bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistent Eastward EEJ Enhancement During the Geomagnetic Storm Recovery Phases
Authors: Li Qiaoling , Zhang Ruilong , Liu Libo , Kuai Jiawei , Yang Na , Zhong Jiahao , Wan Xin , Liu Jing
Published: April 2022

Recent case studies disclosed that sometimes the dayside ionospheric equatorial electric field underwent persistent long‐duration (>4 hr) eastward enhancements during geomagnetic storm recovery phases, rather than anticipated decrease or reversal. However, it is still unknown the occurrence and morphology of the persistent enhancement as well as its impact on the low‐latitude ionospheric plasma distribution. For the first time, we examined the issue with superposed epoch analyses of equatorial electrojet (EEJ) and GNSS total electron content (TEC) responses in the American (49°W) and Indian (78°E) sectors. The occurrence rates of the persistent enhancement during storm recovery phases are more than 30%, with higher occurrence rates in second to fourth days of the recovery phase, equinoxes, and American sector. The corresponding averaged EEJ and TEC responses were disclosed and compared with those storm samples without the persistent enhancement. On the first day of recovery phase, the dayside equatorial ionosphere was dominated by the prevalent westward electric field and causative inhibited equatorial fountain. In contrast, after the first day, the dayside morphologies showed different patterns: (a) for the persistent cases, the large eastward EEJ and TEC enhancement indicated the enhanced eastward electric field at forenoon and causative intensified equatorial fountain. (b) For the storms without the persistent cases, the general westward EEJ and equatorial TEC enhancements were dominated. Our study indicates that dayside eastward enhancement is an important disturbed pattern of equatorial ionospheric electric field during the late recovery phases, and the enhancement generally causes the intensification of equatorial ionization anomaly.
PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission
Authors: Gao Qingtao , Tian Runyi , Han Hailong , Slone Jesse , Wang Caifang , Ke Xiao , Zhang Tongmei , Li Xiangyu , He Yuhong , Liao Panlin , Wang Fang , Chen Ye , Fu Shiqing , Zhang Kexuan , Zeng Fangfang , Yang Yingxuan , Li Zhuo , Tan Jieqiong , Li Jiada , Lu Youming , Huang Taosheng , Hu Zhonghua , Zhang Zhuohua
Published: April 2022

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here thatPink1knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation inPink1KO neurons. Notably, mice harboring a knockin (KI) phosphor-nullDrp1S616Arecapitulate spine immaturity and synaptic abnormality identified inPink1KO mice. Chemical LTP (cLTP) induces Drp1S616phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616Drestores reduced dendritic spine localization of mitochondria inPink1KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.
RNF8 up-regulates AR/ARV7 action to contribute to advanced prostate cancer progression
Authors: Zhou Tingting , Wang Shengli , Song Xiaoyu , Liu Wensu , Dong Fang , Huo Yunlong , Zou Renlong , Wang Chunyu , Zhang Siyi , Liu Wei , Sun Ge , Lin Lin , Zeng Kai , Dong Xiang , Guo Qiqiang , Yi Fei , Wang Zhuo , Li Xiaoman , Jiang Bo , Cao Liu , Zhao Yue
Published: April 2022

Androgen receptor (AR) signaling drives prostate cancer (PC) progression. Androgen deprivation therapy (ADT) is temporally effective, whereas drug resistance inevitably develops. Abnormal expression of AR/ARV7 (the most common AR splicing variant) is critical for endocrine resistance, while the detailed mechanism is still elusive. In this study, bioinformatics and immunohistochemical analyses demonstrate that RNF8 is high expressed in PC and castration-resistant PC (CRPC) samples and the expression of RNF8 is positively correlated with the Gleason score. The high expression of RNF8 in PCs predicts a poor prognosis. These results provide a potential function of RNF8 in PC progression. Furthermore, the mRNA expression of RNF8 is positively correlated with that of AR in PC. Mechanistically, we find that RNF8 upregulates c-Myc-induced AR transcription via altering histone modifications at the c-Myc binding site within the AR gene. RNF8 also acts as a co-activator of AR, promoting the recruitment of AR/ARV7 to the KLK3 (PSA) promoter, where RNF8 modulates histone modifications. These functions of RNF8 are dependent on its E3 ligase activity. RNF8 knockdown further reduces AR transactivation and PSA expression in CRPC cells with enzalutamide treatment. RNF8 depletion restrains cell proliferation and alleviates enzalutamide resistance in CRPC cells. Our findings indicate that RNF8 may be a potential therapeutic target for endocrine resistance in PC.
KDM5B promotes tumorigenesis of Ewing sarcoma via FBXW7/CCNE1 axis
Authors: Chen Binbin , Chen Huimou , Lu Suying , Zhu Xiaoqin , Que Yi , Zhang Yu , Huang Junting , Zhang Li , Zhang Yu , Sun Feifei , Wang Juan , Zhu Jia , Zhen Zijun , Zhang Yizhuo
Published: April 2022

Ewing sarcoma (EwS) is an aggressive tumor that affects children and young adults. Patients with relapsed/refractory diseases have limited treatment options. Targeting the driver fusion oncoproteins of EwS remains a technical problem. Epigenetic mechanisms have been pointed out as key players and alternative therapeutic targets in EwS. Here, we reported that lysine demethylase 5B (KDM5B), a histone demethylase that specifically demethylates tri- and di-methylated H3 Lys-4 (H3K4), was upregulated in EwS and overexpressed KDM5B was correlated with poor outcomes of patients. KDM5B knockdown and KDM5B inhibitor AS-8351 suppressed EwS cell proliferation and induced cell cycle arrest. Bioinformatics analysis revealed that KDM5B mainly influenced the cell cycle pathways in EwS. In mechanistic studies, we found that overexpression of KDM5B resulted in increased CCNE1 protein level, but did not affect the mRNA level of CCNE1. KDM5B upregulation blocked the degradation pathway of CCNE1 by reducing the expression of FBXW7. KDM5B downregulated FBXW7 gene by demethylation of H3K4me3 at promoter region. Moreover, AS-8351 could inhibit tumor growth in nude mice models, indicating the antitumor effect of targeting KDM5B in EwS. Our study uncovered that KDM5B in EwS attenuated FBXW7 transcription and accumulated CCNE1 protein, leading to malignant proliferation of EwS. Epigenetic drug targeting KDM5B could be a potential treatment for EwS.
SIRT1 restoration enhances chondrocyte autophagy in osteoarthritis through PTEN-mediated EGFR ubiquitination
Authors: Lu Qunshan , Liu Peilai , Miao Zhuang , Luo Desu , Li Songlin , Lu Mei
Published: April 2022

The pharmacological interventions aimed at activating pathways inducing chondrocyte autophagy or reversing extracellular matrix degradation may be promising approaches for the management of osteoarthritis (OA). Evidence exists suggesting that sirtuin 1 (SIRT1) is involved in the pathogenesis of OA. The present study aimed to explore the regulatory role and downstream mechanisms of SIRT1 in OA. Bioinformatics predictions identified downstream factors phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) in OA. We validated poorly expressed SIRT1 and EGFR and highly expressed PTEN in cartilage tissues of OA patients. OA was induced in vitro by exposing human primary chondrocytes to IL-1β and in vivo by destabilization of the medial meniscus (DMM) in a mouse model. SIRT1 knockdown was found to augment IL-1β-stimulated inflammation and chondrocyte metabolic imbalance. Knockdown of SIRT1 diminished PTEN acetylation and then enhanced PTEN expression. PTEN inactivation decreased EGFR ubiquitination and promoted EGFR expression by destabilizing the EGFR-Cbl complex, which in turn inhibited extracellular matrix degradation in cartilage tissues and activated chondrocyte autophagy. In the DMM mouse model, knockdown of SIRT1 inhibited chondrocyte autophagy, promoted metabolic imbalance, thus accelerating osteoarthritic process. In conclusion, SIRT1 represses the ubiquitination of EGFR by down-regulating PTEN, inhibits extracellular matrix degradation and activates chondrocyte autophagy, thereby performing an OA-alleviating role.
Rhesus negative males have an enhanced IFNγ-mediated immune response to influenza A virus
Authors: Sugrue Jamie A. , Smith Megan , Posseme Celine , Charbit Bruno ,   Milieu Interieur Consortium, Abel Laurent , Alcover Andres , Aschard Hugues , Bousso Philippe , Bourke Nollaig , Brodin Petter , Bruhns Pierre , Cerf-Bensussan Nadine , Cumano Ana , D’Enfert Christophe , Deriano Ludovic , Dillies Marie-Agnès , Santo James Di , Dromer Françoise , Eberl Gérard , Enninga Jost , Fellay Jacques , Gomperts-Boneca Ivo , Hasan Milena , Hedestam Gunilla Karlsson , Hercberg Serge , Ingersoll Molly A. , Lantz Olivier , Kenny Rose Anne , Ménager Mickaël , Mouquet Hugo , O’Farrelly Cliona , Patin Etienne , Pellegrini Sandra , Rausell Antonio , Rieux-Laucat Frédéric , Rogge Lars , Fontes Magnus , Sakuntabhai Anavaj , Schwartz Olivier , Schwikowski Benno , Shorte Spencer , Tangy Frédéric , Toubert Antoine , Touvier Mathilde , Ungeheuer Marie-Noëlle , Zimmer Christophe , Albert Matthew L. , Duffy Darragh , Quintana-Murci Lluis , Bourke Nollaig M. , Duffy Darragh , O’Farrelly Cliona
Published: April 2022

The Rhesus D antigen (RhD) has been associated with susceptibility to several viral infections. Reports suggest that RhD-negative individuals are better protected against infectious diseases and have overall better health. However, potential mechanisms contributing to these associations have not yet been defined. Here, we used transcriptomic and genomic data from the Milieu Interieur cohort of 1000 healthy individuals to explore the effect of Rhesus status on the immune response. We used the rs590787 SNP in the RHD gene to classify the 1000 donors as either RhD-positive or -negative. Whole blood was stimulated with LPS, polyIC, and the live influenza A virus and the NanoString human immunology panel of 560 genes used to assess donor immune response and to investigate sex-specific effects. Using regression analysis, we observed no significant differences in responses to polyIC or LPS between RhD-positive and -negative individuals. However, upon sex-specific analysis, we observed over 40 differentially expressed genes (DEGs) between RhD-positive (n = 384) and RhD-negative males (n = 75) after influenza virus stimulation. Interestingly these Rhesus-associated differences were not seen in females. Further investigation, using gene set enrichment analysis, revealed enhanced IFNγ signalling in RhD-negative males. This amplified IFNγ signalling axis may explain the increased viral resistance previously described in RhD-negative individuals.
Validation of accelerometry as a digital phenotyping measure of negative symptoms in schizophrenia
Authors: Strauss Gregory P. , Raugh Ian M. , Zhang Luyu , Luther Lauren , Chapman Hannah C. , Allen Daniel N. , Kirkpatrick Brian , Cohen Alex S.
Published: April 2022

Negative symptoms are commonly assessed via clinical rating scales; however, these measures have several inherent limitations that impact validity and utility for their use in clinical trials. Objective digital phenotyping measures that overcome some of these limitations are now available. The current study evaluated the validity of accelerometry (ACL), a passive digital phenotyping method that involves collecting data on the presence, vigor, and variability of movement. Outpatients with schizophrenia (SZ: n = 50) and demographically matched healthy controls (CN: n = 70) had ACL continuously recorded from a smartphone and smartband for 6 days. Active digital phenotyping assessments, including surveys related to activity context, were also collected via 8 daily surveys throughout the 6 day period. SZ participants had lower scores on phone ACL variables reflecting vigor and variability of movement compared to CN. ACL variables demonstrated convergent validity as indicated by significant correlations with active digital phenotyping self-reports of time spent in goal-directed activities and clinical ratings of negative symptoms. The discriminant validity of ACL was demonstrated by low correlations with clinical rating scale measures of positive, disorganized, and total symptoms. Collectively, findings suggest that ACL is a valid objective measure of negative symptoms that may complement traditional approaches to assessing the construct using clinical rating scales.
Study on partial discharge characteristics of C6F12O mixed gas
Authors: Rao Xiajin , Li Dajian , Zhang Xiaoxing , Xia Xiaofei , Su Yi , Lu Yufeng , Peng Boya
Published: April 2022

The greenhouse effect of SF6 increasingly limits its application in various gas insulated equipment. C6F12O combines the advantages of insulation resistance, safety and environmental protection. When mixed with buffer gas, C6F12O is considered to have potential application prospects in medium and low voltage equipment. In this paper, about the partial discharge characteristics of the mixed gas, an experimental study was carried out. The partial discharge initiation voltage and discharge extinction voltage of mixed gas under power frequency voltage are measured and compared with the breakdown voltage. The results show that the breakdown voltage is greatly improved after adding C6F12O, with the increase of mixing ratio, the partial discharge initiation voltage and extinction voltage of mixed gas gradually increase, and the effect of gas pressure on high mixing ratio is obvious. The difference between the partial discharge inception voltage and the breakdown voltage is larger than that of pure N2. The research in this paper can provide an important reference for the application, operation and protection of C6F12O mixed gas in medium and low voltage equipment.
Misfolding-induced chronic pancreatitis in CPA1 N256K mutant mice is unaffected by global deletion of Ddit3/Chop
Authors: Németh Balázs Csaba , Demcsák Alexandra , Geisz Andrea , Sahin-Tóth Miklós
Published: April 2022

Genetic mutations in pancreatic digestive enzymes may cause protein misfolding, endoplasmic reticulum (ER) stress and chronic pancreatitis. The CPA1 N256K mouse model carries the human p.N256K carboxypeptidase A1 (CPA1) mutation, a classic example of a pancreatitis-associated misfolding variant. CPA1 N256K mice develop spontaneous, progressive chronic pancreatitis with moderate acinar atrophy, acinar-to-ductal metaplasia, fibrosis, and macrophage infiltration. Upregulation of the ER-stress associated pro-apoptotic transcription factor Ddit3/Chop mRNA was observed in the pancreas of CPA1 N256K mice suggesting that acinar cell death might be mediated through this mechanism. Here, we crossed the CPA1 N256K strain with mice containing a global deletion of the Ddit3/Chop gene (Ddit3-KO mice) and evaluated the effect of DDIT3/CHOP deficiency on the course of chronic pancreatitis. Surprisingly, CPA1 N256K x Ddit3-KO mice developed chronic pancreatitis with a similar time course and features as the CPA1 N256K parent strain. In contrast, Ddit3-KO mice showed no pancreas pathology. The observations indicate that DDIT3/CHOP plays no significant role in the development of misfolding-induced chronic pancreatitis in CPA1 N256K mice and this transcription factor is not a viable target for therapeutic intervention in this disease.
Feasibility of circulating tumor DNA analysis in dogs with naturally occurring malignant and benign splenic lesions
Authors: Favaro Patricia Filippsen , Stewart Samuel D. , McDonald Bradon R. , Cawley Jacob , Contente-Cuomo Tania , Wong Shukmei , Hendricks William P. D. , Trent Jeffrey M. , Khanna Chand , Murtaza Muhammed
Published: April 2022

Comparative studies of naturally occurring canine cancers have provided new insight into many areas of cancer research. Development and validation of circulating tumor DNA (ctDNA) analysis in pet dogs can help address diagnostic needs in veterinary as well as human oncology. Dogs have high incidence of naturally occurring spontaneous cancers, demonstrate molecular heterogeneity and clonal evolution during therapy, allow serial sampling of blood from the same individuals during the course of disease progression, and have relatively compressed intervals for disease progression amenable to longitudinal studies. Here, we present a feasibility study of ctDNA analysis performed in 48 dogs including healthy dogs and dogs with either benign splenic lesions or malignant splenic tumors (hemangiosarcoma) using shallow whole genome sequencing (sWGS) of cell-free DNA. To enable detection and quantification of ctDNA using sWGS, we adapted two informatic approaches and compared their performance for the canine genome. At the time of initial clinical presentation, mean ctDNA fraction in dogs with malignant splenic tumors was 11.2%, significantly higher than dogs with benign lesions (3.2%; p = 0.001). ctDNA fraction was 14.3% and 9.0% in dogs with metastatic and localized disease, respectively (p = 0.227). In dogs treated with surgical resection of malignant tumors, mean ctDNA fraction decreased from 11.0% prior to resection to 7.9% post-resection (p = 0.047 for comparison of paired samples). Our results demonstrate that ctDNA analysis is feasible in dogs with hemangiosarcoma using a cost-effective approach such as sWGS. Additional studies are needed to validate these findings, and determine the role of ctDNA to assess burden of disease and treatment response in dogs with cancer.
An integrated systems-level model of ochratoxin A toxicity in the zebrafish (Danio rerio) embryo based on NMR metabolic profiling
Authors: Eeza Muhamed N. H. , Bashirova Narmin , Zuberi Zain , Matysik Jörg , Berry John P. , Alia A.
Published: April 2022

Ochratoxin A (OTA) is one of the most widespreadmycotoxincontaminants of agricultural crops. Despite being associated with a range of adverse health effects, a comprehensive systems-level mechanistic understanding of the toxicity of OTA remains elusive. In the present study, metabolic profiling by high-resolution magic angle spinning (HRMAS) NMR, coupled to intact zebrafish embryos, was employed to identify metabolic pathways in relation to a systems-level model of OTA toxicity. Embryotoxicity was observed at sub-micromolar exposure concentrations of OTA. Localization of OTA, based on intrinsic fluorescence, as well as a co-localization of increased reactive oxygen species production, was observed in the liver kidney, brain and intestine of embryos. Moreover, HRMAS NMR showed significant alteration of metabolites related to targeting of the liver (i.e., hepatotoxicity), and pathways associated with detoxification and oxidative stress, and mitochondrial energy metabolism. Based on metabolic profiles, and complementary assays, an integrated model of OTA toxicity is, thus, proposed. Our model suggests that OTA hepatotoxicity compromises detoxification and antioxidant pathways, leading to mitochondrial membrane dysfunction manifested by crosstalk between pathways of energy metabolism. Interestingly, our data additionally aligns with a possible role of mitochondrial fusion as a “passive mechanism” to rescue mitochondrial integrity during OTA toxicity.
Thermo-mechanical properties of 3D printed photocurable shape memory resin for clear aligners
Authors: Lee Se Yeon , Kim Hoon , Kim Hyun-Joong , Chung Chooryung J. , Choi Yoon Jeong , Kim Su-Jung , Cha Jung-Yul
Published: April 2022

To overcome the limitations of the conventional vacuum thermoforming manufacturing method, direct 3D printing of clear aligners has been developed. The present study investigated the thermo-mechanical and viscoelastic properties of a photocurable resin TC-85, which is a new material for the direct 3D printed clear aligners, comparing to a conventional thermoplastic material polyethylene terephthalate glycol. Dynamic mechanical analysis was performed to analyse the mechanical behaviours of the two materials at 37 °C and 80 °C, respectively. Furthermore, the shape memory property of the two materials was evaluated using a U-shape bending test, and the shape recovery ratio for 60 min at 37 °C was calculated. The results indicate that TC-85 can constantly apply a light force to the teeth when used for the 3D printed clear aligners, owing to its flexibility and viscoelastic properties. In addition, it is expected that the force decay induced by repeated insertion of the clear aligners will be reduced and a constant orthodontic force will be maintained. Furthermore, its geometric stability at high temperatures and the shape memory properties provide advantages for the clinical application.
Development of a paper printed colorimetric sensor based on Cu-Curcumin nanoparticles for evolving point-of-care clinical diagnosis of sodium
Authors: Chandran Neeli , Janardhanan Prajit , Bayal Manikanta , Pilankatta Rajendra , Nair Swapna S.
Published: April 2022

The homeostatic control of Sodium (Na+) ion in the human body assumes paramount relevance owing to its physiological importance. Any deviation from the normal level causes serious health problems like hypernatremia, hyponatremia, stroke, kidney problems etc. Therefore, quantification of Na+ levels in body fluids has significant diagnostic and prognostic importance. However, interfering ions like Potassium ion (K+) is the major hurdle in sodium detection. In this work, we synthesized the clusters of 3–9 nm-sized highly stable and pure Copper nanoparticles surface functionalised with curcumin, through chemical reduction method. Each cluster of particles is encapsulated in a curcumin layer which is clearly visible in TEM images. The results show that these curcumin functionalized Cu NPs (CuC) are highly selective to the colorimetric detection of Na+. The ions like K+, Mg2+ and Zn2+ did not interfere with the Na+ in this sensing technique. Low-cost paper-based sensor strips are fabricated and calibrated for the sensing of sodium in the physiological range and shade cards were developed as a calorimetric guide for estimation of Na+ which makes them ideal point of care diagnostic platform. We demonstrate that the proposed CuC paper strip can be used for detecting Na+ concentration within the whole physiological range in both blood serum and urine.
Predictors of drought-induced crop yield/losses in two agroecologies of southern Tigray, Northern Ethiopia
Authors: Eze Emmanuel , Girma Atkilt , Zenebe Amanuel , Okolo Chukwuebuka Christopher , Kourouma Jean Moussa , Negash Emnet
Published: April 2022

The consequences of prolonged precipitation-deficient periods are primarily substantial water deficit. The spatial characteristics of drylands and various socioeconomic factors worsen droughts’ impacts and deepen poverty among agrarian communities, with attendant food security (stability dimension) implications. This study utilizes a combination of climate, remote sensing and field survey data to obtain first-hand information on the impacts of recent (2015 and 2017) droughts on crop yield in southern Tigray, northern Ethiopia. Annual and seasonal rainfall, annual and seasonal Normalized Difference Vegetation Index (NDVI) and Deviation of NDVI (Dev-NDVI), and monthly Standardized Precipitation Index (SPI) (SPI-1, SPI-3 and SPI-12) for June to October, were considered as likely factors that could relate with yield and yield loss in the area. Correlation and multiple linear stepwise regression statistical techniques were used to determine drought-yield relationships, and identify more accurate predictors of yield and yield losses in each of the drought years. The area witnessed a more widespread precipitation deficit in 2015 than in 2017, where the lowland area recorded entire crop (sorghum) losses. Also, droughts manifested spatiotemporal variations and impacts across the two different agroecologies—primarily reduction in vegetation amounts, coinciding with the planting and maturing stages of barley and sorghum. Crop failures, therefore, translated to food shortages and reduced income of smallholder farmers, which denotes food insecurity in the time of droughts. Seasonal rainfall and June Dev-NDVI predicted 66.9% of 2015 barley and sorghum yield-loss, while NDVI predicted 2017 sorghum yield by 96%. Spate irrigation should be further popularized in the low-lying areas of Raya Azebo to augment for future deficiencies in the kiremt rainfall.
A quantitative approach to the spread of variance in translational research using Monte Carlo simulation
Authors: Cukurova Feyza , Gustavson Britta P. , Griborio-Guzman Andres G. , Levin Leonard A.
Published: April 2022

The translation of promising preclinical research into successful trials often fails. One contributing factor is the “Princess and the Pea” problem, which refers to how an initially significant effect size dissipates as research transitions to more complex systems. This work aimed to quantify the effects of spreading variability on sample size requirements. Sample size estimates were performed by Monte Carlo simulation. To simulate the process of progressing from preclinical to clinical studies, nested sigmoidal dose–response transformations with modifiable input parameter variability were used. The results demonstrated that adding variabilty to the dose–response parameters substantially increases sample size requirements compared to standared calculations. Increasing the number of consecutive studies further increases the sample size. These results quantitatively demonstrate how the spread of variability in translational research, which is not typically accounted for, can result in drastic increases in the sample size required to maintain a desired study power.
A retrospective analysis of changes in distant and breast cancer related disease-free survival events in adjuvant breast cancer trials over time
Authors: Wilson Brooke E. , Desnoyers Alexandra , Al-Showbaki Laith , Nadler Michelle B. , Amir Eitan
Published: April 2022

Disease-free survival (DFS) comprises both breast cancer and non-breast cancer events. DFS has not been validated as a surrogate endpoint for overall survival (OS) in most breast cancer subtypes. We assessed changes to the type of events contributing to DFS over time. We identified adjuvant studies in breast cancer (BC) from 2000 to 2020 where the endpoint was DFS. We examined change in distant DFS events and the BC-related DFS using univariable and multivariable linear regression. Data were reported quantitatively using the Burnand criteria irrespective of statistical significance. We included 84 studies (88 cohorts), comprising 212,191 participants, 41,604 DFS events and 23,205 distant DFS events. The DFS event rate/100 participants/year has declined modestly over time (ß − 0.34, p = 0.001). Start year was negatively associated with distant DFS events (ß − 0.58, p < 0.0001); however, the effect was lost after adjusting for follow-up time (ß − 0.18, p = 0.096). The average number of BC-related events/100 participants/year also declined over time (ß − 0.28, p = 0.009). In multivariable analysis, start year and ER expression were quantitatively associated with distant DFS events and BC-related DFS events. DFS events have declined over time driven by a reduction in BC related events. As DFS events are increasingly defined by non-BC events, there will be limited surrogacy between DFS and OS.
ITO film stack engineering for low-loss silicon optical modulators
Authors: Lotkov Evgeniy S. , Baburin Aleksandr S. , Ryzhikov Ilya A. , Sorokina Olga S. , Ivanov Anton I. , Zverev Alexander V. , Ryzhkov Vitaly V. , Bykov Igor V. , Baryshev Alexander V. , Panfilov Yuri V. , Rodionov Ilya A.
Published: April 2022

The Indium Tin Oxide (ITO) platform is one of the promising solutions for state-of-the-art integrated optical modulators towards low-loss silicon photonics applications. One of the key challenges on this way is to optimize ITO-based thin films stacks for electro-optic modulators with both high extinction ratio and low insertion loss. In this paper we demonstrate the e-beam evaporation technology of 20 nm-thick ITO films with low extinction coefficient of 0.14 (Nc = 3.7·1020 cm−3) at 1550 nm wavelength and wide range of carrier concentrations (from 1 to 10 × 1020 cm−3). We investigate ITO films with amorphous, heterogeneously crystalline, homogeneously crystalline with hidden coarse grains and pronounced coarsely crystalline structure to achieve the desired optical and electrical parameters. Here we report the mechanism of oxygen migration in ITO film crystallization based on observed morphological features under low-energy growth conditions. Finally, we experimentally compare the current–voltage and optical characteristics of three electro-optic active elements based on ITO film stacks and reach strong ITO dielectric permittivity variation induced by charge accumulation/depletion (Δn = 0.199, Δk = 0.240 at λ = 1550 nm under ± 16 V). Our simulations and experimental results demonstrate the unique potential to create integrated GHz-range electro-optical modulators with sub-dB losses.
SAR and optical images correlation illuminates post-seismic landslide motion after the Mw 7.8 Gorkha earthquake (Nepal)
Authors: Lacroix Pascal , Gavillon Théo , Bouchant Clément , Lavé Jérôme , Mugnier Jean-Louis , Dhungel Samir , Vernier Flavien
Published: April 2022

In the days to weeks following an earthquake, landslides can display specific post-seismic motions, including delayed initiations and post-seismic relaxations. These motions have an uncertain origin, sometimes attributed to specificities of the landslide basal interface or to fluid transports in the landslide basal shear zone. Here we address this question, by documenting the co- and post-seismic motions of slow-moving landslides accelerated by the Gorkha earthquake (Mw 7.8, 25/04/2015, Nepal). We detect 11 slow-moving landslides over an area of 750 km$$^2$$

2

in the near field of the earthquake, and monitor their motions thanks to a time-series of Pléiades optical satellite images and SAR Sentinel-1 images. The post-seismic landslide motions are much larger than the co-seismic ones, reaching up to $$34 \,\pm\, 0.6$$

34

±

0.6

 m accommodated over 2 months. A delayed initiation of several days (> 4 days) is also measured for at least two of the landslides. We analyze our findings in regards with all the previous observations on slow-moving landslides accelerated by earthquakes, and propose that the post-seismic motions are caused by diffusion of groundwater from co-seismic material contraction up to the landslide basal shear zone or from internal landslide reconfiguration. Our observations strongly suggest the main control of the hydrology in the landslide processes under seismic forcings.
Imaging of the medial rectus muscle predicts the development of optic neuropathy in thyroid eye disease
Authors: Berger Marcel , Matlach Juliane , Pitz Susanne , Berres Manfred , Axmacher Franz , Kahaly George J. , Brockmann Marc A. , Müller-Eschner Matthias
Published: April 2022

Goal of the study was to evaluate bony orbit remodeling and extraocular muscle (EOM) volume in thyroid eye disease (TED) and their role as predicting factors for development of dysthyroid optic neuropathy (DON). Orbital computed tomography of 92 patients with TED with (76 orbits) or without DON (98 orbits) were retrospectively evaluated. Orbits (n = 40) of subjects without TED served as controls. Measurements of the bony orbit as well as EOM volume were incorporated into a generalized linear mixed model to predict DON. The angle of the medial orbital wall was significantly smaller (p < 0.001) in patients with TED (− 2.3 ± 3.6°) compared to patients with TED + DON (1.0 ± 4.1°). Both groups differed significantly from controls (− 4.2 ± 2.7°). Bowing of the medial orbital wall correlated positively with muscle volume (r = 0.564; p < 0.001). Total EOM volume was significantly larger in TED + DON (7.6 ± 2.5cm3) compared to TED only (5.6 ± 3.0cm3; p < 0.001) or controls (2.6 ± 0.5cm3). Multivariate analysis revealed the medial rectus muscle volume (TED: 1.06 ± 0.48cm3 vs. TED + DON: 2.16 ± 0.84cm3) as the strongest predictor, achieving a specifity of 86.7% and a sensitivity of 73.7% in diagnosing DON in univariate analysis. Though characterized by a wide range of variability, increased medial rectus muscle volume is the strongest predictor for DON in our patient cohort with TED when analyzing a single muscle.
Oogenesis and lipid metabolism in the deep-sea sponge Phakellia ventilabrum (Linnaeus, 1767)
Authors: Koutsouveli Vasiliki , Balgoma David , Checa Antonio , Hedeland Mikael , Riesgo Ana , Cárdenas Paco
Published: April 2022

Sponges contain an astounding diversity of lipids that serve in several biological functions, including yolk formation in their oocytes and embryos. The study of lipid metabolism during reproduction can provide information on food-web dynamics and energetic needs of the populations in their habitats, however, there are no studies focusing on the lipid metabolism of sponges during their seasonal reproduction. In this study, we used histology, lipidome profiling (UHPLC-MS), and transcriptomic analysis (RNA-seq) on the deep-sea sponge Phakellia ventilabrum (Demospongiae, Bubarida), a key species of North-Atlantic sponge grounds, with the goal to (i) assess the reproductive strategy and seasonality of this species, (ii) examine the relative changes in the lipidome signal and the gene expression patterns of the enzymes participating in lipid metabolism during oogenesis. Phakellia ventilabrum is an oviparous and most certainly gonochoristic species, reproducing in May and September in the different studied areas. Half of the specimens were reproducing, generating two to five oocytes per mm2. Oocytes accumulated lipid droplets and as oogenesis progressed, the signal of most of the unsaturated and monounsaturated triacylglycerides increased, as well as of a few other phospholipids. In parallel, we detected upregulation of genes in female tissues related to triacylglyceride biosynthesis and others related to fatty acid beta-oxidation. Triacylglycerides are likely the main type of lipid forming the yolk in P. ventilabrum since this lipid category has the most marked changes. In parallel, other lipid categories were engaged in fatty acid beta-oxidation to cover the energy requirements of female individuals during oogenesis. In this study, the reproductive activity of the sponge P. ventilabrum was studied for the first time uncovering their seasonality and revealing 759 lipids, including 155 triacylglycerides. Our study has ecological and evolutionary implications providing essential information for understanding the molecular basis of reproduction and the origins and formation of lipid yolk in early-branching metazoans.
Protective effects of the postbiotic deriving from cow’s milk fermentation with L. paracasei CBA L74 against Rotavirus infection in human enterocytes
Authors: Bruno Cristina , Paparo Lorella , Pisapia Laura , Romano Alessia , Cortese Maddalena , Punzo Erika , Berni Canani Roberto
Published: April 2022

Rotavirus (RV) is the leading cause of acute gastroenteritis-associated mortality in early childhood. Emerging clinical evidence suggest the efficacy of the postbiotic approach based on cow’s milk fermentation with the probiotic Lacticaseibacillus paracasei CBAL74 (FM-CBAL74) in preventing pediatric acute gastroenteritis, but the mechanisms of action are still poorly characterized. We evaluated the protective action of FM-CBAL74 in an in vitro model of RV infection in human enterocytes. The number of infected cells together with the relevant aspects of RV infection were assessed: epithelial barrier damage (tight-junction proteins and transepithelial electrical resistance evaluation), and inflammation (reactive oxygen species, pro-inflammatory cytokines IL-6, IL-8 and TNF-α, and mitogen-activated protein kinase pathway activation). Pre-incubation with FM-CBA L74 resulted in an inhibition of epithelial barrier damage and inflammation mediated by mitogen-activated protein kinase pathway activation induced by RV infection. Modulating several protective mechanisms, the postbiotic FM-CBAL74 exerted a preventive action against RV infection. This approach could be a disrupting nutritional strategy against one of the most common killers for the pediatric age.
Transcriptome analysis reveals anthocyanin regulation in Chinese cabbage (Brassica rapa L.) at low temperatures
Authors: Dai Yun , Zhang Lei , Sun Xiao , Li Fei , Zhang Shifan , Zhang Hui , Li Guoliang , Fang Zhiyuan , Sun Rifei , Hou Xilin , Zhang Shujiang
Published: April 2022

Chinese cabbage that prefers cold conditions is also affected by low-temperature stress, such as the accumulation of leaf anthocyanins. Research on anthocyanin biosynthesis and regulation mechanisms has made great progress. However, research on anthocyanin accumulation for resistance to biological and non-biological stress is still lacking. To study the relationship between anthocyanin accumulation of Chinese cabbage and resistance under low-temperature conditions, RNA sequencing (RNA-seq) was performed on Chinese cabbage ‘Xiao Baojian’ grown at a low temperature for four time periods and at a control temperature for five time periods. In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, 7954 differentially expressed genes (DEGs) were enriched, of which 587 DEGs belonged to "biosynthesis of other secondary metabolites." Gene temporal expression patterns were used to discover enriched genes related to phenylpropanoid biosynthesis; flavonoid biosynthesis and anthocyanin biosynthesis pathways were found in cluster 1. The interaction networks were constructed, and hub genes were selected, showing that flavonoid biosynthesis pathway genes (DFR,ANS,F3H,FLS1,CHS1,CHS3, andTT8) and defense mechanisms-related genes (DFR,SNL6, andTKPR1) interact with each other. Anthocyanin biosynthesis DEGs in Chinese cabbage were evaluated under low-temperature conditions to map the relevant pathways, and expression maps of transcription factors in the flavonoid pathway were created at various periods. Low temperature upregulated the expression of genes related to anthocyanin biosynthesis. Taken together, our results provide further analysis of the relationship between plant anthocyanin synthesis and stress resistance and may also provide further insights for the future development of high-quality color and cold-tolerant Chinese cabbage germplasm resources.
Sterolight as imaging tool to study sterol uptake, trafficking and efflux in living cells
Authors: Králová Jarmila , Popr Martin , Valečka Jan , Bartůněk Petr
Published: April 2022

Information about cholesterol subcellular localization and transport pathways inside cells is essential for understanding and treatment of cholesterol-related diseases. However, there is a lack of reliable tools to monitor it. This work follows the fate of Sterolight, a BODIPY-labelled sterol, within the cell and demonstrates it as a suitable probe for visualization of sterol/lipid trafficking. Sterolight enters cells through an energy-independent process and knockdown experiments suggest caveolin-1 as its potential cellular carrier. Intracellular transport of Sterolight is a rapid process, and transfer from ER and mitochondria to lysosomes and later to lipid droplets requires the participation of active microtubules, as it can be inhibited by the microtubule disruptor nocodazole. Excess of the probe is actively exported from cells, in addition to being stored in lipid droplets, to re-establish the sterol balance. Efflux occurs through a mechanism requiring energy and may be selectively poisoned with verapamil or blocked in cells with mutated cholesterol transporter NPC1. Sterolight is efficiently transferred within and between different cell populations, making it suitable for monitoring numerous aspects of sterol biology, including the live tracking and visualization of intracellular and intercellular transport.
The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer
Authors: Ishihara Shota , Hata Kenji , Hirose Katsutoshi , Okui Tatsuo , Toyosawa Satoru , Uzawa Narikazu , Nishimura Riko , Yoneda Toshiyuki
Published: April 2022

Metabolic reprogramming is a malignant phenotype of cancer. Cancer cells utilize glycolysis to fuel rapid proliferation even in the presence of oxygen, and elevated glycolysis is coupled to lactate fermentation in the cancer microenvironment. Although lactate has been recognized as a metabolic waste product, it has become evident that lactate functions as not only an energy source but a signaling molecule through the lactate receptor G-protein-coupled receptor 81 (GPR81) under physiological conditions. However, the pathological role of GPR81 in cancer remains unclear. Here, we show that GPR81 regulates the malignant phenotype of breast cancer cell by reprogramming energy metabolism. We found that GPR81 is highly expressed in breast cancer cell lines but not in normal breast epithelial cells. Knockdown of GPR81 decreased breast cancer cell proliferation, and tumor growth. Mechanistically, glycolysis and lactate-dependent ATP production were impaired in GPR81-silenced breast cancer cells. RNA sequencing accompanied by Gene Ontology enrichment analysis further demonstrated a significant decrease in genes associated with cell motility and silencing of GPR81 suppressed cell migration and invasion. Notably, histological examination showed strong expression of GPR81 in clinical samples of human breast cancer. Collectively, our findings suggest that GPR81 is critical for malignancy of breast cancer and may be a potential novel therapeutic target for breast carcinoma.
Piezo1 activation using Yoda1 inhibits macropinocytosis in A431 human epidermoid carcinoma cells
Authors: Kuriyama Masashi , Hirose Hisaaki , Masuda Toshihiro , Shudou Masachika , Arafiles Jan Vincent V. , Imanishi Miki , Maekawa Masashi , Hara Yuji , Futaki Shiroh
Published: April 2022

Macropinocytosis is a type of endocytosis accompanied by actin rearrangement-driven membrane deformation, such as lamellipodia formation and membrane ruffling, followed by the formation of large vesicles, macropinosomes. Ras-transformed cancer cells efficiently acquire exogenous amino acids for their survival through macropinocytosis. Thus, inhibition of macropinocytosis is a promising strategy for cancer therapy. To date, few specific agents that inhibit macropinocytosis have been developed. Here, focusing on the mechanosensitive ion channel Piezo1, we found that Yoda1, a Piezo1 agonist, potently inhibits macropinocytosis induced by epidermal growth factor (EGF). The inhibition of ruffle formation by Yoda1 was dependent on the extracellular Ca2+ influx through Piezo1 and on the activation of the calcium-activated potassium channel KCa3.1. This suggests that Ca2+ ions can regulate EGF-stimulated macropinocytosis. We propose the potential for macropinocytosis inhibition through the regulation of a mechanosensitive channel activity using chemical tools.
The role of epiphytes in seagrass productivity under ocean acidification
Authors: Berlinghof Johanna , Peiffer Friederike , Marzocchi Ugo , Munari Marco , Quero Grazia M. , Dennis Laura , Wild Christian , Cardini Ulisse
Published: April 2022

Ocean Acidification (OA), due to rising atmospheric CO2, can affect the seagrass holobiont by changing the plant's ecophysiology and the composition and functioning of its epiphytic community. However, our knowledge of the role of epiphytes in the productivity of the seagrass holobiont in response to environmental changes is still very limited. CO2vents off Ischia Island (Italy) naturally reduce seawater pH, allowing to investigate the adaptation of the seagrassPosidonia oceanicaL. (Delile) to OA. Here, we analyzed the percent cover of different epiphytic groups and the epiphytic biomass ofP. oceanicaleaves, collected inside (pH 6.9–7.9) and outside (pH 8.1–8.2) the CO2vents. We estimated the contribution of epiphytes to net primary production (NPP) and respiration (R) of leaf sections collected from the vent and ambient pH sites in laboratory incubations. Additionally, we quantified net community production (NCP) and community respiration (CR) of seagrass communities in situ at vent and ambient pH sites using benthic chambers. Leaves at ambient pH sites had a 25% higher total epiphytic cover with encrusting red algae (32%) dominating the community, while leaves at vent pH sites were dominated by hydrozoans (21%). Leaf sections with and without epiphytes from the vent pH site produced and respired significantly more oxygen than leaf sections from the ambient pH site, showing an average increase of 47 ± 21% (mean ± SE) in NPP and 50 ± 4% in R, respectively. Epiphytes contributed little to the increase in R; however, their contribution to NPP was important (56 ± 6% of the total flux). The increase in productivity of seagrass leaves adapted to OA was only marginally reflected by the results from the in situ benthic chambers, underlining the complexity of the seagrass community response to naturally occurring OA conditions.
Intracellular pH affects mitochondrial homeostasis in cultured human corneal endothelial cells prepared for cell injection therapy
Authors: Deguchi Hideto , Yamashita Tomoko , Hiramoto Nao , Otsuki Yohei , Mukai Atsushi , Ueno Morio , Sotozono Chie , Kinoshita Shigeru , Hamuro Junji
Published: April 2022

This study aimed to uncover the mechanism responsible for the clinical efficacy of cell injection therapy with fully differentiated cultured cells. Analysis of polarized expression of ion transporters on cultured human corneal endothelial cells (CECs) subpopulations (SPs) was performed. The intracellular pH (pHi) between two CEC SPs, distinct in the proportion of differentiated cells, was measured, and the association with mitochondrial respiration homeostasis was investigated. The effects of the ion transporter inhibition by their selective inhibitors or siRNA transfection were also explored. Na+/K+-ATPase, Aquaporin 1, SLC4A11, NBCe1, NHE1 as transporters, and ZO-1, were all selectively expressed in differentiated SPs, but were almost null in the cell-state-transitioned SPs. We also confirmed that the pHi of CEC SPs affected their mitochondrial respiration by modulating the expression of these ion transporters via inhibitors or siRNA transfection. Ion and water transporters might participate in the maintenance of pHi and mitochondria homeostasis in differentiated SPs, which may contribute, combined with integral barrier functions, to efficient water efflux. The differences in intracellular pH between the two SPs is attributed to variations in the expression profile of specific ion transporters and mitochondrial functions, which may associate with the efficacy of the SPs in cell injection therapy.
Topological magnon modes on honeycomb lattice with coupling textures
Authors: Huang Hong , Kariyado Toshikaze , Hu Xiao
Published: April 2022

Topological magnon modes are expected to be useful for novel applications such as robust information propagation, since they are immune to backscattering and robust against disorder. Although there are several theoretical proposals for topological magnon modes and growing experimental efforts for realizing them by now, it is still desirable to add complementary insights on this important phenomenon. Here, we propose a new scheme to achieve topological magnon where only nearest-neighbour exchange couplings on honeycomb lattice are necessary. In both ferromagnets and antiferromagnets, tuning exchange couplings between and inside hexagonal unit cells induces a topological state accompanied by a band inversion between p-orbital and d-orbital like magnon modes. Topological magnon modes appear at the interface between a topological domain and a trivial domain with magnon currents, which counterpropagate depending on pseudospins originated from orbital angular momenta of magnon modes. This mimics the spin-momentum locking phenomenon in the quantum spin Hall effect.