bluuebunny/crossref_metadata_2025 huggingface dataset:
On large-deviation probabilities for the empirical distribution of branching random walks with heavy tails
Authors: Zhang Shuxiong
Published: March 2022

Given a branching random walk
$(Z_n)_{n\geq0}$
on
$\mathbb{R}$
, let
$Z_n(A)$
be the number of particles located in interval A at generation n. It is well known that under some mild conditions,
$Z_n(\sqrt nA)/Z_n(\mathbb{R})$
converges almost surely to
$\nu(A)$
as
$n\rightarrow\infty$
, where
$\nu$
is the standard Gaussian measure. We investigate its large-deviation probabilities under the condition that the step size or offspring law has a heavy tail, i.e. a decay rate of
$\mathbb{P}(Z_n(\sqrt nA)/Z_n(\mathbb{R})>p)$
as
$n\rightarrow\infty$
, where
$p\in(\nu(A),1)$
. Our results complete those in Chen and He (2019) and Louidor and Perkins (2015).
Does accommodation work? Mainstream party strategies and the success of radical right parties
Authors: Krause Werner , Cohen Denis , Abou-Chadi Tarik
Published: March 2022

This research note investigates how mainstream party strategies affect the success of radical right parties (RRPs). It is a widespread view that mainstream party accommodation of radical right core issue positions would reduce the radical right's success. Empirical evidence for this claim, however, remains inconclusive. Using party level data as well as micro-level voter transitions between mainstream and RRPs, we re-evaluate the effectiveness of accommodative strategies and also test whether they work contingent on specific conditions, e.g., the newness of radical right challengers or the existence of a cordon sanitaire. We do not find any evidence that accommodative strategies reduce radical right support. If anything, our results suggest that they lead to more voters defecting to the radical right. Our findings have important implications for the study of multi-party competition as they challenge what has become a core assumption of this literature: that accommodative strategies reduce niche party success.
Signposts for an Eastern Orthodox inclusive anthropological ethics
Authors: Maican Petre
Published: March 2022

Despite the strong interest of Eastern Orthodox theologians in the area of anthropology, their reflection has almost never included intellectual disability. The article aims to take the discussion further by providing the contours of an inclusive anthropological ethics. In this sense, it will develop constructively the three main principles of Dumitru Stăniloae's dialogical anthropology: (1) that each human being is a person because she is called to dialogue with God from the womb of her mother; (2) that this dialogue with God is mediated by one's neighbour; (3) that the materiality of creation is meant to be transformed into a gift of communion with other humans and God.
Democratization and the Practices of Voting in Habsburg Austria, 1896–1914: New Directions in Research
Authors: Bader-Zaar Birgitta
Published: March 2022

From the mid-1890s, Habsburg Austria began to follow European trends and experienced a gradual democratization of voting rights, which involved not only an expansion of the electorate but also an innovation of procedures that attempted to modernize elections. In this context, the article calls for a more systematic study of voting practices and attempts to point at some issues that have thus far received insufficient analysis. These include not only the occasional massive violent conflicts at elections that could accompany democratization until World War I but also the presence of women as voters at local and diet elections and the gradual introduction of polling booths. Measures such as allowing single women to cast their vote personally in a few crownlands or attempting to guard the secrecy of the vote suggest the level of experimentation in this period. The state's objective of orderly, “modern” elections is particularly called into question when we consider the extent to which government agents, including policemen and the army, were involved in election conflicts that resulted in fraud and sometimes bloodshed.
Distribution and community structure of fish in relation with water physico-chemical parameters of floodplain rivers in the Alitash National Park, Ethiopia
Authors: Eyayu Alamrew , Getahun Abebe
Published: March 2022

Riverine ecosystems are highly exposed to different forms of human activities and fish distribution in such habitats can be affected by different features of water. Tributaries of the Abbay and Tekeze Basins are supporting all life requesting activities in Ethiopia. Fisheries of these habitats are also the mainstay of livelihoods. However, brutal human activities are affecting these ecosystems and the fish therein. This study was thus undertaken to examine fish distribution and community structure in relation to water parameters in Ayima, Gelegu and Shinfa Rivers. 2719 fish specimens identified into 43 species were sampled using gillnets, cast nets and electro-fishing on a seasonal campaign. Based on frequency of occurrence (%FO), 5 species fell in the category of ‘euconstant occurrence’ or their FO was ≥75%, while many species were laid in the ‘constant occurrence’. Among others, site depth, total phosphorus, dissolved oxygen and river channel diameter were key environmental factors determining fish community structure. Similarity percentage produced an overall average Bray-Curtis dissimilarity of 60.8% between the fish communities of the three rivers. The final model accounted for 77.2% of the total variance in fish composition, and all canonical axes were significant (Monte Carlo test 499, p = 0.002). Generally, this study was conducted in areas where no ecological studies are undertaken and the results obtained from this study could be important for sustainable utilization of Ethiopian fisheries.
Framing the Socialist City as Practice
Authors: DeHaan Heather D.
Published: March 2022

The publication of Stephen Kotkin's Magnetic Mountain in the mid-1990s transformed the field of Soviet studies. He presented Soviet socialism as a civilisation born of the Enlightenment, inspired by science's ability to sculpt society, and driven by the pursuit of an alternative to capitalism. His phrase ‘speaking Bolshevik’ spawned productive debate, as did his use of the Foucauldian paradigm. In something akin to a clarion call for urbanists, he proposed the socialist city as a metonym for this new Soviet world: Soviet socialism, he noted, was inherently industrial. Authorities regarded the city as a hallmark of socialist modernity, an endpoint and changing ideal toward which to strive, all of which makes the city a fruitful centre of investigation.
Transcatheter closure of an acquired post-operative aorta to right ventricle shunt in a child with complex univentricular heart
Authors: Haddad Raymond N. , Bonnet Damien , Khraiche Diala , Malekzadeh-Milani Sophie
Published: March 2022

KONAR-MultifunctionalTM VSD Occluder (Lifetech, Shenzhen, China) is one of the most recent additions to the armamentarium of device closure interventions offering special features to tackle complex cardiac anatomies. Herein, we report the first use of the KONAR-MFO in an 8.5-year-old female patient (27 kg/129 cm) with stage III palliated univentricular heart to close an acquired post-operative tunnel-like communication (5 mm long × 2.6 mm large) between the right anterior non-coronary aortic sinus and the rudimentary right ventricular cavity. The shunt was diagnosed two and a half years after bulboventricular foramen surgical enlargement. The 5× 3 mm KONAR-MFO was retrogradely implanted under ultrasound and biplane fluoroscopic guidance. Immediate and 12-month follow-up confirmed successful outcomes with complete shunt closure and preserved aortic valve competence.
Harnessing the Power of Structural Oncology
Authors: Solares Maria J. , Kelly Deborah F.
Published: March 2022

Microscopy has evolved through centuries of desire to see the unseen world. Modern technologies have pushed the limits of what's possible, inspiring the field of structural biology. Coupled with advances in biochemistry, scientists can now study the fine details of tiny intruders in the body as well as the molecular culprits of disease. Despite these monumental achievements, human health still suffers from persistent dysfunctions in biological molecules. Through cryo-electron microscopy (cryo-EM) imaging technology we can create more translatable models to uncover the atomic details of macromolecules gone awry. For instance, the tumor suppressor p53 is one of the most popular proteins in cancer research, yet there is little structural information about its complete 3D organization. The Center for Structural Oncology (CSO) at Penn State University is working to address these impactful uncertainties. Using a wealth of cryo-EM resources in the CSO, we capture dynamic snapshots of p53 assemblies while preserving their disease-related context for drug discovery and therapeutic development. With these tools in hand, the CSO is working to engineer new molecular paradigms in creating a world without cancer.
Can Appeals for Peace Promote Tolerance and Mitigate Support for Extremism? Evidence from an Experiment with Adolescents in Burkina Faso
Authors: Grossman Allison N. , Nomikos William G. , Siddiqui Niloufer A.
Published: March 2022

Recent efforts to improve attitudes toward outgroups and reduce support for extremists in violent settings report mixed results. Donors and aid organizations have spent millions of dollars to amplify the voices of moderate religious figures to counter violent extremism in West Africa, the Middle East, and South Asia. Despite this investment, we know little about whether such messaging persuades the primary recruits of violent extremist organizations: at-risk youth in fragile settings. In this paper, we consider whether pro-peace religious messaging can promote social cohesion among school-age respondents in Burkina Faso. Using a survey experiment, we find little evidence that such messages affect reported attitudes or behaviors toward religious extremism and find instead that it can have the unintended effect of increasing intolerance toward ethnic others. Our findings carry lessons about the inadvertent priming of ethnic identities that can result in a backlash effect among certain societal segments.
Atmospheric CO2 and Sea Surface Temperature Variability Cannot Explain Recent Decadal Variability of the Ocean CO2 Sink
Authors: DeVries Tim
Published: March 2022

The ocean is one of the most important sinks for anthropogenic CO2 emissions. Here, I use an ocean circulation inverse model (OCIM), ocean biogeochemical models, and pCO2 interpolation products to examine trends and variability in the oceanic CO2 sink. The OCIM quantifies the impacts of rising atmospheric CO2, changing sea surface temperatures, and gas transfer velocities on the oceanic CO2 sink. Together, these effects account for an oceanic CO2 uptake of 2.2 ± 0.1 PgC yr−1 from 1994 to 2007, and a net increase in the oceanic carbon inventory of 185 PgC from 1780 to 2020. However, these effects cannot account for the majority of the decadal variability shown in data‐based reconstructions of the ocean CO2 sink over the past 30 years. This implies that decadal variability of the ocean CO2 sink is predominantly driven by changes in ocean circulation or biology that act to redistribute both natural and anthropogenic carbon in the ocean.
Determining the Beaming of Io Decametric Emissions: A Remote Diagnostic to Probe the Io‐Jupiter Interaction
Authors: Lamy L. , Colomban L. , Zarka P. , Prangé R. , Marques M. S. , Louis C. K. , Kurth W. S. , Cecconi B. , Girard J. N. , Grießmeier J.‐M. , Yerin S.
Published: March 2022

We investigate the beaming of 11 Io‐Jupiter decametric (Io‐DAM) emissions observed by Juno/Waves, the Nançay Decameter Array, and NenuFAR. Using an up‐to‐date magnetic field model and three methods to position the active Io Flux Tube (IFT), we accurately locate the radiosources and determine their emission angle θ from the local magnetic field vector. These methods use (a) updated models of the IFT equatorial lead angle, (b) ultraviolet (UV) images of Jupiter's aurorae, and (c) multi‐point radio measurements. The kinetic energy Ee− of source electrons is then inferred from θ in the framework of the Cyclotron Maser Instability. The precise position of the active IFT achieved from methods (b and c) can be used to test the effective plasma density of the Io torus. Simultaneous radio/UV observations reveal that multiple Io‐DAM arcs are associated with multiple UV spots and provide the first direct evidence of an Io‐DAM arc associated with a trans‐hemispheric beam UV spot. Multi‐point radio observations probe the Io‐DAM sources at various altitudes, times and hemispheres. Overall, θ varies a function of frequency (altitude), by decreasing from 75°−80° to 70°−75° over 10−40 MHz with slightly larger values in the northern hemisphere, and independently varies as a function of time (or longitude of Io). Its uncertainty of a few degrees is dominated by the error on the longitude of the active IFT. The inferred values of Ee− also vary as a function of altitude and time. For the 11 investigated cases, they range from 3 to 16 keV, with a 6.6 ± 2.7 keV average.
Notch signaling pathway: architecture, disease, and therapeutics
Authors: Zhou Binghan , Lin Wanling , Long Yaling , Yang Yunkai , Zhang Huan , Wu Kongming , Chu Qian
Published: March 2022

The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
Pseudomonas aeruginosa polysaccharide Psl supports airway microbial community development
Authors: Stoner Sara N , Baty Joshua J , Scoffield Jessica A
Published: March 2022

Pseudomonas aeruginosa dominates the complex polymicrobial cystic fibrosis (CF) airway and is a leading cause of death in persons with CF. Oral streptococcal colonization has been associated with stable CF lung function. However, no studies have demonstrated how Streptococcus salivarius, the most abundant streptococcal species found in individuals with stable CF lung disease, potentially improves lung function or becomes incorporated into the CF airway biofilm. By utilizing a two-species biofilm model to probe interactions between S. salivarius and P. aeruginosa, we discovered that the P. aeruginosa exopolysaccharide Psl promoted S. salivarius biofilm formation. Further, we identified a S. salivarius maltose-binding protein (MalE) that is required for promotion of biofilm formation both in vitro and in a Drosophila melanogaster co-infection model. Finally, we demonstrate that promotion of dual biofilm formation with S. salivarius is common among environmental and clinical P. aeruginosa isolates. Overall, our data supports a model in which S. salivarius uses a sugar-binding protein to interact with P. aeruginosa exopolysaccharide, which may be a strategy by which S. salivarius establishes itself within the CF airway microbial community.
Sleep’s role in updating aversive autobiographical memories
Authors: Azza Yasmine , Wilhelm Frank H. , Seifritz Erich , Junghanns Klaus , Kleim Birgit , Wilhelm Ines
Published: March 2022

Aversive autobiographical memories play a key role in the development and maintenance of many mental disorders. Imagery rescripting is a well-established psychotherapeutic intervention aiming to create a more adaptive version of an aversive memory by modifying its interpretation. Sleep has been shown to support reconsolidation of updated neutral memories. Here, we investigated in healthy participants whether a 90-min nap compared to wake supports the adaptive reconsolidation of autobiographical memories. Forty-four university students received a single 50-min imagery rescripting session. Thereafter, half of the participants took a 90-min nap, whereas the other half stayed awake. Subjective (arousal ratings, reports of emotions and dysfunctional cognitions) and heart rate (HR) responses to individual memory scripts were measured before the intervention (pre), after the 90-min retention interval (post 1) and 7 days later (post 2). Results demonstrate a significant decrease in distress of aversive memories pre to post imagery rescripting. The nap group showed less distressing dysfunctional cognitions along with a lower HR in response to the negative memory script as compared to the wake group at post 1. These differences were no longer evident 1 week later (post 2). Central sleep spindle density during the nap was correlated with the reduction in HR in response to the negative memory script from pre to post 1. Our results provide first evidence for sleep benefitting adaptive reconsolidation of aversive autobiographical memories. Future research should expand this approach to clinical populations and investigate precise conditions under which sleep may benefit psychotherapeutic interventions utilizing reconsolidation mechanisms.
No increase in inflammation in late-life major depression screened to exclude physical illness
Authors: Luning Prak Eline T. , Brooks Thomas , Makhoul Walid , Beer Joanne C. , Zhao Ling , Girelli Tommaso , Skarke Carsten , Sheline Yvette I.
Published: March 2022

Depression is a common and debilitating disorder in the elderly. Late-life depression (LLD) has been associated with inflammation and elevated levels of proinflammatory cytokines including interleukin (IL)-1β, tumor necrosis factor-alpha, and IL-6, but often depressed individuals have comorbid medical conditions that are associated with immune dysregulation. To determine whether depression has an association with inflammation independent of medical illness, 1120 adults were screened to identify individuals who had clinically significant depression but not medical conditions associated with systemic inflammation. In total, 66 patients with LLD screened to exclude medical conditions associated with inflammation were studied in detail along with 26 age-matched controls (HC). At baseline, circulating cytokines were low and similar in LLD and HC individuals. Furthermore, cytokines did not change significantly after treatment with either an antidepressant (escitalopram 20 mg/day) or an antidepressant plus a COX-2 inhibitor or placebo, even though depression scores improved in the non-placebo treatment arms. An analysis of cerebrospinal fluid in a subset of individuals for IL-1β using an ultrasensitive digital enzyme-linked immunosorbent assay revealed low levels in both LLD and HC at baseline. Our results indicate that depression by itself does not result in systemic or intrathecal elevations in cytokines and that celecoxib does not appear to have an adjunctive antidepressant role in older patients who do not have medical reasons for having inflammation. The negative finding for increased inflammation and the lack of a treatment effect for celecoxib in this carefully screened depressed population taken together with multiple positive results for inflammation in previous studies that did not screen out physical illness support a precision medicine approach to the treatment of depression that takes the medical causes for inflammation into account.
Disruption of 5-hydroxytryptamine 1A receptor and orexin receptor 1 heterodimer formation affects novel G protein-dependent signaling pathways and has antidepressant effects in vivo
Authors: Zhang Rumin , Li Dandan , Mao Huiling , Wei Xiaonan , Xu MingDong , Zhang Shengnan , Jiang Yunlu , Wang Chunmei , Xin Qing , Chen Xiaoyu , Li Guorong , Ji Bingyuan , Yan Maocai , Cai Xin , Dong Bo , Randeva Harpal S. , Liu Chuanxin , Chen Jing
Published: March 2022

G protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of depression. Increasing evidence supports the importance of serotonergic and orexin-producing neurons in numerous physiological processes, possibly via a crucial interaction between 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 1 (OX1R). However, little is known about the function of 5-HT1AR/OX1R heterodimers. It is unclear how the transmembrane domains (TMs) of the dimer affect its function and whether its modulation mediates antidepressant-like effects. Here, we examined the mechanism of 5-HT1AR/OX1R dimerization and downstream G protein-dependent signaling. We found that 5-HT1AR and OX1R form constitutive heterodimers that induce novel G protein-dependent signaling, and that this heterodimerization does not affect recruitment of β-arrestins to the complex. In addition, we found that the structural interface of the active 5-HT1AR/OX1R dimer transforms from TM4/TM5 in the basal state to TM6 in the active conformation. We also used mutation analyses to identify key residues at the interface (5-HT1AR R1514.40, 5-HT1AR Y1985.41, and OX1R L2305.54). Injection of chronic unpredictable mild stress (CUMS) rats with TM4/TM5 peptides improved their depression-like emotional status and decreased the number of endogenous 5-HT1AR/OX1R heterodimers in the rat brain. These antidepressant effects may be mediated by upregulation of BDNF levels and enhanced phosphorylation and activation of CREB in the hippocampus and medial prefrontal cortex. This study provides evidence that 5-HT1AR/OX1R heterodimers are involved in the pathological process of depression. Peptides including TMs of the 5-HT1AR/OX1R heterodimer interface are candidates for the development of compounds with fast-acting antidepressant-like effects.
Complex roles of nicotinamide N-methyltransferase in cancer progression
Authors: Wang Weixuan , Yang Changmei , Wang Tianxiang , Deng Haiteng
Published: March 2022

Nicotinamide N-methyltransferase (NNMT) is an intracellular methyltransferase, catalyzing the N-methylation of nicotinamide (NAM) to form 1-methylnicotinamide (1-MNAM), in which S-adenosyl-l-methionine (SAM) is the methyl donor. High expression of NNMT can alter cellular NAM and SAM levels, which in turn, affects nicotinamide adenine dinucleotide (NAD+)-dependent redox reactions and signaling pathways, and remodels cellular epigenetic states. Studies have revealed that NNMT plays critical roles in the occurrence and development of various cancers, and analysis of NNMT expression levels in different cancers from The Cancer Genome Atlas (TCGA) dataset indicated that NNMT might be a potential biomarker and therapeutic target for tumor diagnosis and treatment. This review provides a comprehensive understanding of recent advances on NNMT functions in different tumors and deciphers the complex roles of NNMT in cancer progression.
CircTHBS1 drives gastric cancer progression by increasing INHBA mRNA expression and stability in a ceRNA- and RBP-dependent manner
Authors: Qiu Shengkui , Li Bowen , Xia Yiwen , Xuan Zhe , Li Zheng , Xie Li , Gu Chao , Lv Jialun , Lu Chen , Jiang Tianlu , Fang Lang , Xu Penghui , Yang Jing , Li Ying , Chen Zetian , Zhang Lu , Wang Linjun , Zhang Diancai , Xu Hao , Wang Weizhi , Xu Zekuan
Published: March 2022

Circular RNAs (circRNAs) play vital regulatory roles in the progression of multiple cancers. In our study, transcriptome analysis and self-organizing maps (SOM) were applied to screen backbone circRNAs in gastric cancer (GC). Upon validation of the expression patterns of screened circRNAs, gain- and loss-of-function assays were performed in vitro and in vivo. Underlying mechanisms were investigated using RNA pull-down, luciferase reporter assay and RNA immunoprecipitation. The expression of circTHBS1 was significantly increased in GC and associated with poor prognosis. CircTHBS1 facilitated the malignant behavior and epithelial-to-mesenchymal transition of GC cells. Mechanistically, circTHBS1 sponged miR-204-5p to promote the expression of Inhibin Subunit Beta A (INHBA). Moreover, circTHBS1 could enhance the HuR-mediated mRNA stability of INHBA, which subsequently activated the TGF-β pathway. Our research identified circTHBS1 as an oncogenic circRNA that enhances GC malignancy by elevating INHBA expression, providing new insight and a feasible target for the diagnosis and treatment of GC.
Detection of cracked teeth using a mechanoluminescence phosphor with a stretchable photodetector array
Authors: Kim Ha Jun , Ji Sangyoon , Han Ju Yeon , Cho Han Bin , Park Young-Geun , Choi Dongwhi , Cho Hoonsung , Park Jang-Ung , Im Won Bin
Published: March 2022

Cracked tooth syndrome (CTS) is an incomplete fracture of a human tooth that commonly arises from chewing hard foods. Although it is a very common syndrome, CTS is often difficult to diagnose owing to the common small size of tooth cracks. Conventional techniques for the detection of cracks, such as transillumination and radiographic methods, are inaccurate and have poor imaging resolution. In this study, we devise a novel method for the in vivo detection of tooth microcracks by exploiting the mechanoluminescence (ML) phenomenon. ZrO2:Ti4+ (ZRT) phosphor particles are pasted onto suspected regions of tooth cracks and emit cyan-colored light as a result of masticatory forces. Then, a stretchable and self-healable photodetector (PD) array laminated on top of the phosphor particles converts the emitted photons into a photocurrent, which facilitates the two-dimensional mapping of the tooth cracks. Because of the high photosensitivity of the PD, intense ML and small size of ZRT phosphor particles, it is possible to image submicron- to micron-sized cracks with high resolution. Furthermore, the uniqueness of this technique over the conventional techniques stems from the application of a simple optical phenomenon, i.e., ML, for obtaining precise information regarding the locations, depth, and length of tooth cracks.
Harnessing DSB repair to promote efficient homology-dependent and -independent prime editing
Authors: Peterka Martin , Akrap Nina , Li Songyuan , Wimberger Sandra , Hsieh Pei-Pei , Degtev Dmitrii , Bestas Burcu , Barr Jack , van de Plassche Stijn , Mendoza-Garcia Patricia , Šviković Saša , Sienski Grzegorz , Firth Mike , Maresca Marcello
Published: March 2022

Prime editing recently emerged as a next-generation approach for precise genome editing. Here we exploit DNA double-strand break (DSB) repair to develop two strategies that install precise genomic insertions using an SpCas9 nuclease-based prime editor (PEn). We first demonstrate that PEn coupled to a regular prime editing guide RNA (pegRNA) efficiently promotes short genomic insertions through a homology-dependent DSB repair mechanism. While PEn editing leads to increased levels of by-products, it can rescue pegRNAs that perform poorly with a nickase-based prime editor. We also present a small molecule approach that yields increased product purity of PEn editing. Next, we develop a homology-independent PEn editing strategy, which installs genomic insertions at DSBs through the non-homologous end joining pathway (NHEJ). Lastly, we show that PEn-mediated insertions at DSBs prevent Cas9-induced large chromosomal deletions and provide evidence that continuous Cas9-mediated cutting is one of the mechanisms by which Cas9-induced large deletions arise. Altogether, this work expands the current prime editing toolbox by leveraging distinct DNA repair mechanisms including NHEJ, which represents the primary pathway of DSB repair in mammalian cells.
A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome
Authors: Skuladottir Astros Th. , Bjornsdottir Gyda , Ferkingstad Egil , Einarsson Gudmundur , Stefansdottir Lilja , Nawaz Muhammad Sulaman , Oddsson Asmundur , Olafsdottir Thorunn A. , Saevarsdottir Saedis , Walters G. Bragi , Magnusson Sigurdur H. , Bjornsdottir Anna , Sveinsson Olafur A. , Vikingsson Arnor , Hansen Thomas Folkmann , Jacobsen Rikke Louise , Erikstrup Christian , Schwinn Michael , Brunak Søren , Banasik Karina , Ostrowski Sisse Rye , Troelsen Anders , Henkel Cecilie , Pedersen Ole Birger ,   DBDS Genetic Consortium, Andersen Steffen , Burgdorf Kristoffer , Didriksen Maria , Dinh Khoa Manh , Hjalgrim Henrik , Jemec Gregor , Jennum Poul , Johansson Pär Ingemar , Larsen Margit Anita Hørup , Mikkelsen Susan , Nielsen Kasper Rene , Nyegaard Mette , Stefánsson Hreinn , Sækmose Susanne , Sørensen Erik , Thorsteinsdottir Unnur , Bruun Mie Topholm , Ullum Henrik , Werge Thomas , Jonsdottir Ingileif , Gudbjartsson Daniel F. , Sulem Patrick , Thorgeirsson Thorgeir E. , Stefansson Hreinn , Stefansson Kari
Published: March 2022

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10−24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.
Automated multilabel diagnosis on electrocardiographic images and signals
Authors: Sangha Veer , Mortazavi Bobak J. , Haimovich Adrian D. , Ribeiro Antônio H. , Brandt Cynthia A. , Jacoby Daniel L. , Schulz Wade L. , Krumholz Harlan M. , Ribeiro Antonio Luiz P. , Khera Rohan
Published: March 2022

The application of artificial intelligence (AI) for automated diagnosis of electrocardiograms (ECGs) can improve care in remote settings but is limited by the reliance on infrequently available signal-based data. We report the development of a multilabel automated diagnosis model for electrocardiographic images, more suitable for broader use. A total of 2,228,236 12-lead ECGs signals from 811 municipalities in Brazil are transformed to ECG images in varying lead conformations to train a convolutional neural network (CNN) identifying 6 physician-defined clinical labels spanning rhythm and conduction disorders, and a hidden label for gender. The image-based model performs well on a distinct test set validated by at least two cardiologists (average AUROC 0.99, AUPRC 0.86), an external validation set of 21,785 ECGs from Germany (average AUROC 0.97, AUPRC 0.73), and printed ECGs, with performance superior to signal-based models, and learning clinically relevant cues based on Grad-CAM. The model allows the application of AI to ECGs across broad settings.
Ultrafast photothermoelectric effect in Dirac semimetallic Cd3As2 revealed by terahertz emission
Authors: Lu Wei , Fan Zipu , Yang Yunkun , Ma Junchao , Lai Jiawei , Song Xiaoming , Zhuo Xiao , Xu Zhaoran , Liu Jing , Hu Xiaodong , Zhou Shuyun , Xiu Faxian , Cheng Jinluo , Sun Dong
Published: March 2022

The thermoelectric effects of topological semimetals have attracted tremendous research interest because many topological semimetals are excellent thermoelectric materials and thermoelectricity serves as one of their most important potential applications. In this work, we reveal the transient photothermoelectric response of Dirac semimetallic Cd3As2, namely the photo-Seebeck effect and photo-Nernst effect, by studying the terahertz (THz) emission from the transient photocurrent induced by these effects. Our excitation polarization and power dependence confirm that the observed THz emission is due to photothermoelectric effect instead of other nonlinear optical effect. Furthermore, when a weak magnetic field (~0.4 T) is applied, the response clearly indicates an order of magnitude enhancement on transient photothermoelectric current generation compared to the photo-Seebeck effect. Such enhancement supports an ambipolar transport nature of the photo-Nernst current generation in Cd3As2. These results highlight the enhancement of thermoelectric performance can be achieved in topological Dirac semimetals based on the Nernst effect, and our transient studies pave the way for thermoelectric devices applicable for high field circumstance when nonequilibrium state matters. The large THz emission due to highly efficient photothermoelectric conversion is comparable to conventional semiconductors through optical rectification and photo-Dember effect.
BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation
Authors: Kapalczynska Marta , Lin Manqiang , Maertzdorf Jeroen , Heuberger Julian , Muellerke Stefanie , Zuo Xiangsheng , Vidal Ramon , Shureiqi Imad , Fischer Anne-Sophie , Sauer Sascha , Berger Hilmar , Kidess Evelyn , Mollenkopf Hans-Joachim , Tacke Frank , Meyer Thomas F. , Sigal Michael
Published: March 2022

Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here, we studied the interplay between gastric epithelial stem cells and their stromal niche under homeostasis and upon H. pylori infection. We find that gastric epithelial stem cell differentiation is orchestrated by subsets of stromal cells that either produce BMP inhibitors in the gland base, or BMP ligands at the surface. Exposure to BMP ligands promotes a feed-forward loop by inducing Bmp2 expression in the epithelial cells themselves, enforcing rapid lineage commitment to terminally differentiated mucous pit cells. H. pylori leads to a loss of stromal and epithelial Bmp2 expression and increases expression of BMP inhibitors, promoting self-renewal of stem cells and accumulation of gland base cells, which we mechanistically link to IFN-γ signaling. Mice that lack IFN-γ signaling show no alterations of BMP gradient upon infection, while exposure to IFN-γ resembles H. pylori-driven mucosal responses.
Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers
Authors: Serebriiskii Ilya G. , Pavlov Valery , Tricarico Rossella , Andrianov Grigorii , Nicolas Emmanuelle , Parker Mitchell I. , Newberg Justin , Frampton Garrett , Meyer Joshua E. , Golemis Erica A.
Published: March 2022

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.
Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression
Authors: Yoo Seungyeul , Sinha Abhilasha , Yang Dawei , Altorki Nasser K. , Tandon Radhika , Wang Wenhui , Chavez Deebly , Lee Eunjee , Patel Ayushi S. , Sato Takashi , Kong Ranran , Ding Bisen , Schadt Eric E. , Watanabe Hideo , Massion Pierre P. , Borczuk Alain C. , Zhu Jun , Powell Charles A.
Published: March 2022

Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma.
A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens
Authors: Roberts Kade D. , Zhu Yan , Azad Mohammad A. K. , Han Mei-Ling , Wang Jiping , Wang Lynn , Yu Heidi H. , Horne Andrew S. , Pinson Jo-Anne , Rudd David , Voelcker Nicolas H. , Patil Nitin A. , Zhao Jinxin , Jiang Xukai , Lu Jing , Chen Ke , Lomovskaya Olga , Hecker Scott J. , Thompson Philip E. , Nation Roger L. , Dudley Michael N. , Griffith David C. , Velkov Tony , Li Jian
Published: March 2022

The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.
Mechanistic insights into the regulation of plant phosphate homeostasis by the rice SPX2 – PHR2 complex
Authors: Guan Zeyuan , Zhang Qunxia , Zhang Zhifei , Zuo Jiaqi , Chen Juan , Liu Ruiwen , Savarin Julie , Broger Larissa , Cheng Peng , Wang Qiang , Pei Kai , Zhang Delin , Zou Tingting , Yan Junjie , Yin Ping , Hothorn Michael , Liu Zhu
Published: March 2022

Phosphate (Pi) starvation response (PHR) transcription factors play key roles in plant Pi homeostasis maintenance. They are negatively regulated by stand-alone SPX proteins, cellular receptors for inositol pyrophosphate (PP-InsP) nutrient messengers. How PP-InsP-bound SPX interacts with PHRs is poorly understood. Here, we report crystal structures of the rice SPX2/InsP6/PHR2 complex and of the PHR2 DNA binding (MYB) domain in complex with target DNA at resolutions of 3.1 Å and 2.7 Å, respectively. In the SPX2/InsP6/PHR2 complex, the signalling-active SPX2 assembles into a domain-swapped dimer conformation and binds two copies of PHR2, targeting both its coiled-coil (CC) oligomerisation domain and MYB domain. Our results reveal that the SPX2 senses PP-InsPs to inactivate PHR2 by establishing severe steric clashes with the PHR2 MYB domain, preventing DNA binding, and by disrupting oligomerisation of the PHR2 CC domain, attenuating promoter binding. Our findings rationalize how PP-InsPs activate SPX receptor proteins to target PHR family transcription factors.
Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease
Authors: Sun Hui , Li Hui , Yan Jie , Wang Xiangdong , Xu Mengyuan , Wang Mingxia , Fan Baozhen , Liu Jieying , Lin Ninghua , Wang Xin , Li Li , Zhao Shengtian , Gong Yongfeng
Published: March 2022

Although mature podocytes lack tight junctions, tight junction integral membrane protein claudin-5 (CLDN5) is predominantly expressed on plasma membranes of podocytes under normal conditions. Using podocyte-specific Cldn5 knockout mice, we identify CLDN5 as a crucial regulator of podocyte function and reveal that Cldn5 deletion exacerbates podocyte injury and proteinuria in a diabetic nephropathy mouse model. Mechanistically, CLDN5 deletion reduces ZO1 expression and induces nuclear translocation of ZONAB, followed by transcriptional downregulation of WNT inhibitory factor-1 (WIF1) expression, which leads to activation of WNT signaling pathway. Podocyte-derived WIF1 also plays paracrine roles in tubular epithelial cells, as evidenced by the finding that animals with podocyte-specific deletion of Cldn5 or Wif1 have worse kidney fibrosis after unilateral ureteral obstruction than littermate controls. Systemic delivery of WIF1 suppresses the progression of diabetic nephropathy and ureteral obstruction-induced renal fibrosis. These findings establish a function for podocyte CLDN5 in restricting WNT signaling in kidney.
Superfast precipitation of energetic electrons in the radiation belts of the Earth
Authors: Zhang Xiao-Jia , Artemyev Anton , Angelopoulos Vassilis , Tsai Ethan , Wilkins Colin , Kasahara Satoshi , Mourenas Didier , Yokota Shoichiro , Keika Kunihiro , Hori Tomoaki , Miyoshi Yoshizumi , Shinohara Iku , Matsuoka Ayako
Published: March 2022

Energetic electron precipitation from Earth’s outer radiation belt heats the upper atmosphere and alters its chemical properties. The precipitating flux intensity, typically modelled using inputs from high-altitude, equatorial spacecraft, dictates the radiation belt’s energy contribution to the atmosphere and the strength of space-atmosphere coupling. The classical quasi-linear theory of electron precipitation through moderately fast diffusive interactions with plasma waves predicts that precipitating electron fluxes cannot exceed fluxes of electrons trapped in the radiation belt, setting an apparent upper limit for electron precipitation. Here we show from low-altitude satellite observations, that ~100 keV electron precipitation rates often exceed this apparent upper limit. We demonstrate that such superfast precipitation is caused by nonlinear electron interactions with intense plasma waves, which have not been previously incorporated in radiation belt models. The high occurrence rate of superfast precipitation suggests that it is important for modelling both radiation belt fluxes and space-atmosphere coupling.
Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation
Authors: Wang Liang-Jie , Chen Chie-Pein , Lee Yun-Shien , Ng Pui-Sze , Chang Geen-Dong , Pao Yu-Hsuan , Lo Hsiao-Fan , Peng Chao-Hsiang , Cheong Mei-Leng , Chen Hungwen
Published: March 2022

The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.
Intratumoral in vivo staging of breast cancer by multi-tracer PET and advanced analysis
Authors: Griessinger Jennifer , Schwab Julian , Chen Qian , Kühn Anna , Cotton Jonathan , Bowden Gregory , Preibsch Heike , Reischl Gerald , Quintanilla-Martinez Leticia , Mori Hidetoshi , Dang An Nguyen , Kohlhofer Ursula , Aina Olulanu H. , Borowsky Alexander D. , Pichler Bernd J. , Cardiff Robert D. , Schmid Andreas M.
Published: March 2022

The staging and local management of breast cancer involves the evaluation of the extent and completeness of excision of both the invasive carcinoma component and also the intraductal component or ductal carcinoma in situ. When both invasive ductal carcinoma and coincident ductal carcinoma in situ are present, assessment of the extent and localization of both components is required for optimal therapeutic planning. We have used a mouse model of breast cancer to evaluate the feasibility of applying molecular imaging to assess the local status of cancers in vivo. Multi-tracer positron emission tomography (PET) and magnetic resonance imaging (MRI) characterize the transition from premalignancy to invasive carcinoma. PET tracers for glucose consumption, membrane synthesis, and neoangiogenesis in combination with a Gaussian mixture model-based analysis reveal image-derived thresholds to separate the different stages within the whole-lesion. Autoradiography, histology, and quantitative image analysis of immunohistochemistry further corroborate our in vivo findings. Finally, clinical data further support our conclusions and demonstrate translational potential. In summary, this preclinical model provides a platform for characterizing multistep tumor progression and provides proof of concept that supports the utilization of advanced protocols for PET/MRI in clinical breast cancer imaging.
Sticky-MARTINI as a reactive coarse-grained model for molecular dynamics simulations of silica polymerization
Authors: Carvalho André P. , Santos Sérgio M. , Pérez-Sánchez Germán , Gouveia José D. , Gomes José R. B. , Jorge Miguel
Published: March 2022

We report a molecular modeling paradigm to describe silica polymerization reactions in aqueous solutions at conditions that are representative of realistic experimental processes like biosilicification or porous silica synthesis – i.e. at close to ambient temperatures and over a wide range of pH. The key point is to describe the Si-O-Si chemical bond formation and breakage processes through a continuous potential with a balance between attractive and repulsive interactions between suitably placed virtual sites and sticky particles. The simplicity of the model, its applicability in standard parallelized molecular dynamics codes, and its compatibility with the widely used MARTINI coarse-grained force-field allows for the study of systems containing millions of atoms over microsecond time scales. The model is calibrated to match experimental results for the temporal evolution of silica polymerization in aqueous solution close to the isoelectric point, and can describe silica polymerization and self-assembly processes during encapsulation of a surfactant micelle.