2000), https://doi.org/10.1029/1999ja900344, Ozeke et al. (2014), https://doi.org/10.1002/2013ja019204, and Liu et al. (2016), https://doi.org/10.1002/2015gl067398 parameterizations are used.
Simulating the Climatic Effects of Irrigation Over China by Using the WRF‐Noah Model System With Mosaic Approach
Authors: Liu Guoshuai , Wang Weiguang , Shao Quanxi , Wei Jia , Zheng Jiazhong , Liu Bingjun , Chen Zefeng
Published: July 2021

Investigation on the climatic effects of irrigation is of great significance to fully understand the impact of water management on the Earth's environment and hydrological cycle. To comprehensively explore the effects of irrigation across different climatic regions over China, we propose a novel combined irrigation scheme (including dynamic and fixed irrigation schemes) into the Weather Research and Forecasting (WRF)‐Noah‐mosaic model. Two experiments (with and without irrigation) are designed to simulate the impacts of irrigation over China on regional climate. As irrigation increases the latent heat flux but decreases the sensible heat flux and surface temperature, and the magnitudes of corresponding change are highly dependent on the irrigation amounts and irrigation fraction, the evaporative cooling effects significantly reduce the warm bias over extensive irrigation area during crop growing seasons. Meanwhile, irrigation increases soil moisture during both irrigated and non‐irrigated seasons. Compared with the dynamic irrigation scheme, the fixed irrigation scheme results in relatively higher subsurface runoffs due to the continuous infiltration. In addition, the irrigation‐induced changes on precipitation during spring (March–May) are weaker than that during summer (June–August). The opposed effects of irrigation cooling and wetting on generating convective precipitation, and the irrigation‐induced changes in large‐scale circulation jointly give rise to the heterogeneous changes of precipitation. Besides, the subgrid‐scale irrigation scheme can capture the climatic effects of irrigation in some grids where the dominant land use types are not cropland, indicating that in mesoscale simulation, climate model coupled with subgrid‐scale irrigation scheme may improve climate variables trends attribution studies.
Nitrogen and Phosphorus Control Soil Methane Uptake in Tropical Montane Forests
Authors: Martinson Guntars O. , Müller Anke K. , Matson Amanda L. , Corre Marife D. , Veldkamp Edzo
Published: July 2021

Tropical forests contribute about one third to global annual CH4 uptake by soils. Understanding the factors that control the soil‐atmosphere exchange of CH4 at a large scale is a critical step to improve the CH4 flux estimate for tropical soils, which is presently poorly constrained. Since tropical forest degradation often involves shifts in nutrient availabilities, it is critical to evaluate how this will affect soil CH4 flux. Here, we report how nitrogen (N; 50 kg N ha−1 yr−1), phosphorus (P; 10 kg P ha−1 yr−1), and combined N + P additions affect soil CH4 fluxes across an elevation gradient of tropical montane forests. We measured soil CH4 fluxes in a nutrient application experiment at different elevations over a period of 5 years. Nutrient additions increased soil CH4 uptake after 4–5 years of treatment but effects were not uniform across elevations. At 1,000 m, where total soil P was high, we detected mainly N limitation of soil CH4 uptake. At 2,000 m, where total soil P was low, a strong P limitation of soil CH4 uptake was observed. At 3,000 m, where total P was low in the organic layer but high in mineral soil, we found N limitation of soil CH4 uptake. Our results show that projected increases of N and P depositions may increase soil CH4 uptake in tropical montane forests but the direction, magnitude, and timing of the effects will depend on forests' nutrient status and plant‐microbial competition for N and P.
Atmospheric Humic‐Like Substances (HULIS) Act as Ice Active Entities
Authors: Chen J. , Wu Z. J. , Zhao X. , Wang Y. J. , Chen J. C. , Qiu Y. T. , Zong T. M. , Chen H. X. , Wang B. B. , Lin P. , Liu W. , Guo S. , Yao M. S. , Zeng L. M. , Wex H. , Liu X. , Hu M. , Li S. M.
Published: July 2021

We investigated the ice nucleation activities of humic‐like substances (HULIS), an important component of organic aerosol (OA), derived from atmospheric and biomass burning aerosols, and produced from aqueous‐phase chemical reactions. Respective HULIS can effectively trigger heterogeneous IN under mixed‐phase cloud conditions. HULIS ice active entities (IAE) were aggregates in size between 0.02 and 0.10 μm. At −20°C, the IAE numbers per unit HULIS mass varied from 213 to 8.7 × 104 mg−1. Such results were different than those detected in aquatic humic substances (HS) from previous studies, implying using HS as surrogates may not robustly estimate the IAE concentrations in the real atmosphere. Combining the abundance of atmospheric HULIS with the present results suggests that HULIS could be an important IAE contributor in the atmosphere where other ice nucleating particle species, such as dust and biological particles, are either low in concentration or absent.
Global Estimation of Suspended Particulate Matter From Satellite Ocean Color Imagery
Authors: Wei Jianwei , Wang Menghua , Jiang Lide , Yu Xiaolong , Mikelsons Karlis , Shen Fang
Published: July 2021

The suspended particulate matter (SPM) concentration (unit: mg l−1) in surface waters is an essential measure of water quality and clarity. Satellite remote sensing provides a powerful tool to derive the SPM with synoptic and repeat coverage. In this study, we developed a new global SPM algorithm utilizing the remote sensing reflectance (Rrs(λ)) at near‐infrared (NIR), red, green, and blue bands (NIR‐RGB) as input. The evaluations showed that the NIR‐RGB algorithm could predict SPM with the median absolute percentage difference of ∼35%–39% over a wide range from ∼0.01 to >2,000 mg l−1. The uncertainty is smaller (29%–37%) for turbid waters where Rrs(671) ≥ 0.0012 sr−1 and slightly higher (41%–44%) for clear waters where Rrs(671) < 0.0012 mg l−1. The algorithm was implemented with the global Rrs(λ) data from the Visible Infrared Imaging Radiometer Suite (VIIRS) onboard the Suomi National Polar‐orbiting Partnership (SNPP) satellite. We provided a brief characterization of the spatial distribution and temporal trends of the SPM products in global waters based on the monthly SPM composites. Case studies of the SPM time series in coastal and inland waters suggest that the satellite SPM estimations registered spatial and seasonal variation and episodic events in regional scales as well. The VIIRS‐generated global SPM maps provide a valuable addition to the existing ocean color products for environmental and climate applications.
An Atmospheric Constraint on the Seasonal Air‐Sea Exchange of Oxygen and Heat in the Extratropics
Authors: Morgan Eric J. , Manizza Manfredi , Keeling Ralph F. , Resplandy Laure , Mikaloff‐Fletcher Sara E. , Nevison Cynthia D. , Jin Yuming , Bent Jonathan D. , Aumont Olivier , Doney Scott C. , Dunne John P. , John Jasmin , Lima Ivan D. , Long Matthew C. , Rodgers Keith B.
Published: July 2021

The air‐sea exchange of oxygen (O2) is driven by changes in solubility, biological activity, and circulation. The total air‐sea exchange of O2 has been shown to be closely related to the air‐sea exchange of heat on seasonal timescales, with the ratio of the seasonal flux of O2 to heat varying with latitude, being higher in the extratropics and lower in the subtropics. This O2/heat ratio is both a fundamental biogeochemical property of air‐sea exchange and a convenient metric for testing earth system models. Current estimates of the O2/heat flux ratio rely on sparse observations of dissolved O2, leaving it fairly unconstrained. From a model ensemble we show that the ratio of the seasonal amplitude of two atmospheric tracers, atmospheric potential oxygen (APO) and the argon‐to‐nitrogen ratio (Ar/O2), exhibits a close relationship to the O2/heat ratio of the extratropics (40–). The amplitude ratio, /, is relatively constant within the extratropics of each hemisphere due to the zonal mixing of the atmosphere. / is not sensitive to atmospheric transport, as most of the observed spatial variability in the seasonal amplitude of APO is compensated by similar variations in (Ar/). From the relationship between /heat and / in the model ensemble, we determine that the atmospheric observations suggest hemispherically distinct /heat flux ratios of 3.3 0.3 and 4.7 0.8 nmol between 40 and in the Northern and Southern Hemispheres respectively, providing a useful constraint for and heat air‐sea fluxes in earth system models and observation‐based data products.
Age patterns in overweight and wasting prevalence of under 5-year-old children from low- and middle-income countries
Authors: Ricardo Luiza I. C. , Gatica-Domínguez Giovanna , Crochemore-Silva Inácio , Neves Paulo A. R. , dos Santos Vaz Juliana , Barros Aluisio J. D. , Victora Cesar Gomes
Published: July 2021

Objectives

To describe how overweight and wasting prevalence varies with age among children under 5 years in low- and middle-income countries (LMICs).

Methods

We used data from nationally representative Demographic and Health Surveys and Multiple Indicator Cluster Surveys. Overweight and wasting prevalence were defined as the proportions of children presenting mean weight for length/height (WHZ) more than 2 standard deviations above or below 2 standard deviations from the median value of the 2006 WHO standards, respectively. Descriptive analyses include national estimates of child overweight and wasting prevalence, mean, and standard deviations of WHZ stratified by age in years. National results were pooled using the population of children aged under 5 years in each country as weight. Fractional polynomials were used to compare mean WHZ with both overweight and wasting prevalence.

Results

Ninety national surveys from LMICs carried out between 2010 and 2019 were included. The overall prevalence of overweight declined with age from 6.3% for infants (aged 0–11 months) to 3.0% in 4 years olds (p = 0.03). In all age groups, lower prevalence was observed in low-income compared to upper-middle-income countries. Wasting was also more frequent among infants, with a slight decrease between the first and second year of life, and little variation thereafter. Lower-middle-income countries showed the highest wasting prevalence in all age groups. On the other hand, mean WHZ was stable over the first 5 years of life, but the median standard deviation for WHZ decreased from 1.39 in infants to 1.09 in 4-year-old children (p < 0.001). For any given value of WHZ, both overweight and wasting prevalence were higher in infants than in older children.

Conclusion

The higher values of WHZ standard deviations in infants suggest that declining prevalence in overweight and wasting by age may be possibly due to measurement error or rapid crossing of growth channels by infants.
Investigation of a complete squeeze-film damping model for MEMS devices
Authors: Lu Qianbo , Fang Weidong , Wang Chen , Bai Jian , Yao Yuan , Chen Jiaxiao , Xu Xiang , Huang Wei
Published: July 2021

Dynamic performance has long been critical for micro-electro-mechanical system (MEMS) devices and is significantly affected by damping. Different structural vibration conditions lead to different damping effects, including border and amplitude effects, which represent the effect of gas flowing around a complicated boundary of a moving plate and the effect of a large vibration amplitude, respectively. Conventional models still lack a complete understanding of damping and cannot offer a reasonably good estimate of the damping coefficient for a case with both effects. Expensive efforts have been undertaken to consider these two effects, yet a complete model has remained elusive. This paper investigates the dynamic performance of vibrated structures via theoretical and numerical methods simultaneously, establishing a complete model in consideration of both effects in which the analytical expression is given, and demonstrates a deviation of at least threefold lower than current studies by simulation and experimental results. This complete model is proven to successfully characterize the squeeze-film damping and dynamic performance of oscillators under comprehensive conditions. Moreover, a series of simulation models with different dimensions and vibration statuses are introduced to obtain a quick-calculating factor of the damping coefficient, thus offering a previously unattainable damping design guide for MEMS devices.
Overexpression of glycosyltransferase 8 domain containing 2 confers ovarian cancer to CDDP resistance by activating FGFR/PI3K signalling axis
Authors: Huang Shuting , Liang Suiying , Chen Guandi , Chen Jing , You Keli , Ye Haiyan , Li Zhigang , He Shanyang
Published: July 2021

It has been reported that chemotherapy resistance mainly contributed to treatment failure and poor survival in patients with ovarian cancer. Therefore, clarifying the molecular mechanism and identifying effective strategies to overcome drug resistance may play an important clinical impact on this malignant tumor. In our study, we found that the expression of Glycosyltransferase 8 domain containing 2 (GLT8D2) was significantly upregulated in ovarian cancer samples with CDDP (Cis-dichlorodiammine-platinum) resistance. Biological experiment demonstrate that GLT8D2 overexpression confers CDDP resistance on ovarian cancer cells; however, inhibition of GLT8D2 sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. By using affinity purification/mass spectrometry (IP/MS) and reciprocal co-immunoprecipitation (co-IP) analyses, we found that GLT8D2 interacts with fibroblast growth factor receptor 1(FGFR1) in ovarian cancer cells. Furthermore, overexpression of GLT8D2 activated FGFR/PI3K signaling axis and upregulated the phosphorylation levels of FRS2a and AKT (AKT serine/threonine kinase). Importantly, pharmacological inhibition of FGFR and PI3K (phosphatidylinositol 3-kinase) signaling pathway significantly counteracted GLT8D2-induced chemoresistance and enhanced platinum’s therapeutic efficacy in ovarian cancer. Therefore, our findings suggest that GLT8D2 is a potential therapeutic target for the treatment of ovarian cancer; targeting GLT8D2/FGFR/PI3K/AKT signaling axis may represent a promising strategy to enhance platinum response in patients with chemoresistant ovarian cancer.
Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer
Authors: Velez Miguel Gonzalez , Kosiorek Heidi E. , Egan Jan B. , McNatty Andrea L. , Riaz Irbaz B. , Hwang Steven R. , Stewart Glenn A. , Ho Thai H. , Moore Cassandra N. , Singh Parminder , Sharpsten Renee K. , Costello Brian A. , Bryce Alan H.
Published: July 2021

Background

Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment.

Methods

We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan–Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ2 test and Kruskal–Wallis rank sum test. Cox regression was used for univariate and multivariable analyses.

Results

We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3–26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8–10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8–13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1–not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7–12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8–24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42–3.96; P < 0.001).

Conclusions

The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms.
Coral-associated nitrogen fixation rates and diazotrophic diversity on a nutrient-replete equatorial reef
Authors: Moynihan Molly A , Goodkin Nathalie F , Morgan Kyle M , Kho Phyllis Y Y , Lopes dos Santos Adriana , Lauro Federico M , Baker David M , Martin Patrick
Published: July 2021

The role of diazotrophs in coral physiology and reef biogeochemistry remains poorly understood, in part because N2 fixation rates and diazotrophic community composition have only been jointly analyzed in the tissue of one tropical coral species. We performed field-based 15N2 tracer incubations during nutrient-replete conditions to measure diazotroph-derived nitrogen (DDN) assimilation into three species of scleractinian coral (Pocillopora acuta, Goniopora columna, Platygyra sinensis). Using multi-marker metabarcoding (16S rRNA, nifH, 18S rRNA), we analyzed DNA- and RNA-based communities in coral tissue and skeleton. Despite low N2 fixation rates, DDN assimilation supplied up to 6% of the holobiont’s N demand. Active coral-associated diazotrophs were chiefly Cluster I (aerobes or facultative anaerobes), suggesting that oxygen may control coral-associated diazotrophy. Highest N2 fixation rates were observed in the endolithic community (0.20 µg N cm−2 per day). While the diazotrophic community was similar between the tissue and skeleton, RNA:DNA ratios indicate potential differences in relative diazotrophic activity between these compartments. In Pocillopora, DDN was found in endolithic, host, and symbiont compartments, while diazotrophic nifH sequences were only observed in the endolithic layer, suggesting a possible DDN exchange between the endolithic community and the overlying coral tissue. Our findings demonstrate that coral-associated diazotrophy is significant, even in nutrient-rich waters, and suggest that endolithic microbes are major contributors to coral nitrogen cycling on reefs.
Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays
Authors: Mulvey Bernard , Dougherty Joseph D.
Published: July 2021

Family and population studies indicate clear heritability of major depressive disorder (MDD), though its underlying biology remains unclear. The majority of single-nucleotide polymorphism (SNP) linkage blocks associated with MDD by genome-wide association studies (GWASes) are believed to alter transcriptional regulators (e.g., enhancers, promoters) based on enrichment of marks correlated with these functions. A key to understanding MDD pathophysiology will be elucidation of which SNPs are functional and how such functional variants biologically converge to elicit the disease. Furthermore, retinoids can elicit MDD in patients and promote depressive-like behaviors in rodent models, acting via a regulatory system of retinoid receptor transcription factors (TFs). We therefore sought to simultaneously identify functional genetic variants and assess retinoid pathway regulation of MDD risk loci. Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1000 SNPs prioritized from 39 neuropsychiatric trait/disease GWAS loci, selecting SNPs based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. We identified >100 SNPs with allelic effects on expression in a retinoid-responsive model system. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs), with additional allelic differences unmasked by treatment with all-trans retinoic acid (ATRA). Finally, motifs overrepresented across functional SNPs corresponded to TFs highly specific to serotonergic neurons, suggesting an in vivo site of action. Our application of MPRAs to screen MDD-associated SNPs suggests a shared transcriptional-regulatory program across loci, a component of which is unmasked by retinoids.
Cepharanthine sensitizes human triple negative breast cancer cells to chemotherapeutic agent epirubicin via inducing cofilin oxidation-mediated mitochondrial fission and apoptosis
Authors: Shen Li-wen , Jiang Xiu-xing , Li Zhi-qiang , Li Jie , Wang Mei , Jia Guan-fei , Ding Xin , Lei Ling , Gong Qi-hai , Gao Ning
Published: July 2021

Inhibition of autophagy has been accepted as a promising therapeutic strategy in cancer, but its clinical application is hindered by lack of effective and specific autophagy inhibitors. We previously identified cepharanthine (CEP) as a novel autophagy inhibitor, which inhibited autophagy/mitophagy through blockage of autophagosome-lysosome fusion in human breast cancer cells. In this study we investigated whether and how inhibition of autophagy/mitophagy by cepharanthine affected the efficacy of chemotherapeutic agent epirubicin in triple negative breast cancer (TNBC) cells in vitro and in vivo. In human breast cancer MDA-MB-231 and BT549 cells, application of CEP (2 μM) greatly enhanced cepharanthine-induced inhibition on cell viability and colony formation. CEP interacted with epirubicin synergistically to induce apoptosis in TNBC cells via the mitochondrial pathway. We demonstrated that co-administration of CEP and epirubicin induced mitochondrial fission in MDA-MB-231 cells, and the production of mitochondrial superoxide was correlated with mitochondrial fission and apoptosis induced by the combination. Moreover, we revealed that co-administration of CEP and epirubicin markedly increased the generation of mitochondrial superoxide, resulting in oxidation of the actin-remodeling protein cofilin, which promoted formation of an intramolecular disulfide bridge between Cys39 and Cys80 as well as Ser3 dephosphorylation, leading to mitochondria translocation of cofilin, thus causing mitochondrial fission and apoptosis. Finally, in mice bearing MDA-MB-231 cell xenografts, co-administration of CEP (12 mg/kg, ip, once every other day for 36 days) greatly enhanced the therapeutic efficacy of epirubicin (2 mg/kg) as compared with administration of either drug alone. Taken together, our results implicate that a combination of cepharanthine with chemotherapeutic agents could represent a novel therapeutic strategy for the treatment of breast cancer.
De novo and cell line models of human mammary cell transformation reveal an essential role for Yb-1 in multiple stages of human breast cancer
Authors: Lefort Sylvain , El-Naggar Amal , Tan Susanna , Colborne Shane , Negri Gian Luca , Pellacani Davide , Hirst Martin , Gusterson Barry , Morin Gregg B. , Sorensen Poul H. , Eaves Connie J.
Published: July 2021

Breast cancer heterogeneity has made it challenging to identify mechanisms critical to the initial stages of their genesis in vivo. Here, we sought to interrogate the role of YB-1 in newly arising human breast cancers as well as in established cell lines. In a first series of experiments, we found that short-hairpin RNA-mediated knockdown of YB-1 in MDA-MB-231 cells blocked both their local tumour-forming and lung-colonising activity in immunodeficient mice. Conversely, upregulated expression of YB-1 enhanced the poor in vivo tumorigenicity of T47D cells. We then found that YB-1 knockdown also inhibits the initial generation in mice of invasive ductal carcinomas and ductal carcinomas in situ from freshly isolated human mammary cells transduced, respectively, with KRASG12D or myristoylated-AKT1. Interestingly, increased expression of HIF1α and G3BP1, two YB-1 translational targets and elements of a stress-adaptive programme, mirrored the levels of YB-1 in both transformed primary and established MDA-MB-231 breast cancer cells.
PSMC2/CCND1 axis promotes development of ovarian cancer through regulating cell growth, apoptosis and migration
Authors: Zhu Dawei , Huang Jie , Liu Ning , Li Wei , Yan Limei
Published: July 2021

Ovarian cancer is known as one of the most common malignancies of the gynecological system, whose treatment is still not satisfactory because of the unclear understanding of molecular mechanism. PSMC2 is an essential component of 19 S regulatory granules in 26 S proteasome and its relationship with ovarian cancer is still not clear. In this study, we found that PSMC2 was upregulated in ovarian cancer tissues, associated with tumor grade and could probably predict poor prognosis. Knocking down the endogenous PSMC2 expression in ovarian cancer cells could decrease colony formation ability, cell motility and cell proliferation rate, along with increasing cell apoptosis rate. Cells models or xenografts formed by cells with relatively lower expression of PSMC2 exhibited weaker oncogenicity and slower growth rate in vivo. Moreover, gene microarray was used to analyze the alteration of gene expression profiling of ovarian cancer induced by PSMC2 knockdown and identify CCND1 as a potential downstream of PSMC2. Further study revealed the mutual regulation between PSMC2 and CCND1, and demonstrated that knockdown of CCND1 could enhance the regulatory effects induced by PSMC2 knockdown and overexpression of CCND1 reverses it. In summary, PSMC2 may promote the development of ovarian cancer through CCND1, which may predict poor prognosis of ovarian cancer patients.
Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages
Authors: Prados Belén , del Toro Raquel , MacGrogan Donal , Gómez-Apiñániz Paula , Papoutsi Tania , Muñoz-Cánoves Pura , Méndez-Ferrer Simón , de la Pompa José Luis
Published: July 2021

Bone morphogenetic protein (Bmp) signaling is critical for organismal development and homeostasis. To elucidate Bmp2 function in the vascular/hematopoietic lineages we generated a new transgenic mouse line in which ectopic Bmp2 expression is controlled by the Tie2 promoter. Tie2CRE/+;Bmp2tg/tg mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably, Tie2CRE/+;Bmp2tg/tg mice develop extensive soft tissue bone formation typical of acquired forms of heterotopic ossification (HO) and genetic bone disorders, such as Fibrodysplasia Ossificans Progressiva (FOP). Ectopic ossification in Tie2CRE/+;Bmp2tg/tg transgenic animals is accompanied by increased bone marrow hematopoietic, fibroblast and osteoblast precursors and circulating pro-inflammatory cells. Transplanting wild-type bone marrow hematopoietic stem cells into lethally irradiated Tie2CRE/+;Bmp2tg/tg mice significantly delays HO onset but does not prevent it. Moreover, transplanting Bmp2-transgenic bone marrow into wild-type recipients does not result in HO, but hematopoietic progenitors contribute to inflammation and ectopic bone marrow colonization rather than to endochondral ossification. Conversely, aberrant Bmp2 signaling activity is associated with fibroblast accumulation, skeletal muscle fiber damage, and expansion of a Tie2+ fibro-adipogenic precursor cell population, suggesting that ectopic bone derives from a skeletal muscle resident osteoprogenitor cell origin. Thus, Tie2CRE/+;Bmp2tg/tg mice recapitulate HO pathophysiology, and might represent a useful model to investigate therapies seeking to mitigate disorders associated with aberrant extra-skeletal bone formation.
The regulation of ferroptosis by MESH1 through the activation of the integrative stress response
Authors: Lin Chao-Chieh , Ding Chien-Kuang Cornelia , Sun Tianai , Wu Jianli , Chen Kai-Yuan , Zhou Pei , Chi Jen-Tsan
Published: July 2021

All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation “alarmone” (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.
Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells
Authors: Karakas Bahriye , Aka Yeliz , Giray Asli , Temel Sehime Gulsun , Acikbas Ufuk , Basaga Huveyda , Gul Ozgur , Kutuk Ozgur
Published: July 2021

Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-β in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.
Machine learning based energy-free structure predictions of molecules, transition states, and solids
Authors: Lemm Dominik , von Rudorff Guido Falk , von Lilienfeld O. Anatole
Published: July 2021

The computational prediction of atomistic structure is a long-standing problem in physics, chemistry, materials, and biology. Conventionally, force-fields or ab initio methods determine structure through energy minimization, which is either approximate or computationally demanding. This accuracy/cost trade-off prohibits the generation of synthetic big data sets accounting for chemical space with atomistic detail. Exploiting implicit correlations among relaxed structures in training data sets, our machine learning model Graph-To-Structure (G2S) generalizes across compound space in order to infer interatomic distances for out-of-sample compounds, effectively enabling the direct reconstruction of coordinates, and thereby bypassing the conventional energy optimization task. The numerical evidence collected includes 3D coordinate predictions for organic molecules, transition states, and crystalline solids. G2S improves systematically with training set size, reaching mean absolute interatomic distance prediction errors of less than 0.2 Å for less than eight thousand training structures — on par or better than conventional structure generators. Applicability tests of G2S include successful predictions for systems which typically require manual intervention, improved initial guesses for subsequent conventional ab initio based relaxation, and input generation for subsequent use of structure based quantum machine learning models.
Decision-related feedback in visual cortex lacks spatial selectivity
Authors: Quinn Katrina R. , Seillier Lenka , Butts Daniel A. , Nienborg Hendrikje
Published: July 2021

Feedback in the brain is thought to convey contextual information that underlies our flexibility to perform different tasks. Empirical and computational work on the visual system suggests this is achieved by targeting task-relevant neuronal subpopulations. We combine two tasks, each resulting in selective modulation by feedback, to test whether the feedback reflected the combination of both selectivities. We used visual feature-discrimination specified at one of two possible locations and uncoupled the decision formation from motor plans to report it, while recording in macaque mid-level visual areas. Here we show that although the behavior is spatially selective, using only task-relevant information, modulation by decision-related feedback is spatially unselective. Population responses reveal similar stimulus-choice alignments irrespective of stimulus relevance. The results suggest a common mechanism across tasks, independent of the spatial selectivity these tasks demand. This may reflect biological constraints and facilitate generalization across tasks. Our findings also support a previously hypothesized link between feature-based attention and decision-related activity.
Quantum gravitational decoherence from fluctuating minimal length and deformation parameter at the Planck scale
Authors: Petruzziello Luciano , Illuminati Fabrizio
Published: July 2021

Schemes of gravitationally induced decoherence are being actively investigated as possible mechanisms for the quantum-to-classical transition. Here, we introduce a decoherence process due to quantum gravity effects. We assume a foamy quantum spacetime with a fluctuating minimal length coinciding on average with the Planck scale. Considering deformed canonical commutation relations with a fluctuating deformation parameter, we derive a Lindblad master equation that yields localization in energy space and decoherence times consistent with the currently available observational evidence. Compared to other schemes of gravitational decoherence, we find that the decoherence rate predicted by our model is extremal, being minimal in the deep quantum regime below the Planck scale and maximal in the mesoscopic regime beyond it. We discuss possible experimental tests of our model based on cavity optomechanics setups with ultracold massive molecular oscillators and we provide preliminary estimates on the values of the physical parameters needed for actual laboratory implementations.
Structure of the molecular bushing of the bacterial flagellar motor
Authors: Yamaguchi Tomoko , Makino Fumiaki , Miyata Tomoko , Minamino Tohru , Kato Takayuki , Namba Keiichi
Published: July 2021

The basal body of the bacterial flagellum is a rotary motor that consists of several rings (C, MS and LP) and a rod. The LP ring acts as a bushing supporting the distal rod for its rapid and stable rotation without much friction. Here, we use electron cryomicroscopy to describe the LP ring structure around the rod, at 3.5 Å resolution, from Salmonella Typhimurium. The structure shows 26-fold rotational symmetry and intricate intersubunit interactions of each subunit with up to six partners, which explains the structural stability. The inner surface is charged both positively and negatively. Positive charges on the P ring (the part of the LP ring that is embedded within the peptidoglycan layer) presumably play important roles in its initial assembly around the rod with a negatively charged surface.