bluuebunny/crossref_metadata_2025 huggingface dataset:
Large deviations for a class of tempered subordinators and their inverse processes
Authors: Leonenko Nikolai , Macci Claudio , Pacchiarotti Barbara
Published: January 2021

We consider a class of tempered subordinators, namely a class of subordinators with one-dimensional marginal tempered distributions which belong to a family studied in [3]. The main contribution in this paper is a non-central moderate deviations result. More precisely we mean a class of large deviation principles that fill the gap between the (trivial) weak convergence of some non-Gaussian identically distributed random variables to their common law, and the convergence of some other related random variables to a constant. Some other minor results concern large deviations for the inverse of the tempered subordinators considered in this paper; actually, in some results, these inverse processes appear as random time-changes of other independent processes.
Dietary acrylamide intake and risk of women’s cancers: a systematic review and meta-analysis of prospective cohort studies
Authors: Benisi-Kohansal Sanaz , Salari-Moghaddam Asma , Seyed Rohani Zahraalsadat , Esmaillzadeh Ahmad
Published: January 2021

This systematic review and meta-analysis was done to review earlier publications on the association between dietary acrylamide intake and risk of breast, endometrial and ovarian cancers. We performed a systematic search in the online databases of PubMed, ISI Web of Science and Scopus for relevant publications up to August 2020. Prospective cohort studies that considered dietary acrylamide as the exposure variable and breast, endometrial or ovarian cancer as the main outcome variable or as one of the outcome variables were included in this systematic review and meta-analysis. A total of fourteen cohort studies were included in the meta-analysis. We found no significant association between dietary acrylamide intake and the risk of breast (relative risk (RR) 0·95; 95 % CI 0·90, 1·01), endometrial (RR 1·03; 95 % CI 0·89, 1·19) and ovarian cancers (RR 1·02; 95 % CI 0·84, 1·24). In addition, we observed no significant association between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers in different subgroup analyses by smoking status, menopausal status, BMI status and different types of breast cancer. In conclusion, no significant association was found between dietary acrylamide intake and the risk of breast, endometrial and ovarian cancers.
The contribution of provitamin A biofortified cassava to vitamin A intake in Nigerian pre-schoolchildren
Authors: Afolami Ibukun , Samuel Folake , Borgonjen-van den Berg Karin , Mwangi Martin N. , Kalejaiye Olatundun , Sanusi Rasaki A. , Putri Linda Ayu Rizka , Brivio Francesca , Brouwer Inge D. , Melse-Boonstra Alida
Published: January 2021

Biofortified yellow cassava has been developed to alleviate vitamin A deficiency. We examined the potential contribution of yellow cassava to total retinol activity equivalent (RAE) intake if replacing white by yellow cassava among pre-school Nigerian children. Dietary intake was assessed as part of a randomised controlled trial. Pre-schoolchildren (n 176) were randomly assigned to receive either white cassava (WC) or yellow cassava (YC) for 17 weeks. Dietary intake assessments were conducted during the intervention and 1 month after, when children had resumed their habitual diet. Differences in RAE intake between groups and time points were compared using a linear mixed model regression analysis. During intervention, median RAE intake was 536 µg/d in the YC group and 301 µg/d in the WC group (P < 0·0001). YC contributed approximately 40 % to total RAE intake. Of the children, 9 % in the YC group and 29 % in the WC group had RAE intake below the Estimated Average Requirement. After intervention, median RAE intake was 300 µg/d and did not differ between intervention groups (P = 0·5). The interaction effect of group and time showed a 37 % decrease in RAE intake in the YC group after the intervention (Exp(β) = 0·63; 95 % CI 0·56, 0·72). If WC was replaced by YC after intervention, the potential contribution of YC to total RAE intake was estimated to be approximately 32 %. YC increased total RAE intake and showed a substantially lower inadequacy of intake. It is therefore recommended as a good source of provitamin A in cassava-consuming regions.
No effect of salmon fish protein on 2-h glucose in adults with increased risk of type 2 diabetes: a randomised controlled trial
Authors: Hustad K. S. , Ottestad I. , Hjorth M. , Dalen K. T. , Sæther T. , Sheikh N. A. , Strømnes M. , Ulven S. M. , Holven K. B.
Published: January 2021

The association between fish consumption and decreased risk of CVD is well documented. However, studies on health effects of fish consumption suggest that other components than n-3 PUFA have beneficial cardiometabolic effects, including effects on glucose metabolism. The aim of the present study was to investigate effects of salmon fish protein on cardiometabolic risk markers in a double-blind, randomised controlled parallel trial. We hypothesised that daily intake of a salmon fish protein supplement for 8 weeks would improve glucose tolerance in persons with increased risk of type 2 diabetes mellitus (T2DM). Our primary outcome measure was serum glucose (s-glucose) 2 h after a standardised oral glucose tolerance test. In total, eighty-eight adults with elevated s-glucose levels were randomised to 7·5 g of salmon fish protein/d or placebo, and seventy-four participants were included in the analysis. We found no significant effect of salmon fish protein supplementation on our primary outcome or other markers related to glucose tolerance, serum lipids, weight or blood pressure compared with placebo. The present study does not support the hypothesis that daily intake of a salmon fish protein supplement for 8 weeks improves glucose tolerance in persons with increased risk of T2DM.
POLYCENTRICITY AND POLYPHONY IN INTERNATIONAL LAW: INTERPRETING THE CORPORATE RESPONSIBILITY TO RESPECT HUMAN RIGHTS
Authors: Partiti Enrico
Published: January 2021

Complex multi-actors and multi-level governance structures have emerged in areas that were traditionally exclusively the preserve of the State and treaty-making. The adoption of the United Nations Guiding Principles on Business and Human Rights (UNGP) affirmed a corporate responsibility to respect human rights to be implemented through human rights due diligence (HRDD), ie via management processes. The open-ended character of the UNGP generated the emergence of other soft instruments offering guidance to corporations in structuring HRDD. This contribution conceptualises the UNGP from the perspective of regulation as a principles-based exercise in polycentric governance reliant on regulatory intermediaries for interpretation. It then assesses the role of various sui generis normative instruments in providing interpretation to the UNGP and, how the presence of an additional layer of interpretative material contributes to the institutionalisation of responsible corporate conduct. The analysis of instruments drafted by international, non-governmental and business organisations reveals both a decentralising tension between different intermediaries due to disagreements and divergence concerning the precise extent of corporate human rights responsibilities, as well as attempts to centralise the interpretation of the UNGP. The article concludes by recommending some caution towards the employment of polycentric governance regimes and their lack of centralised interpretive authority in this domain of international law and suggests possible ways to formally establish centralised interpretation.
ACCIDENT AND DESIGN: RECOGNISING VICTIMS OF AGGRESSION IN INTERNATIONAL LAW
Authors: Darcy Shane
Published: January 2021

International law has not traditionally recognised individuals as victims of the crime of aggression. Recent developments may precipitate a departure from this approach. The activation of the jurisdiction of the International Criminal Court over the crime of aggression opens the way for the future application of the Court's regime of victim participation and reparation in the context of prosecutions for this crime. The determination by the United Nations Human Rights Committee in General Comment No. 36 that any deprivation of life resulting from an act of aggression violates Article 6 of the International Covenant on Civil and Political Rights serves to recognise a previously overlooked class of victims. This article explores these recent developments, by discussing their background, meaning and implications for international law and the rights of victims.
Network Centrality and Managerial Market-Timing Ability
Authors: Evgeniou Theodoros , Peress Joel , Vermaelen Theo , Yue Ling
Published: January 2021

We document that long-run excess returns following announcements of share buyback authorizations and insider purchases are a U-shaped function of firm centrality in the input–output trade-flow network. These results conform to a model of investors endowed with a large but finite capacity for analyzing firms. Additional links weaken insiders’ informational advantage in peripheral firms (simple firms whose cash flows depend on few economic links), provided investors’ capacity is large enough, but eventually amplify that advantage in central firms (firms with many links) as a result of investors’ limited capacity. These findings shed light on the sources of managerial market-timing ability.
Macromolecular room temperature crystallography
Authors: Fischer Marcus
Published: January 2021

X-ray crystallography enables detailed structural studies of proteins to understand and modulate their function. Conducting crystallographic experiments at cryogenic temperatures has practical benefits but potentially limits the identification of functionally important alternative protein conformations that can be revealed only at room temperature (RT). This review discusses practical aspects of preparing, acquiring, and analyzing X-ray crystallography data at RT to demystify preconceived impracticalities that freeze progress of routine RT data collection at synchrotron sources. Examples are presented as conceptual and experimental templates to enable the design of RT-inspired studies; they illustrate the diversity and utility of gaining novel insights into protein conformational landscapes. An integrative view of protein conformational dynamics enables opportunities to advance basic and biomedical research.
Setting up and operating a cryo-EM laboratory
Authors: Mills Deryck J.
Published: January 2021

Cryo-electron microscopy (cryo-EM) has become the technique of choice for structural biology of macromolecular assemblies, after the ‘resolution revolution’ that has occurred in this field since 2012. With a suitable instrument, an appropriate electron detector and, last but not least, a cooperative sample it is now possible to collect images from which macromolecular structures can be determined to better than 2 Å resolution, where reliable atomic models can be built. By electron tomography and sub-tomogram averaging of cryo-samples, it is also possible to reconstruct subcellular structures to sub-nanometre resolution. This review describes the infrastructure that is needed to achieve this goal. Ideally, a cryo-EM lab will have a dedicated 300 kV electron microscope for data recording and a 200 kV instrument for screening cryo-samples, both with direct electron detectors, and at least one 120 kV EM for negative-stain screening at room temperature. Added to this should be ancillary equipment for specimen preparation, including a light microscope, carbon coater, plasma cleaner, glow discharge unit, a device for fast, robotic sample freezing, liquid nitrogen storage Dewars and a ready supply of clean liquid nitrogen. In practice, of course, the available budget will determine the number and types of microscopes and how elaborate the lab can be. The cryo-EM lab should be designed with adequate space for the electron microscopes and ancillary equipment, and should allow for sufficient storage space. Each electron microscope room should be connected to the image-processing computers by fibre-optic cables for the rapid transfer of large datasets. The cryo-EM lab should be overseen by a facility manager whose responsibilities include the day-to-day tasks to ensure that all microscopes are operating perfectly, organising service and repairs to minimise downtime, and controlling the budget. Large facilities will require additional support staff who help to oversee the operation of the facility and instruct new users.
Modeling of Inverse Kinematic of 3-DoF Robot, Using Unit Quaternions and Artificial Neural Network
Authors: Jiménez-López Eusebio , Servín de la Mora-Pulido Daniel , Reyes-Ávila Luis Alfonso , Servín de la Mora-Pulido Raúl , Melendez-Campos Javier , López-Martínez Aldo Augusto
Published: January 2021

This paper presents a novel method for modeling a 3-degree of freedom open kinematic chain using quaternions algebra and neural network to solve the inverse kinematic problem. The structure of the network was composed of 3 hidden layers with 25 neurons per layer and 1 output layer. The network was trained using the Bayesian regularization backpropagation. The inverse kinematic problem was modeled as a system of six nonlinear equations and six unknowns. Finally, both models were tested using a straight path to compare the results between the Newton–Raphson method and the network training.
A Mathematical Model for an Integrated Assembly Line Regarding Learning and Fatigue Effects
Authors: Eslamipoor Reza , Nobari Arash
Published: January 2021

In this paper, an integrated mathematical model for the balancing and sequencing problems of a mixed-model assembly line (MMAL) is developed. The proposed model minimizes the total overload and idleness times. For the sake of reality, the impact of operator’s learning and fatigue issues on the optimization of the assembly line balancing and sequencing problems is considered. Furthermore, it is assumed that the Japanese mechanism is used in this assembly line to deal with the overload issue. With respect to the complexity level of the proposed model, a genetic algorithm is developed to solve the model. In order to set the parameters of the developed genetic algorithm, the well-known Taguchi method is used and the efficiency of this solution method is compared with the GAMS software using several test problems with different sizes. Finally, the sensitivity of the balancing and sequencing problems to the parameters such as station length, learning rate, and fatigue rate are analyzed and the impact of changing these parameters on the model is studied.
An evaluation of COVID-19 transmission control in Wenzhou using a modified SEIR model
Authors: Li Wenning , Gong Jianhua , Zhou Jieping , Zhang Lihui , Wang Dongchuan , Li Jing , Shi Chenhui , Fan Hongkui
Published: January 2021

In December 2019, the first confirmed case of pneumonia caused by a novel coronavirus was reported. Coronavirus disease 2019 (COVID-19) is currently spreading around the world. The relationships among the pandemic and its associated travel restrictions, social distancing measures, contact tracing, mask-wearing habits and medical consultation efficiency have not yet been extensively assessed. Based on the epidemic data reported by the Health Commission of Wenzhou, we analysed the developmental characteristics of the epidemic and modified the Susceptible-Exposed-Infectious-Removed (SEIR) model in three discrete ways. (1) According to the implemented preventive measures, the epidemic was divided into three stages: initial, outbreak and controlled. (2) We added many factors, such as health protections, travel restrictions and social distancing, close-contact tracing and the time from symptom onset to hospitalisation (TSOH), to the model. (3) Exposed and infected people were subdivided into isolated and free-moving populations. For the parameter estimation of the model, the average TSOH and daily cured cases, deaths and imported cases can be obtained through individual data from epidemiological investigations. The changes in daily contacts are simulated using the intracity travel intensity (ICTI) from the Baidu Migration Big Data platform. The optimal values of the remaining parameters are calculated by the grid search method. With this model, we calculated the sensitivity of the control measures with regard to the prevention of the spread of the epidemic by simulating the number of infected people in various hypothetical situations. Simultaneously, through a simulation of a second epidemic, the challenges from the rebound of the epidemic were analysed, and prevention and control recommendations were made. The results show that the modified SEIR model can effectively simulate the spread of COVID-19 in Wenzhou. The policy of the lockdown of Wuhan, the launch of the first-level Public Health Emergency Preparedness measures on 23 January 2020 and the implementation of resident travel control measures on 31 January 2020 were crucial to COVID-19 control.
Neighbourhood exceptionalism and racial liberalism in the Great Society city: integration as civic showpiece at St Louis’ LaClede Town
Authors: Looker Benjamin
Published: January 2021

This article analyses the role of LaClede Town, a nationally lauded housing development in St Louis (USA), in metropolitan and national contests over race, segregation and urban equity from the 1960s to 1990s. Built on the site of a massive slum-clearance project, the federally supported complex gained widespread fame for its startlingly heterogeneous racial mix and ostensibly colour-blind lifestyles. As the article argues, the quasi-utopian language applied to the neighbourhood illustrates the contours and limitations of a 1960s racial liberalism that sought to overcome structural inequalities through face-to-face neighbourly contact. Yet the project's 1990s demise signals that older ideology's supersession by a newly dominant urban neoliberalism.
DNA methyltransferase inhibitors modulate histone methylation: epigenetic crosstalk between H3K4me3 and DNA methylation during sperm differentiation
Authors: Burlibaşa Liliana , Nicu Alina-Teodora , Domnariu Carmen
Published: January 2021

The process of cytodifferentiation in spermatogenesis is governed by a unique genetic and molecular programme. In this context, accurate ‘tuning’ of the regulatory mechanisms involved in germ cells differentiation is required, as any error could have dramatic consequences on species survival and maintenance. To study the processes that govern the spatial–temporal expression of genes, as well as analyse transmission of epigenetic information to descendants, an integrated approach of genetics, biochemistry and cytology data is necessary. As information in the literature on interplay between DNA methylation and histone H3 lysine 4 trimethylation (H3K4me3) in the advanced stages of murine spermatogenesis is still scarce, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, at the cytological level using immunocytochemistry methodology. Our results revealed a particular distribution of H3K4me3 during sperm cell differentiation and highlighted an important role for regulation of DNA methylation in controlling histone methylation and chromatin remodelling during spermatogenesis.
Understanding productivity effects of hydraulic fracturing in unconventional natural gas deposits and implications for adoption in the developing world
Authors: Fitzgerald Timothy , Mason Charles F.
Published: January 2021

Hydraulic fracturing (HF) has transformed the North American oil and gas industry, leading to increased consumer surplus and reduced carbon emissions. While HF may have similar potential for the developing world, adoption has been limited to date, plausibly because of perceptions of potential local costs and the need to develop technical proficiency. We empirically evaluate the incremental contribution of HF in the United States. We find considerable evidence of differences in application and productivity across operating firms and vertical pairings of firms, suggesting intellectual property and learning by doing may both play important roles. At the same time, secrecy regarding the chemical composition of fluids used in HF is a potential deterrent to its application for fear of local costs. Developing countries must accommodate these characteristics if adoption of HF is to help meet energy demands and achieve climate policy goals.
Genetic resources of Asian palmyrah palm (Borassus flabelliferL.): a comprehensive review on diversity, characterization and utilization
Authors: Siju S. , Sabu K. K.
Published: January 2021

Asian palmyrah palm (Borassus flabelliferL.) is a multipurpose, economically important tree widely distributed in the Indian subcontinent and Southeast Asia. The multifaceted uses (~800 uses) of the tree as food, wood and medicine make it a viable industrial crop. However, the dioecious nature of the tree coupled with long juvenile phase (12–20 years to initiate flowering), long stature and considerable variations in the productivity of male and female trees necessitates the application of new biotechnological tools for crop improvement. This review provides comprehensive information on the extent of genetic diversity of the crop, problems associated with palmyrah cultivation along with its multifaceted application and research gaps to be addressed for the effective utilization and conservation of palmyrah palm genetic resources.
Angle and polarization-independent miniaturized UWB FSS design
Authors: Yuan Yanning , Zhao Yuchen , Xi Xiaoli
Published: January 2021

A single-layer ultra-wideband (UWB) stop-band frequency selective surface (FSS) has several advantages in wireless systems, including a simple design, low debugging complexity, and an appropriate thickness. This study proposes a miniaturized UWB stop-band FSS design. The proposed FSS structure consists of a square-loop and metalized vias that are arranged on a single layer substrate; it has an excellent angle and polarization-independent characteristics. At an incident angle of 60°, the polarization response frequencies of the transverse electric and magnetic modes only shifted by 0.003 f0 and 0.007 f0, respectively. The equivalent circuit models of the square-loop and metallized vias structure are analysed and the accuracy of the calculation is evaluated by comparing the electromagnetic simulation. The 20 × 20 array constitutes an FSS reflector with a unit size of 4.2 mm × 4.2 mm (less than one-twentieth of the wavelength of 3 GHz), which realizes an UWB quasi-constant gain enhancement (in-band flatness is <0.5 dB). Finally, the simulation results were verified through sample processing and measurement; consistent results were obtained. The FSS miniaturization design method proposed in this study could be applied to the design of passband FSS (complementary structure), antennas and filters, among other applications.
Daily Physical Activity in Older Age
Authors: Wilhelm Lea O. , Pauly Theresa , Ashe Maureen C. , Hoppmann Christiane A.
Published: January 2021

Abstract. Affective barriers like negative affect (time-varying subjective state) or fear of falling (person-trait) may reduce daily physical activity among older adults. A group of 123 community-dwelling older adults ( Mage = 71.83, range = 64–85, 63% women) from Canada participated in a 10-day time-sampling study. We used accelerometer-assessed physical activity, assessing negative affect three times per day and fear of falling once prior to the 10-day period. Using multilevel models, we noted considerable variability in physical activity between days (activity counts: 47%; steps: 55%). We found time-varying negative associations between daily physical activity and daily negative affect. Fear of falling was not related to daily physical activity. Findings point to the merit of examining time-varying differences in subjective experiences when looking for physical activity barriers in older age.
METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner
Authors: Pan Xiaoping , Hong Xiaolv , Li Sumei , Meng Ping , Xiao Feng
Published: January 2021

Breast cancer (BC) is the most prevalent malignant neoplasm among women and is the fifth most common cause of cancer-associated death worldwide. Acquired chemoresistance driven by genetic and epigenetic alterations is a significant clinical challenge in treating BC. However, the mechanism of BC cell resistance to adriamycin (ADR) remains to be elucidated. In this study, we identified the methyltransferase-like 3/microRNA-221-3p/homeodomain-interacting protein kinase 2/Che-1 (METTL3/miR-221-3p/HIPK2/Che-1) axis as a novel signaling event that may be responsible for resistance of BC cells to ADR. A dual-luciferase reporter gene assay was employed to test the presence of miR-221-3p binding sites in the 3′UTR of HIPK2. Drug resistance was evaluated by immunoblotting multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). Cultured ADR-resistant MCF-7 cells were assayed for their half maximal inhibitory concentration (IC50) values and apoptosis using an MTT assay and Annexin V-FITC/PI-labeled flow cytometry, and the cells were then xenografted into nude mice. METTL3 knockdown was shown to reduce the expression of miR-221-3p by reducing pri-miR-221-3p m6A mRNA methylation, thereby reducing the IC50 value of ADR-resistant MCF-7 cells, reducing the expression of MDR1 and BCRP, and inducing apoptosis. Mechanistically, miR-221-3p was demonstrated to negatively regulate HIPK2 and upregulate its direct target Che-1, thus leading to enhanced drug resistance in ADR-resistant MCF-7 cells. In vitro results were reproduced in nude mice xenografted with ADR-resistant MCF-7 cells. Our work elucidates an epigenetic mechanism of acquired chemoresistance in BC, in support of the METTL3/miR-221-3p/HIPK2/Che-1 axis as a therapeutic target for the improvement of chemotherapy.
Role of connexin 43 in odontoblastic differentiation and structural maintenance in pulp damage repair
Authors: Yin Jiaxin , Xu Jue , Cheng Ran , Shao Meiying , Qin Yuandong , Yang Hui , Hu Tao
Published: January 2021

Dental pulp can initiate its damage repair after an injury of the pulp–dentin complex by rearrangement of odontoblasts and formation of newly differentiated odontoblast-like cells. Connexin 43 (Cx43) is one of the gap junction proteins that participates in multiple tissue repair processes. However, the role of Cx43 in the repair of the dental pulp remains unclear. This study aimed to determine the function of Cx43 in the odontoblast arrangement patterns and odontoblastic differentiation. Human teeth for in vitro experiments were acquired, and a pulp injury model in Sprague-Dawley rats was used for in vivo analysis. The odontoblast arrangement pattern and the expression of Cx43 and dentin sialophosphoprotein (DSPP) were assessed. To investigate the function of Cx43 in odontoblastic differentiation, we overexpressed or inhibited Cx43. The results indicated that polarized odontoblasts were arranged along the pulp–dentin interface and had high levels of Cx43 expression in the healthy teeth; however, the odontoblast arrangement pattern was slightly changed concomitant to an increase in the Cx43 expression in the carious teeth. Regularly arranged odontoblast-like cells had high levels of the Cx43 expression during the formation of mature dentin, but the odontoblast-like cells were not regularly arranged beneath immature osteodentin in the pulp injury models. Subsequent in vitro experiments demonstrated that Cx43 is upregulated during odontoblastic differentiation of the dental pulp cells, and inhibition or overexpression of Cx43 influence the odontoblastic differentiation. Thus, Cx43 may be involved in the maintenance of odontoblast arrangement patterns, and influence the pulp repair outcomes by the regulation of odontoblastic differentiation.
Novel MSX1 variants identified in families with nonsyndromic oligodontia
Authors: Zheng Jinglei , Yu Miao , Liu Haochen , Cai Tao , Feng Hailan , Liu Yang , Han Dong
Published: January 2021

The goal of this study was to identifyMSX1gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia, and a series of bioinformatics databases were used for variant confirmation and functional prediction. Phenotypic characterization of the members of these families was described, and an in vitro analysis was performed for functional evaluation. Five novelMSX1heterozygous variants were identified: three missense variants [c.662A>C (p.Q221P), c.670C>T (p.R224C), and c.809C>T (p.S270L)], one nonsense variant [c.364G>T (p.G122*)], and one frameshift variant [c.277delG (p.A93Rfs*67)]. Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P, p.R224C, p.G122*, and p.A93Rfs*67 variants compared to the wild type. Three variants (p.Q221P, p.G122*, and p.A93Rfs*67) were classified as pathogenic or likely pathogenic, while p.S270L and p.R224C were of uncertain significance in the current data. Moreover, we summarized and analysed theMSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss. Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.
TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia
Authors: Ochiiwa Hiroaki , Ailiken Guzhanuer , Yokoyama Masataka , Yamagata Kazuyuki , Nagano Hidekazu , Yoshimura Chihoko , Muraoka Hiromi , Ishida Keiji , Haruma Tomonori , Nakayama Akitoshi , Hashimoto Naoko , Murata Kazutaka , Nishimura Motoi , Kawashima Yusuke , Ohara Osamu , Ohkubo Shuichi , Tanaka Tomoaki
Published: January 2021

TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.
Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma
Authors: Xu Yinyin , Guo Jing , Liu Jing , Xie Ying , Li Xin , Jiang Hongmei , Wang Jingjing , Peng Ziyi , Wang Jingya , Wang Sheng , Wan Chao , Chen Lanting , Zhong Yuping , Liu Beizhong , Liu Zhiqiang
Published: January 2021

Myeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotesDKK1expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activateDKK1transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.
Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance
Authors: Yoshida Kosuke , Yokoi Akira , Sugiyama Mai , Oda Shingo , Kitami Kazuhisa , Tamauchi Satoshi , Ikeda Yoshiki , Yoshikawa Nobuhisa , Nishino Kimihiro , Niimi Kaoru , Suzuki Shiro , Kikkawa Fumitaka , Yokoi Tsuyoshi , Kajiyama Hiroaki
Published: January 2021

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.
β-Trcp and CK1δ-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma
Authors: Lu Yanwei , Li Xudong , Liu Hongli , Xue Jun , Zeng Zhen , Dong Xiaorong , Zhang Tao , Wu Gang , Yang Kunyu , Xu Shuangbing
Published: January 2021

Distant metastasis is the leading cause of treatment failure in patients with hepatocellular carcinoma (HCC). However, the underlying mechanisms have not been fully elucidated. Here, we report that Leucine zipper tumor suppressor 2 (LZTS2) is downregulated and correlated with poor prognosis in HCC. Furthermore, we provide evidence that LZTS2 associates with p85 to inhibit the activation of PI3K/AKT signaling and impairs HCC tumorigenesis and metastasis in vitro and in vivo. Moreover, we identify LZTS2 as a bona fide substrate of the E3 ligase β-Trcp and protein kinase CK1δ, which are responsible for the ubiquitination and degradation of LZTS2. Importantly, we show that the β-Trcp and CK1δ-mediated degradation of LZTS2 promotes HCC progression and metastasis by activating PI3K/AKT signaling. Collectively, our study not only illustrates the roles of LZTS2 in regulating HCC tumorigenesis and metastasis but also reveals a novel posttranslational modification of LZTS2 by β-Trcp and CK1δ, indicating that the β-Trcp/CK1δ/LZTS2/PI3K axis may be a novel oncogenic driver involved in HCC progression and metastasis.
Loss and revival of androgen receptor signaling in advanced prostate cancer
Authors: Formaggio Nicolò , Rubin Mark A. , Theurillat Jean-Philippe
Published: January 2021

Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.
Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype
Authors: Varešlija Damir , Ward Elspeth , Purcell Siobhan P. , Cosgrove Nicola S. , Cocchiglia Sinéad , O’Halloran Philip J. , Charmsaz Sara , Bane Fiona T. , Brett Francesca M. , Farrell Michael , Cryan Jane , Beausang Alan , Hudson Lance , Turnbul Arran K. , Dixon J. Michael , Hill Arnold D. K. , Priedigkeit Nolan , Oesterreich Steffi , Lee Adrian V. , Sims Andrew H. , Redmond Aisling M. , Carroll Jason S. , Young Leonie S.
Published: January 2021

Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER+ metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER+ metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions.
Hypoxia-induced PLOD1 overexpression contributes to the malignant phenotype of glioblastoma via NF-κB signaling
Authors: Wang Zhenlin , Shi Yuping , Ying Chenting , Jiang Yang , Hu Jiangfeng
Published: January 2021

Procollagen lysyl hydroxylase 1 (PLOD1) is highly expressed in malignant tumors such as esophageal squamous cell carcinoma, gastric cancer, and colorectal cancer. Bioinformatics analysis revealed that PLOD1 is associated with the progression of GBM, particularly the most malignant mesenchymal subtype (MES). Moreover, in the TCGA and CGGA datasets, the mean survival time of patients with high PLOD1 expression was significantly shorter than that of patients with low expression. The clinical samples confirmed this result. Therefore, we aimed to investigate the effect of PLOD1 on the development of mesenchymal GBM in vitro and in vivo and its possible mechanisms. Molecular experiments were conducted on the patient-derived glioma stem cells and found that PLOD1 expressed higher in tumor tissues and cancer cell lines of patients with GBM, especially in the MES. PLOD1 also enhanced tumor viability, proliferation, migration, and promoted MES transition while inhibited apoptosis. Tumor xenograft results also indicated that PLOD1 overexpression significantly promotes malignant behavior of tumors. Mechanistically, bioinformatics analysis further revealed that PLOD1 expression was closely associated with the NF-κB signaling pathway. Besides, we also found that hypoxic environments also enhanced the tumor-promoting effects of PLOD1. In conclusion, overexpression of PLOD1 may be an important factor in the enhanced invasiveness and MES transition of GBM. Thus, PLOD1 is a potential treatment target for mesenchymal GBM or even all GBM.
A novel role of MNT as a negative regulator of REL and the NF-κB pathway
Authors: Liaño-Pons Judit , Lafita-Navarro M. Carmen , García-Gaipo Lorena , Colomer Carlota , Rodríguez Javier , von Kriegsheim Alex , Hurlin Peter J. , Ourique Fabiana , Delgado M. Dolores , Bigas Anna , Espinosa Lluis , León Javier
Published: January 2021

MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT–REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT–REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.
Significant salivary changes in relation to oral mucositis following autologous hematopoietic stem cell transplantation
Authors: van Leeuwen S. J. M. , Proctor G. B. , Laheij A. M. G. A. , Potting C. M. J. , Smits O. , Bronkhorst E. M. , Hazenberg M. D. , Haverman T. M. , Brennan M. T. , von Bültzingslöwen I. , Raber-Durlacher J. E. , Huysmans M. C. D. N. J. M. , Rozema F. R. , Blijlevens N. M. A.
Published: January 2021

The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI [0.36, 3.58], SWS: p < 0.001 95% CI [1.14, 3.29]). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI [0.49, 1.29], SWS: p < 0.001 95% CI [0.72, 1.45]). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.
Tailoring the d-band center of N-doped carbon nanotube arrays with Co4N nanoparticles and single-atom Co for a superior hydrogen evolution reaction
Authors: Cao Bo , Hu Minghao , Cheng Yan , Jing Peng , Liu Baocang , Zhou Bo , Wang Xi , Gao Rui , Sun Xiaolei , Du Yaping , Zhang Jun
Published: January 2021

A 3D self-supported integrated electrode, consisting of heteroatomic nitrogen-doped carbon nanotube arrays on carbon cloth with confined ultrafine Co4N nanoparticles and a distribution of anchored single-atom Co, is fabricated via a cobalt-catalyzed growth strategy using dicyandiamide as the nitrogen and carbon source and a layered cobalt hydroxide-nitrate salt as the precursor. The abundance of exposed active sites, namely, the Co4N nanoparticles, single-atom Co, and heteroatomic N-doped carbon nanotubes, and multiple synergistic effects among these components provide suitable tailoring of thed-band center for facilitating vectorial electron transfer and efficient electrocatalysis. Benefiting from the merits of its structural features and electronic configuration, the prepared electrode exhibits robust performance toward the hydrogen evolution reaction with overpotentials of only 78 and 86 mV at 10 mA cm−2in acidic and basic electrolytes, respectively. Density functional theory calculations and X-ray photoelectron spectroscopy valence band measurements reveal that the effective tailoring of thed-band center by Co4N nanoparticles plays a crucial role in optimizing the hydrogen adsorption free energy to a more thermoneutral value for efficient electrocatalysis.
Highly stretchable metal-polymer hybrid conductors for wearable and self-cleaning sensors
Authors: Yoon Sunyoung , Kim Yong Jun , Lee Yu Rim , Lee Nae-Eung , Won Yoochan , Gandla Srinivas , Kim Sunkook , Kim Han-Ki
Published: January 2021

We fabricated semitransparent and stretchable hybrid Ag-polytetrafluoroethylene (PTFE) conductors on a polyurethane (PU) substrate for use in high-performance wearable and self-cleaning sensors. The highly conductive Ag metal and stretchable PTFE polymer matrix were cosputtered, embedding the self-formed Ag in the PTFE matrix. Depending on the cosputtering RF and DC power ratio, the Ag-PTFE conductors showed a sheet resistance of 3.09–17.23 Ω/square and an optical transparency of 25.27–38.49% at a wavelength of 550 nm. Under the optimal cosputtering conditions, the Ag-PTFE electrode showed outstanding stretchability (strain 20%) and reversible hysteresis, enabling the production of stretchable and semitransparent conductors. In addition, the very small critical inward/outward bending radius near 1 mm and the hydrophobic surface indicate that the Ag-PTFE films could also be applied in wearable and self-cleaning devices. The suitability of the high stretchability and low sheet resistance of the sputtered Ag-PTFE conductor was verified by using it as a stretchable interconnector for commercial ELs, LEDs, and strain sensors. We applied the Ag-PTFE film as a semitransparent conductor for stretchable touch panels and electromyography sensors. Cosputtered Ag-PTFE films are promising stretchable conductors for a variety of applications in next-generation wearable devices.