bluuebunny/crossref_metadata_2025 huggingface dataset:
SET-VALUED PERFORMANCE APPROXIMATIONS FOR THE QUEUE GIVEN PARTIAL INFORMATION
Authors: Chen Yan , Whitt Ward
Published: September 2020

In order to understand queueing performance given only partial information about the model, we propose determining intervals of likely values of performance measures given that limited information. We illustrate this approach for the mean steady-state waiting time in the$GI/GI/K$queue. We start by specifying the first two moments of the interarrival-time and service-time distributions, and then consider additional information about these underlying distributions, in particular, a third moment and a Laplace transform value. As a theoretical basis, we apply extremal models yielding tight upper and lower bounds on the asymptotic decay rate of the steady-state waiting-time tail probability. We illustrate by constructing the theoretically justified intervals of values for the decay rate and the associated heuristically determined interval of values for the mean waiting times. Without extra information, the extremal models involve two-point distributions, which yield a wide range for the mean. Adding constraints on the third moment and a transform value produces three-point extremal distributions, which significantly reduce the range, producing practical levels of accuracy.
New insights into English count and mass nouns – the Cognitive Grammar perspective
Authors: DROŻDŻ GRZEGORZ
Published: September 2020

The article deals with two of the long-standing problems in English linguistics: whether it is possible that each noun can have both count and mass senses, and the problem of determining a complete list of the regularities of count-to-mass and mass-to-count changes. While there have been numerous attempts to solve each of these problems, this article shows the results of applying Cognitive Grammar to them.

The analysis covers a set of concrete nouns representative of English – sixty nouns with different ontological properties and all frequencies of occurrence. These are nouns that are classified by dictionaries as solely count and solely mass. Because of its usage-based character, the analysis scrutinises over 1,700 real-life utterances produced by native speakers of English. The analysis shows that even such nouns possess senses whose properties are the reverse of the properties of the nouns’ basic senses. A thorough examination of the nouns’ basic and extended senses leads to certain grammatical regularities of count-to-mass and mass-to-count changes. The analysis not only systematises the grammatical regularities determined so far and solves many problems that can be noticed about them, but also proposes novel regularities.
An Apprenticeship and Its Stocktakings: Leibowitz, Boulez, Messiaen, and the Discourse and Practice of New Music
Authors: ERWIN MAX
Published: September 2020

The textbook historical account of post-war New Music describes a logical and radical succession from Schoenberg to Webern to the Darmstadt School. Against this narrative of inevitability, I provide a more contingent account of the institutionalization of a particular discourse of New Music in the aftermath of the Second World War in Europe. What is contingent here is not so much why or how certain figures – chiefly Pierre Boulez and René Leibowitz – were important, but the shape and the logic by which this importance was established and maintained. Accordingly, this article first of all provides a summary of just what it meant for Leibowitz's understanding of New Music to be reproduced in an institutional capacity. From here, I undertake close critical reading of Boulez's break with Leibowitz in order to discover what, exactly, Boulez began to do differently to establish a new practice.
Morainal Bank Evolution and Impact on Terminus Dynamics During a Tidewater Glacier Stillstand
Authors: Eidam E. F. , Sutherland D. A. , Duncan D. , Kienholz C. , Amundson J. M. , Motyka R. J.
Published: September 2020

Sedimentary processes are known to help facilitate tidewater glacier advance, but their role in modulating retreat is uncertain and poorly quantified. In this study we use repeated seafloor bathymetric surveys and satellite‐derived terminus positions from LeConte Glacier, Alaska, to evaluate the evolution of a morainal bank and related changes in terminus dynamics over a 17‐year period. The glacier experienced a rapid retreat between 1994 and 1999, before stabilizing at a constriction in the fjord. Since then, the glacier terminus has remained stabilized while constructing a morainal bank up to 140 m high in water depths of 240–260 m, with rates of sediment delivery of 3.3 × 105 to 3.8 × 105 m3 a−1. Based on repeated interannual surveys between 2016 and 2018, the moraine is a dynamic feature characterized by push ridges, evidence of active gravity flows, and bulldozing by the glacier at rates of up to meters per day. Beginning in 2016, the summertime terminus has become increasingly retracted, revealing a newly emerging basin potentially signaling the onset of renewed retreat. Between 2000 and 2016, the growing moraine reduced the exposed submarine area of the terminus by up to 22%, altered the geometry of the terminus during seasonal advances, and altered the terminus stress balance. These feedbacks for calving, melting, and ice flow likely represent mechanisms whereby moraine growth may delay glacier retreat, in a system where readvance is unlikely.
Sea Level Rise Will Drive Divergent Sediment Transport Patterns on Fore Reefs and Reef Flats, Potentially Causing Erosion on Atoll Islands
Authors: Bramante James F. , Ashton Andrew D. , Storlazzi Curt D. , Cheriton Olivia M. , Donnelly Jeffrey P.
Published: September 2020

Atoll reef islands primarily consist of unconsolidated sediment, and their ocean‐facing shorelines are maintained by sediment produced and transported across their reefs. Changes in incident waves can alter cross‐shore sediment exchange and, thus, affect the sediment budget and morphology of atoll reef islands. Here we investigate the influence of sea level rise and projected wave climate change on wave characteristics and cross‐shore sediment transport across an atoll reef at Kwajalein Island, Republic of the Marshall Islands. Using a phase‐resolving model, we quantify the influence on sediment transport of quantities not well captured by wave‐averaged models, namely, wave asymmetry and skewness and flow acceleration. Model results suggest that for current reef geometry, sea level, and wave climate, potential bedload transport is directed onshore, decreases from the fore reef to the beach, and is sensitive to the influence of flow acceleration. We find that a projected 12% decrease in annual wave energy by 2100 CE has negligible influence on reef flat hydrodynamics. However, 0.5–2.0 m of sea level rise increases wave heights, skewness, and shear stress on the reef flat and decreases wave skewness and shear stress on the fore reef. These hydrodynamic changes decrease potential sediment inputs onshore from the fore reef where coral production is greatest but increase potential cross‐reef sediment transport from the outer reef flat to the beach. Assuming sediment production on the fore reef remains constant or decreases due to increasing ocean temperatures and acidification, these processes have the potential to decrease net sediment delivery to atoll islands, causing erosion.
Modeling the Impact of Marine DMS Emissions on Summertime Air Quality Over the Coastal East China Seas
Authors: Li Shanshan , Sarwar Golam , Zhao Junri , Zhang Yan , Zhou Shengqian , Chen Ying , Yang Guipeng , Saiz‐Lopez Alfonso
Published: September 2020

Biogenic emission of dimethyl sulfide (DMS) from seawater is the major natural source of sulfur into the atmosphere. In this study, we use an advanced air quality model (CMAQv5.2) with DMS chemistry to examine the impact of DMS emissions from seawater on summertime air quality over China. A national scale database of DMS concentration in seawater is established based on a 5‐year observational record in the East China seas including the Bohai Sea, the Yellow Sea, and the East China Sea. We employ a commonly used global database and also the newly developed local database of oceanic DMS concentration, calculate DMS emissions using three different parameterization schemes, and perform five different model simulations for July, 2018. Results indicate that in large coastal areas of China, the average DMS emissions flux obtained with the local database is 3 times higher than that resulting from the global database, with a mean value of 9.1 μmol m−2 day−1 in the Bohai Sea, 8.4 μmol m−2 day−1 in the Yellow Sea, and 13.4 μmol m−2 day−1 in the East China Sea. The total DMS emissions flux calculated with the Nightingale scheme is 42% higher than that obtained with the Liss and Merlivat scheme but is 15% lower than that obtained with the Wanninkhof scheme. Among the three parameterizations, results of the Liss and Merlivat scheme agree better with the ship‐based observations over China's coastal waters. DMS emissions with the Liss and Merlivat parametrization increase atmospheric sulfur dioxide (SO2) and sulfate (SO42−) concentration over the East China seas by 6.4% and 3.3%, respectively. Our results indicate that although the anthropogenic source is still the dominant contributor of atmospheric sulfur burden in China, biogenic DMS emissions source is nonnegligible.
Demystifying Critical Zone Science to Make It More Inclusive
Authors: Singha Kamini , Sullivan Pamela , Li Li , Gasparini Nicole
Published: September 2020

A new network that embraces scientists with wide-ranging experiences and expertise aims to solve the challenges of Earth’s critical zone.
Rainfall Nowcasting Using Commercial Microwave Links
Authors: Imhoff R. O. , Overeem A. , Brauer C. C. , Leijnse H. , Weerts A. H. , Uijlenhoet R.
Published: September 2020

Accurate and timely precipitation forecasts are crucial for early warning. Rainfall nowcasting, the process of statistically extrapolating recent rainfall observations, is increasingly used for short‐term forecasting. Nowcasts are generally constructed with high‐resolution radar observations. As a proof of concept, we construct nowcasts with country‐wide rainfall maps estimated from signal level data of commercial microwave links (CMLs) for 12 summer days in the Netherlands. CML nowcasts compare well to radar rainfall nowcasts. Provided well‐calibrated CML rainfall estimates are employed, CML nowcasts can outperform unadjusted real‐time radar nowcasts for high rainfall rates, which are underestimated as compared to a reference. Care should be taken with the sensitivity of the advection field derivation to areas with low CML coverage and the inherent measurement scale of CML data, which can be larger than the application scale. We see potential for rainfall nowcasting with CML data, for example, in regions where weather radars are absent.
Evaluating Processing Choices for the Geodetic Estimation of Earth Orientation Parameters With Numerical Models of Global Geophysical Fluids
Authors: Dill R. , Dobslaw H. , Hellmers H. , Kehm A. , Bloßfeld M. , Thomas M. , Seitz F. , Thaller D. , Hugentobler U. , Schönemann E.
Published: September 2020

Different Earth orientation parameter (EOP) time series are publicly available that typically arise from the combination of individual space geodetic technique solutions. The applied processing strategies and choices lead to systematically differing signal and noise characteristics particularly at the shortest periods between 2 and 8 days. We investigate the consequences of typical choices by introducing new experimental EOP solutions obtained from combinations at either normal equation level processed by Deutsches Geodätisches Forschungsinstitut at the Technical University of Munich (DGFI‐TUM) and Federal Agency for Cartography and Geodesy (BKG), or observation level processed by European Space Agency (ESA). All those experiments contribute to an effort initiated by ESA to develop an independent capacity for routine EOP processing and prediction in Europe. Results are benchmarked against geophysical model‐based effective angular momentum functions processed by Helmholtz Centre Potsdam GFZ German Research Centre for Geosciences (ESMGFZ). We find, that a multitechnique combination at normal equation level that explicitly aligns a priori station coordinates to the ITRF2014 frequently outperforms the current International Earth Rotation and Reference Systems Service (IERS) standard solution 14C04. A multi‐Global Navigation Satellite System (GNSS)‐only solution already provides very competitive accuracies for the equatorial components. Quite similar results are also obtained from a short combination at observation level experiment using multi‐GNSS solutions and SLR from Sentinel‐3A and Sentinel‐3B to realize space links. For ΔUT1, however, very long baseline interferometry (VLBI) information is known to be critically important so that experiments combining only GNSS and possibly SLR at observation level perform worse than combinations of all techniques at normal equation level. The low noise floor and smooth spectra obtained from the multi‐GNSS solution nevertheless illustrates the potential of this most rigorous combination approach so that further efforts to include in particular VLBI are strongly recommended.
LncRNA BCYRN1 inhibits glioma tumorigenesis by competitively binding with miR-619-5p to regulate CUEDC2 expression and the PTEN/AKT/p21 pathway
Authors: Mu Maolin , Niu Wanxiang , Zhang Xiaoming , Hu Shanshan , Niu Chaoshi
Published: September 2020

Glioma is the most common malignant tumor in the central nervous system. Altered long noncoding RNAs (lncRNAs) are playing regulatory roles in physiological and pathogenic processes in cancer. Here, we uncovered a differentially expressed lncRNA called brain cytoplasmic RNA 1 (BCYRN1), and elucidated its function and molecular mechanism in the progression and development of glioma. Three fresh tumor tissues from glioma patients and three normal brain tissues from craniocerebral trauma patients were prepared for high-throughput RNA sequencing. Differential RNA transcripts and BCYRN1 were identified by RT-qPCR in glioma samples and controls. CCK-8, colony formation assays, flow cytometry, TUNEL assays, cell migration assays, wound-healing assays, and xenograft model were established to investigate the biological function of BCYRN1 both in vitro and in vivo. Various bioinformatics analysis, dual-luciferase reporter assays, biotinylated RNA pulldown assays, and rescue experiments were conducted to reveal the underlying mechanisms of competitive endogenous RNAs (ceRNAs). 183 lncRNAs were identified with significant dysregulation in glioma and randomly selected differential RNAs were further confirmed by RT-qPCR. Among them, BCYRN1 was the most downregulated lncRNA, and its low expression positively correlated with glioma progression. Functionally, BCYRN1 overexpression inhibited cell proliferation, migration in glioma cell lines, whereas BCYRN1 depletion resulted in the opposite way. MiR-619-5p was further confirmed as the direct target of BCYRN1. Mechanistically, miR-619-5p specifically targeted the CUE domain containing protein 2 (CUEDC2), and BCYRN1/miR-619-5p suppressed glioma tumorigenesis by inactivating PTEN/AKT/p21 pathway in a CUEDC2-dependent manner. Overall, our data presented that the reduced expression of BCYRN1 was associated with poor patient outcome in glioma. BCYRN1 functioned as a ceRNA to inhibit glioma progression by sponging miR-619-5p to regulate CUEDC2 expression and PTEN/AKT/p21 pathway. Our results indicated that BCYRN1 exerted tumor suppressor potential and might be a candidate in the diagnosis and treatment of glioma.
The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression
Authors: Jessen Christina , Kreß Julia K. C. , Baluapuri Apoorva , Hufnagel Anita , Schmitz Werner , Kneitz Susanne , Roth Sabine , Marquardt André , Appenzeller Silke , Ade Carsten P. , Glutsch Valerie , Wobser Marion , Friedmann-Angeli José Pedro , Mosteo Laura , Goding Colin R. , Schilling Bastian , Geissinger Eva , Wolf Elmar , Meierjohann Svenja
Published: September 2020

The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy
Authors: Lunger Lukas , Retz Margitta , Bandur Miriam , Souchay Marc , Vitzthum Elisabeth , Jäger Marion , Weirich Gregor , Schuster Tibor , Autenrieth Michael , Kübler Hubert , Maurer Tobias , Thalgott Mark , Herkommer Kathleen , Koll Florestan , Gschwend Jürgen E. , Nawroth Roman , Heck Matthias M.
Published: September 2020

Background

Lymph-node (LN) metastasis in prostate cancer (PC) is a main risk factor for tumor recurrence after radical prostatectomy (RP). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP.

Methods

The expression of kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostate-specific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2) and transient receptor potential cation channel subfamily M member 8 (TRPM8) was assessed using qPCR. We analyzed LNs from 111 patients (intermediate PC, n = 32 (29%); high-risk PC, n = 79 (71%)) who underwent RP and extended pelvic lymph-node dissection without neoadjuvant treatment.

Results

Overall, 2411 LNs were examined by molecular and histopathologic examination. Histopathology detected 69 LN metastases in 28 (25%) patients. KLK2 and KLK3 diagnostically performed best and classified all pN1-patients correctly as molecular node-positive (molN1/pN1). The concordance on LN level was best for KLK3 (96%). KLK2, KLK3, KLK4, PSMA, TMPRSS2, and TRPM8 reclassified 27 (24%), 32 (29%), 29 (26%), 8 (7%), 13 (12%), and 23 (21%) pN0-patients, respectively, as node-positive (pN0/molN1). On multivariable cox regression analysis molecular LN status (molN1 vs. molN0) using KLK3 (HR 4.0, p = 0.04) and TMPRSS2 (HR 5.1, p = 0.02) were independent predictors of bRFS. Median bRFS was shorter in patients with only molecular positive LNs (molN1/pN0) for KLK3 (24 months, p = 0.001) and for TMPRSS2 (12 months, p < 0.001) compared to patients with negative nodes (molN0/pN0) (median bRFS not reached).

Conclusions

For diagnostic purposes, KLK3 showed highest concordance with histopathology for detection of LN metastases in PC patients undergoing RP. For prognostic purposes, KLK3 and TMPRSS2 expression were superior to histopathologic LN status and other transcripts tested for molecular LN status. We suggest a combined KLK3/TMPRSS2 panel as a valuable diagnostic and prognostic tool for molecular LN analysis.
Population-scale predictions of DPD and TPMT phenotypes using a quantitative pharmacogene-specific ensemble classifier
Authors: Zhou Yitian , Dagli Hernandez Carolina , Lauschke Volker M.
Published: September 2020

Background

Inter-individual differences in dihydropyrimidine dehydrogenase (DPYDencoding DPD) and thiopurine S-methyltransferase (TPMT) activity are important predictors for fluoropyrimidine and thiopurine toxicity. While several variants in these genes are known to decrease enzyme activities, many additional genetic variations with unclear functional consequences have been identified, complicating informed clinical decision-making in the respective carriers.

Methods

We used a novel pharmacogenetically trained ensemble classifier to analyseDPYDandTPMTgenetic variability based on sequencing data from 138,842 individuals across eight populations.

Results

The algorithm accurately predicted in vivo consequences ofDPYDandTPMTvariants (accuracy 91.4% compared to 95.3% in vitro). Further analysis showed high genetic complexity of DPD deficiency, advocating for sequencing-basedDPYDprofiling, whereas genotyping of four variants inTPMTwas sufficient to explain >95% of phenotypic TPMT variability. Lastly, we provided population-scale profiles of ethnogeographic variability in DPD and TPMT phenotypes, and revealed striking interethnic differences in frequency and genetic constitution of DPD and TPMT deficiency.

Conclusion

These results provide the most comprehensive data set ofDPYDandTPMTvariability published to date with important implications for population-adjusted genetic profiling strategies of fluoropyrimidine and thiopurine risk factors and precision public health.
Multi-omics analysis identifies FoxO1 as a regulator of macrophage function through metabolic reprogramming
Authors: Yan Kai , Da Tian-Tian , Bian Zhen-Hua , He Yi , Liu Meng-Chu , Liu Qing-Zhi , Long Jie , Li Liang , Gao Cai-Yue , Yang Shu-Han , Zhao Zhi-Bin , Lian Zhe-Xiong
Published: September 2020

Macrophages are plastic cells that can switch among different states according to bioenergetic or biosynthetic requirements. Our previous work demonstrated that the transcription factor Forkhead Box Protein 1 (FoxO1) plays a pivotal role in regulating the function of macrophages, but the underlying mechanisms are still unclear. Here we identify FoxO1 as a regulator of macrophage function through metabolic reprogramming. Transcriptomic and proteomic analyses showed that the deficiency of FoxO1 results in an alternatively activated (M2) phenotype of macrophages, with lower expression of inflammatory response- and migration-associated genes. Using the high content screening and analysis technology, we found that deletion of FoxO1 in macrophages slows their migration rate and impairs their function to limit tumor cell growth in vitro. Next, we demonstrated that glycolysis is inhibited in FoxO1-deficient macrophages, which leads to the observed functional changes and the reduced tumor suppression capability. This prospective study shows that FoxO1 serves as a bridge between metabolism and macrophage function.
Correction: Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER stress
Authors: Abhari Behnaz Ahangarian , McCarthy Nicole , Le Berre Marie , Kilcoyne Michelle , Joshi Lokesh , Agostinis Patrizia , Fulda Simone
Published: September 2020

Since online publication of this article, the authors noticed that Fig. 3b does not show the correct graph for Bortezomib. The corrected graph for Fig. 3b is provided below. This unintentional mistake does not alter the conclusions of the study. The authors apologise for any inconvenience caused.
Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems
Authors: Joshi Piyush , Bodnya Caroline , Rasmussen Megan L. , Romero-Morales Alejandra I. , Bright Anna , Gama Vivian
Published: September 2020

Intrinsic apoptosis relies on the ability of the BCL-2 family to induce the formation of pores on the outer mitochondrial membrane. Previous studies have shown that both BAX and BAK are essential during murine embryogenesis, and reports in human cancer cell lines identified non-canonical roles for BAX and BAK in mitochondrial fission during apoptosis. BAX and BAK function in human brain development remains elusive due to the lack of appropriate model systems. Here, we generated BAX/BAK double knockout human-induced pluripotent stem cells (hiPSCs), hiPSC-derived neural progenitor cells (hNPCs), neural rosettes, and cerebral organoids to uncover the effects of BAX and BAK deletion in an in vitro model of early human brain development. We found that BAX and BAK-deficient cells have abnormal mitochondrial morphology and give rise to aberrant cortical structures. We suggest crucial functions for BAX and BAK during human development, including maintenance of homeostatic mitochondrial morphology, which is crucial for proper development of progenitors and neurons of the cortex. Human pluripotent stem cell-derived systems can be useful platforms to reveal novel functions of the apoptotic machinery in neural development.
Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?
Authors: Rada Patricia , González-Rodríguez Águeda , García-Monzón Carmelo , Valverde Ángela M.
Published: September 2020

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD stages range from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis and hepatocellular carcinoma. One of the crucial events clearly involved in NAFLD progression is the lipotoxicity resulting from an excessive fatty acid (FFA) influx to hepatocytes. Hepatic lipotoxicity occurs when the capacity of the hepatocyte to manage and export FFAs as triglycerides (TGs) is overwhelmed. This review provides succinct insights into the molecular mechanisms responsible for lipotoxicity in NAFLD, including ER and oxidative stress, autophagy, lipoapotosis and inflammation. In addition, we highlight the role of CD36/FAT fatty acid translocase in NAFLD pathogenesis. Up-to-date, it is well known that CD36 increases FFA uptake and, in the liver, it drives hepatosteatosis onset and might contribute to its progression to NASH. Clinical studies have reinforced the significance of CD36 by showing increased content in the liver of NAFLD patients. Interestingly, circulating levels of a soluble form of CD36 (sCD36) are abnormally elevated in NAFLD patients and positively correlate with the histological grade of hepatic steatosis. In fact, the induction of CD36 translocation to the plasma membrane of the hepatocytes may be a determining factor in the physiopathology of hepatic steatosis in NAFLD patients. Given all these data, targeting the fatty acid translocase CD36 or some of its functional regulators may be a promising therapeutic approach for the prevention and treatment of NAFLD.
Photoreduced nanocomposites of graphene oxide/N-doped carbon dots toward all-carbon memristive synapses
Authors: Lin Ya , Wang Zhongqiang , Zhang Xue , Zeng Tao , Bai Liang , Kang Zhenhui , Wang Changhua , Zhao Xiaoning , Xu Haiyang , Liu Yichun
Published: September 2020

An all-carbon memristive synapse is highly desirable for hardware implementation in future wearable neuromorphic computing systems. Graphene oxide (GO) can exhibit resistive switching (RS) and may be a feasible candidate to achieve this objective. However, the digital-type RS often occurring in GO-based memristors restricts the biorealistic emulation of synaptic functions. Here, an all-carbon memristive synapse with analog-type RS behavior was demonstrated through photoreduction of GO and N-doped carbon quantum dot (NCQD) nanocomposites. Ultraviolet light irradiation induced the local reduction of GO near the NCQDs, therefore forming multiple weak conductive filaments and demonstrating analog RS with a continuous conductance change. This analog RS enabled the close emulation of several essential synaptic plasticity behaviors; more importantly, the high linearity of the conductance change also facilitated the implementation of pattern recognition with high accuracy. Furthermore, the all-carbon memristive synapse can be transferred onto diverse substrates, showing good flexibility and 3D conformality. Memristive potentiation/depression was stably performed at 450 K, indicating the resistance of the synapse to high temperature. The photoreduction method provides a new path for the fabrication of all-carbon memristive synapses, which supports the development of wearable neuromorphic electronics.
Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level
Authors: Yuan Xinyue , Schröter Manuel , Obien Marie Engelene J. , Fiscella Michele , Gong Wei , Kikuchi Tetsuhiro , Odawara Aoi , Noji Shuhei , Suzuki Ikuro , Takahashi Jun , Hierlemann Andreas , Frey Urs
Published: September 2020

Chronic imaging of neuronal networks in vitro has provided fundamental insights into mechanisms underlying neuronal function. Current labeling and optical imaging methods, however, cannot be used for continuous and long-term recordings of the dynamics and evolution of neuronal networks, as fluorescent indicators can cause phototoxicity. Here, we introduce a versatile platform for label-free, comprehensive and detailed electrophysiological live-cell imaging of various neurogenic cells and tissues over extended time scales. We report on a dual-mode high-density microelectrode array, which can simultaneously record in (i) full-frame mode with 19,584 recording sites and (ii) high-signal-to-noise mode with 246 channels. We set out to demonstrate the capabilities of this platform with recordings from primary and iPSC-derived neuronal cultures and tissue preparations over several weeks, providing detailed morpho-electrical phenotypic parameters at subcellular, cellular and network level. Moreover, we develop reliable analysis tools, which drastically increase the throughput to infer axonal morphology and conduction speed.
Migratory functionalization of unactivated alkyl bromides for construction of all-carbon quaternary centers via transposed tert-C-radicals
Authors: Zhu Chuan , Liu Ze-Yao , Tang Luning , Zhang Heng , Zhang Yu-Feng , Walsh Patrick J. , Feng Chao
Published: September 2020

Despite remarkable recent advances in transition-metal-catalyzed C(sp3)−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary-C(sp3)−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp3) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert-alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials.
Transfer learning enables the molecular transformer to predict regio- and stereoselective reactions on carbohydrates
Authors: Pesciullesi Giorgio , Schwaller Philippe , Laino Teodoro , Reymond Jean-Louis
Published: September 2020

Organic synthesis methodology enables the synthesis of complex molecules and materials used in all fields of science and technology and represents a vast body of accumulated knowledge optimally suited for deep learning. While most organic reactions involve distinct functional groups and can readily be learned by deep learning models and chemists alike, regio- and stereoselective transformations are more challenging because their outcome also depends on functional group surroundings. Here, we challenge the Molecular Transformer model to predict reactions on carbohydrates where regio- and stereoselectivity are notoriously difficult to predict. We show that transfer learning of the general patent reaction model with a small set of carbohydrate reactions produces a specialized model returning predictions for carbohydrate reactions with remarkable accuracy. We validate these predictions experimentally with the synthesis of a lipid-linked oligosaccharide involving regioselective protections and stereoselective glycosylations. The transfer learning approach should be applicable to any reaction class of interest.
Poly(ADP-ribose) glycohydrolase coordinates meiotic DNA double-strand break induction and repair independent of its catalytic activity
Authors: Janisiw Eva , Raices Marilina , Balmir Fabiola , Paulin Luis F. , Baudrimont Antoine , von Haeseler Arndt , Yanowitz Judith L. , Jantsch Verena , Silva Nicola
Published: September 2020

Poly(ADP-ribosyl)ation is a reversible post-translational modification synthetized by ADP-ribose transferases and removed by poly(ADP-ribose) glycohydrolase (PARG), which plays important roles in DNA damage repair. While well-studied in somatic tissues, much less is known about poly(ADP-ribosyl)ation in the germline, where DNA double-strand breaks are introduced by a regulated program and repaired by crossover recombination to establish a tether between homologous chromosomes. The interaction between the parental chromosomes is facilitated by meiotic specific adaptation of the chromosome axes and cohesins, and reinforced by the synaptonemal complex. Here, we uncover an unexpected role for PARG in coordinating the induction of meiotic DNA breaks and their homologous recombination-mediated repair in Caenorhabditis elegans. PARG-1/PARG interacts with both axial and central elements of the synaptonemal complex, REC-8/Rec8 and the MRN/X complex. PARG-1 shapes the recombination landscape and reinforces the tightly regulated control of crossover numbers without requiring its catalytic activity. We unravel roles in regulating meiosis, beyond its enzymatic activity in poly(ADP-ribose) catabolism.
Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer
Authors: Fan Ming , Xia Pingping , Clarke Robert , Wang Yue , Li Lihua
Published: September 2020

Advanced tumours are often heterogeneous, consisting of subclones with various genetic alterations and functional roles. The precise molecular features that characterize the contributions of multiscale intratumour heterogeneity to malignant progression, metastasis, and poor survival are largely unknown. Here, we address these challenges in breast cancer by defining the landscape of heterogeneous tumour subclones and their biological functions using radiogenomic signatures. Molecular heterogeneity is identified by a fully unsupervised deconvolution of gene expression data. Relative prevalence of two subclones associated with cell cycle and primary immunodeficiency pathways identifies patients with significantly different survival outcomes. Radiogenomic signatures of imaging scale heterogeneity are extracted and used to classify patients into groups with distinct subclone compositions. Prognostic value is confirmed by survival analysis accounting for clinical variables. These findings provide insight into how a radiogenomic analysis can identify the biological activities of specific subclones that predict prognosis in a noninvasive and clinically relevant manner.
Publisher Correction: Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep
Authors: Feng Hui , Wen Si-Yi , Qiao Qi-Cheng , Pang Yu-Jie , Wang Sheng-Yun , Li Hao-Yi , Cai Jiao , Zhang Kai-Xuan , Chen Jing , Hu Zhi-An , Luo Fen-Lan , Wang Guan-Zhong , Yang Nian , Zhang Jun
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Occurrence, distribution, and health risk assessment of quinolone antibiotics in water, sediment, and fish species of Qingshitan reservoir, South China
Authors: Huang Liangliang , Mo Yuanmin , Wu Zhiqiang , Rad Saeed , Song Xiaohong , Zeng Honghu , Bashir Safdar , Kang Bin , Chen Zhongbing
Published: September 2020

The residual antibiotics in the environment have lately caused widespread concerns. However, little information is available on the antibiotic bioaccumulation and its health risk in drinking water resources of South China. Therefore, the occurrence, distribution, and health risk of four quinolone antibiotics including ofloxacin (OFX), norfloxacin (NOR), ciprofloxacin (CIP), and enrofloxacin (ENR) in the Qingshitan reservoir using high-performance liquid chromatography were investigated. Results revealed that the concentrations in water, sediment, and edible fish ranged from 3.49–660.13 ng/L, 1.03–722.18 μg/kg, and 6.73–968.66 μg/kg, respectively. The ecological risk assessment via the risk quotient (RQ) method showed that the values in sediment were all greater than 1, posing a high risk to the environment. The health risk index of water samples was at the maximum acceptable level, with OFX at the top while the rest were at the medium risk level. The main edible fish kinds of the reservoir had high dietary safety and the highest contaminations were found in carnivorous feeding habits and demersal habitat fishes with OFX as the highest magnitude. Source identification and correlation analysis using SPSS showed significant relationships between NOR with pH and turbidity (in water), as well as total phosphor (TP) and total organic carbon (TOC) in sediment. NOR was the highest in sediment which mostly sourced from livestock wastewater, croplands irrigation drain water, and stormwater. Correlations between CIP and ENR with TP were significant, while OFX was positively associated with total nitrogen (TN) which mainly originated from urban sewage as well as directly dosed drugs in fish farms. In conclusion, our results are of great significance for ensuring the safety of drinking water and aquatic products in this region.
Cannabinoids affect the mouse visual acuity via the cannabinoid receptor type 2
Authors: Cécyre Bruno , Bachand Ismaël , Papineau François , Brochu Chloé , Casanova Christian , Bouchard Jean-François
Published: September 2020

Recently, there have been increasing indications that the endocannabinoid (eCB) system is involved in vision. Multiple research teams studied the cannabinoid receptor type 2 (CB2R) expression and function in the mouse retina. Here, we examined the consequence of CB2R modulation on visual acuity using genetic and pharmacologic tools. We found that Cnr2 knockout mice show an enhanced visual acuity, CB2R activation decreased visual acuity while CB2R blockade with the inverse agonist AM630 increased it. The inhibition of 2-arachidonylglycerol (2-AG) synthesis and degradation also greatly increased and decreased visual acuity, respectively. No differences were seen when the cannabinoid receptor type 1 (CB1R) was deleted, blocked or activated implying that CB2R exclusively mediates cannabinoid modulation of the visual acuity. We also investigated the role of cannabinoids in retinal function using electroretinography (ERG). We found that modulating 2-AG levels affected many ERG components, such as the a-wave and oscillatory potentials (OPs), suggesting an impact on cones and amacrine cells. Taken together, these results reveal that CB2R modulates visual acuity and that eCBs such as 2-AG can modulate both visual acuity and retinal sensitivity. Finally, these findings establish that CB2R is present in visual areas and regulates vision-related functions.
Comparison of gut microbiota in exclusively breast-fed and formula-fed babies: a study of 91 term infants
Authors: Ma Jingran , Li Zhenghong , Zhang Wenjuan , Zhang Chunli , Zhang Yuheng , Mei Hua , Zhuo Na , Wang Hongyun , Wang Lin , Wu Dan
Published: September 2020

To compare gut microbiota of healthy infants that were exclusively breast-fed or formula-fed, we recruited 91 infants, who were assigned into three different groups and fed by breast milk (30 babies), formula A (30 babies) or formula B (31 babies) exclusively for more than 4 months after birth. Faecal bacterial composition was tested. Among different groups, α diversity was lower in breast-fed group than formula-fed groups in 40 days of age, but increased significantly in 6 months of age. The Bifidobacterium represented the most predominant genus and Enterobacteriaceae the second in all groups. In 40 days of age, Bifidobacterium and Bacteroides were significantly higher, while Streptococcus and Enterococcus were significantly lower in breast-fed group than they were in formula A-fed group. Lachnospiraceae was lower in breast-fed than formula B-fed group. Veillonella and Clostridioides were lower in breast-fed than formula-fed groups. In 3 months of age there were less Lachnospiraceae and Clostridioides in breast-fed group than formula-fed groups. There were also significant differences of microbiota between formula A-fed and formula B-fed groups. Those differences may have impacts on their long-term health.
A vertebrate model to reveal neural substrates underlying the transitions between conscious and unconscious states
Authors: Bedell Victoria M. , Meng Qing C. , Pack Michael A. , Eckenhoff Roderic G.
Published: September 2020

The field of neuropharmacology has not yet achieved a full understanding of how the brain transitions between states of consciousness and drug-induced unconsciousness, or anesthesia. Many small molecules are used to alter human consciousness, but the repertoire of underlying molecular targets, and thereby the genes, are incompletely understood. Here we describe a robust larval zebrafish model of anesthetic action, from sedation to general anesthesia. We use loss of movement under three different conditions, spontaneous movement, electrical stimulation or a tap, as a surrogate for sedation and general anesthesia, respectively. Using these behavioral patterns, we find that larval zebrafish respond to inhalational and IV anesthetics at concentrations similar to mammals. Additionally, known sedative drugs cause loss of spontaneous larval movement but not to the tap response. This robust, highly tractable vertebrate model can be used in the detection of genes and neural substrates involved in the transition from consciousness to unconsciousness.
The tetraspanin CD151 marks a unique population of activated human T cells
Authors: Perez Mildred D. , Seu Lillian , Lowman Kelsey E. , Moylan David C. , Tidwell Christopher , Samuel Shekwonya , Duverger Alexandra , Wagner Frederic H. , Carlin Eric , Sharma Vishal , Pope Brandon , Raman Chander , Erdmann Nathan , Locke Jayme , Hu Hui , Sabbaj Steffanie , Kutsch Olaf
Published: September 2020

Tetraspanins are a family of proteins with an array of functions that are well studied in cancer biology, but their importance in immunology is underappreciated. Here we establish the tetraspanin CD151 as a unique marker of T-cell activation and, in extension, an indicator of elevated, systemic T-cell activity. Baseline CD151 expression found on a subset of T-cells was indicative of increased activation of the MAPK pathway. Following TCR/CD3 activation, CD151 expression was upregulated on the overall T-cell population, a quintessential feature of an activation marker. CD151+ T-cell frequencies in the spleen, an organ with increased immune activity, were twice as high as in paired peripheral blood samples. This CD151+ T-cell frequency increase was not paralleled by an increase of CD25 or CD38, demonstrating that CD151 expression is regulated independently of other T-cell activation markers. CD151+ T-cells were also more likely to express preformed granzyme B, suggesting that CD151+ T cells are pro-inflammatory. To this end, HIV-1 patients on antiretroviral therapy who are reported to exhibit chronically elevated levels of immune activity, had significantly higher CD4+CD151+ T-cell frequencies than healthy controls, raising the possibility that proinflammatory CD151+ T cells could contribute to the premature immunological aging phenotype observed in these patients.
Detection of ferromagnetic resonance from 1 nm-thick Co
Authors: Yoshii Shugo , Ohshima Ryo , Ando Yuichiro , Shinjo Teruya , Shiraishi Masashi
Published: September 2020

To explore the further possibilities of nanometer-thick ferromagnetic films (ultrathin ferromagnetic films), we investigated the ferromagnetic resonance (FMR) of 1 nm-thick Co film. Whilst an FMR signal was not observed for the Co film grown on a SiO2 substrate, the insertion of a 3 nm-thick amorphous Ta buffer layer beneath the Co enabled the detection of a salient FMR signal, which was attributed to the smooth surface of the amorphous Ta. This result implies the excitation of FMR in an ultrathin ferromagnetic film, which can pave the way to controlling magnons in ultrathin ferromagnetic films.
DNA-based genealogy reconstruction of Nebbiolo, Barbera and other ancient grapevine cultivars from northwestern Italy
Authors: Raimondi Stefano , Tumino Giorgio , Ruffa Paola , Boccacci Paolo , Gambino Giorgio , Schneider Anna
Published: September 2020

Northwestern Italy is a wine region of the world with the highest of reputations, where top quality wines of remarkable economic value are produced from traditional, long-cultivated varieties. Kinship analyses were performed using 32 microsatellite loci and more than 10 K single-nucleotide polymorphism markers on 227 traditional grapes mostly from Northwestern Italy—including those that have been neglected or are threatened. This was done to better understand the genetic grapevine origins and history of this reputable wine producing area, thus enhancing its cultural value and the marketing appeal of its wines. The work revealed a complex network of genetic relationships among varieties, with little contribution of genotypes from other areas. It revealed the major role played by a few ancient grape varieties as parents of numerous offspring, including some that are endangered today. The ancestry of many cultivars is proposed. Among these are Dolcetto, Barbera and Riesling italico. Through the inference of parent–offspring and sibling relations, marker profiles of ungenotyped putative parents were reconstructed, suggesting kinship relations and a possible parentage for Nebbiolo, one of the most ancient wine grapes worldwide. Historic and geographic implications from the resulting kinships are discussed.
Publisher Correction: Genomic content typifying a prevalent clade of bovine mastitis-associated Escherichia coli
Authors: Goldstone Robert J. , Harris Susan , Smith David G. E.
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.