bluuebunny/crossref_metadata_2025 huggingface dataset:
Phonological vs. natural gender cues in the acquisition of German by simultaneous and sequential bilinguals (German–Russian)
Authors: KUPISCH Tanja , MITROFANOVA Natalia , WESTERGAARD Marit
Published: May 2021

We investigate German–Russian bilingual children's sensitivity to formal and semantic cues when assigning gender to nouns in German. Across languages, young children have been shown to primarily rely on phonological cues, whereas sensitivity to semantic and syntactic cues increases with age. With its semi-transparent gender assignment system, where both formal and semantic cues are psycho linguistically relevant, German has weak phonological cues compared to other languages, and children have been argued to acquire semantic and phonological rules in tandem. German–Russian bilingual children face the challenge of acquiring two different gender assignment systems simultaneously. We tested 45 bilingual children (ages 4–10 years) and monolingual controls. Results show that the children are clearly sensitive to phonological cues, while semantic cues play a minor role. However, monolingual and bilingual children have different defaulting strategies, with monolinguals defaulting to neuter and bilinguals to feminine gender.
Humanity should colonize space in order to survive but not with embryo space colonization
Authors: Szocik Konrad
Published: May 2021

The embryo space colonization (ESC) concept is an interesting, very rational and quite effective way to guarantee the survival of the human species, as long as the technology is achieved and no unforeseen complications arise during even many millions of years journey to an exoplanet. Despite these formal advantages of the concept, this paper points to a number of arguments against its validity. These arguments revolve around two issues. One is to point out that while the concept of saving the Homo sapiens species is noble and should be supported, the way of saving humanity envisioned by the ESC departs from what should be understood by the concept of saving humanity through space colonization. The second issue is to draw attention to the ethical controversies that make this concept perhaps unsuitable for implementation at all. At least some of these objections do not address the concept of saving humanity by sending adult living persons on space missions.
Causal effect of tooth loss on depression: evidence from a population-wide natural experiment in the USA
Authors: Matsuyama Y. , Jürges H. , Dewey M. , Listl S.
Published: May 2021

Aims

Depression severely affects people's health and well-being. Oral diseases have been suggested to be associated with depression, but so far, there is no causal evidence. This study aimed to identify the causal effect of tooth loss on depression among US adults in a natural experiment study.

Methods

Instrumental variable analysis was conducted using data from 169 061 respondents born in 1940–1978 who participated in the 2006, 2008 or 2010 waves of the Behavioral Risk Factor Surveillance System (BRFSS). Random variation in tooth loss due to differential childhood exposure to drinking water fluoride was exploited as an instrument.

Results

US adults who were exposed to drinking water fluoride in childhood had more remaining teeth, therefore providing a robust instrument (F = 73.4). For each additional tooth loss, depressive symptoms according to the eight-item Patient Health Questionnaire depression (PHQ-8) score increased by 0.146 (95% CI 0.008–0.284), and the probability of having clinical depression (PHQ ⩾10) increased by 0.81 percentage points (95% CI −0.12 to 1.73).

Conclusions

Tooth loss causally increased depression among US adults. Losing ten or more teeth had an impact comparable to adults with major depressive disorder not receiving antidepressant drugs.
Non‐Stationary Probabilistic Tsunami Hazard Assessments Incorporating Climate‐Change‐Driven Sea Level Rise
Authors: Sepúlveda Ignacio , Haase Jennifer S. , Liu Philip L.‐F. , Grigoriu Mircea , Winckler Patricio
Published: May 2021

We face a new era in the assessment of multiple natural hazards whose statistics are becoming alarmingly non‐stationary due to ubiquitous long‐term changes in climate. One particular case is tsunami hazard affected by climate‐change‐driven sea level rise (SLR). A traditional tsunami hazard assessment approach where SLR is omitted or included as a constant sea‐level offset in a probabilistic calculation may misrepresent the impacts of climate‐change. In this paper, a general method called non‐stationary probabilistic tsunami hazard assessment (nPTHA), is developed to include the long‐term time‐varying changes in mean sea level. The nPTHA is based on a non‐stationary Poisson process model, which takes advantage of the independence of arrivals within non‐overlapping time‐intervals to specify a temporally varying hazard mean recurrence rate, affected by SLR. The nPTHA is applied to the South China Sea (SCS) for tsunamis generated by earthquakes in the Manila Subduction Zone. The method provides unique and comprehensive results for inundation hazard, combining tsunami and SLR at a specific location over a given exposure time. The results show that in the SCS, SLR has a significant impact when its amplitude is comparable to that of tsunamis with moderate probability of exceedance. The SLR and its associated uncertainty produce an impact on nPTHA results comparable to that caused by the uncertainty in the earthquake recurrence model. These findings are site‐specific and must be analyzed for different regions. The proposed methodology, however, is sufficiently general to include other non‐stationary phenomena and can be exploited for other hazards affected by SLR.
Record-Setting Flare Spotted on the Nearest Star to the Sun
Authors: Kornei Katherine
Published: May 2021

Proxima Centauri recently let loose a blast of radiation, and ground- and space-based telescopes detected the record-setting event at wavelengths ranging from radio to the ultraviolet.
Application of Turbulent Diffusion Term of Aerosols in Mesoscale Model
Authors: Jia Wenxing , Zhang Xiaoye , Zhang Hongsheng , Ren Yan
Published: May 2021

The presence of unfavorable meteorological conditions triggers pollution, and then further weakens turbulence, especially in the stable boundary layer (SBL), which is a frequent situation in heavy pollution episodes in China. The inapplicability of the classical Monin‐Obukhov similarity theory and the uncertainty of the planetary boundary layer height can lead to large deviation of turbulent diffusion in the SBL in numerical simulations. However, in current mesoscale models, no term has been used to accurately describe the turbulent diffusion of aerosols. Therefore, we use the Mixing‐Length theory to obtain the turbulent diffusion term of aerosols based on high‐resolution observational data, and, for the first time, embed this term into a mesoscale model, which makes the turbulent diffusion process of aerosols more truly depicted. Results from a two‐way coupled atmospheric‐chemistry mesoscale model demonstrate that the turbulent diffusion term of aerosols can improve the problem of overestimated PM2.5 concentration in Eastern China.
Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics
Authors: Lam Max , Chen Chia-Yen , Ge Tian , Xia Yan , Hill David W. , Trampush Joey W. , Yu Jin , Knowles Emma , Davies Gail , Stahl Eli A. , Huckins Laura , Liewald David C. , Djurovic Srdjan , Melle Ingrid , Christoforou Andrea , Reinvang Ivar , DeRosse Pamela , Lundervold Astri J. , Steen Vidar M. , Espeseth Thomas , Räikkönen Katri , Widen Elisabeth , Palotie Aarno , Eriksson Johan G. , Giegling Ina , Konte Bettina , Hartmann Annette M. , Roussos Panos , Giakoumaki Stella , Burdick Katherine E. , Payton Antony , Ollier William , Chiba-Falek Ornit , Koltai Deborah C. , Need Anna C. , Cirulli Elizabeth T. , Voineskos Aristotle N. , Stefanis Nikos C. , Avramopoulos Dimitrios , Hatzimanolis Alex , Smyrnis Nikolaos , Bilder Robert M. , Freimer Nelson B. , Cannon Tyrone D. , London Edythe , Poldrack Russell A. , Sabb Fred W. , Congdon Eliza , Conley Emily Drabant , Scult Matthew A. , Dickinson Dwight , Straub Richard E. , Donohoe Gary , Morris Derek , Corvin Aiden , Gill Michael , Hariri Ahmad R. , Weinberger Daniel R. , Pendleton Neil , Bitsios Panos , Rujescu Dan , Lahti Jari , Le Hellard Stephanie , Keller Matthew C. , Andreassen Ole A. , Deary Ian J. , Glahn David C. , Huang Hailiang , Liu Chunyu , Malhotra Anil K. , Lencz Todd
Published: May 2021

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway
Authors: Lu Yuheng , Liu Liangliang , Pan Jianying , Luo Bingsheng , Zeng Hua , Shao Yan , Zhang Hongbo , Guan Hong , Guo Dong , Zeng Chun , Zhang Rongkai , Bai Xiaochun , Zhang Haiyan , Cai Daozhang
Published: May 2021

Milk fat globule-epidermal growth factor (EGF) factor 8 (MFG-E8), as a necessary bridging molecule between apoptotic cells and phagocytic cells, has been widely studied in various organs and diseases, while the effect of MFG-E8 in osteoarthritis (OA) remains unclear. Here, we identified MFG-E8 as a key factor mediating chondrocyte senescence and macrophage polarization and revealed its role in the pathology of OA. We found that MFG-E8 expression was downregulated both locally and systemically as OA advanced in patients with OA and in mice after destabilization of the medial meniscus surgery (DMM) to induce OA. MFG-E8 loss caused striking progressive articular cartilage damage, synovial hyperplasia, and massive osteophyte formation in OA mice, which was relieved by intra-articular administration of recombinant mouse MFG-E8 (rmMFG-E8). Moreover, MFG-E8 restored chondrocyte homeostasis, deferred chondrocyte senescence and reprogrammed macrophages to the M2 subtype to alleviate OA. Further studies showed that MFG-E8 was inhibited by miR-99b-5p, expression of which was significantly upregulated in OA cartilage, leading to exacerbation of experimental OA partially through activation of NF-κB signaling in chondrocytes. Our findings established an essential role of MFG-E8 in chondrocyte senescence and macrophage reprogramming during OA, and identified intra-articular injection of MFG-E8 as a potential therapeutic target for OA prevention and treatment.
Muscle regeneration controlled by a designated DNA dioxygenase
Authors: Wang Hongye , Huang Yile , Yu Ming , Yu Yang , Li Sheng , Wang Huating , Sun Hao , Li Bing , Xu Guoliang , Hu Ping
Published: May 2021

Tet dioxygenases are responsible for the active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2, but not Tet1 and Tet3, is specifically required for muscle regeneration in vivo. Loss of Tet2 leads to severe muscle regeneration defects. Further analysis indicates that Tet2 regulates myoblast differentiation and fusion. Tet2 activates transcription of the key differentiation modulator Myogenin (MyoG) by actively demethylating its enhancer region. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 enhances MyoD binding by demethylating the flanking CpG sites of E boxes to facilitate the recruitment of active histone modifications and increase chromatin accessibility and activate its transcription. These findings shed new lights on DNA methylation and pioneer transcription factor activity regulation.
FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation
Authors: Vaz Sara , Ferreira Fábio J. , Macedo Joana C. , Leor Gil , Ben-David Uri , Bessa José , Logarinho Elsa
Published: May 2021

Inhibition of spindle microtubule (MT) dynamics has been effectively used in cancer treatment. Although the mechanisms by which MT poisons elicit mitotic arrest are fairly understood, efforts are still needed towards elucidating how cancer cells respond to antimitotic drugs owing to cytotoxicity and resistance side effects. Here, we identified the critical G2/M transcription factor Forkhead box M1 (FOXM1) as a molecular determinant of cell response to antimitotics. We found FOXM1 repression to increase death in mitosis (DiM) due to upregulation of the BCL-2 modifying factor (BMF) gene involved in anoikis, an apoptotic process induced upon cell detachment from the extracellular matrix. FOXM1 binds to a BMF intronic cis-regulatory element that interacts with both the BMF and the neighbor gene BUB1B promoter regions, to oppositely regulate their expression. This mechanism ensures that cells treated with antimitotics repress BMF and avoid DiM when FOXM1 levels are high. In addition, we show that this mechanism is partly disrupted in anoikis/antimitotics-resistant tumor cells, with resistance correlating with lower BMF expression but in a FOXM1-independent manner. These findings provide a stratification biomarker for antimitotic chemotherapy response.
Long non-coding RNA Xist regulates oocyte loss via suppressing miR-23b-3p/miR-29a-3p maturation and upregulating STX17 in perinatal mouse ovaries
Authors: Zhou Meng , Liu Xiaoqiu , Qiukai E. , Shang Yanxing , Zhang Xiaoqian , Liu Shuting , Zhang Xuesen
Published: May 2021

The fecundity of female mammals is resolved by the limited size of the primordial follicle (PF) pool formed perinatally. The establishment of PF pool is accompanied by a significant programmed oocyte death. Long non-coding RNAs (lncRNA) are central modulators in regulating cell apoptosis or autophagy in multiple diseases, however, the significance of lncRNAs governing perinatal oocyte loss remains unknown. Here we find that Yin-Yang 1 (YY1) directly binds to the lncRNA X-inactive-specific transcript (Xist) promoter and facilitates Xist expression in the perinatal mouse ovaries. Xist is highly expressed in fetal ovaries and sharply downregulated along with the establishment of PF pool after birth. Gain or loss of function analysis reveals that Xist accelerates oocyte autophagy, mainly through binding to pre-miR-23b or pre-miR-29a in the nucleus and preventing the export of pre-miR-23b/pre-miR-29a to the cytoplasm, thus resulting in decreased mature of miR-23b-3p/miR-29a-3p expression and upregulation miR-23b-3p/miR-29a-3p co-target, STX17, which is essential for timely control of the degree of oocyte death in prenatal mouse ovaries. Overall, these findings identify Xist as a key non-protein factor that can control the biogenesis of miR-23b-3p/miR-29a-3p, and this YY1-Xist-miR-23b-3p/miR-29a-3p-STX17 regulatory axis is responsible for perinatal oocyte loss through autophagy.
Understanding disorder and linker deficiency in porphyrinic zirconium-based metal–organic frameworks by resolving the Zr8O6 cluster conundrum in PCN-221
Authors: Koschnick Charlotte , Stäglich Robert , Scholz Tanja , Terban Maxwell W. , von Mankowski Alberto , Savasci Gökcen , Binder Florian , Schökel Alexander , Etter Martin , Nuss Jürgen , Siegel Renée , Germann Luzia S. , Ochsenfeld Christian , Dinnebier Robert E. , Senker Jürgen , Lotsch Bettina V.
Published: May 2021

Porphyrin-based metal–organic frameworks (MOFs), exemplified by MOF-525, PCN-221, and PCN-224, are promising systems for catalysis, optoelectronics, and solar energy conversion. However, subtle differences between synthetic protocols for these three MOFs give rise to vast discrepancies in purported product outcomes and description of framework topologies. Here, based on a comprehensive synthetic and structural analysis spanning local and long-range length scales, we show that PCN-221 consists of Zr6O4(OH)4 clusters in four distinct orientations within the unit cell, rather than Zr8O6 clusters as originally published, and linker vacancies at levels of around 50%, which may form in a locally correlated manner. We propose disordered PCN-224 (dPCN-224) as a unified model to understand PCN-221, MOF-525, and PCN-224 by varying the degree of orientational cluster disorder, linker conformation and vacancies, and cluster–linker binding. Our work thus introduces a new perspective on network topology and disorder in Zr-MOFs and pinpoints the structural variables that direct their functional properties.
Twin boundary defect engineering improves lithium-ion diffusion for fast-charging spinel cathode materials
Authors: Wang Rui , Chen Xin , Huang Zhongyuan , Yang Jinlong , Liu Fusheng , Chu Mihai , Liu Tongchao , Wang Chaoqi , Zhu Weiming , Li Shuankui , Li Shunning , Zheng Jiaxin , Chen Jie , He Lunhua , Jin Lei , Pan Feng , Xiao Yinguo
Published: May 2021

Defect engineering on electrode materials is considered an effective approach to improve the electrochemical performance of batteries since the presence of a variety of defects with different dimensions may promote ion diffusion and provide extra storage sites. However, manipulating defects and obtaining an in-depth understanding of their role in electrode materials remain challenging. Here, we deliberately introduce a considerable number of twin boundaries into spinel cathodes by adjusting the synthesis conditions. Through high-resolution scanning transmission electron microscopy and neutron diffraction, the detailed structures of the twin boundary defects are clarified, and the formation of twin boundary defects is attributed to agminated lithium atoms occupying the Mn sites around the twin boundary. In combination with electrochemical experiments and first-principles calculations, we demonstrate that the presence of twin boundaries in the spinel cathode enables fast lithium-ion diffusion, leading to excellent fast charging performance, namely, 75% and 58% capacity retention at 5 C and 10 C, respectively. These findings demonstrate a simple and effective approach for fabricating fast-charging cathodes through the use of defect engineering.
Dynamic manipulation of droplets using mechanically tunable microtextured chemical gradients
Authors: Mazaltarim Ali J. , Bowen John J. , Taylor Jay M. , Morin Stephen A.
Published: May 2021

Materials and strategies applicable to the dynamic transport of microdroplets are relevant to surface fluidics, self-cleaning materials, thermal management systems, and analytical devices. Techniques based on electrowetting, topographic micropatterns, and thermal/chemical gradients have advanced considerably, but dynamic microdroplet transport remains a challenge. This manuscript reports the fabrication of mechano-tunable, microtextured chemical gradients on elastomer films and their use in controlled microdroplet transport. Specifically, discreet mechanical deformations of these films enabled dynamic tuning of the microtextures and thus transport along surface-chemical gradients. The interplay between the driving force of the chemical gradient and the microtopography was characterized, facilitating accurate prediction of the conditions (droplet radius and roughness) which supported transport. In this work, the use of microtextured surface chemical gradients in mechano-adaptive materials with microdroplet manipulation functionality was highlighted.
Epigenomic profiling of primate lymphoblastoid cell lines reveals the evolutionary patterns of epigenetic activities in gene regulatory architectures
Authors: García-Pérez Raquel , Esteller-Cucala Paula , Mas Glòria , Lobón Irene , Di Carlo Valerio , Riera Meritxell , Kuhlwilm Martin , Navarro Arcadi , Blancher Antoine , Di Croce Luciano , Gómez-Skarmeta José Luis , Juan David , Marquès-Bonet Tomàs
Published: May 2021

Changes in the epigenetic regulation of gene expression have a central role in evolution. Here, we extensively profiled a panel of human, chimpanzee, gorilla, orangutan, and macaque lymphoblastoid cell lines (LCLs), using ChIP-seq for five histone marks, ATAC-seq and RNA-seq, further complemented with whole genome sequencing (WGS) and whole genome bisulfite sequencing (WGBS). We annotated regulatory elements (RE) and integrated chromatin contact maps to define gene regulatory architectures, creating the largest catalog of RE in primates to date. We report that epigenetic conservation and its correlation with sequence conservation in primates depends on the activity state of the regulatory element. Our gene regulatory architectures reveal the coordination of different types of components and highlight the role of promoters and intragenic enhancers (gE) in the regulation of gene expression. We observe that most regulatory changes occur in weakly active gE. Remarkably, novel human-specific gE with weak activities are enriched in human-specific nucleotide changes. These elements appear in genes with signals of positive selection and human acceleration, tissue-specific expression, and particular functional enrichments, suggesting that the regulatory evolution of these genes may have contributed to human adaptation.
Yeast cell fate control by temporal redundancy modulation of transcription factor paralogs
Authors: Wu Yan , Wu Jiaqi , Deng Minghua , Lin Yihan
Published: May 2021

Recent single-cell studies have revealed that yeast stress response involves transcription factors that are activated in pulses. However, it remains unclear whether and how these dynamic transcription factors temporally interact to regulate stress survival. Here we show that budding yeast cells can exploit the temporal relationship between paralogous general stress regulators, Msn2 and Msn4, during stress response. We find that individual pulses of Msn2 and Msn4 are largely redundant, and cells can enhance the expression of their shared targets by increasing their temporal divergence. Thus, functional redundancy between these two paralogs is modulated in a dynamic manner to confer fitness advantages for yeast cells, which might feed back to promote the preservation of their redundancy. This evolutionary implication is supported by evidence from Msn2/Msn4 orthologs and analyses of other transcription factor paralogs. Together, we show a cell fate control mechanism through temporal redundancy modulation in yeast, which may represent an evolutionarily important strategy for maintaining functional redundancy between gene duplicates.
Rapid fabrication of complex nanostructures using room-temperature ultrasonic nanoimprinting
Authors: Ge Junyu , Ding Bin , Hou Shuai , Luo Manlin , Nam Donguk , Duan Hongwei , Gao Huajian , Lam Yee Cheong , Li Hong
Published: May 2021

Despite its advantages of scalable process and cost-effectiveness, nanoimprinting faces challenges with imprinting hard materials (e.g., crystalline metals) at low/room temperatures, and with fabricating complex nanostructures rapidly (e.g., heterojunctions of metal and oxide). Herein, we report a room temperature ultrasonic nanoimprinting technique (named nanojackhammer) to address these challenges. Nanojackhammer capitalizes on the concentration of ultrasonic energy flow at nanoscale to shape bulk materials into nanostructures. Working at room temperature, nanojackhammer allows rapid fabrication of complex multi-compositional nanostructures made of virtually all solid materials regardless of their ductility, hardness, reactivity and melting points. Atomistic simulations reveal a unique alternating dislocation generation and recovery mechanism that significantly reduces the imprinting force under ultrasonic cyclic loading. As a proof-of-concept, a metal-oxide-metal plasmonic nanostructure with built-in nanogap is rapidly fabricated and employed for biosensing. As a fast, scalable, and cost-effective nanotechnology, nanojackhammer will enable various unique applications of complex nanostructures in optoelectronics, biosensing, catalysis and beyond.
The use of live food as a vehicle of soybean meal for nutritional programming of largemouth bass Micropterus salmoides
Authors: Molinari Giovanni S. , Wojno Michal , Kwasek Karolina
Published: May 2021

Nutritional Programming (NP) has been studied as a means of improving dietary plant protein (PP) utilization in different fish species. This study investigated the use of enriched live feed as a vehicle for NP in larval fish. The objective of this study was to determine the effect of NP induced during the larval stage via PP-enriched live feed on: (1) growth performance; (2) expression of genes associated with inflammation and any morphological changes in the intestine; and (3) muscle free amino acid composition in largemouth bass (Micropterus salmoides) during its later life stages. Two diets were used in this study, a fish meal (FM)-based diet, and a soybean mean (SBM)-based diet, serving as the PP diet. There were 4 groups in this study. The two control groups, ( +) Control and (−) Control, were not programmed and received the FM-diet and SBM-diet, respectively throughout the whole trial after the live feed stage (27–122 days post hatch (dph). The next group, programmed, was programmed with SBM-enriched Artemia nauplii during the live feed stage (4–26 dph) and challenged with the SBM-diet during the final stage of the study (79–122 dph). The final group, non-programmed, did not receive any programming and, was challenged with the SBM-diet during the final stage of the study. The programmed group experienced a significantly higher (%) weight gain during the PP-Challenge than the non-programmed group. In addition, the live feed programming resulted in significantly longer distal villi, and a higher villi length to width ratio, compared to the non-programmed group. No significant effects on free amino acid composition and gene expression were observed between the programmed and non-programmed group, except for an increased post-prandial concentration of free proline in the programmed group. The results of this study support use of live feed as a vehicle for nutritional programming and improving the growth performance of largemouth bass fed with a SBM-based diet.
Comprehensive assessment of left atrial and ventricular remodeling in paroxysmal atrial fibrillation by the cardiovascular magnetic resonance myocardial extracellular volume fraction and feature tracking strain
Authors: Yamada Akimasa , Hashimoto Naoki , Fujito Hidesato , Hatta Takumi , Saito Yuki , Otsuka Naoto , Wakamatsu Yuji , Arai Masaru , Watanabe Ryuta , Kurokawa Sayaka , Kitano Daisuke , Nagashima Koichi , Yoda Shunichi , Okumura Yasuo
Published: May 2021

Atrial fibrillation (AF) is a progressive disease that starts with structural or functional changes in the left atrium and left ventricle, and evolves from paroxysmal toward sustained forms. Early detection of structural or functional changes in the left atrium and left ventricle in the paroxysmal stage could be useful for identifying a higher risk of progression to persistent AF and future cardio-cerebrovascular events. The aim of this study was to test the hypothesis that the feature tracking (FT) left atrial (LA) strain and left ventricular (LV) extracellular volume fraction (ECV) derived from cardiovascular magnetic resonance (CMR) could detect early changes in remodeling of the left atrium and ventricle in the paroxysmal AF (PAF) stage. The participants were comprised of 106 PAF patients (age, 66.1 ± 10.7 years; 66% male) who underwent clinical CMR before pulmonary vein isolation and 20 control subjects (age, 68.3 ± 8.6 years; 55% male). The CMR-FT LA strain/phasic function and LV-ECV were compared between the PAF and control groups. The total and passive LA empty fraction (LAEF) and LA strain (corresponding to LA reservoir and conduit function) were decreased in the PAF group as compared to the control group. However, active LAEF (corresponding to the LA booster pump function) did not differ significantly between the PAF group (33.9 ± 10.9%) and control group (37.9 ± 13.3%, p = 0.15), while the active LA strain (corresponding to the LA booster pump function) was significantly decreased in the PAF group (11.4 ± 4.3 vs. 15.2 ± 5.6%, p = 0.002). The LV-ECV was significantly greater in the PAF group (28.7 ± 2.8%) than control group (26.6 ± 2.0%, p = 0.002). In the PAF group, the LV-ECV correlated significantly with the E/e′ and LA volume index. Regarding the LA strain, correlations were seen between the LV-ECV and both the reservoir function and conduit function. CMR-FT LA strain in combination with the LV-ECV in a single clinical study offers a potential imaging marker that identifies LA/LV remodeling including subtle LA booster pump dysfunction undetectable by the conventional booster pump LAEF in the PAF stage.
Kinship of conditionally immortalized cells derived from fetal bone to human bone-derived mesenchymal stroma cells
Authors: Marozin S. , Simon-Nobbe B. , Irausek S. , Chung L. W. K. , Lepperdinger G.
Published: May 2021

The human fetal osteoblast cell line (hFOB 1.19) has been proposed as an accessible experimental model for study of osteoblast biology relating to drug development and biomaterial engineering. For their multilineage differentiation potential, hFOB has been compared to human mesenchymal progenitor cells and used to investigate bone-metabolism in vitro. Hereby, we studied whether and to what extent the conditionally immortalized cell line hFOB 1.19 can serve as a surrogate model for bone-marrow derived mesenchymal stromal cells (bmMSC). hFOB indeed exhibit specific characteristics reminiscent of bmMSC, as colony formation, migration capacity and the propensity to grow as multicellular aggregates. After prolonged culture, in contrast to the expected effect of immortalization, hFOB acquired a delayed growth rate. In close resemblance to bmMSC at increasing passages, also hFOB showed morphological abnormalities, enlargement and finally reduced proliferation rates together with enhanced expression of the cell cycle inhibitors p21 and p16. hFOB not only have the ability to undergo multilineage differentiation but portray several important aspects of human bone marrow mesenchymal stromal cells. Superior to primary MSC and osteoblasts, hFOB enabled the generation of continuous cell lines. These provide an advanced basis for investigating age-related dysfunctions of MSCs in an in vitro 3D-stem cell microenvironment.
Analysis of glucose metabolism by 18F-FDG-PET imaging and glucose transporter expression in a mouse model of intracerebral hemorrhage
Authors: Han Xiaoning , Ren Honglei , Nandi Ayon , Fan Xuanjia , Koehler Raymond C.
Published: May 2021

The relationship between cerebral glucose metabolism and glucose transporter expression after intracerebral hemorrhage (ICH) is unclear. Few studies have used positron emission tomography (PET) to explore cerebral glucose metabolism after ICH in rodents. In this study, we produced ICH in mice with an intrastriatal injection of collagenase to investigate whether glucose metabolic changes in 18F-fluoro-2-deoxy-D-glucose (FDG)-PET images are associated with expression of glucose transporters (GLUTs) over time. On days 1 and 3 after ICH, the ipsilateral striatum exhibited significant hypometabolism. However, by days 7 and 14, glucose metabolism was significantly higher in the ipsilateral striatum than in the contralateral striatum. The contralateral hemisphere did not show hypermetabolism at any time after ICH. Qualitative immunofluorescence and Western blotting indicated that the expression of GLUT1 in ipsilateral striatum decreased on days 1 and 3 after ICH and gradually returned to baseline by day 21. The 18F-FDG uptake after ICH was associated with expression of GLUT1 but not GLUT3 or GLUT5. Our data suggest that ipsilateral cerebral glucose metabolism decreases in the early stage after ICH and increases progressively in the late stage. Changes in 18F-FDG uptake on PET imaging are associated with the expression of GLUT1 in the ipsilateral striatum.
Controllable multichannel acousto-optic modulator and frequency synthesizer enabled by nonlinear MEMS resonator
Authors: Pillai Gayathri , Li Sheng-Shian
Published: May 2021

Nonlinear physics-based harmonic generators and modulators are critical signal processing technologies for optical and electrical communication. However, most optical modulators lack multi-channel functionality while frequency synthesizers have deficient control of output tones, and they additionally require vacuum, complicated setup, and high-power configurations. Here, we report a piezoelectrically actuated nonlinear Microelectromechanical System (MEMS) based Single-Input-Multiple-Output multi-domain signal processing unit that can simultaneously generate programmable parallel information channels (> 100) in both frequency and spatial domain. This significant number is achieved through the combined electromechanical and material nonlinearity of the Lead Zirconate Titanate thin film while still operating the device in an ambient environment at Complementary-Metal–Oxide–Semiconductor compatible voltages. By electrically detuning the operation point along the nonlinear regime of the resonator, the number of electrical and light-matter interaction signals generated based on higher-order non-Eigen modes can be controlled meticulously. This tunable multichannel generation enabled microdevice is a potential candidate for a wide variety of applications ranging from Radio Frequency communication to quantum photonics with an attractive MEMS-photonics monolithic integration ability.
Generation of somatic mitochondrial DNA-replaced cells for mitochondrial dysfunction treatment
Authors: Maeda Hideki , Kami Daisuke , Maeda Ryotaro , Shikuma Akira , Gojo Satoshi
Published: May 2021

Mitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.
Efficient and accurate identification of ear diseases using an ensemble deep learning model
Authors: Zeng Xinyu , Jiang Zifan , Luo Wen , Li Honggui , Li Hongye , Li Guo , Shi Jingyong , Wu Kangjie , Liu Tong , Lin Xing , Wang Fusen , Li Zhenzhang
Published: May 2021

Early detection and appropriate medical treatment are of great use for ear disease. However, a new diagnostic strategy is necessary for the absence of experts and relatively low diagnostic accuracy, in which deep learning plays an important role. This paper puts forward a mechanic learning model which uses abundant otoscope image data gained in clinical cases to achieve an automatic diagnosis of ear diseases in real time. A total of 20,542 endoscopic images were employed to train nine common deep convolution neural networks. According to the characteristics of the eardrum and external auditory canal, eight kinds of ear diseases were classified, involving the majority of ear diseases, such as normal, Cholestestoma of the middle ear, Chronic suppurative otitis media, External auditory cana bleeding, Impacted cerumen, Otomycosis external, Secretory otitis media, Tympanic membrane calcification. After we evaluate these optimization schemes, two best performance models are selected to combine the ensemble classifiers with real-time automatic classification. Based on accuracy and training time, we choose a transferring learning model based on DensNet-BC169 and DensNet-BC1615, getting a result that each model has obvious improvement by using these two ensemble classifiers, and has an average accuracy of 95.59%. Considering the dependence of classifier performance on data size in transfer learning, we evaluate the high accuracy of the current model that can be attributed to large databases. Current studies are unparalleled regarding disease diversity and diagnostic precision. The real-time classifier trains the data under different acquisition conditions, which is suitable for real cases. According to this study, in the clinical case, the deep learning model is of great use in the early detection and remedy of ear diseases.
Micron-scale human enamel layer characterization after orthodontic bracket debonding by intensity-based layer segmentation in optical coherence tomography images
Authors: Ravichandran Naresh Kumar , Lakshmikantha Hemanth Tumkur , Park Hyo-Sang , Jeon Mansik , Kim Jeehyun
Published: May 2021

In clinical orthodontic practice, fixed brackets are widely used for tooth movement and adjustments. Although years of research and development have improved the workability of fixed orthodontic brackets, there are still controversies regarding its plausible destructive influence on the enamel surface of tooth. This, in turn, makes the quantitative assessment of the enamel surface after specific orthodontic treatment procedures important in order to opt for the most effective treatment procedure. Through this study, we show the practical applicability of optical coherence tomography (OCT) as a non-ionizing and nondestructive assessment tool for measuring enamel loss after each step of orthodontic bracket bonding. Two-dimensional and volumetric OCT images are used for the evaluation of the tooth enamel. From the depth intensity profile analysis of cross-sectional OCT images, the changes in the individual internal layer thickness are calculated. A software algorithm was developed to evaluate the structural connectivity in the enamel for analyzing enamel loss on the tooth surface and for detecting enamel abrasion. An intensity-based layer segmentation algorithm is also developed to analyze and evaluate enamel wear in the tooth after each step. Using the proposed algorithms, the total enamel present after each treatment procedure was measured and tabulated for analysis.
Modified leaky competing accumulator model of decision making with multiple alternatives: the Lie-algebraic approach
Authors: Lo Chi-Fai , Ip Ho-Yan
Published: May 2021

In this communication, based upon the stochastic Gompertz law of population growth, we have reformulated the Leaky Competing Accumulator (LCA) model with multiple alternatives such that the positive-definiteness of evidence accumulation is automatically satisfied. By exploiting the Lie symmetry of the backward Kolmogorov equation (or Fokker–Planck equation) assoicated with the modified model and applying the Wei–Norman theorem, we have succeeded in deriving theN-dimensional joint probability density function (p.d.f.) and marginal p.d.f. for each alternative in closed form. With this joint p.d.f., a likelihood function can be constructed and thus model-fitting procedures become feasible. We have also demonstrated that the calibration of model parameters based upon the Monte Carlo simulated time series is indeed both efficient and accurate. Moreover, it should be noted that the proposed Lie-algebraic approach can also be applied to tackle the modified LCA model with time-varying parameters.
Gut microbiota composition in health-care facility-and community-onset diarrheic patients with Clostridioides difficile infection
Authors: Herrera Giovanny , Vega Laura , Patarroyo Manuel Alfonso , Ramírez Juan David , Muñoz Marina
Published: May 2021

The role of gut microbiota in the establishment and development of Clostridioides difficile infection (CDI) has been widely discussed. Studies showed the impact of CDI on bacterial communities and the importance of some genera and species in recovering from and preventing infection. However, most studies have overlooked important components of the intestinal ecosystem, such as eukaryotes and archaea. We investigated the bacterial, archaea, and eukaryotic intestinal microbiota of patients with health-care-facility- or community-onset (HCFO and CO, respectively) diarrhea who were positive or negative for CDI. The CDI-positive groups (CO/+, HCFO/+) showed an increase in microorganisms belonging to Bacteroidetes, Firmicutes, Proteobacteria, Ascomycota, and Opalinata compared with the CDI-negative groups (CO/−, HCFO/−). Patients with intrahospital-acquired diarrhea (HCFO/+, HCFO/−) showed a marked decrease in bacteria beneficial to the intestine, and there was evidence of increased Archaea and Candida and Malassezia species compared with the CO groups (CO/+, CO/−). Characteristic microbiota biomarkers were established for each group. Finally, correlations between bacteria and eukaryotes indicated interactions among the different kingdoms making up the intestinal ecosystem. We showed the impact of CDI on microbiota and how it varies with where the infection is acquired, being intrahospital-acquired diarrhea one of the most influential factors in the modulation of bacterial, archaea, and eukaryotic populations. We also highlight interactions between the different kingdoms of the intestinal ecosystem, which need to be evaluated to improve our understanding of CDI pathophysiology.
The prognostic value of galactosylceramide-sulfotransferase (Gal3ST1) in human renal cell carcinoma
Authors: Porubsky Stefan , Nientiedt Malin , Kriegmair Maximilian C. , Siemoneit Jörn-Helge Heinrich , Sandhoff Roger , Jennemann Richard , Borgmann Hendrik , Gaiser Timo , Weis Cleo-Aron , Erben Philipp , Hielscher Thomas , Popovic Zoran V.
Published: May 2021

Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.
Efficacy, safety and tolerability of drugs studied in phase 3 randomized controlled trials in solid tumors over the last decade
Authors: Ribnikar Domen , Goldvaser Hadar , Veitch Zachary W. , Ocana Alberto , Templeton Arnoud J. , Šeruga Boštjan , Amir Eitan
Published: May 2021

Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials. Less is known about the balance between efficacy and toxicity of drugs studied in unselected phase 3 randomized controlled trials (RCTs) including those not resulting in regulatory approval. We searched Clinicaltrials.gov to identify phase 3 RCTs in patients with advanced breast, colorectal, lung, or prostate cancer completed between January 2005 and October 2016. We extracted efficacy and safety data from publications. For efficacy hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were extracted. For safety, we computed odds ratios (ORs) and 95% confidence intervals (CIs) for toxic death, treatment discontinuation without progression and commonly reported grade 3/4 adverse events (AEs). Data were then pooled in a meta-analysis. Of 377 RCTs identified initially, 143 RCTs comprising 88,603 patients were included in the analysis. Of these, 79 (57%) trials met their primary endpoint. Compared to control groups, both PFS (HR 0.80; 95% CI 0.78–0.82) and OS (HR 0.87; 95% CI 0.85–0.89) were improved with experimental drugs. Toxic death (OR 1.14; 95% CI 1.03–1.27), treatment discontinuation without progression (OR 1.64; 95% CI 1.56–1.71) and grade 3/4 AEs were also more common with experimental drugs compared to respective control group therapy. Just over half of phase 3 RCTs in common solid tumors met their primary endpoint and in nearly half, experimental therapy had worse safety compared to control arms.
Efficacy of continuous apical negative ultrasonic irrigation (CANUI) in penetration of simulated lateral canals in extracted teeth
Authors: Castelo-Baz Pablo , Lozano Francisco J. Rodríguez , Ginzo-Villamayor María J. , Vila Ramón Miguéns , Seoane-Romero Juan , Martín-Cruces José , Martín-Biedma Benjamín
Published: May 2021

The aim of this study was to evaluate the efficacy of continuous apical negative ultrasonic irrigation into simulated lateral canals and the apical third in straight and curved root canals. Two simulated lateral canals were created 2, 4 and 6 mm from the working length in 120 single-rooted teeth (6 canals/tooth, n = 360 straight, n = 360 curved). The teeth were randomly divided into 3 experimental groups: positive pressure irrigation (PPI) (n = 20); passive ultrasonic irrigation (PUI) (n = 20); continuous apical negative ultrasonic irrigation (CANUI) (n = 20). 20% Chinese ink was added to a 5% sodium hypochlorite solution and delivered into the root canals. The results showed a significantly higher (P < 0.05) penetration of irrigant into the lateral canals and up to working length in the CANUI group for straight and curved roots. CANUI improves penetration into the lateral canals and up to the working length of the cleared teeth in straight and curved roots.