bluuebunny/crossref_metadata_2025 huggingface dataset:
Mental Well-Being of University Students in Social	Isolation
Authors: Lukács Andrea
Published: January 2021

Abstract. Background: The novel coronavirus disease has caused a worldwide pandemic and has been distressing for the general population including the student population in higher education. Aims: This study assesses the changes in the lives of university students, and finds an association between fear of COVID-19 and mental well-being controlled by demographic and socio-psychological factors. Method: Students from one of the largest universities of Hungary were sampled responding to multidimensional questions about their life situations prior to and after social isolation measures, 4–6 weeks after the COVID-19 outbreak in Hungary. The questionnaire packet included the 8-item version of the Center for Epidemiological Studies-Depression Scale for evaluating mental well-being. Results: Students experienced significant negative changes after 4–6 weeks of confinement in terms of physical activity, relationship with family, friends, studies, financial situation, perceived health, future prospects, and life satisfaction. Desirable changes were observed in smoking habits, cannabis use, and alcohol consumption, including binge drinking. Explanatory variables of favorable mental well-being were younger age, better-perceived health status, higher life satisfaction, and more optimism about future prospects. Limitations: Mental well-being was measured only during social isolation. The pre-pandemic status of the students was reported retrospectively, making it prone to recall bias. Conclusion: Findings suggest that the pandemic with its associated social isolation measures negatively affected students’ everyday life and well-being, however, the fear of the coronavirus did not contribute to it. Higher institutions should offer a wide range of measures to mitigate the downstream mental health consequences of the COVID-19 outbreak in university population.
Evaluation of MODIS and Himawari‐8 Low Clouds Retrievals Over the Southern Ocean With In Situ Measurements From the SOCRATES Campaign
Authors: Kang Litai , Marchand Roger , Smith William
Published: January 2021

Aircraft observations collected during the Southern Ocean Cloud Radiation Aerosol Transport Experimental Study in January‐February of 2018 are used to evaluate cloud properties from three satellite‐imager datasets: (1) the Moderate Resolution Imaging Spectroradiometer level 2 (collection 6.1) cloud product, (2) the CERES‐MODIS Edition 4 cloud product, and (3) the NASA SatCORPS Himawari‐8 cloud product. Overall the satellite retrievals compare well with the in situ observations, with little bias and modest to good correlation coefficients when considering all aircraft profiles for which there are coincident MODIS observations. The Himawari‐8 product does, however, show a statistically significant mean bias of about 1.2 μm for effective radius (re) and 2.6 for optical depth (τ) when applied to a larger set of profiles with coincident Himawari‐8 observations. The low overall mean‐bias in the re retrievals is due in part to compensating errors between cases that are non‐ or lightly precipitating, with cases that have heavier precipitation. re is slightly biased high (by about 0.5–1.0 μm) for non‐ and lightly precipitating cases and biased low by about 3–4 μm for heavily precipitating cases when precipitation exits near cloud top. The bias in non‐ and lightly precipitating conditions is due to (at least in part) having assumed a drop size distribution in the retrieval that is too broad. These biases in the re ultimately propagate into the retrieved liquid water path and number concentration.
A Thermo‐Compositional Model of the Cratonic Lithosphere of South America
Authors: Finger N.‐P. , Kaban M. K. , Tesauro M. , Haeger C. , Mooney W. D. , Thomas M.
Published: January 2021

New seismic data on the crust and upper mantle of South America have recently become available and describe its deep structure with unprecedented resolution. Here, seismic data are combined with gravity data and mineral physics constraints to develop self‐consistent models of the temperature, composition, and density of the South American lithospheric and sub‐lithospheric upper mantle. A new model of the crustal structure was developed, including sediment and average crustal density and depth to the Moho. This crustal model was used to correct the gravity field and obtain the residual topography. Then, an initial temperature model, derived from seismic tomography and mineral physics, was improved through an iterative process based on the joint inversion of gravity and residual topography. The results reveal deep cratonic roots present under wide parts of the Amazon, São Francisco, and Paranapanema Cratons, but not under the Rio de la Plata and Parnaíba Cratons. These cratons probably never developed lithospheric roots or were rejuvenated during subsequent tectonic events. We hypothesize that the root of the northwestern Amazon craton was removed by upwelling of hot mantle material under the Guyana highlands. Temperature and density anomalies evident beneath the São Francisco Craton appear to be connected with those of the Paranapanema Craton, which could indicate a westward shift of its root. Depletion south of the Paranapanema Craton probably denotes remnants of a previously larger craton that was rejuvenated by the upwelling of hot mantle material leading to emplacement of the Paraná Flood Basalts.
Source‐to‐Sink Terrestrial Analogs for the Paleoenvironment of Gale Crater, Mars
Authors: Thorpe Michael T. , Hurowitz Joel A. , Siebach Kirsten L.
Published: January 2021

In the Late Noachian to Early Hesperian period, rivers transported detritus from igneous source terrains to a downstream lake within Gale crater, creating a stratified stack of fluviolacustrine rocks that is currently exposed along the slopes of Mount Sharp. Controversy exists regarding the paleoclimate that supported overland flow of liquid water at Gale crater, in large part because little is known about how chemical and mineralogical paleoclimate indicators from mafic‐rock dominated source‐to‐sink systems are translated into the rock record. Here, we compile data from basaltic terrains with varying climates on Earth in order to provide a reference frame for the conditions that may have prevailed during the formation of the sedimentary strata in Gale crater, particularly focusing on the Sheepbed and Pahrump Hills members. We calculate the chemical index of alteration for weathering profiles and fluvial sediments to better constrain the relationship between climate and chemical weathering in mafic terrains, a method that best estimates the cooler limit of climate conditions averaged over time. We also compare X‐ray diffraction patterns and mineral abundances from fluvial sediments in varying terrestrial climates and martian mudstones to better understand the influence of climate on secondary mineral assemblages in basaltic terrains. We show that the geochemistry and mineralogy of most of the fine‐grained sedimentary rocks in Gale crater display first‐order similarities with sediments generated in climates that resemble those of present‐day Iceland, while other parts of the stratigraphy indicate even colder baseline climate conditions. None of the lithologies examined at Gale crater resemble fluvial sediments or weathering profiles from warm (temperate to tropical) terrestrial climates.
Variations in Mid‐ to Late Holocene Nitrogen Supply to Northern Great Barrier Reef Halimeda Macroalgal Bioherms
Authors: McNeil Mardi , Nothdurft Luke , Erler Dirk , Hua Quan , Webster Jody M.
Published: January 2021

The northern Great Barrier Reef (GBR) Halimeda bioherms have accumulated on the outer continental shelf from calcium carbonate algal sediments over the past ∼10,000 years and cover >6,000 km2 of shelf area. As such, Halimeda bioherms play a key role in the shallow marine carbon cycle over millennial timescales. The main source of nitrogen (N) to these bioherms is thought to be westward transport of upwelled NO3‐‐rich water from the Coral Sea. However, the primary N source has not been traced geochemically, and we have no understanding of any temporal variation. Here, we reconstruct patterns of N supply to Halimeda bioherms in the GBR since the mid‐Holocene using the 15N/14N ratio of skeletal‐bound organic N (δ15N‐skeletal organic material [SOM]) in modern and fossil Halimeda sediment cores. Average Halimeda skeletal δ15N‐SOM was 6.28 ± 0.26‰, consistent with δ15N‐NO3‐ from western tropical South Pacific (WTSP) thermocline waters. Thus, geochemically validating shelf‐break upwelling of an oceanic N source that regulates bioherm spatial distribution. Halimeda δ15N‐SOM decreased by 1‰–2‰ from 5,000 to 2,000 cal. yr BP, reaching a minima of 5.5‰ that persisted for almost 1,000 years. The Halimeda δ15N‐SOM variation reflects mid‐ to late Holocene changes in regional climate and intensified El Niño activity that likely facilitated elevated N2 fixation in the WTSP, thereby lowering thermocline δ15N‐NO3‐. Thus, Halimeda skeletal material provides a valuable high‐resolution geochemical archive of past oceanographic and climatic processes over centennial to millennial timescales, complementing existing paleoclimate proxy records.
Holocene Moisture Variability and Its Lagged Response to Summer Insolation Revealed by Eolian Deposits in the Lake Qinghai Basin, NE Tibetan Plateau
Authors: Ding Zhiyong , Lu Ruijie , Wang Lindong
Published: January 2021

The evolution of the East Asian Summer Monsoon (EASM) and its mechanism since the Holocene remains controversial. Here, we investigate four eolian sediment sequences in the Lake Qinghai Basin (LQB), Northeastern Tibetan Plateau (NETP), in the marginal zone of the modern EASM. The results indicate that paleoclimatological interpretation of the color parameters and CaCO3 in eolian sand‐paleosol sequence from LQB region are different from the loess‐paleosol sequence in Loess Plateau, and a comprehensive analysis that combines lithostratigraphic and other proxy data is required. Changes in the EASM dominated climate change in the NETP, with a gradual increase in moisture from the beginning of the early‐Holocene, however the environment was relatively cold and dry with strong regional eolian sand activity. During 8.5–3.3 ka, the intensity of the EASM and effective moisture levels in the LQB reached a peak. Eolian activity was weak and dunes were effectively fixed in place, while pedogenesis processes were enhanced and paleosols developed widely across the region. Moisture levels decreased after 3.3 ka and the dunes were reactivated, eolian activity was enhanced, and there was extensive accumulation of eolian sand and sandy loess. These records show that moisture variability has been controlled by the EASM system in east Asia since at least the Holocene, and has generally responded to changes in northern hemisphere summer insolation with a lag of 3–5 ka, through mechanisms that are modulated by high‐latitude ice‐volume forcing and large‐scale ocean‐atmospheric circulation patterns.
Characterizing the Source of the Eastern Galicia Magnetic Anomaly (NW Spain): The Role of Extension in the Origin of Magnetization at the Central Iberian Arc
Authors: Ayarza Puy , Villalaín Juan José , Martínez Catalán José Ramón , Álvarez Lobato Fernando , Durán Oreja Manuela , Calvín Pablo , Recio Clemente , Suárez Barrios Mercedes , Gómez Martín Elena
Published: January 2021

The Eastern Galicia Magnetic Anomaly is the best studied anomaly of the Central Iberian Arc. This is due to its location, on the Lugo‐Sanabria gneiss dome, and to the fact that its source rocks crop out in the Xistral Tectonic Window. Multiple studies of this anomaly have been carried out, but still, new results keep on shedding light on its understanding. This paper presents the first results on rock magnetic analyses, natural remanent magnetization, anisotropy of the magnetic susceptibility, X‐ray diffraction, and stable isotopes geochemistry carried out on the source rocks of this anomaly. Results suggest that magnetization responds to the increase in oxygen fugacity underwent by rocks affected by late Variscan (330‐300 Ma) extensional tectonics. Extensional detachments were the pathways that allowed the entrance of fluids that led to syntectonic crystallization of magnetite and hematite in metasediments and inhomogeneous S‐Type granitoids derived from their partial melting. Accordingly, magnetization is not linked to lithologies, but to extensional structures developed in the late Carboniferous/earliest Permian, during the Kiaman reverse superchron. Systematic reverse magnetic remanence exhibited by hematite‐bearing samples confirms the age of the magnetization and adds complexity to the interpretation of the anomaly. Understanding the EGMA contributes to the interpretation of other anomalies existing in the CIA, also located on thermal domes. The observed extension‐related magnetization probably affected most of the NW Iberian Massif, thus hindering the study of previous tectonics by paleomagnetic techniques. This work aims to provide new hints to interpret magnetic anomalies located in extensional tectonic contexts worldwide.
East Tacheng (Qoqek) Fault Zone: Late Quaternary Tectonics and Slip Rate of a Left‐Lateral Strike‐Slip Fault Zone North of the Tian Shan
Authors: Yu Jingxing , Walker R. T. , Rhodes E. J. , Zhang Peizhen , Li Chaopeng , Wang Siyu , Wang Yizhou , Liu Fangbin , Hao Yuqi
Published: January 2021

Although the Tacheng Basin may play an important role in accommodating crustal shortening north of the Tian Shan and west of the Junggar Basin based on observations of several conspicuous surface ruptures in satellite imagery, little is known about its late Quaternary tectonic activity. We analyze the tectonic geomorphology of the East Tacheng fault zone, including the subparallel NE‐SW trending East Tacheng and Wuerkashier faults, using field observations, interpretations of satellite imagery, and construction of decimeter‐scale digital elevation models from unmanned aerial vehicle surveys. Geomorphological features such as displaced stream channels and terrace risers, negligible vertical offset, opposite facing directions of a single fault scarp, and linear fault traces suggest that the East Tacheng fault is a nearly pure left‐lateral subvertical strike‐slip fault. The late Quaternary horizontal slip rate is estimated to be 0.4–2.0 mm/year, likely ∼0.7 mm/year. Paleoearthquake studies in trenches reveal that the most recent earthquake occurred between 3.1 and 0.5 ka. The Wuerkashier fault, which shows pristine surface ruptures along a total length of ∼67 km, is also a nearly pure left‐lateral strike‐slip fault. The most recent earthquake along this fault is dated to be 7.9–0.5 ka. Combining GPS velocity and active fault kinematics in the northern Tian Shan and western Junggar, we suggest that the western Junggar is controlled by regional N‐S crustal shortening related to the India‐Eurasia collision, and the reactivated Paleozoic fault zones in the western Junggar play a key role in transferring deformation northeastward into the Altai and Mongolia.
Sequential Data Assimilation for Streamflow Forecasting: Assessing the Sensitivity to Uncertainties and Updated Variables of a Conceptual Hydrological Model at Basin Scale
Authors: Piazzi G. , Thirel G. , Perrin C. , Delaigue O.
Published: January 2021

Skillful streamflow forecasts provide key support to several water‐related applications. Because of the critical impact of initial conditions (ICs) on forecast accuracy, ever‐growing interest is focused on improving their estimates via data assimilation (DA). This study aims to assess the sensitivity of the DA‐based estimation of forecast ICs to several sources of uncertainty and the update of different model states and parameters of a lumped conceptual rainfall–runoff model over 232 watersheds in France. The performance of two sequential ensemble‐based techniques, namely, the ensemble Kalman filter (EnKF) and the particle filter (PF), is compared in terms of efficiency and temporal persistence (up to 10 days) of the updating effect through the assimilation of observed discharges. Several experiments specifically address the impact of the meteorological, state, and parameter uncertainties. Results show that an accurate estimate of the initial level of the routing store of the conceptual model ensures the most benefit to the DA‐based estimation of forecast ICs. While EnKF‐based forecasts outperform PF‐based ones when accounting for meteorological uncertainty, the more comprehensive representation of the state uncertainty makes it possible to greatly improve the accuracy of PF‐based predictions, with a longer‐lasting updating effect. Conversely, forecasting skill is undermined when accounting for parameter uncertainty, owing to the change in hydrological responsiveness. This study extensively addresses several sensitivity analyses in order to provide useful recommendations for designing DA‐based streamflow forecasting systems and for diagnosing possible deficiencies in existing systems.
Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data
Authors: Wharton Sean , Astrup Arne , Endahl Lars , Lean Michael E. J. , Satylganova Altynai , Skovgaard Dorthe , Wadden Thomas A. , Wilding John P. H.
Published: January 2021

In the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity.
Self-powered ammonia synthesis under ambient conditions via N2 discharge driven by Tesla turbine triboelectric nanogenerators
Authors: Han Kai , Luo Jianjun , Chen Jian , Chen Baodong , Xu Liang , Feng Yawei , Tang Wei , Wang Zhong Lin
Published: January 2021

Ammonia synthesis using low-power consumption and eco-friendly methods has attracted increasing attention. Here, based on the Tesla turbine triboelectric nanogenerator (TENG), we designed a simple and effective self-powered ammonia synthesis system by N2 discharge. Under the driving of the simulated waste gas, the Tesla turbine TENG showed high rotation speed and high output. In addition, the performance of two Tesla turbine TENGs with different gas path connections was systematically investigated and discussed. A controllable series-parallel connection with the control of gas supply time was also proposed. Taking advantage of the intrinsic high voltage, corona discharge in a N2 atmosphere was simply realized by a Tesla turbine TENG. With the flow of N2, the generated high-energy plasma can immediately react with water molecules to directly produce ammonia. The self-powered system achieved a yield of 2.14 μg h−1 (0.126 μmol h−1) under ambient conditions, showing great potential for large-scale synthesis.
Acoustic radiation-free surface phononic crystal resonator for in-liquid low-noise gravimetric detection
Authors: Gao Feng , Bermak Amine , Benchabane Sarah , Robert Laurent , Khelif Abdelkrim
Published: January 2021

Acoustic wave resonators are promising candidates for gravimetric biosensing. However, they generally suffer from strong acoustic radiation in liquid, which limits their quality factor and increases their frequency noise. This article presents an acoustic radiation-free gravimetric biosensor based on a locally resonant surface phononic crystal (SPC) consisting of periodic high aspect ratio electrodes to address the above issue. The acoustic wave generated in the SPC is slower than the sound wave in water, hence it prevents acoustic propagation in the fluid and results in energy confinement near the electrode surface. This energy confinement results in a significant quality factor improvement and reduces frequency noise. The proposed SPC resonator is numerically studied by finite element analysis and experimentally implemented by an electroplating-based fabrication process. Experimental results show that the SPC resonator exhibits an in-liquid quality factor 15 times higher than a conventional Rayleigh wave resonator at a similar operating frequency. The proposed radiation suppression method using SPC can also be applied in other types of acoustic wave resonators. Thus, this method can serve as a general technique for boosting the in-liquid quality factor and sensing performance of many acoustic biosensors.
Novel therapeutic evaluation biomarkers of lipid metabolism targets in uncomplicated pulmonary tuberculosis patients
Authors: Chen Jia-Xi , Han Yu-Shuai , Zhang Shan-Qiang , Li Zhi-Bin , Chen Jing , Yi Wen-Jing , Huang Huai , Jiang Ting-Ting , Li Ji-Cheng
Published: January 2021

Currently, the management of pulmonary tuberculosis (TB) lacks potent medications and accurate efficacy evaluation biomarkers. In view of the fact that the host lipids are the important energy source of Mycobacterium tuberculosis (Mtb), UPLC-MS/MS based on lipid metabolism was used to monitor the plasma lipid spectrum of TB patients from the initial diagnosis to cured. The analysis showed that TB patients presented aberrant metabolism of phospholipids, glycerides, and sphingolipids. Upon the treatment, the abnormal expression of Cer (d18:1/24:0), CerP (d18:1/20:3), LPE (0:0/22:0), LPA (0:0/16:0), and LPA (0:0/18:0) in TB patients were gradually normalized, indicating that the intervention of lipid metabolism could block energy metabolism and inhibit the cell wall synthesis of Mtb. Furthermore, the increase in ceramide (Cer) levels could promote autophagosome–lysosome fusion. LPA (0:0/16:0) and LPA (0:0/18:0) had a great potential in the early diagnosis (both sensitivity and specificity were 100%) and efficacy evaluation (both sensitivity and specificity were 100%) of TB, indicating that the above lipid metabolites could be used as potential biomarkers for TB.
DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life
Authors: Sasaki Aya , Eng Margaret E. , Lee Abigail H. , Kostaki Alisa , Matthews Stephen G.
Published: January 2021

Synthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.
Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice
Authors: Mejias Rebeca , Rodriguez-Gotor Juan J. , Niwa Minae , Krasnova Irina N. , Adamczyk Abby , Han Mei , Thomas Gareth M. , Xi Zheng-Xiong , Huganir Richard L. , Pletnikov Mikhail V. , Sawa Akira , Cadet Jean-Lud , Wang Tao
Published: January 2021

Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.
Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response
Authors: Chen Ting-Yu , Huang Bu-Miin , Tang Tang K. , Chao Yu-Ying , Xiao Xiao-Yi , Lee Pei-Rong , Yang Li-Yun , Wang Chia-Yih
Published: January 2021

The DNA-PK maintains cell survival when DNA damage occurs. In addition, aberrant activation of the DNA-PK induces centrosome amplification, suggesting additional roles for this kinase. Here, we showed that the DNA-PK-p53 cascade induced primary cilia formation (ciliogenesis), thus maintaining the DNA damage response under genotoxic stress. Treatment with genotoxic drugs (etoposide, neocarzinostatin, hydroxyurea, or cisplatin) led to ciliogenesis in human retina (RPE1), trophoblast (HTR8), lung (A459), and mouse Leydig progenitor (TM3) cell lines. Upon genotoxic stress, several DNA damage signaling were activated, but only the DNA-PK-p53 cascade contributed to ciliogenesis, as pharmacological inhibition or genetic depletion of this pathway decreased genotoxic stress-induced ciliogenesis. Interestingly, in addition to localizing to the nucleus, activated DNA-PK localized to the base of the primary cilium (mother centriole) and daughter centriole. Genotoxic stress also induced autophagy. Inhibition of autophagy initiation or lysosomal degradation or depletion of ATG7 decreased genotoxic stress-induced ciliogenesis. Besides, inhibition of ciliogenesis by depletion of IFT88 or CEP164 attenuated the genotoxic stress-induced DNA damage response. Thus, our study uncovered the interplay among genotoxic stress, the primary cilium, and the DNA damage response.
Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’s disease
Authors: Dong Jianjian , Wang Xun , Xu Chenchen , Gao Manli , Wang Shijing , Zhang Jin , Tong Haiyang , Wang Lulu , Han Yongzhu , Cheng Nan , Han Yongsheng
Published: January 2021

Wilson’s disease (WD) is an inherited disorder characterized by excessive accumulation of copper in the body, particularly in the liver and brain. In the central nervous system (CNS), extracellular copper accumulation triggers pathological microglial activation and subsequent neurotoxicity. Growing evidence suggests that levels of inflammatory cytokines are elevated in the brain of murine WD models. However, the mechanisms associated with copper deposition to neuroinflammation have not been completely elucidated. In this study, we investigated how the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to copper-mediated neuroinflammation in an animal model of WD. Elevated levels of interleukin-1β, interleukin-18, interleukin-6, and tumor necrosis factor-α were observed in the sera of WD patients and toxic milk (TX) mice. The protein levels of inflammasome adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), cleaved caspase-1, and interleukin-1β were upregulated in the brain regions of the TX mice. The NLRP3 inflammasome was activated in the TX mice brains. Furthermore, the activation of NLRP3 inflammasome was noted in primary microglia treated with CuCl2, accompanied by the increased levels of cleaved caspase-1, ASC, and interleukin-1β. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1β and interleukin-18 production, thereby effectively mitigating cognitive decline, locomotor behavior impairment, and neurodegeneration in TX mice. Overall, our study demonstrates the contribution of copper overload-mediated activation of NLRP3 inflammasome to progressive neuropathology in the CNS of a murine model of WD. Therefore, blockade of the NLRP3 inflammasome activation could be a potential therapeutic strategy for WD.
Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment
Authors: Yu Yongbo , Liang Ye , Li Dan , Wang Liping , Liang Zhijuan , Chen Yuanbin , Ma Guofeng , Wu Hui , Jiao Wei , Niu Haitao
Published: January 2021

Programmed death receptor-ligand 1 (PD-L1) plays a crucial role in immune evasion by tumour cells. Most tumour cells exhibit energy dependency and acquire energy from glycolysis. However, the relationship between glucose metabolism and PD-L1 expression remains unclear. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glucose deficiency and recovery, and PD-L1 could inversely regulate glycolysis. In addition, the possible signalling pathways activated by a low level of glucose to regulate PD-L1 were tested experimentally. The results showed that glucose deficiency could upregulate PD-L1 expression in two renal cancer cell lines, 786-O and OS-RC-2. Although the native levels of PD-L1 differed in the two cell lines, the upregulated PD-L1 expression was repristinated after glucose recovery. Moreover, epidermal growth factor receptor (EGFR) expression was upregulated in both cell lines with glucose deficiency. The use of an EGFR inhibitor reversed the upregulation of PD-L1 expression induced by glucose deficiency and inhibited the phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2). EGFR activated by epidermal growth factor (EGF) induced PD-L1 expression and ERK1/2 phosphorylation. Furthermore, an ERK1/2 inhibitor inhibited the phosphorylation of c-Jun and decreased the elevated PD-L1 expression induced by glucose deficiency. In addition, this study also showed that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase 3 or PFKFB3) mediated upregulation of the level of glycolysis to improve the adverse environment through PD-L1 induction. Therefore, glucose metabolism can regulate the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer, and elevated PD-L1 can also regulate glycolysis by improving the expression of PFKFB3. The findings of this study could provide a new multiple target treatment for renal cell carcinoma (RCC) therapy.
Kibble-Zurek exponent and chiral transition of the period-4 phase of Rydberg chains
Authors: Chepiga Natalia , Mila Frédéric
Published: January 2021

Chains of Rydberg atoms have emerged as an amazing playground to study quantum physics in 1D. Playing with inter-atomic distances and laser detuning, one can in particular explore the commensurate-incommensurate transition out of density waves through the Kibble-Zurek mechanism, and the possible presence of a chiral transition with dynamical exponent z > 1. Here, we address this problem theoretically with effective blockade models where the short-distance repulsions are replaced by a constraint of no double occupancy. For the period-4 phase, we show that there is an Ashkin-Teller transition point with exponent ν = 0.78 surrounded by a direct chiral transition with a dynamical exponent z = 1.11 and a Kibble-Zurek exponent μ = 0.41. For Rydberg atoms with a van der Waals potential, we suggest that the experimental value μ = 0.25 is due to a chiral transition with z ≃ 1.9 and ν ≃ 0.47 surrounding an Ashkin-Teller transition close to the 4-state Potts universality.
A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy
Authors: Iriguchi Shoichi , Yasui Yutaka , Kawai Yohei , Arima Suguru , Kunitomo Mihoko , Sato Takayuki , Ueda Tatsuki , Minagawa Atsutaka , Mishima Yuta , Yanagawa Nariaki , Baba Yuji , Miyake Yasuyuki , Nakayama Kazuhide , Takiguchi Maiko , Shinohara Tokuyuki , Nakatsura Tetsuya , Yasukawa Masaki , Kassai Yoshiaki , Hayashi Akira , Kaneko Shin
Published: January 2021

Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.
Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy
Authors: Deshpande Divija , Agarwal Nitin , Fleming Thomas , Gaveriaux-Ruff Claire , Klose Christoph S. N. , Tappe-Theodor Anke , Kuner Rohini , Nawroth Peter
Published: January 2021

Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
Structural analysis of cross α-helical nanotubes provides insight into the designability of filamentous peptide nanomaterials
Authors: Wang Fengbin , Gnewou Ordy , Modlin Charles , Beltran Leticia C. , Xu Chunfu , Su Zhangli , Juneja Puneet , Grigoryan Gevorg , Egelman Edward H. , Conticello Vincent P.
Published: January 2021

The exquisite structure-function correlations observed in filamentous protein assemblies provide a paradigm for the design of synthetic peptide-based nanomaterials. However, the plasticity of quaternary structure in sequence-space and the lability of helical symmetry present significant challenges to the de novo design and structural analysis of such filaments. Here, we describe a rational approach to design self-assembling peptide nanotubes based on controlling lateral interactions between protofilaments having an unusual cross-α supramolecular architecture. Near-atomic resolution cryo-EM structural analysis of seven designed nanotubes provides insight into the designability of interfaces within these synthetic peptide assemblies and identifies a non-native structural interaction based on a pair of arginine residues. This arginine clasp motif can robustly mediate cohesive interactions between protofilaments within the cross-α nanotubes. The structure of the resultant assemblies can be controlled through the sequence and length of the peptide subunits, which generates synthetic peptide filaments of similar dimensions to flagella and pili.
Dynamic memristor-based reservoir computing for high-efficiency temporal signal processing
Authors: Zhong Yanan , Tang Jianshi , Li Xinyi , Gao Bin , Qian He , Wu Huaqiang
Published: January 2021

Reservoir computing is a highly efficient network for processing temporal signals due to its low training cost compared to standard recurrent neural networks, and generating rich reservoir states is critical in the hardware implementation. In this work, we report a parallel dynamic memristor-based reservoir computing system by applying a controllable mask process, in which the critical parameters, including state richness, feedback strength and input scaling, can be tuned by changing the mask length and the range of input signal. Our system achieves a low word error rate of 0.4% in the spoken-digit recognition and low normalized root mean square error of 0.046 in the time-series prediction of the Hénon map, which outperforms most existing hardware-based reservoir computing systems and also software-based one in the Hénon map prediction task. Our work could pave the road towards high-efficiency memristor-based reservoir computing systems to handle more complex temporal tasks in the future.
Author Correction: Three-phase electric power driven electroluminescent devices
Authors: Ji Junpeng , Perepichka Igor F. , Bai Junwu , Hu Dan , Xu Xiuru , Liu Ming , Wang Tao , Zhao Changbin , Meng Hong , Huang Wei
Published: January 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-20976-0.
Observation of stress corrosion cracking using real-time in situ high-speed atomic force microscopy and correlative techniques
Authors: Moore S. , Burrows R. , Kumar D. , Kloucek M. B. , Warren A. D. , Flewitt P. E. J. , Picco L. , Payton O. D. , Martin T. L.
Published: January 2021

Contact-mode high-speed atomic force microscopy (HS-AFM) has been utilised to measure in situ stress corrosion cracking (SCC) with nanometre resolution on AISI Type 304 stainless steel in an aggressive salt solution. SCC is an important failure mode in many metal systems but has a complicated mechanism that makes failure difficult to predict. Prior to the in situ experiments, the contributions of microstructure, environment and stress to SCC were independently studied using HS-AFM. During SCC measurements, uplift of grain boundaries before cracking was observed, indicating a subsurface contribution to the cracking mechanism. Focussed ion beam milling revealed a network of intergranular cracks below the surface lined with a thin oxide, indicating that the SCC process is dominated by local stress at oxide-weakened boundaries. Subsequent analysis by atom probe tomography of a crack tip showed a layered oxide composition at the surface of the crack walls. Oxide formation is posited to be mechanistically linked to grain boundary uplift. This study shows how in situ HS-AFM observations in combination with complementary techniques can give important insights into the mechanisms of SCC.
Stress and mindfulness in Parkinson’s disease – a survey in 5000 patients
Authors: van der Heide Anouk , Speckens Anne E. M. , Meinders Marjan J. , Rosenthal Liana S. , Bloem Bastiaan R. , Helmich Rick C.
Published: January 2021

Many Parkinson’s disease (PD) patients notice that motor symptoms worsen during stress, and experience stress-related neuropsychiatric symptoms such as anxiety and depression. Here we investigated which personal and disease characteristics are associated with perceived stress in PD, which PD symptoms are sensitive to stress, and we assessed self-reported benefits of stress-reducing strategies such as mindfulness. We sent an online survey to the Fox Insight cohort (n = 28,385 PD patients, n = 11,413 healthy controls). The survey included specific questions about the influence of stress on PD symptoms, use of stress-reducing strategies, and several validated scales measuring perceived stress, anxiety, dispositional mindfulness, rumination, and self-compassion. We received completed surveys from 5000 PD patients and 1292 controls. Patients perceived more stress than controls. Among patients, stress was correlated with increased rumination (R = 0.65), lower quality of life (R = −0.56), lower self-compassion (R = −0.65), and lower dispositional mindfulness (R = −0.48). Furthermore, patients indicated that stress significantly worsened both motor symptoms – especially tremor – and non-motor symptoms. Physical exercise was most frequently used to reduce stress (83.1%). Mindfulness was practiced by 38.7% of PD respondents, who noticed improvement in both motor and non-motor symptoms. Among non-users, 43.4% were interested in gaining mindfulness skills. We conclude that PD patients experience greater levels of stress than controls, and that stress worsens both motor and non-motor symptoms. Mindfulness may improve PD symptom severity, with the strongest effects on anxiety and depressed mood. These findings justify further controlled studies to establish the merits of mindfulness and other stress-alleviating interventions.
A conjoined universal helper epitope can unveil antitumor effects of a neoantigen vaccine targeting an MHC class I-restricted neoepitope
Authors: Swartz Adam M. , Congdon Kendra L. , Nair Smita K. , Li Qi-Jing , Herndon James E. , Suryadevara Carter M. , Riccione Katherine A. , Archer Gary E. , Norberg Pamela K. , Sanchez-Perez Luis A. , Sampson John H.
Published: January 2021

Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.
Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia
Authors: Chumduri Cindrilla , Gurumurthy Rajendra Kumar , Berger Hilmar , Dietrich Oliver , Kumar Naveen , Koster Stefanie , Brinkmann Volker , Hoffmann Kirstin , Drabkina Marina , Arampatzi Panagiota , Son Dajung , Klemm Uwe , Mollenkopf Hans-Joachim , Herbst Hermann , Mangler Mandy , Vogel Jörg , Saliba Antoine-Emmanuel , Meyer Thomas F.
Published: January 2021

The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.