bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical considerations during cochlear implantation: the utility of temporal bone computed tomography
Authors: Jun Beomcho , Song Sunwha
Published: February 2021

Objective

This paper describes the construction of portals for electrode placement during cochlear implantation and emphasises the utility of pre-operative temporal bone three-dimensional computed tomography.

Methods

Temporal bone three-dimensional computed tomography was used to plan portal creation for electrode insertion.

Results

Pre-operative temporal bone three-dimensional computed tomography can be used to determine the orientation of temporal bone structures, which is important for mastoidectomy, posterior tympanotomy and cochleostomy, and when using the round window approach.

Conclusion

It is essential to create appropriate portals (from the mastoid cortex to the cochlea) in a step-by-step manner, to ensure the safe insertion of electrodes into the scala tympani. Pre-operative three-dimensional temporal bone computed tomography is invaluable in this respect.
Development of Hybrid Prandtl–Ishlinskii and Constitutive Models for Hysteresis of Shape-Memory-Alloy-Driven Actuators
Authors: Shakiba Saeid , Ayati Moosa , Yousefi-Koma Aghil
Published: February 2021

Prandtl–Ishlinskii (PI) model has an excellent compromise to characterize an asymmetric saturated hysteresis behavior of shape-memory-alloy (SMA)-driven systems, but it cannot consider thermomechanical relations between components of SMA-driven systems. On the other hand, constitutive models are composed of these relations, but their precision needs to be improved. In this paper, PI model is proposed to boost constitutive models in two cases. In the first case, PI model is used to characterize martensite volume fraction (MVF) called hybrid model. In the second case, the model is applied as a regulator in the output of a constitutive model called PI-based output (PIO) regulator. Due to simplicity and ability of Liang–Rogers (LR) model in transformation phases, it is considered as an MVF in the original constitutive model. The performance of both proposed models is compared with the original LR-based constitutive model. Unknown parameters of all three models are identified using genetic algorithm in MATLAB Toolbox. The performance of the three models is investigated at three different frequencies of

\[\frac{{2\pi }}{8}\]

,

\[\frac{{2\pi }}{{15}}\]

, and

\[\frac{{2\pi }}{{30}}\]

Hz because the excitation frequency changes the hysteresis behavior. Results show that the proposed hybrid model keeps the precision of the original constitutive model at different frequencies. In addition, the proposed PIO model shows the best performance to predict hysteresis behavior at different frequencies.
ITERATIONS OF DEPENDENT RANDOM MAPS AND EXOGENEITY IN NONLINEAR DYNAMICS
Authors: Debaly Zinsou Max , Truquet Lionel
Published: February 2021

We discuss the existence and uniqueness of stationary and ergodic nonlinear autoregressive processes when exogenous regressors are incorporated into the dynamic. To this end, we consider the convergence of the backward iterations of dependent random maps. In particular, we give a new result when the classical condition of contraction on average is replaced with a contraction in conditional expectation. Under some conditions, we also discuss the dependence properties of these processes using the functional dependence measure of Wu (2005, Proceedings of the National Academy of Sciences 102, 14150–14154) that delivers a central limit theorem giving a wide range of applications. Our results are illustrated with conditional heteroscedastic autoregressive nonlinear models, Generalized AutoRegressive Conditional Heteroskedasticity (GARCH) processes, count time series, binary choice models, and categorical time series for which we provide many extensions of existing results.
Productivity and the acquisition of gender
Authors: BJÖRNSDÓTTIR Sigríður Mjöll
Published: February 2021

Children's differing learning trajectories cross-linguistically have been at the forefront of gender acquisition research, often with conflicting results and conclusions. As a result, the source of children's different learning behaviors in gender acquisition has been unclear. I argue that children's gender acquisition is driven by the search for productive patterns. First, I provide corpus studies where the predictions of a learning model (Yang, 2016) are formulated. Second, I report the results of an elicited production task on Icelandic-speaking children (N = 26, ages 2;6-6;3 years) and adults (N = 18) that puts these predictions to test. The results suggest that Icelandic-speaking children and adults draw a categorical distinction between productive and unproductive suffixes in Icelandic gender assignment. I discuss the implications of these findings for morphological learning beyond gender acquisition.
INVERSE OF FREQUENTLY HYPERCYCLIC OPERATORS
Authors: Menet Quentin
Published: February 2021

We show that there exists an invertible frequently hypercyclic operator on
$\ell ^1(\mathbb {N})$
whose inverse is not frequently hypercyclic.
Indigenous peoples' displacement and jaguar survival in a warming planet
Authors: Craighead Kimberly A. , Yacelga Milton
Published: February 2021

Non-technical summary

Climate change threatens tropical forests, ecosystem services, and indigenous peoples. The effects of climate change will force the San Blas Island communities of the indigenous Guna people to relocate to one of the most extensive, intact forests in Panama. In this paper, we argue that the impacts of climate change, and the proposed resettlement, will synergistically affect the jaguar. As apex predators, jaguars are sensitive to landscape change and require intact forests with ample prey to survive. Proactively planning for the intrinsically related issues of climate change, human displacement, and jaguar conservation is a complex but essential management task.

Technical summary

Tropical rainforest, coastal, and island communities are on the front line of increasing temperatures and sea-level rise associated with climate change. Future impacts on the interconnectedness of biological and cultural diversity (biocultural heritage) remain unknown. We review the interplay between the impacts of climate change and the displacement of the indigenous Guna people from the San Blas Islands, the relocation back to their mainland territory, and the implications for jaguar persistence. We highlight one of the most significant challenges to using resettlement as an adaptive strategy to climate change, securing a location where the Guna livelihoods, traditions, and culture may continue without significant change while protecting ecosystem services (e.g. biodiversity, carbon sequestration, and water). We posit that developing management plans that strive to meet social needs without sacrificing environmental principles will meet these objectives.

Social media summary

A biocultural approach increases adaptive capacity for ecological and human social systems threatened by climate change.
Behandlung schwer verkalkter Koronarläsionen
Authors: Patrascu Alexandru , Cieslik Maciej , Templin Christian
Published: February 2021

Zusammenfassung. In der Schweiz und anderen Industrienationen ist die koronare Herzkrankheit (KHK) die häufigste Todesursache im Erwachsenenalter. Die KHK ist eine chronische Erkrankung bei der meistens Stenosen der epikardialen Herzkranzgefässe eine Mangeldurchblutung des Herzmuskelgewebes verursachen, wodurch es zu Angina Pectoris-Beschwerden, Herzinfarkt, Herzinsuffizienz oder Herzrhythmusstörungen und schliesslich zu einer erheblichen Morbidität und Mortalität kommen kann. Seit der ersten perkutanen Koronarintervention (PCI) am 16. September 1977 am Universitätsspital Zürich durch Andreas Grüntzig hat die interventionelle Kardiologie bemerkenswerte Fortschritte bei der Behandlung der KHK erlebt, insbesondere mit der Einführung und Weiterentwicklung von Koronarstents. Nichtsdestotrotz stellen verkalkte Koronarstenosen eine Herausforderung im interventionellen Alltag dar, da sie die Stentimplantation oder dessen korrekte -expansion verhindern oder mit einer höheren Komplikationsrate vergesellschaftet sind. Bis heute gibt es leider keine etablierten Verfahren zur Verhinderung der Kalkbildung in den Herzkranzgefässen. Es gibt jedoch einige Therapieansätze, die eine PCI in verkalkten Gefässen ermöglichen, und diese stehen im Mittelpunkt dieser Arbeit.
Bioresorbierbare vaskuläre Scaffolds
Authors: Gänsbacher Julia , Lutz Matthias
Published: February 2021

Zusammenfassung. Das Prinzip der bioresorbierbaren vaskulären Scaffolds ist ein guter Ansatz zur Lösung der residuellen Problematik der perkutanen Koronar-Interventionen, die trotz Einführung und immensen Weiterentwicklungen der Metall-Stents eine kontinuierliche Zunahme von unerwünschten Ereignissen über die Jahre hinweg aufweisen. Als Vorteil können die bioresorbierbaren vaskulären Scaffolds zum einen die Wiederherstellung der physiologischen Gefässeigenschaften gewährleisten; zum anderen fehlt – nach der Resorption – im Unterschied zu permanenten Metall-Implantaten, die Ursache für die Entstehung von In-Stent-Re-Stenosen oder späten Stent-Thrombosen, welche noch immer die grösste Limitation der Metall-Stents darstellen [1]. Zwar konnte der erste richtige Vertreter der bioresorbierbaren vaskulären Scaffolds (Absorb) nach anfänglich guten Ergebnissen, diese im weiteren Verlauf seiner Anwendung nicht bestätigen, sodass er vom Markt genommen wurde. Allerdings konnten aus den Fehler-Analysen wichtige Erkenntnisse gewonnen werden, die die Weiterentwicklung der aktuell zugelassenen Scaffolds beeinflusst haben, sodass inzwischen Scaffolds auf dem Markt sind, die eine mit Metall-Stents vergleichbare Strebendicke aufweisen und dabei gute Studienergebnisse hervorbringen. Auch wenn die Anzahl der behandelten Patienten und die Studien-Qualität noch nicht ausreichen, um die aktuellen europäischen Leitlinien zu ändern, die aktuell nur auf den Absorb-Daten beruhen, so zeigt sich doch eine erfolgsversprechende Datenlage im Vergleich zu 2018, als die Leitlinien verfasst wurden. Die erfolgsversprechenden Studienergebnisse bei der Behandlung von infrapoplitealen Stenosen und die Bereitschaft der Hersteller, an weiteren Produktgenerationen zu arbeiten, zeigen, dass die Therapie mittels bioresorbierbaren vaskulären Scaffolds noch lange nicht am Ende steht, sondern – nach einem holprigen Beginn – sich jetzt am Anfang einer Renaissance befindet.
Wie erleben und beurteilen Pflegende das Screening von stationären onkologischen Patient_innen mit dem Belastungsthermometer?
Authors: Götz Anna , Kröner Anja , Jenewein Josef , Spirig Rebecca
Published: February 2021

Zusammenfassung. Hintergrund: Krebserkrankte Menschen können psychosozial so belastet sein, dass sie Unterstützung benötigen. Seit 2012 sollen Pflegefachpersonen (PFP) im Universitätsspital Zürich alle eintretende Krebspatienten mit Hilfe des Belastungsthermometers (BT) screenen, um den Unterstützungsbedarf zu erkennen. Nach fünf Jahren war die Screeningrate mit 40 % sowie die Rate der psychoonkologischen Konsile mit 7,9 % wider Erwarten niedrig. Ziel: Das Ziel dieser qualitativen Studie bestand darin, zu beschreiben, wie PFP das Screening mit dem BT erlebten und wie sie die geringe Screening- bzw. Überweisungsrate interpretierten. Dies sollte ein besseres Verständnis der Einflussfaktoren ermöglichen. Methode: Die Auswertung von drei Fokusgruppeninterviews mit 14 PFP erfolgte mithilfe der qualitativen Inhaltsanalyse nach Mayring. Ergebnisse: Die Analyse ergab vier Hauptkategorien. „Der Versuch, das nützliche Screening im komplexen Alltag anzuwenden “ steht im Mittelpunkt. Die drei Unterkategorien lauten: „Das hilfreiche Screening für eine ganzheitliche Pflege nutzen“, „Der beste Weg, die Individualität des Gegenübers zu erfassen“ und „An strukturellen und menschlichen Hindernissen scheitern“. Drei weitere Hauptkategorien zur persönlichen Haltung der PFP ergänzen das Screeningerleben: „Weniger Schwierigkeiten durch Kompetenz und Erfahrung erleben“, „Aufgrund von Hemmschwellen vorsichtig sein“ und „Die eigene Zuständigkeit hinterfragen“. Schlussfolgerungen: Die PFP möchten das BT nutzen. Sie benötigen jedoch praktische und wissenschaftliche Unterstützung, um es gewinnbringend in den Alltag zu integrieren.
Seasonal and Geographical Variability of the Martian Ionosphere From Mars Express Observations
Authors: González‐Galindo F. , Eusebio D. , Němec F. , Peter K. , Kopf A. , Tellmann S. , Paetzold M.
Published: February 2021

We study the seasonal and geographical variability of the peak electron density and the altitude of the main ionospheric peak at Mars. For this purpose, we use the data obtained by the ESA Mars Express mission, namely by the radar MARSIS and the radio occultation experiment MaRS. The accumulation of data during the long lifetime of Mars Express provides for the first time an almost complete seasonal and geographical coverage. We first remove the dominant variability factors affecting the main ionospheric peak, namely the effect of changes in the solar zenith angle (SZA), and the changes in the solar ultraviolet radiation output at the Sun. When averaging results obtained at all latitudes, we find that the seasonal variation of both the peak density and the peak altitude can be well reproduced by sinusoidal functions with amplitudes about 8%–9% of the annually averaged peak density, and between 8 and 9.5 km for the peak altitude. We also find elevated peak electron densities in the region of strong crustal fields and latitudinal asymmetries in both the peak density and altitude. Comparing the seasonal evolution of the peak altitude during Mars Year 28, a year with a global dust storm, and the rest of the years, we find that the global dust storm raised the altitude of the ionospheric peak by about 10–15 km.
Geological Factors Impacted Cadmium Availability and use as an Alternative Cofactor for Zinc in the Carbon Fixation Pathways of Marine Diatoms
Authors: Srivastava Naman , Spielman Stephanie J. , Morrison Shaunna M. , Moore Eli K.
Published: February 2021

Transition metal cofactors are crucial for many biological processes. Despite being primarily considered to be toxic, the transition metal cadmium (Cd) was discovered to be a substitute cofactor for zinc (Zn) in photosynthetic carbon fixation pathways of marine diatoms. However, it is not known how conditions in the geosphere impacted Cd availability and its incorporation as an alternative metal cofactor for phytoplankton. We employed mineral chemistry network analysis to investigate which geochemical factors may have influenced the availability of Cd and Zn during the putative time period that the alternative Cd‐based pathway evolved. Our results show that Zn minerals are more chemically diverse than are Cd minerals, but Zn‐ and Cd‐containing minerals have similar network centrality values when specifically considering sulfur (S)‐containing species. Cadmium and Zn sulfides are the most common Cd‐ and Zn‐containing mineral species over the past 500 million years. In particular, the Cd and Zn sulfides, respectively greenockite and sphalerite, were highly abundant during this time period. Furthermore, S‐containing Cd and Zn minerals are commonly co‐located in geologic time, allowing them to be weathered and transported to the ocean in tandem, rather than from separate sources. We suggest that the simultaneous weathering of Cd and Zn sulfides allowed for Cd to be a bioavailable direct substitute for Zn in protein complexes during periods of Zn depletion. The biogeochemical cycles of Zn and Cd exemplify the importance of the coevolution of the geosphere and biosphere in shaping primary production in the modern ocean.
Designing With Information Feedbacks: Forecast Informed Reservoir Sizing and Operation
Authors: Bertoni F. , Giuliani M. , Castelletti A. , Reed P. M.
Published: February 2021

The value of streamflow forecasts to inform water infrastructure operations has been extensively studied. Yet, their value in informing infrastructure design is still unexplored. In this work, we investigate how dam design is shaped by information feedbacks supporting the implementation of flexible operating policies informed by streamflow forecasts to enable the design of less costly reservoirs relative to alternatives that do not rely on forecast information. Our approach initially explores the maximum potential gain attainable by searching and using the most valuable forecast information and lead time. We then analyze the results? sensitivities relative to existing and synthetic biased forecasts. We demonstrate our approach through an ex post analysis of the Kariba Dam in the Zambezi River Basin. Results show that informing dam design with perfect forecasts enables attaining the same hydropower production of the existing dam, while reducing infrastructure size and associated capital costs by 20%. A forecast‐informed operation of the existing system can instead facilitate an annual average increase of 60 GWh in hydropower production. This finding, extrapolated to the new planned dams in the basin, suggests that forecast informed policies could yield power production benefits equal to 75% of the current annual electricity consumption of the Zambian agricultural sector. The use of biased forecasts substantially reduces this gain, showing that the ESP forecasts value is marginal and that informed infrastructure designs are particularly vulnerable to forecast overestimation. Advancing information feedbacks may therefore become a valuable asset for the ongoing hydropower expansion in the basin.
Antarctic Lava Yields Clues to Earth’s Past Magnetic Field
Authors: Stanley Sarah
Published: February 2021

A new analysis suggests that a widely accepted approximation of ancient magnetic field strength may be less accurate for the past 5 million years than previously thought.
LncRNA SNHG1 and RNA binding protein hnRNPL form a complex and coregulate CDH1 to boost the growth and metastasis of prostate cancer
Authors: Tan Xiao , Chen Wen-bin , Lv Dao-jun , Yang Tao-wei , Wu Kai-hui , Zou Li-bin , Luo Junqi , Zhou Xu-min , Liu Guo-chang , Shu Fang-peng , Mao Xiang-ming
Published: February 2021

The interaction between LncRNA and RNA-binding protein (RBPs) plays an essential role in the regulation over the malignant progression of tumors. Previous studies on the mechanism of SNHG1, an emerging lncRNA, have primarily focused on the competing endogenous RNA (ceRNA) mechanism. Nevertheless, the underlying mechanism between SNHG1 and RBPs in tumors remains to be explored, especially in prostate cancer (PCa). SNHG1 expression profiles in PCa were determined through the analysis of TCGA data and tissue microarray at the RNA level. Gain- and loss-of-function experiments were performed to investigate the biological role of SNHG1 in PCa initiation and progression. RNA-seq, immunoblotting, RNA pull-down and RNA immunoprecipitation analyses were utilized to clarify potential pathways with which SNHG1 might be involved. Finally, rescue experiments were carried out to further confirm this mechanism. We found that SNHG1 was dominantly expressed in the nuclei of PCa cells and significantly upregulated in PCa patients. The higher expression level of SNHG1 was dramatically correlated with tumor metastasis and patient survival. Functionally, overexpression of SNHG1 in PCa cells induced epithelial–mesenchymal transition (EMT), accompanied by down-regulation of the epithelial marker, E-cadherin, and up-regulation of the mesenchymal marker, vimentin. Increased proliferation and migration, as well as accelerated xenograft tumor growth, were observed in SNHG1-overexpressing PCa cells, while opposite effects were achieved in SNHG1-silenced cells. Mechanistically, SNHG1 competitively interacted with hnRNPL to impair the translation of protein E-cadherin, thus activating the effect of SNHG1 on the EMT pathway, eventually promoting the metastasis of PCa. Our findings demonstrate that SNHG1 is a positive regulator of EMT activation through the SNHG1-hnRNPL-CDH1 axis. SNHG1 may serve as a novel potential therapeutic target for PCa.
LncRNA LTSCCAT promotes tongue squamous cell carcinoma metastasis via targeting the miR-103a-2-5p/SMYD3/TWIST1 axis
Authors: Liu Mo , Liu Qingwen , Fan Song , Su Feng , Jiang Chun , Cai Guanming , Wang Youyuan , Liao Guiqing , Lei Xinyuan , Chen Weixiong , Bi Junming , Cheng Weiqi , Zhao LuoDan , Ruan Yi , Li Jinsong
Published: February 2021

Abnormal expression of long-noncoding RNA is involved in the tumorigenesis and progression of various cancers, but the potential molecular regulatory mechanisms are unclear. Microbial flora and chronic inflammation, such as periodontitis, which is associated with oral cancer, affect the occurrence and progression of tumors. Accordingly, we stimulated the tongue squamous cell carcinoma (TSCC) cell lines CAL27 and SCC15 with a low concentration of lipopolysaccharide (LPS) from Porphyromonas gingivalis (P.g) for 6 days and then performed LncRNA sequencing on P.g-LPS-treated CAL27 cells and untreated CAL27 cells. LTSCCAT was upregulated in P.g-LPS-treated CAL27 cells compared with untreated CAL27 cells. LTSCCAT induced epithelial–mesenchymal transition and promoted the invasion and metastasis of TSCC in vitro and in vivo. LncRNA LTSCCAT was upregulated in TSCC patients with periodontitis and was correlated with metastasis and poor prognosis. We predicted through an online database and confirmed by dual-luciferase reporter assays that LTSCCAT is a competitive endogenous RNA for the regulation of miR-103a-2-5p. Another dual-luciferase reporter assay confirmed that miR-103a-2-5p has a binding site at the 3′-UTR of the histone methylation transferase SMYD3 and inhibits its translation. Chromatin immunoprecipitation experiments demonstrated that SMYD3 binds directly to the promoter region of TWIST1 and promotes its transcription, which is related to H3K4 trimethylation. The effect of pcDNA/LTSCCAT on expression was attenuated by miR-103a-2-5p mimics. The RF and SVM classifier predicts that LTSCCAT can bind to SMYD3, whereas the RNA immunoprecipitation (RIP) assay confirms that it cannot. In addition, we predicted the combination of LTSCCAT and SMYD3 through software, but the RIP assay confirmed that LTSCCAT could not be combined with SMYD3. For the first time, we showed that periodontitis promotes the invasion and metastasis of TSCC and clarified the molecular mechanism of LTSCCAT to promote invasion and metastasis of TSCC, providing a potential therapeutic target for clinical treatment of TSCC.
HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target
Authors: Cheng Chun , Yang Jun , Li Si-Wei , Huang Guofu , Li Chenxi , Min Wei-Ping , Sang Yi
Published: February 2021

Histone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.
CircRILPL1 promotes muscle proliferation and differentiation via binding miR-145 to activate IGF1R/PI3K/AKT pathway
Authors: Shen Xuemei , Tang Jia , Jiang Rui , Wang Xiaogang , Yang Zhaoxin , Huang Yongzhen , Lan Xianyong , Lei Chuzhao , Chen Hong
Published: February 2021

Many novel non-coding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), are involved in various physiological and pathological processes. The PI3K/AKT signaling pathway is important for its role in regulating skeletal muscle development. In this study, molecular and biochemical assays were used to confirm the role of miRNA-145 (miR-145) in myoblast proliferation and apoptosis. Based on sequencing data and bioinformatics analysis, we identified a new circRILPL1, which acts as a sponge for miR-145. The interactions between circRILPL1 and miR-145 were examined by bioinformatics, a luciferase assay, and RNA immunoprecipitation. Mechanistically, knockdown or exogenous expression of circRILPL1 in the primary myoblasts was performed to prove the functional significance of circRILPL1. We investigated the inhibitory effect of miR-145 on myoblast proliferation by targeting IGF1R to regulate the PI3K/AKT signaling pathway. A novel circRILPL1 was identified that could sponge miR-145 and is related to AKT activation. In addition, circRILPL1 was positively correlated with muscle proliferation and differentiation in vitro and could inhibit cell apoptosis. The newly identified circRILPL1 functions as a miR-145 sponge to regulate the IGF1R gene and rescue the inhibitory effect of miR-145 on the PI3K/AKT signaling pathway, thereby promoting myoblast growth.
Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer
Authors: Klemke Luisa , De Oliveira Tiago , Witt Daria , Winkler Nadine , Bohnenberger Hanibal , Bucala Richard , Conradi Lena-Christin , Schulz-Heddergott Ramona
Published: February 2021

Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.
Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation
Authors: Xia Weiwei , Li Yuanyuan , Wu Mengying , Jin Qianqian , Wang Qian , Li Shuzhen , Huang Songming , Zhang Aihua , Zhang Yue , Jia Zhanjun
Published: February 2021

Pyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.
A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3
Authors: Chen Zhefan Stephen , Huang Xiaoying , Talbot Kevin , Chan Ho Yin Edwin
Published: February 2021

Polyglutamine (polyQ) diseases comprise Huntington’s disease and several subtypes of spinocerebellar ataxia, including spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded polyQ domain-containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin–proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. In this study, we identified an E3 ligase, pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded ataxin-3 (ATXN3-polyQ), disease protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated protein ubiquitination pathway in SCA3 pathogenesis.
AAV1.NT-3 gene therapy for X-linked Charcot–Marie–Tooth neuropathy type 1
Authors: Ozes Burcak , Myers Morgan , Moss Kyle , Mckinney Jennifer , Ridgley Alicia , Chen Lei , Bai Shasha , Abrams Charles K. , Freidin Mona M. , Mendell Jerry R. , Sahenk Zarife
Published: February 2021

X-linked Charcot-Marie-Tooth neuropathy (CMTX) is caused by mutations in the gene encoding Gap Junction Protein Beta-1 (GJB1)/Connexin32 (Cx32) in Schwann cells. Neurotrophin-3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. Improvements in these parameters have been shown previously in a CMT1 model, TremblerJ mouse, with NT-3 gene transfer therapy. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 3-month-old Cx32 knockout (KO) mice. Measurable levels of NT-3 were found in the serum at 6-month post gene delivery. The outcome measures included functional, electrophysiological and histological assessments. At 9-months of age, NT-3 treated mice showed no functional decline with normalized compound muscle action potential amplitudes. Myelin thickness and nerve conduction velocity significantly improved compared with untreated cohort. A normalization toward age-matched wildtype histopathological parameters included increased number of Schmidt-Lanterman incisures, and muscle fiber diameter. Collectively, these findings suggest a translational application to CMTX1.
Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm)
Authors: Runcharoen Chakkaphan , Fukunaga Koya , Sensorn Insee , Iemwimangsa Nareenart , Klumsathian Sommon , Tong Hang , Vo Nam Sy , Le Ly , Hlaing Tin Maung , Thant Myo , Zain Shamsul Mohd , Mohamed Zahurin , Pung Yuh-Fen , Capule Francis , Nevado Jose , Silao Catherine Lynn , Al-Mahayri Zeina N. , Ali Bassam R. , Yuliwulandari Rika , Prayuni Kinasih , Zahroh Hilyatuz , Noor Dzul Azri Mohamed , Xangsayarath Phonepadith , Xayavong Dalouny , Kounnavong Sengchanh , Sayasone Somphou , Kordou Zoe , Liopetas Ioannis , Tsikrika Athina , Tsermpini Evangelia-Eirini , Koromina Maria , Mitropoulou Christina , Patrinos George P. , Kesornsit Aumpika , Charoenyingwattana Angkana , Wattanapokayakit Sukanya , Mahasirimongkol Surakameth , Mushiroda Taisei , Chantratita Wasun
Published: February 2021

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.
Filopodia-based contact stimulation of cell migration drives tissue morphogenesis
Authors: Bischoff Maik C. , Lieb Sebastian , Renkawitz-Pohl Renate , Bogdan Sven
Published: February 2021

Cells migrate collectively to form tissues and organs during morphogenesis. Contact inhibition of locomotion (CIL) drives collective migration by inhibiting lamellipodial protrusions at cell–cell contacts and promoting polarization at the leading edge. Here, we report a CIL-related collective cell behavior of myotubes that lack lamellipodial protrusions, but instead use filopodia to move as a cohesive cluster in a formin-dependent manner. We perform genetic, pharmacological and mechanical perturbation analyses to reveal the essential roles of Rac2, Cdc42 and Rho1 in myotube migration. These factors differentially control protrusion dynamics and cell–matrix adhesion formation. We also show that active Rho1 GTPase localizes at retracting free edge filopodia and that Rok-dependent actomyosin contractility does not mediate a contraction of protrusions at cell–cell contacts, but likely plays an important role in the constriction of supracellular actin cables. Based on these findings, we propose that contact-dependent asymmetry of cell–matrix adhesion drives directional movement, whereas contractile actin cables contribute to the integrity of the migrating cell cluster.
Mechanism of pore opening in the calcium-activated chloride channel TMEM16A
Authors: Lam Andy K. M. , Dutzler Raimund
Published: February 2021

The anion channel TMEM16A is activated by intracellular Ca2+ in a highly cooperative process. By combining electrophysiology and autocorrelation analysis, we investigated the mechanism of channel activation and the concurrent rearrangement of the gate in the narrow part of the pore. Features in the fluctuation characteristics of steady-state current indicate the sampling of intermediate conformations that are successively occupied during gating. The initial step is related to conformational changes induced by Ca2+ binding, which is ensued by rearrangements that open the pore. Mutations in the gate shift the equilibrium of transitions in a manner consistent with a progressive destabilization of this region during pore opening. We come up with a mechanism of channel activation where the binding of Ca2+ induces conformational changes in the protein that, in a sequential manner, propagate from the binding site and couple to the gate in the narrow pore to allow ion permeation.
Recognition of non-CpG repeats in Alu and ribosomal RNAs by the Z-RNA binding domain of ADAR1 induces A-Z junctions
Authors: Nichols Parker J. , Bevers Shaun , Henen Morkos , Kieft Jeffrey S. , Vicens Quentin , Vögeli Beat
Published: February 2021

Adenosine-to-inosine (A-to-I) editing of eukaryotic cellular RNAs is essential for protection against auto-immune disorders. Editing is carried out by ADAR1, whose innate immune response-specific cytoplasmic isoform possesses a Z-DNA binding domain (Zα) of unknown function. Zα also binds to CpG repeats in RNA, which are a hallmark of Z-RNA formation. Unexpectedly, Zα has been predicted — and in some cases even shown — to bind to specific regions within mRNA and rRNA devoid of such repeats. Here, we use NMR, circular dichroism, and other biophysical approaches to demonstrate and characterize the binding of Zα to mRNA and rRNA fragments. Our results reveal a broad range of RNA sequences that bind to Zα and adopt Z-RNA conformations. Binding is accompanied by destabilization of neighboring A-form regions which is similar in character to what has been observed for B-Z-DNA junctions. The binding of Zα to non-CpG sequences is specific, cooperative and occurs with an affinity in the low micromolar range. This work allows us to propose a model for how Zα could influence the RNA binding specificity of ADAR1.
Probiotics as a treatment for prenatal maternal anxiety and depression: a double-blind randomized pilot trial
Authors: Browne Pamela D. , Bolte Antoinette C. , Besseling-van der Vaart Isolde , Claassen Eric , de Weerth Carolina
Published: February 2021

Probiotic use may be an efficacious treatment option to effectively manage symptoms of prenatal maternal anxiety and depression. Our primary aim was to test feasibility and acceptability for a probiotic randomized controlled trial (RCT) in pregnant women with pre-existing symptoms. This double-blind pilot RCT included 40 pregnant women with low-risk pregnancies and elevated depressive symptoms and/or anxiety. Once daily, participants orally consumed a probiotic (Ecologic Barrier) or a placebo, from 26 to 30 weeks gestation until delivery. A priori key progression criteria for primary outcomes were determined to decide whether or not a full RCT was feasible and acceptable. Secondary outcomes included depressive symptoms, anxiety, stress, and maternal bonding to offspring. In 19 months, 1573 women were screened; following screening, 155 women (10%) were invited for participation, of whom 135 (87%) received study information, and 40 women (30%) were included. Four out of six a priori determined criteria for success on feasibility and acceptability were met. After 8 weeks of intervention, there was no significant difference between the probiotic and placebo groups for secondary outcomes. The pilot trial was feasible and acceptable, but hampered by recruitment method and study design. Secondary endpoints did not reveal differences between the groups for improving maternal mood.
Surface slicks are pelagic nurseries for diverse ocean fauna
Authors: Whitney Jonathan L. , Gove Jamison M. , McManus Margaret A. , Smith Katharine A. , Lecky Joey , Neubauer Philipp , Phipps Jana E. , Contreras Emily A. , Kobayashi Donald R. , Asner Gregory P.
Published: February 2021

Most marine animals have a pelagic larval phase that develops in the coastal or open ocean. The fate of larvae has profound effects on replenishment of marine populations that are critical for human and ecosystem health. Larval ecology is expected to be tightly coupled to oceanic features, but for most taxa we know little about the interactions between larvae and the pelagic environment. Here, we provide evidence that surface slicks, a common coastal convergence feature, provide nursery habitat for diverse marine larvae, including > 100 species of commercially and ecologically important fishes. The vast majority of invertebrate and larval fish taxa sampled had mean densities 2–110 times higher in slicks than in ambient water. Combining in-situ surveys with remote sensing, we estimate that slicks contain 39% of neustonic larval fishes, 26% of surface-dwelling zooplankton (prey), and 75% of floating organic debris (shelter) in our 1000 km2 study area in Hawai‘i. Results indicate late-larval fishes actively select slick habitats to capitalize on concentrations of diverse prey and shelter. By providing these survival advantages, surface slicks enhance larval supply and replenishment of adult populations from coral reef, epipelagic, and deep-water ecosystems. Our findings suggest that slicks play a critically important role in enhancing productivity in tropical marine ecosystems.
Impact of domestic travel restrictions on transmission of COVID-19 infection using public transportation network approach
Authors: Murano Yayoi , Ueno Ryo , Shi Shoi , Kawashima Takayuki , Tanoue Yuta , Tanaka Shiori , Nomura Shuhei , Shoji Hiromichi , Shimizu Toshiaki , Nguyen Huy , Miyata Hiroaki , Gilmour Stuart , Yoneoka Daisuke
Published: February 2021

The international spread of COVID-19 infection has attracted global attention, but the impact of local or domestic travel restriction on public transportation network remains unclear. Passenger volume data for the domestic public transportation network in Japan and the time at which the first confirmed COVID-19 case was observed in each prefecture were extracted from public data sources. A survival approach in which a hazard was modeled as a function of the closeness centrality on the network was utilized to estimate the risk of importation of COVID-19 in each prefecture. A total of 46 prefectures with imported cases were identified. Hypothetical scenario analyses indicated that both strategies of locking down the metropolitan areas and restricting domestic airline travel would be equally effective in reducing the risk of importation of COVID-19. While caution is necessary that the data were limited to June 2020 when the pandemic was in its initial stage and that no other virus spreading routes have been considered, domestic travel restrictions were effective to prevent the spread of COVID-19 on public transportation network in Japan. Instead of lockdown that might seriously damage the economy, milder travel restrictions could have the similar impact on controlling the domestic transmission of COVID-19.
Discovery of novel chemical reactions by deep generative recurrent neural network
Authors: Bort William , Baskin Igor I. , Gimadiev Timur , Mukanov Artem , Nugmanov Ramil , Sidorov Pavel , Marcou Gilles , Horvath Dragos , Klimchuk Olga , Madzhidov Timur , Varnek Alexandre
Published: February 2021

The “creativity” of Artificial Intelligence (AI) in terms of generating de novo molecular structures opened a novel paradigm in compound design, weaknesses (stability & feasibility issues of such structures) notwithstanding. Here we show that “creative” AI may be as successfully taught to enumerate novel chemical reactions that are stoichiometrically coherent. Furthermore, when coupled to reaction space cartography, de novo reaction design may be focused on the desired reaction class. A sequence-to-sequence autoencoder with bidirectional Long Short-Term Memory layers was trained on on-purpose developed “SMILES/CGR” strings, encoding reactions of the USPTO database. The autoencoder latent space was visualized on a generative topographic map. Novel latent space points were sampled around a map area populated by Suzuki reactions and decoded to corresponding reactions. These can be critically analyzed by the expert, cleaned of irrelevant functional groups and eventually experimentally attempted, herewith enlarging the synthetic purpose of popular synthetic pathways.
A longitudinal, randomized experimental pilot study to investigate the effects of airborne infrasound on human mental health, cognition, and brain structure
Authors: Ascone L. , Kling C. , Wieczorek J. , Koch C. , Kühn S.
Published: February 2021

Airborne infrasound (IS; emitted by e.g., large machinery, wind farms) is ubiquitous in technologized environments. Health hazards are controversially discussed at present. This study investigated long-term effects of IS on brain (regional grey matter volume; rGMV) and behavior in humans. Specifically engineered infrasonic (6 Hz, 80–90 dB) vs. sham devices were installed in participants’ (N = 38) bedrooms and active for 28 nights. Somatic and psychiatric symptoms, sound-sensitivity, sleep quality, cognitive performance, and structural MRI were assessed pre-post. Null findings emerged for all behavioral variables. Exploratory analyses revealed a trend (p = .083) with individuals exposed to IS reporting more physical weakness at post-test (d = 0.38). Voxel-based morphometry (VBM) revealed no rGMV increases, but there were decreases within clusters in the cerebellum VIIIa (bilateral) and left angular gyrus (BA39) in verum. In conclusion, IS does not affect healthy individuals on a global scale. However, future trials should consider more fine-grained specific effects, combining self-report with physiological assessments, particularly directed at bodily sensations and perception. As no brain-behavior-links could be established, the identified grey matter decline cannot be interpreted in terms of potential harmfulness vs. improvement through IS-exposure. Parameters that may best reflect brain changes as established in the present study include motor function, sensory processing/ bodily- and motor-perceptions, working memory, and higher auditory processing (i.e., language-related tasks), which are hence potential target variables for further research.