bluuebunny/crossref_metadata_2025 huggingface dataset:
“Cuba, Nicaragua, Unidas Vencerán”: Official Collaborations between the Sandinista and Cuban Revolutions
Authors: Snyder Emily
Published: October 2021

The Cuban and Sandinista Revolutions stand together as Latin America's two socialist revolutions achieved through guerrilla insurgency in the latter half of the twentieth century. But beyond studies that demonstrate that Cuba militarily trained and supported the Sandinistas before, during, and after their guerrilla phase, and observations that the two countries were connected by the bonds of socialist revolution, the nature of Cuba and Nicaragua's revolutionary relationship remains little explored. This article traces exchanges of people and expertise between each revolutionary state's Ministry of Foreign Relations and Ministry of Culture. It employs diplomatic and institutional archives, personal collections, and oral interviews to demonstrate the deep involvement of Cuban experts in building the Sandinista state. Yet, Cuban advice may have exacerbated tensions within Nicaragua. This article also shows that tensions marked the day-to-day realities of Cubans and Nicaraguans tasked with carrying out collaborations, revealing their layered and often contradictory nature. Illuminating high-level policy in terms of Cuban-Nicaraguan exchanges and how they unfolded on the ground contributes to new international histories of the Sandinista and Cuban revolutions by shifting away from North-South perspectives to focus instead on how the Sandinistas navigated collaboration with their most important regional ally.
Unterschiede im epaAC© bei Patient_innen mit Herzinsuffizienz mit oder ohne Rehospitalisation
Authors: Höhn Eva-Maria , Hediger Hannele , Hermann Matthias , Petry Heidi , Schmid-Mohler Gabriela
Published: October 2021

Zusammenfassung. Hintergrund: Herzinsuffizienz ist einer der häufigsten Gründe für eine Hospitalisation bei älteren Menschen. Rund 22,8 % der Betroffenen werden innerhalb von 30 Tagen nach einer stationären Betreuung wieder hospitalisiert. Das pflegerische Assessmentinstrument epaAC könnte Hinweise zu Risikofaktoren für eine Rehospitalisation geben. Ziel: Das Ziel war es, Gruppenunterschiede in den Items und Scores des epaAC Austrittsassessment zu identifizieren hinsichtlich des Endpunktes einer ungeplanten Rehospitalisation bis 30 Tage nach Index-Hospitalisation. Methoden: Unter Verwendung eines retrospektiven Fall-Kontroll-Designs wurden Unterschiede in den epaAC Variablen mittels deskriptiver und vergleichender Statistik untersucht. Chi-Quadrat-Test, Wilcoxon-Test und t-Test wurden mit zweiseitigem Alpha-Niveau α < 0,05 durchgeführt. Die Alphafehler-Kumulierung wurde mittels Benjamini & Hochberg-Korrektur berücksichtigt. Ergebnisse: Es wurden keine signifikanten Gruppenunterschiede in allen Items und Scores des Austritts-epaAC gefunden. Es liegt nur ein schwacher Hinweis vor, dass eine akute respiratorische Beeinträchtigung zum Zeitpunkt der Entlassung bei den Patient_innen mit Rehospitalisation häufiger vorliegt, als bei denjenigen ohne Rehospitalisation. Schlussfolgerungen: Die Items und Scores des Pflegeassessmentinstruments epaAC unterschieden sich nicht signifikant zwischen Patient_innen mit und ohne 30-tägiger Rehospitalisation. Weitere Untersuchungen zur Beurteilung des Potenzials des epaAC zur Vorhersage einer Rehospitalisation bei Herzinsuffizienz sind erforderlich.
Seasonality of Solute Flux and Water Source Chemistry in a Coastal Glacierized Watershed Undergoing Rapid Change: Wolverine Glacier Watershed, Alaska
Authors: Bergstrom Anna , Koch Joshua C. , O'Neel Shad , Baker Emily
Published: October 2021

As glaciers around the world rapidly lose mass, the tight coupling between glaciers and downstream ecosystems is resulting in widespread impacts on global hydrologic and biogeochemical cycling. However, a range of challenges make it difficult to conduct research in glacierized systems, and our knowledge of seasonally changing hydrologic processes and solute sources and signatures is limited. This in turn hampers our ability to make predictions on solute composition and flux. We conducted a broad water sampling campaign in order to understand the present‐day partitioning of water sources and associated solutes in Alaska's Wolverine Glacier watershed. We established a relationship between electrical conductivity and streamflow at the watershed outlet to divide the melt season into four hydroclimatic periods. Across hydroclimatic periods, we observed a shift in nonglacial source waters from snowmelt‐dominated overland and shallow subsurface flow paths to deeper groundwater flow paths. We also observed the shift from a low‐ to high‐efficiency subglacial drainage network and the associated flushing of water stored subglacially with higher solute loads. We used calcium, the dominant dissolved ion, from watershed outlet samples to estimate solute fluxes for each hydroclimatic period across two melt seasons. We found between 40% and 55% of Ca2+ export occurred during the late season rainy period. This partitioning of the melt season coupled with a characterization of the chemical makeup and magnitude of solute export provides new insight into a rapidly changing watershed and creates a framework to quantify and predict changes to solute fluxes across a melt season.
The Relationship of Lightning Radio Pulse Amplitudes and Source Altitudes as Observed by LOFAR
Authors: Machado J. G. O. , Hare B. M. , Scholten O. , Buitink S. , Corstanje A. , Falcke H. , Hörandel J. R. , Huege T. , Krampah G. K. , Mitra P. , Mulrey K. , Nelles A. , Pandya H. , Rachen J. P. , Thoudam S. , Trinh T. N. G. , ter Veen S. , Winchen T.
Published: October 2021

When a lightning flash is propagating in the atmosphere it is known that especially the negative leaders emit a large number of very high frequency (VHF) radio pulses. It is thought that this is due to streamer activity at the tip of the growing negative leader. In this work, we have investigated the dependence of the strength of this VHF emission on the altitude of such emission for two lightning flashes as observed by the Low Frequency ARray (LOFAR) radio telescope. We find for these two flashes that the extracted amplitude distributions are consistent with a power‐law, and that the amplitude of the radio emissions decreases very strongly with source altitude, by more than a factor of 2 from 1 km altitude up to 5 km altitude. In addition, we do not find any dependence on the extracted power‐law with altitude, and that the extracted power‐law slope has an average around 3, for both flashes.
Synthesis Analysis of SWOT KaRIn‐Derived Water Surface Heights and Local Cross‐Calibration of the Baseline Roll Knowledge Error Over Lake Baikal
Authors: Du B. , Li J. C. , Jin T. Y. , Zhou M. , Gao X. W.
Published: October 2021

The upcoming Surface Water and Ocean Topography (SWOT) mission provides a promising opportunity for retrieval of high spatiotemporal resolution water surface height (WSH) over inland water bodies. To investigate the accuracy of SWOT derived WSH, the observations over Lake Baikal are simulated and a comprehensive evaluation is conducted in this study. Firstly, compared with Jason‐class altimeter WSH and in situ WSHs, the accuracy of SWOT KaRIn‐derived monthly WSHs and their spatiotemporal characteristics are analyzed. Secondly, a local cross‐calibration method is used to reduce the short wavelength roll error over lakes. The results show that, though SWOT has more observations than Jason‐class altimeter, the accuracy of the SWOT KaRIn‐derived monthly WSHs is difficult to be equivalent with those from Jason‐class altimeter, and varies with the number of duplicated observations, the spatial location and the time interval due to the effect of systematic erros and random errors, but can be significantly improved by local cross‐calibration method, especially at higher spatial resolutions after cross‐calibration associate with external nadir altimeter.
Modeling Untreated Wastewater Evolution and Swimmer Illness for Four Wastewater Infrastructure Scenarios in the San Diego‐Tijuana (US/MX) Border Region
Authors: Feddersen Falk , Boehm Alexandria B. , Giddings Sarah N. , Wu Xiaodong , Liden Doug
Published: October 2021

The popular beaches of the San Diego‐Tijuana (US/MX) border region are often impacted by untreated wastewater sourced from Mexico—via the Tijuana River Estuary (TJRE) and San Antonio de los Buenos outfall at the Pt. Bandera (SAB/PTB) shoreline, leading to impacted beaches and human illness. The US‐Mexico‐Canada trade agreement will fund border infrastructure projects reducing untreated wastewater discharges. However, estimating project benefits such as reduced human illness and beach impacts is challenging. We develop a coupled hydrodynamic, norovirus (NoV) pathogen, and swimmer illness risk model with the wastewater sources for the year 2017. The model is used to evaluate the reduction in human illness and beach impacts under baseline conditions and three infrastructure diversion scenarios which (Scenario A) reduce SAB/PTB discharges and moderately reduce TJRE inflows or (Scenarios B, C) strongly reduce TJRE in inflows only. The model estimates shoreline untreated wastewater and NoV concentrations, and the number of NoV ill swimmers at Imperial Beach CA. In the Baseline, the percentage of swimmers becoming ill is 3.8% over 2017, increasing to 4.5% during the tourist season (Memorial to Labor Day) due to south‐swell driven SAB/PTB plumes. Overall, Scenario A provides the largest reduction in ill swimmers and beach impacts for the tourist season and full year. The 2017 tourist season TJRE inflows were not representative of those in 2020, yet, Scenario A likely still provides the greatest benefit in other years. This methodology can be applied to other coastal regions with wastewater inputs.
Does Phobos Reflect Solar Wind Protons? Mars Express Special Flyby Operations With and Without the Presence of Phobos
Authors: Futaana Yoshifumi , Holmström Mats , Fedorov Andrey , Barabash Stas
Published: October 2021

We characterize the solar wind proton reflection (backscattering) from Phobos using a series of Mars Express operations. The plasma data obtained during the Phobos flyby of Mars Express in January 2016 showed a non‐solar wind signal possibly reflected from the Phobos surface. Similar signatures were previously reported during an earlier Phobos flyby in 2008. On the other hand, although Mars Express has encountered Phobos (within 100 km) more than 10 times, it has thus far detected only two clear cases of reflected protons. The intermittency of the reflected proton detections could indicate that these protons are not from Phobos but are produced by the spacecraft body or solar arrays under a special attitude configuration during the flyby maneuver. To rule out these artifacts as the cause, we conducted three special operations; Mars Express was operated using the identical attitude and solar panel control sequence but without Phobos nearby. All the measured plasma data during the special operations exhibit no additional plasma signatures. These fake flyby experiments indicate that the measured non‐solar wind protons during the real flyby are not from the spacecraft and that Phobos likely reflects solar wind into space. On the other hand, the intermittency of the reflected protons from Phobos remains unexplained. The reflected protons are vital additional plasma components because they inject enough energy to disturb the near‐Phobos plasma environment. In addition, we can utilize these reflected particles to remotely measure the surface precipitation flux.
Bedforms of Thwaites Glacier, West Antarctica: Character and Origin
Authors: Alley R. B. , Holschuh N. , MacAyeal D. R. , Parizek B. R. , Zoet L. , Riverman K. , Muto A. , Christianson K. , Clyne E. , Anandakrishnan S. , Stevens N. ,   GHOST Collaboration
Published: October 2021

Bedforms of Thwaites Glacier, West Antarctica both record and affect ice flow, as shown by geophysical data and simple models. Thwaites Glacier flows across the tectonic fabric of the West Antarctic rift system with its bedrock highs and sedimentary basins. Swath radar and seismic surveys of the glacier bed have revealed soft‐sediment flutes 100 m or more high extending 15 km or more across basins downglacier from bedrock highs. Flutes end at prominent hard‐bedded moats on stoss sides of the next topographic highs. We use simple models to show that ice flow against topography increases pressure between ice and till upglacier along the bed over a distance that scales with the topography. In this basal zone of high pressure, ice‐contact water would be excluded, thus increasing basal drag by increasing ice‐till coupling and till flux, removing till to allow bedrock erosion that creates moats. Till carried across highlands would then be deposited in lee‐side positions forming bedforms that prograde downglacier over time, and that remain soft on top through feedbacks that match till‐deformational fluxes from well upglacier of the topography. The bedforms of the part of Thwaites surveyed here are prominent because ice flow has persisted over a long time on this geological setting, not because ice flow is anomalous. Bedform development likely has caused evolution of ice flow over time as till and lubricating water were redistributed, moats were eroded and bedforms grew.
A Double‐Moment SBU‐YLIN Cloud Microphysics Scheme and Its Impact on a Squall Line Simulation
Authors: Zhao Xi , Lin Yanluan , Luo Yali , Qian Qifeng , Liu Xi , Liu Xiantong , Colle Brian A.
Published: October 2021

A double‐moment version of the SBU‐YLIN cloud microphysical scheme in WRF is introduced. It predicts the mass and number mixing ratios of cloud droplet, rain, cloud ice, and precipitating ice. In addition, a number of physical processes, like rain evaporation, collection between rain and snow are also optimized in the new scheme. The scheme is evaluated and compared with the original one‐moment scheme for a squall line case. We found that the double‐moment approach gives a better representation of rain evaporation, which is critical for the development, morphology, and evolution of the simulated squall line, especially for the enhanced trailing stratiform cloud and leading convective line. The relationship between key microphysical processes and squall line dynamics is investigated to identify the driving mechanisms of the descending rear inflow, cold pool, and slantwise updraft. Furthermore, formation of the transition zone in the simulated squall line strongly depends on the flexible description of ice particle properties, such as size, degree of riming and fall speed.
Realism of Lagrangian Large Eddy Simulations Driven by Reanalysis Meteorology: Tracking a Pocket of Open Cells Under a Biomass Burning Aerosol Layer
Authors: Kazil Jan , Christensen Matthew W. , Abel Steven J. , Yamaguchi Takanobu , Feingold Graham
Published: October 2021

An approach to drive Lagrangian large eddy simulation (LES) of boundary layer clouds with reanalysis data is presented and evaluated using satellite (Spinning Enhanced Visible and Infrared Imager, SEVIRI) and aircraft (Cloud‐Aerosol‐Radiation Interactions and Forcing, CLARIFY) measurements. The simulations follow trajectories of the boundary layer flow. They track the formation and evolution of a pocket of open cells (POC) underneath a biomass burning aerosol layer in the free troposphere. The simulations reproduce the evolution of observed stratocumulus cloud morphology, cloud optical depth, and cloud drop effective radius, and capture the timing of the cloud state transition from closed to open cells seen in the satellite imagery on the three considered trajectories. They reproduce a biomass burning aerosol layer identified by the in‐situ aircraft measurements above the inversion of the POC. Entrainment of aerosol from the biomass burning layer into the POC is limited to the extent of having no impact on cloud‐ or boundary layer properties, in agreement with the CLARIFY observations. The two‐moment bin microphysics scheme used in the simulations reproduces the in‐situ cloud microphysical properties reasonably well. A two‐moment bulk microphysics scheme reproduces the satellite observations in the non‐precipitating closed‐cell state, but overestimates liquid water path and cloud optical depth in the precipitating open‐cell state due to insufficient surface precipitation. A boundary layer cold and dry bias occurring in LES can be counteracted by reducing the grid aspect ratio and by tightening the large scale wind speed nudging towards the surface.
Evolution of Sea Surface Hydrology Along the Western Australian Margin Over the Past 450 kyr
Authors: Pei Renjie , Kuhnt Wolfgang , Holbourn Ann , Jöhnck Janika , Hingst Johanna , Beil Sebastian , Lübbers Julia , Andersen Nils
Published: October 2021

We collected a suite of core top samples during R/V Sonne Cruise SO257 in May 2017 along the southwestern front of the Indo‐Pacific Warm Pool (IPWP) to monitor the variability of Southern Hemisphere tropical and subtropical sea surface hydrology and to assess temperature and salinity reconstructions with data sets reflecting conditions in the post‐monsoonal season. In our core top samples, a steep increase in planktic δ18O, associated with a decrease in sea surface temperature (SST), indicates that the southwestern front of the IPWP is located between 23° and 24°S during austral fall. We additionally reconstructed SST, sea surface salinity ,and δ18O seawater (δ18Osw) over the last 450 kyr in two sediment successions located within and beyond the monsoonal rain belt. Our records show that SST was highly coherent and phase‐locked with atmospheric pCO2 during the last 450 kyr. The regional differences in the δ18Osw records reveal that the Western Australian Margin north of 15°S remained seasonally under the influence of IPWP water masses, even during glacials. The temporal variability in upper ocean hydrology along the Western Australian Margin is not directly coupled to local monsoonal precipitation, but is strongly affected by advective mixing of Indonesian Throughflow derived water masses.
AnnexinA7 promotes epithelial–mesenchymal transition by interacting with Sorcin and contributes to aggressiveness in hepatocellular carcinoma
Authors: Ling Fei , Zhang Huan , Sun Yunliang , Meng Jinyi , Sanches Jaceline Gislaine Pires , Huang He , Zhang Qingqing , Yu Xiao , Wang Bo , Hou Li , Zhang Jun
Published: October 2021

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and metastasis is the major cause of the high mortality of HCC. In this study, we identified that AnnexinA7 (ANXA7) and Sorcin (SRI) are overexpressed and interacting proteins in HCC tissues and cells. In vitro functional investigations revealed that the interaction between ANXA7 and SRI regulated epithelial–mesenchymal transition (EMT), and then affected migration, invasion, and proliferation in HCC cells. Furthermore overexpression/knockdown of ANXA7 was remarkably effective in promoting/inhibiting tumorigenicity and EMT in vivo. Altogether, our study unveiled a mechanism that ANXA7 promotes EMT by interacting with SRI and further contributes to the aggressiveness in HCC, which provides a novel potential therapeutic target for preventing recurrence and metastasis in HCC.
BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma
Authors: Miao Xiaolong , Liu Chen , Jiang Yuancong , Wang Yao , Kong Deqiang , Wu Zelai , Wang Xinyi , Tian Rui , Yu Xing , Zhu Xuhang , Gong Weihua
Published: October 2021

Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.
p32 promotes melanoma progression and metastasis by targeting EMT markers, Akt/PKB pathway, and tumor microenvironment
Authors: Sinha Sunita , Singh Satyendra Kumar , Jangde Nitish , Ray Rashmi , Rai Vivek
Published: October 2021

Melanoma originates from melanin-producing cells called melanocytes. Melanoma poses a great risk because of its rapid ability to spread and invade new organs. Cellular metastasis involves alteration in the gene expression profile and their transformation from epithelial to mesenchymal state. Despite of several advances, metastatic melanoma being a key cause of therapy failure and mortality remains poorly understood. p32 has been found to be involved in various physiological and pathophysiological conditions. However, the role of p32 in melanoma progression and metastasis remains underexplored. Here, we identify the role of p32 in the malignancy of both murine and human melanoma. p32 knockdown leads to reduced cell proliferation, migration, and invasion in murine and human melanoma cells. Furthermore, p32 promotes in vitro tumorigenesis, inducing oncogenes and EMT markers. Mechanistically, we show p32 regulates tumorigenic and metastatic properties through the Akt/PKB signaling pathway in both murine and human melanoma. Furthermore, p32 silencing attenuates melanoma tumor progression and lung metastasis in vivo, modulating the tumor microenvironment by inhibiting the angiogenesis, infiltration of macrophages, and leukocytes in mice. Taken together, our findings identify that p32 drives melanoma progression, metastasis, and regulates the tumor microenvironment. p32 can be a target of a novel therapeutic approach in the regulation of melanoma progression and metastasis.
Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development
Authors: Catlin James P. , Marziali Leandro N. , Rein Benjamin , Yan Zhen , Feltri M. Laura , Schaner Tooley Christine E.
Published: October 2021

N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1−/− mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1−/− mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1−/− mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.
Alterations in the gut microbiota and metabolite profiles of patients with Kashin-Beck disease, an endemic osteoarthritis in China
Authors: Wang Xi , Ning Yujie , Li Cheng , Gong Yi , Huang Ruitian , Hu Minhan , Poulet Blandine , Xu Ke , Zhao Guanghui , Zhou Rong , Lammi Mikko J. , Guo Xiong
Published: October 2021

Kashin-Beck disease (KBD) is a severe osteochondral disorder that may be driven by the interaction between genetic and environmental factors. We aimed to improve our understanding of the gut microbiota structure in KBD patients of different grades and the relationship between the gut microbiota and serum metabolites. Fecal and serum samples collected from KBD patients and normal controls (NCs) were used to characterize the gut microbiota using 16S rDNA gene and metabolomic sequencing via liquid chromatography-mass spectrometry (LC/MS). To identify whether gut microbial changes at the species level are associated with the genes or functions of the gut bacteria in the KBD patients, metagenomic sequencing of fecal samples from grade I KBD, grade II KBD and NC subjects was performed. The KBD group was characterized by elevated levels of Fusobacteria and Bacteroidetes. A total of 56 genera were identified to be significantly differentially abundant between the two groups. The genera Alloprevotella, Robinsoniella, Megamonas, and Escherichia_Shigella were more abundant in the KBD group. Consistent with the 16S rDNA analysis at the genus level, most of the differentially abundant species in KBD subjects belonged to the genus Prevotella according to metagenomic sequencing. Serum metabolomic analysis identified some differentially abundant metabolites among the grade I and II KBD and NC groups that were involved in lipid metabolism metabolic networks, such as that for unsaturated fatty acids and glycerophospholipids. Furthermore, we found that these differences in metabolite levels were associated with altered abundances of specific species. Our study provides a comprehensive landscape of the gut microbiota and metabolites in KBD patients and provides substantial evidence of a novel interplay between the gut microbiome and metabolome in KBD pathogenesis.
miR548ai antagonism attenuates exosome-induced endothelial cell dysfunction
Authors: Xie Xiujie , Guo Lian-Wang , Kent Craig K.
Published: October 2021

Endothelial cell (EC) and smooth muscle cell (SMC) are major cell types adjacent in the vascular wall. Recent progress indicates that their communication is crucial for vascular homeostasis and pathogenesis. In particular, dysfunctional (proliferative) SMCs through exosomes can induce EC dysfunction (impaired growth). The current study suggests that miR548ai, a rarely known microRNA, may provide a molecular target for protection against SMC/exosome-induced EC dysfunction. We performed microarray profiling of microRNAs of dysfunctional human primary aortic SMCs induced by different cytokines (PDGF-BB, TGFβ1, TNFα, IL1β). Among the microRNAs commonly upregulated by these cytokines, miR548ai showed the most robust changes, as also validated through quantitative PCR. This cytokine-induced miR548ai upregulation was recapitulated in the qPCR determination of SMC-derived exosomal microRNAs. Consistent with SMC-to-EC communication, the exosomes extracted from cytokine-stimulated SMCs impaired human EC proliferation and migration. Of particular interest, this SMC exosomal impingement on ECs was countered by transfection of miR548ai inhibitor microRNA into ECs. Furthermore, the miR548ai inhibitor transfected into SMCs attenuated SMC dysfunction/proliferation. Thus, these results identify miR548ai as a novel target; namely, miR548ai inhibitor mitigates EC dysfunction induced by exosomes derived from dysfunctional SMCs. This new knowledge may aid the future development of microRNA-based treatment of vascular disorders.
Overexpression of HMGA1 confers radioresistance by transactivating RAD51 in cholangiocarcinoma
Authors: Song Jianping , Cui Donghai , Wang Jing , Qin Junchao , Wang Shourong , Wang Zixiang , Zhai Xiangyu , Ma Huan , Ma Delin , Liu Yanfeng , Jin Bin , Liu Zhaojian
Published: October 2021

Cholangiocarcinomas (CCAs) are rare but aggressive tumors of the bile ducts. CCAs are often diagnosed at an advanced stage and respond poorly to current conventional radiotherapy and chemotherapy. High mobility group A1 (HMGA1) is an architectural transcription factor that is overexpressed in multiple malignant tumors. In this study, we showed that the expression of HMGA1 is frequently elevated in CCAs and that the high expression of this gene is associated with a poor prognosis. Functionally, HMGA1 promotes CCA cell proliferation/invasion and xenograft tumor growth. Furthermore, HMGA1 transcriptionally activates RAD51 by binding to its promoter through two HMGA1 response elements. Notably, overexpression of HMGA1 promotes radioresistance whereas its knockdown causes radiosensitivity of CCA cells to X-ray irradiation. Moreover, rescue experiments reveal that inhibition of RAD51 reverses the effect of HMGA1 on radioresistance and proliferation/invasion. These findings suggest that HMGA1 functions as a novel regulator of RAD51 and confers radioresistance in cholangiocarcinoma.
BAMboozle removes genetic variation from human sequence data for open data sharing
Authors: Ziegenhain Christoph , Sandberg Rickard
Published: October 2021

The risks associated with re-identification of human genetic data are severely limiting open data sharing in life sciences, even in studies where donor-related genetic variant information is not of primary interest. Here, we developed BAMboozle, a versatile tool to eliminate critical types of sensitive genetic information in human sequence data by reverting aligned reads to the genome reference sequence. Applying BAMboozle to functional genomics data, such as single-cell RNA-seq (scRNA-seq) and scATAC-seq datasets, confirmed the removal of donor-related single nucleotide polymorphisms (SNPs) and indels in a manner that did not disclose the altered positions. Importantly, BAMboozle only removes the genetic sequence variants of the sample (i.e., donor) while preserving other important aspects of the raw sequence data. For example, BAMboozled scRNA-seq data contained accurate cell-type associated gene expression signatures, splice kinetic information, and can be used for methods benchmarking. Altogether, BAMboozle efficiently removes genetic variation in aligned sequence data, which represents a step forward towards open data sharing in many areas of genomics where the genetic variant information is not of primary interest.
Assessing the importance of thermogenic degassing from the Karoo Large Igneous Province (LIP) in driving Toarcian carbon cycle perturbations
Authors: Heimdal Thea H. , Goddéris Yves , Jones Morgan T. , Svensen Henrik H.
Published: October 2021

The emplacement of the Karoo Large Igneous Province (LIP) occurred synchronously with the Toarcian crisis (ca. 183 Ma), which is characterized by major carbon cycle perturbations. A marked increase in the atmospheric concentration of CO2(pCO2) attests to significant input of carbon, while negative carbon isotope excursions (CIEs) in marine and terrestrial records suggest the involvement of a12C-enriched source. Here we explore the effects of pulsed carbon release from the Karoo LIP on atmosphericpCO2and δ13C of marine sediments, using the GEOCLIM carbon cycle model. We show that a total of 20,500 Gt C replicates the ToarcianpCO2and δ13C proxy data, and that thermogenic carbon (δ13C of −36 ‰) represents a plausible source for the observed negative CIEs. Importantly, an extremely isotopically depleted carbon source, such as methane clathrates, is not required in order to replicate the negative CIEs. Although exact values of individual degassing pulses represent estimates, we consider our emission scenario realistic as it incorporates the available geological knowledge of the Karoo LIP and a representative framework for Earth system processes during the Toarcian.
Uncovering the out-of-plane nanomorphology of organic photovoltaic bulk heterojunction by GTSAXS
Authors: Xia Xinxin , Lau Tsz-Ki , Guo Xuyun , Li Yuhao , Qin Minchao , Liu Kuan , Chen Zeng , Zhan Xiaozhi , Xiao Yiqun , Chan Pok Fung , Liu Heng , Xu Luhang , Cai Guilong , Li Na , Zhu Haiming , Li Gang , Zhu Ye , Zhu Tao , Zhan Xiaowei , Wang Xun-Li , Lu Xinhui
Published: October 2021

The bulk morphology of the active layer of organic solar cells (OSCs) is known to be crucial to the device performance. The thin film device structure breaks the symmetry into the in-plane direction and out-of-plane direction with respect to the substrate, leading to an intrinsic anisotropy in the bulk morphology. However, the characterization of out-of-plane nanomorphology within the active layer remains a grand challenge. Here, we utilized an X-ray scattering technique, Grazing-incident Transmission Small-angle X-ray Scattering (GTSAXS), to uncover this new morphology dimension. This technique was implemented on the model systems based on fullerene derivative (P3HT:PC71BM) and non-fullerene systems (PBDBT:ITIC, PM6:Y6), which demonstrated the successful extraction of the quantitative out-of-plane acceptor domain size of OSC systems. The detected in-plane and out-of-plane domain sizes show strong correlations with the device performance, particularly in terms of exciton dissociation and charge transfer. With the help of GTSAXS, one could obtain a more fundamental perception about the three-dimensional nanomorphology and new angles for morphology control strategies towards highly efficient photovoltaic devices.
Improvement of a synthetic live bacterial therapeutic for phenylketonuria with biosensor-enabled enzyme engineering
Authors: Adolfsen Kristin J. , Callihan Isolde , Monahan Catherine E. , Greisen Per , Spoonamore James , Momin Munira , Fitch Lauren E. , Castillo Mary Joan , Weng Lindong , Renaud Lauren , Weile Carl J. , Konieczka Jay H. , Mirabella Teodelinda , Abin-Fuentes Andres , Lawrence Adam G. , Isabella Vincent M.
Published: October 2021

In phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic phenylalanine (Phe), which can result in severe neurological impairment. As a treatment for PKU,Escherichia coliNissle (EcN) strain SYNB1618 was developed under Synlogic’s Synthetic Biotic™ platform to degrade Phe from within the gastrointestinal (GI) tract. This clinical-stage engineered strain expresses the Phe-metabolizing enzyme phenylalanine ammonia lyase (PAL), catalyzing the deamination of Phe to the non-toxic producttrans-cinnamate (TCA). In the present work, we generate a more potent EcN-based PKU strain through optimization of whole cell PAL activity, using biosensor-based high-throughput screening of mutant PAL libraries. A lead enzyme candidate from this screen is used in the construction of SYNB1934, a chromosomally integrated strain containing the additional Phe-metabolizing and biosafety features found in SYNB1618. Head-to-head, SYNB1934 demonstrates an approximate two-fold increase in in vivo PAL activity compared to SYNB1618.
Ion-dependent structure, dynamics, and allosteric coupling in a non-selective cation channel
Authors: Lewis Adam , Kurauskas Vilius , Tonelli Marco , Henzler-Wildman Katherine
Published: October 2021

The selectivity filter (SF) determines which ions are efficiently conducted through ion channel pores. NaK is a non-selective cation channel that conducts Na+ and K+ with equal efficiency. Crystal structures of NaK suggested a rigid SF structure, but later solid-state NMR and MD simulations questioned this interpretation. Here, we use solution NMR to characterize how bound Na+ vs. K+ affects NaK SF structure and dynamics. We find that the extracellular end of the SF is flexible on the ps-ns timescale regardless of bound ion. On a slower timescale, we observe a structural change between the Na+ and K+-bound states, accompanied by increased structural heterogeneity in Na+. We also show direct evidence that the SF structure is communicated to the pore via I88 on the M2 helix. These results support a dynamic SF with multiple conformations involved in non-selective conduction. Our data also demonstrate allosteric coupling between the SF and pore-lining helices in a non-selective cation channel that is analogous to the allosteric coupling previously demonstrated for K+-selective channels, supporting the generality of this model.
Functional metagenomic analysis of quorum sensing signaling in a nitrifying community
Authors: Tan Chuan Hao , Yeo Yee Phan , Hafiz Muhammad , Ng Noele Kai Jing , Subramoni Sujatha , Taj Shireen , Tay Martin , Chao Xie , Kjelleberg Staffan , Rice Scott A.
Published: October 2021

Quorum sensing (QS) can function to shape the microbial community interactions, composition, and function. In wastewater treatment systems, acylated homoserine lactone (AHL)-based QS has been correlated with the conversion of floccular biomass into microbial granules, as well as EPS production and the nitrogen removal process. However, the role of QS in such complex communities is still not fully understood, including the QS-proficient taxa and the functional QS genes involved. To address these questions, we performed a metagenomic screen for AHL genes in an activated sludge microbial community from the Ulu Pandan wastewater treatment plant (WWTP) in Singapore followed by functional validation of luxI activity using AHL biosensors and LC–MSMS profiling. We identified 13 luxI and 30 luxR homologs from the activated sludge metagenome. Of those genes, two represented a cognate pair of luxIR genes belonging to a Nitrospira spp. and those genes were demonstrated to be functionally active. The LuxI homolog synthesized AHLs that were consistent with the dominant AHLs in the activated sludge system. Furthermore, the LuxR homolog was shown to bind to and induce expression of the luxI promoter, suggesting this represents an autoinduction feedback system, characteristic of QS circuits. Additionally, a second, active promoter was upstream of a gene encoding a protein with a GGDEF/EAL domain, commonly associated with modulating the intracellular concentration of the secondary messenger, c-di-GMP. Thus, the metagenomic approach used here was demonstrated to effectively identify functional QS genes and suggests that Nitrospira spp. maybe QS is active in the activated sludge community.
Tunable vertical ferroelectricity and domain walls by interlayer sliding in β-ZrI2
Authors: Ma Xiaonan , Liu Chang , Ren Wei , Nikolaev Sergey A.
Published: October 2021

Vertical ferroelectricity where a net dipole moment appears as a result of in-plane ionic displacements has gained enormous attention following its discovery in transition metal dichalcogenides. Based on first-principles calculations, we report on the evidence of robust vertical ferroelectricity upon interlayer sliding in layered semiconducting β-ZrI2, a sister material of polar semimetals MoTe2 and WTe2. The microscopic origin of ferroelectricity in ZrI2 is attributed to asymmetric shifts of electronic charges within a trilayer, revealing a subtle interplay of rigid sliding displacements and charge redistribution down to ultrathin thicknesses. We further investigate the variety of ferroelectric domain boundaries and predict a stable charged domain wall with a quasi-two-dimensional electron gas and a high built-in electric field that can increase electron mobility and electromechanical response in multifunctional devices. Semiconducting behaviour and a small switching barrier of ZrI2 hold promise for various ferroelectric applications, and our results provide important insights for further development of slidetronics ferroelectricity.
A magnetic levitation based low-gravity simulator with an unprecedented large functional volume
Authors: Sanavandi Hamid , Guo Wei
Published: October 2021

Low-gravity environment can have a profound impact on the behaviors of biological systems, the dynamics of fluids, and the growth of materials. Systematic research on the effects of gravity is crucial for advancing our knowledge and for the success of space missions. Due to the high cost and the limitations in the payload size and mass in typical spaceflight missions, ground-based low-gravity simulators have become indispensable for preparing spaceflight experiments and for serving as stand-alone research platforms. Among various simulator systems, the magnetic levitation-based simulator (MLS) has received long-lasting interest due to its easily adjustable gravity and practically unlimited operation time. However, a recognized issue with MLSs is their highly non-uniform force field. For a solenoid MLS, the functional volume V1%, where the net force results in an acceleration <1% of the Earth’s gravity g, is typically a few microliters (μL) or less. In this work, we report an innovative MLS design that integrates a superconducting magnet with a gradient-field Maxwell coil. Through an optimization analysis, we show that an unprecedented V1% of over 4000 μL can be achieved in a compact coil with a diameter of 8 cm. We also discuss how such an MLS can be made using existing high-Tc-superconducting materials. When the current in this MLS is reduced to emulate the gravity on Mars (gM = 0.38g), a functional volume where the gravity varies within a few percent of gM can exceed 20,000 μL. Our design may break new ground for future low-gravity research.
Computing secure key rates for quantum cryptography with untrusted devices
Authors: Tan Ernest Y.-Z. , Schwonnek René , Goh Koon Tong , Primaatmaja Ignatius William , Lim Charles C.-W.
Published: October 2021

Device-independent quantum key distribution (DIQKD) provides the strongest form of secure key exchange, using only the input–output statistics of the devices to achieve information-theoretic security. Although the basic security principles of DIQKD are now well understood, it remains a technical challenge to derive reliable and robust security bounds for advanced DIQKD protocols that go beyond the previous results based on violations of the CHSH inequality. In this work, we present a framework based on semidefinite programming that gives reliable lower bounds on the asymptotic secret key rate of any QKD protocol using untrusted devices. In particular, our method can in principle be utilized to find achievable secret key rates for any DIQKD protocol, based on the full input–output probability distribution or any choice of Bell inequality. Our method also extends to other DI cryptographic tasks.
Salivary microbiome profiling reveals a dysbiotic schizophrenia-associated microbiota
Authors: Qing Ying , Xu Lihua , Cui Gaoping , Sun Liya , Hu Xiaowen , Yang Xuhan , Jiang Jie , Zhang Juan , Zhang Tianhong , Wang Tao , He Lin , Wang Jijun , Wan Chunling
Published: October 2021

Schizophrenia is a debilitating mental disorder and often has a prodromal period, referred to as clinical high risk (CHR) for psychosis, prior to the first episode. The etiology and pathogenesis of schizophrenia remain unclear. Despite the human gut microbiome being associated with schizophrenia, the role of the oral microbiome, which is a vital player in the mouth–body connection, is not well understood. To address this, we performed 16S rRNA gene sequencing to investigate the salivary microbiome in 85 patients with drug-naïve first-episode schizophrenia (FES), 43 individuals at CHR, and 80 healthy controls (HCs). The salivary microbiome of FES patients was characterized by higher α-diversity and lower β-diversity heterogeneity than those of CHR subjects and HCs. Proteobacteria, the predominant phylum, was depleted, while Firmicutes and the Firmicutes/Proteobacteria ratio was enriched, in a stepwise manner from HC to CHR to FES. H2S-producing bacteria exhibited disease-stage-specific enrichment and could be potential diagnostic biomarkers for FES and CHR. Certain salivary microbiota exhibited disease-specific correlation patterns with symptomatic severities, peripheral pro-inflammatory cytokines, thioredoxin, and S100B in FES. Furthermore, the metabolic functions from inferred metagenomes of the salivary microbiome were disrupted in FES, especially amino acid metabolism, carbohydrate metabolism, and xenobiotic degradation. This study has established a link between salivary microbiome alterations and disease initiation and provided the hypothesis of how the oral microbiota could influence schizophrenia.
Deep learning and alignment of spatially resolved single-cell transcriptomes with Tangram
Authors: Biancalani Tommaso , Scalia Gabriele , Buffoni Lorenzo , Avasthi Raghav , Lu Ziqing , Sanger Aman , Tokcan Neriman , Vanderburg Charles R. , Segerstolpe Åsa , Zhang Meng , Avraham-Davidi Inbal , Vickovic Sanja , Nitzan Mor , Ma Sai , Subramanian Ayshwarya , Lipinski Michal , Buenrostro Jason , Brown Nik Bear , Fanelli Duccio , Zhuang Xiaowei , Macosko Evan Z. , Regev Aviv
Published: October 2021

Charting an organs’ biological atlas requires us to spatially resolve the entire single-cell transcriptome, and to relate such cellular features to the anatomical scale. Single-cell and single-nucleus RNA-seq (sc/snRNA-seq) can profile cells comprehensively, but lose spatial information. Spatial transcriptomics allows for spatial measurements, but at lower resolution and with limited sensitivity. Targeted in situ technologies solve both issues, but are limited in gene throughput. To overcome these limitations we present Tangram, a method that aligns sc/snRNA-seq data to various forms of spatial data collected from the same region, including MERFISH, STARmap, smFISH, Spatial Transcriptomics (Visium) and histological images. Tangram can map any type of sc/snRNA-seq data, including multimodal data such as those from SHARE-seq, which we used to reveal spatial patterns of chromatin accessibility. We demonstrate Tangram on healthy mouse brain tissue, by reconstructing a genome-wide anatomically integrated spatial map at single-cell resolution of the visual and somatomotor areas.