bluuebunny/crossref_metadata_2025 huggingface dataset:
Data quality methods through remote source data verification auditing: results from the Congenital Cardiac Research Collaborative
Authors: Pettus Joelle A. , Pajk Amy L. , Glatz Andrew C. , Petit Christopher J. , Goldstein Bryan H. , Qureshi Athar M. , Nicholson George T. , Meadows Jeffery J. , Zampi Jeffrey D. , Law Mark A. , Shahanavaz Shabana , Kelleman Michael S. , McCracken Courtney M. ,   the Congenital Cardiac Research Collaborative
Published: March 2021

Background:

Multicentre research databases can provide insights into healthcare processes to improve outcomes and make practice recommendations for novel approaches. Effective audits can establish a framework for reporting research efforts, ensuring accurate reporting, and spearheading quality improvement. Although a variety of data auditing models and standards exist, barriers to effective auditing including costs, regulatory requirements, travel, and design complexity must be considered.

Materials and methods:

The Congenital Cardiac Research Collaborative conducted a virtual data training initiative and remote source data verification audit on a retrospective multicentre dataset. CCRC investigators across nine institutions were trained to extract and enter data into a robust dataset on patients with tetralogy of Fallot who required neonatal intervention. Centres provided de-identified source files for a randomised 10% patient sample audit. Key auditing variables, discrepancy types, and severity levels were analysed across two study groups, primary repair and staged repair.

Results:

Of the total 572 study patients, data from 58 patients (31 staged repairs and 27 primary repairs) were source data verified. Amongst the 1790 variables audited, 45 discrepancies were discovered, resulting in an overall accuracy rate of 97.5%. High accuracy rates were consistent across all CCRC institutions ranging from 94.6% to 99.4% and were reported for both minor (1.5%) and major discrepancies type classifications (1.1%).

Conclusion:

Findings indicate that implementing a virtual multicentre training initiative and remote source data verification audit can identify data quality concerns and produce a reliable, high-quality dataset. Remote auditing capacity is especially important during the current COVID-19 pandemic.
Large aneurysms and pseudoaneurysms of surgically reconstructed right ventricular outflow tracts
Authors: Tomasulo Catherine E. , Ravishankar Chitra , Natarajan Shobha , Mascio Christopher E. , Glatz Andrew C.
Published: March 2021

Aneurysm and pseudoaneurysm development is a known, albeit uncommon, complication after right ventricular outflow tract surgical reconstruction. Large right ventricular outflow tract aneurysms and pseudoaneurysms have not been extensively described in recent literature and we report our experience with this unusual complication in five patients at our institution over the last 8 years. Although uncommon, this complication has potentially important clinical implications. Thus, clinicians should be aware of its potential, particularly in certain anatomic conditions.
Cognitive restructuring in the multilingual mind: language-specific effects on processing efficiency of caused motion events in Cantonese–English–Japanese speakers
Authors: Wang Yi , Wei Li
Published: March 2021

The current study explores how multilingual speakers with three typologically different languages (satellite-framed, verb-framed and equipollent-framed) encode and gauge event similarity in the domain of caused motion. Specifically, it addresses whether, and to what extent, the acquisition of an L2-English and an L3-Japanese reconstructs the lexicalization and conceptualization patterns established in the L1-Cantonese when the target language is actively involved in the decision-making process. Results show that multilingual speakers demonstrated an ongoing process of cognitive restructuring towards the target language (L3) in both linguistic encoding (event structures and semantic representations) and non-linguistic conceptualization (reaction time). And the degree of the restructuring is modulated by the amount of language contact with the L2 and L3. The study suggests that learning a language means internalizing a new way of thinking and provides positive evidence for L3-biased cognitive restructuring within the framework of thinking-for-speaking.
Blind spots in stigma research? Broadening our perspective on mental illness stigma by exploring ‘what matters most’ in modern Western societies
Authors: Schomerus G. , Angermeyer M. C.
Published: March 2021

Aims

The theory of ‘what matters most’ (WMM) has been developed to understand differences in mental illness stigma between cultures, postulating that stigma becomes most pervasive in situations that matter most in a specific cultural context. The rise of populism in Western societies demonstrates that also within one cultural context, different values ‘matter most’ to different groups. We expand the WMM framework to explore the spectrum of stigma manifestations within Western societies, relating it to both conservative/authoritarian and liberal/modern values. From our findings, we will develop hypotheses on how further research into value orientations and stigma might address potential blind spots in stigma research.

Methods

Based on a narrative review of the literature on mental illness stigma and value orientations, we apply the WMM framework to cultural mechanisms of stigma within modern Western societies.

Results

There are several studies showing an association between traditional, authoritarian, conservative values with stronger mental illness stigma, while studies examining the stigma within liberal, modern value orientations are scarce. We hypothesise on situations where encountering a person with mental illness could threaten liberal values and thus might provoke stigma among persons with such value orientations. For example, living with a person with mental illness could be seen as consuming energy and time, thereby jeopardising ‘self-actualisation’, the modern value of realising one's own full potential. As a result, a person highly valuing self-actualisation might try to avoid contact with persons with mental illness. Instances of potential ‘liberal stigma’ also include structural stigma or self-stigma, when, e.g. changing assumptions of what is considered ‘normal’ increase perceptions of being fundamentally different when experiencing mental illness.

Conclusions

‘WMM’ appears to be a useful framework to direct research to potential blind spots within the field of stigma research. Looking at instances where liberal values conflict with dealing with a person with mental illness could provide a more comprehensive understanding of stigma experiences among persons with mental illness. However, for measuring stigma, tapping into liberal variations of mental illness stigma is methodologically challenging. Qualitative work could be the first step to elicit potential stigma experiences based on conflicts with liberal values.
Simulation of Fluvial Patterns With GANs Trained on a Data Set of Satellite Imagery
Authors: Nesvold Erik , Mukerji Tapan
Published: March 2021

Models that can generate realistic Earth surface patterns are important both for geomorphological applications and as prior models for underdetermined inverse problems. Generative machine learning methods such as GANs and the increasing availability of large remote sensing data sets represents an exciting combination for this purpose. Several studies show promising results for GANs trained on artificial data sets in geostatistics, but it is necessary to further quantify how well such models reproduce and generalize real data. The conditioning ability of GANs is often evaluated based on output which originates from a trained generator. In reality, geophysical data necessarily arises from elsewhere. Here, we use more realistic training data than in previous studies and evaluate performance using an extensive set of metrics and real images outside the training data set. The data set consists of multispectral satellite imagery of 38 large river deltas, a type of Earth surface pattern which is limited in number. The channel network is used to create training images with four sedimentary facies, which are subsequently used to train a Wasserstein GAN of deltaic 2D patterns. GANs successfully reproduce all training data characteristics and produce manifold the number of combinations with respect to the training data. However, there does not seem to be an infinite number of discrete combinations of facies, and the posterior landscapes are not well‐shaped for efficient exploration in the presence of so‐called hard data. Thus, GANs should have many exciting applications in geosciences, but it will depend on the type of measurement data.
Revisiting the Global Patterns of Seasonal Cycle in Sea Surface Salinity
Authors: Yu Lisan , Bingham Frederick M. , Lee Tong , Dinnat Emmanuel P. , Fournier Severine , Melnichenko Oleg , Tang Wenqing , Yueh Simon H.
Published: March 2021

Argo profiling floats and L‐band passive microwave remote sensing have significantly improved the global sampling of sea surface salinity (SSS) in the past 15 years, allowing the study of the range of SSS seasonal variability using concurrent satellite and in situ platforms. Here, harmonic analysis was applied to four 0.25° satellite products and two 1° in situ products between 2016 and 2018 to determine seasonal harmonic patterns. The 0.25° World Ocean Atlas (WOA) version 2018 was referenced to help assess the harmonic patterns from a long‐term perspective based on the 3‐year period. The results show that annual harmonic is the most characteristic signal of the seasonal cycle, and semiannual harmonic is important in regions influenced by monsoon and major rivers. The percentage of the observed variance that can be explained by harmonic modes varies with products, with values ranging between 50% and 72% for annual harmonic and between 15% and 19% for semiannual harmonic. The large spread in the explained variance by the annual harmonic reflects the large disparity in nonseasonal variance (or noise) in the different products. Satellite products are capable of capturing sharp SSS features on meso‐ and frontal scales and the patterns agree well with the WOA 2018. These products are, however, subject to the impacts of radiometric noises and are algorithm dependent. The coarser‐resolution in situ products may underrepresent the full range of high‐frequency small scale SSS variability when data record is short, which may have enlarged the explained SSS variance by the annual harmonic.
A Global LIS/OTD Climatology of Lightning Flash Extent Density
Authors: Peterson Michael , Mach Douglas , Buechler Dennis
Published: March 2021

Previous lightning climatologies derived from Lightning Imaging Sensor (LIS) and Optical Transient Detector (OTD) total lightning measurements have quantified lightning frequency as a Flash Rate Density (FRD). This approach assumes that lightning flashes can be represented as points and quantifies the frequency of lightning centered in each grid cell. However, lightning has a finite extent that can reach hundreds of kilometers. A new climatology based on Flash Extent Density (FED) is constructed for LIS (including ISS‐LIS) and OTD that accounts for the horizontal dimension of lightning. The FED climatology documents the frequency that an observer can expect lightning to be visible overhead—regardless of where the flash began or ended. This new FED climatology confirms and elaborates on the previous global LIS/OTD FRD and Americas‐only Geostationary Lightning Mapper (GLM) findings. The FED climatology maintains Lake Maracaibo as the global lightning hotspot with an average of 389 flashes/day but designates Karabre in the Democratic Republic of the Congo as the global thunderstorm duty (percent of the total viewtime where lightning is observed) hotspot at 7.29%. Meanwhile, Kuala Lumpur is the national capital city with the most lightning, and its airport (KUL) is the top major airport affected by lightning (in terms of duty). The FED seasonal cycle and month‐to‐month changes in the “center of lightning” for the three continental chimney regions are also discussed.
Climate Change in China Affects Runoff and Terrestrial Ecosystem Water Retention More Than Changes in Leaf Area Index and Land Use/Cover Over the Period 1982–2015
Authors: Zhai Ran , Tao Fulu
Published: March 2021

Climate, land use/cover, and leaf area index (LAI) have changed notably in China since 1980, and these have had major impacts on river runoff and the terrestrial ecosystem water retention (TEWR) service in China. However, the mechanisms underlying the spatiotemporal changes of runoff and TEWR are not understood well. Here, meteorological, LAI, and land use/cover data were applied in a hydrological model (variable infiltration capacity) to quantify their contributions to runoff and TEWR changes during the 1980s, the 1990s, the 2000s, and 1982–2015, respectively. The results show that climate change, particularly precipitation change, was the dominant factor controlling runoff and TEWR changes. Between 1982 and 2015, climate change increased the runoff in large areas in northwestern and southwestern China and the Hai River (HR) basin and improved the TEWR in large areas in northwestern and northeastern China and the Huai River (HuR) basin. However, the magnitudes and signs of the climate change impact varied in different regions and time periods. The LAI increased extensively, which led to decreased runoff and increased TEWR in most of China from 1982 to 2015, especially in the Yellow River basin, HuR basin, and HR basin. The impacts of land use/cover change on runoff and TEWR were in general less than those of climate and LAI changes, nevertheless, they were important in some local areas. This study improves the understanding of the spatiotemporal patterns and the underlying mechanisms of runoff and TEWR changes across China between 1982 and 2015.
A Quarter Century ofWindSpacecraft Discoveries
Authors: Wilson Lynn B. , Brosius Alexandra L. , Gopalswamy Natchimuthuk , Nieves‐Chinchilla Teresa , Szabo Adam , Hurley Kevin , Phan Tai , Kasper Justin C. , Lugaz Noé , Richardson Ian G. , Chen Christopher H. K. , Verscharen Daniel , Wicks Robert T. , TenBarge Jason M.
Published: March 2021

TheWindspacecraft, launched on November 1, 1994, is a critical element in NASA’s Heliophysics System Observatory (HSO)—a fleet of spacecraft created to understand the dynamics of the Sun‐Earth system. The combination of its longevity (>25 years in service), its diverse complement of instrumentation, and high resolution and accurate measurements has led to it becoming the “standard candle” of solar wind measurements.Windhas over 55 selectable public data products with over ∼1,100 total data variables (including OMNI data products) on SPDF/CDAWeb alone. These data have led to paradigm shifting results in studies of statistical solar wind trends, magnetic reconnection, large‐scale solar wind structures, kinetic physics, electromagnetic turbulence, the Van Allen radiation belts, coronal mass ejection topology, interplanetary and interstellar dust, the lunar wake, solar radio bursts, solar energetic particles, and extreme astrophysical phenomena such as gamma‐ray bursts. This review introduces the mission and instrument suites then discusses examples of the contributions byWindto these scientific topics that emphasize its importance to both the fields of heliophysics and astrophysics.
Determination of Auroral Electrodynamic Parameters From AMPERE Field‐Aligned Current Measurements
Authors: Robinson R. M. , Zanetti Larry , Anderson Brian , Vines Sarah , Gjerloev Jesper
Published: March 2021

We calculate high latitude electrodynamic parameters using global maps of field‐aligned currents from the Active Magnetosphere and Planetary Response Experiment (AMPERE). The model is based on previous studies that relate field‐aligned currents to auroral Pedersen and Hall conductances measured by incoherent scatter radar. The field‐aligned currents and conductances are used to solve for the electric potential at high latitudes from which electric fields are computed. The electric fields are then used with the conductances to calculate horizontal ionospheric currents. We validate the results by simulating the SuperMAG magnetic indices for 30 geomagnetically active days. The correlation coefficients between derived and actual magnetic indices were 0.68, 0.76, and 0.84 for the SMU, SML, and SME indices, respectively. We show examples of times when the simulations differ markedly from the measured indices and attribute them to either small‐scale, substorm‐related current structures or the effects of neutral winds. Overall, the performance of the model demonstrates that with few exceptions, auroral electrodynamic parameters can be accurately deduced from the global field‐aligned current distribution provided by AMPERE.
Cancer metastasis as a non-healing wound
Authors: Deyell Matthew , Garris Christopher S. , Laughney Ashley M.
Published: March 2021

Most cancer deaths are caused by metastasis: recurrence of disease by disseminated tumour cells at sites distant from the primary tumour. Large numbers of disseminated tumour cells are released from the primary tumour, even during the early stages of tumour growth. However, only a minority survive as potential seeds for future metastatic outgrowths. These cells must adapt to a relatively inhospitable microenvironment, evade immune surveillance and progress from the micro- to macro-metastatic stage to generate a secondary tumour. A pervasive driver of this transition is chronic inflammatory signalling emanating from tumour cells themselves. These signals can promote migration and engagement of stem and progenitor cell function, events that are also central to a wound healing response. In this review, we revisit the concept of cancer as a non-healing wound, first introduced by Virchow in the 19th century, with a new tumour cell-intrinsic perspective on inflammation and focus on metastasis. Cellular responses to inflammation in both wound healing and metastasis are tightly regulated by crosstalk with the surrounding microenvironment. Targeting or restoring canonical responses to inflammation could represent a novel strategy to prevent the lethal spread of cancer.
USP42 drives nuclear speckle mRNA splicing via directing dynamic phase separation to promote tumorigenesis
Authors: Liu Shuyan , Wang Taishu , Shi Yulin , Bai Lu , Wang Shanshan , Guo Dong , Zhang Yang , Qi Yangfan , Chen Chaoqun , Zhang Jinrui , Zhang Yingqiu , Liu Quentin , Yang Qingkai , Wang Yang , Liu Han
Published: March 2021

Liquid–liquid phase separation is considered a generic approach to organize membrane-less compartments, enabling the dynamic regulation of phase-separated assemblies to be investigated and pivotal roles of protein posttranslational modifications to be demonstrated. By surveying the subcellular localizations of human deubiquitylases, USP42 was identified to form nuclear punctate structures that are associated with phase separation properties. Bioinformatic analysis demonstrated that the USP42 C-terminal sequence was intrinsically disordered, which was further experimentally confirmed to confer phase separation features. USP42 is distributed to SC35-positive nuclear speckles in a positively charged C-terminal residue- and enzymatic activity-dependent manner. Notably, USP42 directs the integration of the spliceosome component PLRG1 into nuclear speckles, and its depletion interferes with the conformation of SC35 foci. Functionally, USP42 downregulation deregulates multiple mRNA splicing events and leads to deterred cancer cell growth, which is consistent with the impact of PLRG1 repression. Finally, USP42 expression is strongly correlated with that of PLRG1 in non-small-cell lung cancer samples and predicts adverse prognosis in overall survival. As a deubiquitylase capable of dynamically guiding nuclear speckle phase separation and mRNA splicing, USP42 inhibition presents a novel anticancer strategy by targeting phase separation.
Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer
Authors: Zhang Jinghui , Fan Jiajun , Zeng Xian , Nie Mingming , Chen Wei , Wang Yichen , Luan Jingyun , Zhu Zeguo , Chang Xusheng , Ju Dianwen , Feng Li , Yin Kai
Published: March 2021

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.
RNA decay in processing bodies is indispensable for adipogenesis
Authors: Maeda Ryotaro , Kami Daisuke , Shikuma Akira , Suzuki Yosuke , Taya Toshihiko , Matoba Satoaki , Gojo Satoshi
Published: March 2021

The RNA decay pathway plays key regulatory roles in cell identities and differentiation processes. Although adipogenesis is transcriptionally and epigenetically regulated and has been thoroughly investigated, how RNA metabolism that contributes to the stability of phenotype-shaping transcriptomes participates in differentiation remains elusive. In this study, we investigated Ddx6, an essential component of processing bodies (PBs) that executes RNA decay and translational repression in the cytoplasm and participates in the cellular transition of reprogramming. Upon adipogenic induction, Ddx6 dynamically accumulated to form PBs with a binding partner, 4E-T, at the early phase prior to emergence of intracellular lipid droplets. In contrast, preadipocytes with Ddx6 knockout (KO) or 4E-T knockdown (KD) failed to generate PBs, resulting in significant suppression of adipogenesis. Transcription factors related to preadipocytes and negative regulators of adipogenesis that were not expressed under adipogenic stimulation were maintained in Ddx6-KO and 4E-T-KD preadipocytes under adipogenic induction. Elimination of Dlk1, a major negative regulator of adipogenesis, in 3T3L1 Ddx6-KO cells did not restore adipogenic differentiation capacity to any extent. Similar to murine cells, human primary mesenchymal stem cells, which can differentiate into adipocytes upon stimulation with adipogenic cocktails, required DDX6 to maturate into adipocytes. Therefore, RNA decay of the entire parental transcriptome, rather than removal of a strong negative regulator, could be indispensable for adipogenesis.
The emerging role of ferroptosis in intestinal disease
Authors: Xu Shu , He Yao , Lin Lihui , Chen Peng , Chen Minhu , Zhang Shenghong
Published: March 2021

Ferroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid peroxidation. It is significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver diseases, and cancer. Ferroptotic cell death has also been associated with dysfunction of the intestinal epithelium, which contributes to several intestinal diseases. Research on ferroptosis may provide a new understanding of intestinal disease pathogenesis that benefits clinical treatment. In this review, we provide an overview of ferroptosis and its underlying mechanisms, then describe its emerging role in intestinal diseases, including intestinal ischaemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), and colorectal cancer (CRC).
Splicing reprogramming of TRAIL/DISC-components sensitizes lung cancer cells to TRAIL-mediated apoptosis
Authors: Voss Oliver H. , Arango Daniel , Tossey Justin C. , Villalona Calero Miguel A. , Doseff Andrea I.
Published: March 2021

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selective killing of cancer cells underlines its anticancer potential. However, poor tolerability and resistance underscores the need to identify cancer-selective TRAIL-sensitizing agents. Apigenin, a dietary flavonoid, sensitizes lung cancer cell lines to TRAIL. It remains unknown, however, whether apigenin sensitizes primary lung cancer cells to TRAIL and its underlying mechanisms. Here we show that apigenin reprograms alternative splicing of key TRAIL/death-inducing-signaling-complex (DISC) components: TRAIL Death Receptor 5 (DR5) and cellular-FLICE-inhibitory-protein (c-FLIP) by interacting with the RNA-binding proteins hnRNPA2 and MSI2, resulting in increased DR5 and decreased c-FLIPS protein levels, enhancing TRAIL-induced apoptosis of primary lung cancer cells. In addition, apigenin directly bound heat shock protein 70 (Hsp70), promoting TRAIL/DISC assembly and triggering apoptosis. Our findings reveal that apigenin directs alternative splicing and inhibits Hsp70 enhancing TRAIL anticancer activity. These findings underscore impactful synergies between diet and cancer treatments opening new avenues for improved cancer treatments.
hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2
Authors: Lee Woo Joo , Shin Chang Hoon , Ji Haein , Jeong Seong Dong , Park Mi-So , Won Hong-Hee , Pandey Poonam R. , Tsitsipatis Dimitrios , Gorospe Myriam , Kim Hyeon Ho
Published: March 2021

Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy. We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. Since LINC00263 was mainly localized in the cytosol and highly enriched in Argonaute 2-immunoprecipitation (Ago2-IP), we hypothesized that LINC00263 acts as a competitive endogenous RNA (ceRNA), and thus sought to identify LINC00263-associated microRNAs. Using small RNA sequencing followed by antisense oligonucleotide pull-down, miR-147a was selected for further study. We found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3′UTR of CAPN2 mRNA. In addition, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression. Furthermore, our findings were validated in various other types of cancer cells including lung cancer, colorectal cancer, neuroblastoma, and melanoma. Collectively, we demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.
Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney
Authors: Cougnon Marc , Carcy Romain , Melis Nicolas , Rubera Isabelle , Duranton Christophe , Dumas Karine , Tanti Jean-François , Pons Catherine , Soubeiran Nicolas , Shkreli Marina , Hauet Thierry , Pellerin Luc , Giraud Sébastien , Blondeau Nicolas , Tauc Michel , Pisani Didier F.
Published: March 2021

Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.
Splicing factor USP39 promotes ovarian cancer malignancy through maintaining efficient splicing of oncogenic HMGA2
Authors: Wang Shourong , Wang Zixiang , Li Jieyin , Qin Junchao , Song Jianping , Li Yingwei , Zhao Ling , Zhang Xiyu , Guo Haiyang , Shao Changshun , Kong Beihua , Liu Zhaojian
Published: March 2021

Aberrant expression of splicing factors was found to promote tumorigenesis and the development of human malignant tumors. Nevertheless, the underlying mechanisms and functional relevance remain elusive. We here show that USP39, a component of the spliceosome, is frequently overexpressed in high-grade serous ovarian carcinoma (HGSOC) and that an elevated level of USP39 is associated with a poor prognosis. USP39 promotes proliferation/invasion in vitro and tumor growth in vivo. Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells. We further demonstrated that USP39 colocalizes with spliceosome components in nuclear speckles. Transcriptomic analysis revealed that USP39 deletion led to globally impaired splicing that is characterized by skipped exons and overrepresentation of introns and intergenic regions. Furthermore, RNA immunoprecipitation sequencing showed that USP39 preferentially binds to exon-intron regions near 5′ and 3′ splicing sites. In particular, USP39 facilitates efficient splicing of HMGA2 and thereby increases the malignancy of ovarian cancer cells. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor in ovarian cancer and represents a potential target for ovarian cancer therapy.
Islet neogenesis associated protein (INGAP) protects pancreatic β cells from IL-1β and IFNγ-induced apoptosis
Authors: Nano Eni , Petropavlovskaia Maria , Rosenberg Lawrence
Published: March 2021

The goal of this study was to determine whether recombinant Islet NeoGenesis Associated Protein (rINGAP) and its active core, a pentadecapeptide INGAP104–118 (Ingap-p), protect β cells against cytokine-induced death. INGAP has been shown to induce islet neogenesis in diabetic animals, to stimulate β-cell proliferation and differentiation, and to improve islet survival and function. Importantly, Ingap-p has shown promising results in clinical trials for diabetes (phase I/II). However, the full potential of INGAP and its mechanisms of action remain poorly understood. Using rat insulinoma cells RINm5F and INS-1 treated with interleukin-1β (IL-1β) and interferon‐gamma (IFN‐γ), we demonstrate here that both rINGAP and Ingap-p inhibit apoptosis, Caspase-3 activation, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and explore the related signaling pathways. As expected, IL-1β induced nuclear factor kappa B (NF-κB), p38, and JNK signaling, whereas interferon‐gamma (IFN‐γ) activated the JAK2/STAT1 pathway and potentiated the IL-1β effects. Both rINGAP and Ingap-p decreased phosphorylation of IKKα/β, IkBα, and p65, although p65 nuclear translocation was not inhibited. rINGAP, used for further analysis, also inhibited STAT3, p38, and JNK activation. Interestingly, all inhibitory effects of rINGAP were observed for the cytokine cocktail, not IL-1β alone, and were roughly equal to reversing the potentiating effects of INFγ. Furthermore, rINGAP had no effect on IL-1β/NF-κB-induced gene expression (e.g., Ccl2, Sod2) but downregulated several IFNγ-stimulated (Irf1, Socs1, Socs3) or IFNγ-potentiated (Nos2) genes. This, however, was observed again only for the cytokine cocktail, not IFNγ alone, and rINGAP did not inhibit the IFNγ-induced JAK2/STAT1 activation. Together, these intriguing results suggest that INGAP does not target either IL-1β or IFNγ individually but rather inhibits the signaling crosstalk between the two, the exact mechanism of which remains to be investigated. In summary, our study characterizes the anti-inflammatory effects of INGAP, both protein and peptide, and suggests a new therapeutic utility for INGAP in the treatment of diabetes.
Control of quantum electrodynamical processes by shaping electron wavepackets
Authors: Wong Liang Jie , Rivera Nicholas , Murdia Chitraang , Christensen Thomas , Joannopoulos John D. , Soljačić Marin , Kaminer Ido
Published: March 2021

Fundamental quantum electrodynamical (QED) processes, such as spontaneous emission and electron-photon scattering, encompass phenomena that underlie much of modern science and technology. Conventionally, calculations in QED and other field theories treat incoming particles as single-momentum states, omitting the possibility that coherent superposition states, i.e., shaped wavepackets, can alter fundamental scattering processes. Here, we show that free electron waveshaping can be used to design interferences between two or more pathways in a QED process, enabling precise control over the rate of that process. As an example, we show that free electron waveshaping modifies both spatial and spectral characteristics of bremsstrahlung emission, leading for instance to enhancements in directionality and monochromaticity. The ability to tailor general QED processes opens up additional avenues of control in phenomena ranging from optical excitation (e.g., plasmon and phonon emission) in electron microscopy to free electron lasing in the quantum regime.
Reversal of carbonate-silicate cation exchange in cold slabs in Earth’s lower mantle
Authors: Lv Mingda , Dorfman Susannah M. , Badro James , Borensztajn Stephan , Greenberg Eran , Prakapenka Vitali B.
Published: March 2021

The stable forms of carbon in Earth’s deep interior control storage and fluxes of carbon through the planet over geologic time, impacting the surface climate as well as carrying records of geologic processes in the form of diamond inclusions. However, current estimates of the distribution of carbon in Earth’s mantle are uncertain, due in part to limited understanding of the fate of carbonates through subduction, the main mechanism that transports carbon from Earth’s surface to its interior. Oxidized carbon carried by subduction has been found to reside in MgCO3throughout much of the mantle. Experiments in this study demonstrate that at deep mantle conditions MgCO3reacts with silicates to form CaCO3. In combination with previous work indicating that CaCO3is more stable than MgCO3under reducing conditions of Earth’s lowermost mantle, these observations allow us to predict that the signature of surface carbon reaching Earth’s lowermost mantle may include CaCO3.
α-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation
Authors: Pavel Mariana , Park So Jung , Frake Rebecca A. , Son Sung Min , Manni Marco M. , Bento Carla F. , Renna Maurizio , Ricketts Thomas , Menzies Fiona M. , Tanasa Radu , Rubinsztein David C.
Published: March 2021

The factors regulating cellular identity are critical for understanding the transition from health to disease and responses to therapies. Recent literature suggests that autophagy compromise may cause opposite effects in different contexts by either activating or inhibiting YAP/TAZ co-transcriptional regulators of the Hippo pathway via unrelated mechanisms. Here, we confirm that autophagy perturbation in different cell types can cause opposite responses in growth-promoting oncogenic YAP/TAZ transcriptional signalling. These apparently contradictory responses can be resolved by a feedback loop where autophagy negatively regulates the levels of α-catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of α-catenins enable autophagy induction to positively regulate YAP/TAZ, while low α-catenins cause YAP/TAZ activation upon autophagy inhibition. These data reveal how feedback loops enable post-transcriptional determination of cell identity and how levels of a single intermediary protein can dictate the direction of response to external or internal perturbations.
Mechanical stress determines the configuration of TGFβ activation in articular cartilage
Authors: Zhen Gehua , Guo Qiaoyue , Li Yusheng , Wu Chuanlong , Zhu Shouan , Wang Ruomei , Guo X. Edward , Kim Byoung Choul , Huang Jessie , Hu Yizhong , Dan Yang , Wan Mei , Ha Taekjip , An Steven , Cao Xu
Published: March 2021

Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGFβ) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGFβ activity is concentrated in the areas of AC with high mechanical stress. A high level of TGFβ disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers αV integrin–mediated TGFβ activation. Knockout of αV integrin in chondrocytes reversed the alteration of TGFβ activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGFβ activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis.
Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer
Authors: Zhang Baotong , Li Yixiang , Wu Qiao , Xie Lin , Barwick Benjamin , Fu Changying , Li Xin , Wu Daqing , Xia Siyuan , Chen Jing , Qian Wei Ping , Yang Lily , Osunkoya Adeboye O. , Boise Lawrence , Vertino Paula M. , Zhao Yichao , Li Menglin , Chen Hsiao-Rong , Kowalski Jeanne , Kucuk Omer , Zhou Wei , Dong Jin-Tang
Published: March 2021

Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.
Revealing 3D structure of gluten in wheat dough by optical clearing imaging
Authors: Ogawa Takenobu , Matsumura Yasuki
Published: March 2021

Gluten, which makes up 85% of endosperm wheat protein, is considered a crucial quality determinant of wheat-based food products. During wheat dough manufacture, the molecular packing of gluten causes formation of large structures that exceed the millimetre scale. However, due to lack of imaging techniques for complex systems composed of giant macromolecules, the entire gluten structure remains unknown. Here, we develop an optical clearing reagent (termed SoROCS) that makes wheat-based products transparent. Combined with two-photon microscopy, we image the three-dimensional (3D) structure of gluten at the size in the millimetre scale and at submicron resolution. Further, we demonstrate how the 3D structure of gluten dramatically changes from a honeycomb-shaped network to sparse large clumps in wheat noodles, depending on the salt added during dough making, thereby reducing stress when compressing the noodle. Moreover, we show that SoROCS can be used for noodle imaging using confocal laser scanning microscopy.
Towards optimising experimental quantification of persistent pain in Parkinson’s disease using psychophysical testing
Authors: Bannister Kirsty , Smith Rory V. , Wilkins Patrick , Cummins Tatum M.
Published: March 2021

People with Parkinson’s disease (PD) may live for multiple decades after diagnosis. Ensuring that effective healthcare provision is received across the range of symptoms experienced is vital to the individual’s wellbeing and quality of life. As well as the hallmark motor symptoms, PD patients may also suffer from non-motor symptoms including persistent pain. This type of pain (lasting more than 3 months) is inconsistently described and poorly understood, resulting in limited treatment options. Evidence-based pain remedies are coming to the fore but therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Since the ability to establish a link between the neurodegenerative changes that underlie PD and those that underlie maladaptive pain processing leading to persistent pain could illuminate mechanisms or risk factors of disease initiation, progression and maintenance, we evaluated the latest research literature seeking to identify causal factors underlying persistent pain in PD through experimental quantification. The majority of previous studies aimed to identify neurobiological alterations that could provide a biomarker for pain/pain phenotype, in PD cohorts. However heterogeneity of patient cohorts, result outcomes and methodology between human psychophysics studies overwhelmingly leads to inconclusive and equivocal evidence. Here we discuss refinement of pain-PD paradigms in order that future studies may enhance confidence in the validity of observed effect sizes while also aiding comparability through standardisation. Encouragingly, as the field moves towards cross-study comparison of data in order to more reliably reveal mechanisms underlying dysfunctional pain processing, the potential for better-targeted treatment and management is high.
Strain derivative of thermoelectric properties as a sensitive probe for nematicity
Authors: Caglieris F. , Wuttke C. , Hong X. C. , Sykora S. , Kappenberger R. , Aswartham S. , Wurmehl S. , Büchner B. , Hess C.
Published: March 2021

The nematic instability is an undebatable ingredient of the physics of iron-based superconductors. Yet, its origin remains enigmatic as it involves a fermiology with an intricate interplay of lattice-, orbital-, and spin degrees of freedom. It is well known that thermoelectric transport is an excellent probe for revealing even subtle signatures of instabilities and pertinent fluctuations. In this paper, we report a strong response of the thermoelectric transport properties of two underdoped 1111 iron-based superconductors to a vanishingly small strain. By introducing the strain derivative of the Seebeck and the Nernst coefficients, we provide a description of the nematic order parameter, proving the existence of an anisotropic Peltier-tensor beside an anisotropic conductivity tensor. Our measurements reveal that the transport nematic phenomenology is the result of the combined effect of both an anisotropic scattering time and Fermi surface distortions, pointing out that in a realistic description, abreast of the spin fluctuations also the orbital character is a fundamental ingredient. In addition, we show that nematic fluctuations universally relax in a Curie–Weiss fashion above TS in all the elasto-transport measurements and we provide evidences that nematicity must be band selective.
Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine
Authors:   LifeTime Community Working Groups, Rajewsky Nikolaus , Almouzni Geneviève , Gorski Stanislaw A. , Aerts Stein , Amit Ido , Bertero Michela G. , Bock Christoph , Bredenoord Annelien L. , Cavalli Giacomo , Chiocca Susanna , Clevers Hans , De Strooper Bart , Eggert Angelika , Ellenberg Jan , Fernández Xosé M. , Figlerowicz Marek , Gasser Susan M. , Hubner Norbert , Kjems Jørgen , Knoblich Jürgen A. , Krabbe Grietje , Lichter Peter , Linnarsson Sten , Marine Jean-Christophe , Marioni John C. , Marti-Renom Marc A. , Netea Mihai G. , Nickel Dörthe , Nollmann Marcelo , Novak Halina R. , Parkinson Helen , Piccolo Stefano , Pinheiro Inês , Pombo Ana , Popp Christian , Reik Wolf , Roman-Roman Sergio , Rosenstiel Philip , Schultze Joachim L. , Stegle Oliver , Tanay Amos , Testa Giuseppe , Thanos Dimitris , Theis Fabian J. , Torres-Padilla Maria-Elena , Valencia Alfonso , Vallot Céline , van Oudenaarden Alexander , Vidal Marie , Voet Thierry
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03287-8.