bluuebunny/crossref_metadata_2025 huggingface dataset:
NNMT promotes the progression of intrahepatic cholangiocarcinoma by regulating aerobic glycolysis via the EGFR-STAT3 axis
Authors: Lu Shounan , Ke Shanjia , Wang Chaoqun , Xu Yanan , Li Zihao , Song Keda , Bai Miaoyu , Zhou Menghua , Yu Hongjun , Yin Bing , Li Xinglong , Feng Zhigang , Hua Yongliang , Pan Shangha , Jiang Hongchi , Li Linqiang , Wu Yaohua , Ma Yong
Published: July 2022

Nicotinamide N-methyltransferase (NNMT), a member of the N-methyltransferase family, plays an important role in tumorigenesis. However, its expression and biological functions in intrahepatic cholangiocarcinoma (iCCA) remain to be established. In our study, we identified NNMT as an oncogene in iCCA and provided mechanistic insights into the roles of NNMT in iCCA progression. High NNMT expression in iCCA tissues was identified using western blotting and immunohistochemistry (IHC). We identified a significantly higher NNMT expression level in human iCCA tissues than that in adjacent normal tissues. Increased NNMT expression promoted iCCA cell proliferation and metastasis in vitro and in vivo. Mechanistically, NNMT inhibited the level of histone methylation in iCCA cells by consuming the methyl donor S-adenosyl methionine (SAM), thereby promoting the expression of epidermal growth factor receptor (EGFR). EGFR may activate the aerobic glycolysis pathway in iCCA cells by activating the STAT3 signaling pathway. In conclusion, we identified NNMT as an oncogene in iCCA and provided mechanistic insights into the roles of NNMT in iCCA progression.
ANGPTL8 is a negative regulator in pathological cardiac hypertrophy
Authors: Hu Lin , Wei Jiarui , Zhang Yue , Wang Ziyuan , Tang Junming , Tang Jian , Gao Yujiu , Zhang Xiaoqiao , Li Yifan , Liu Yantong , Ma Shinan , Guo Xingrong , Zhang Qiufang
Published: July 2022

Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.
JAK2-CHK2 signaling safeguards the integrity of the mitotic spindle assembly checkpoint and genome stability
Authors: Chowdhury Md Al Nayem , Wang Shih-Wei , Suen Ching-Shu , Hwang Ming-Jing , Hsueh Yi-An , Shieh Sheau-Yann
Published: July 2022

Checkpoint kinase 2 (CHK2) plays an important role in safeguarding the mitotic progression, specifically the spindle assembly, though the mechanism of regulation remains poorly understood. Here, we identified a novel mitotic phosphorylation site on CHK2 Tyr156, and its responsible kinase JAK2. Expression of a phospho-deficient mutant CHK2 Y156F or treatment with JAK2 inhibitor IV compromised mitotic spindle assembly, leading to genome instability. In contrast, a phospho-mimicking mutant CHK2 Y156E restored mitotic normalcy in JAK2-inhibited cells. Mechanistically, we show that this phosphorylation is required for CHK2 interaction with and phosphorylation of the spindle assembly checkpoint (SAC) kinase Mps1, and failure of which results in impaired Mps1 kinetochore localization and defective SAC. Concordantly, analysis of clinical cancer datasets revealed that deletion of JAK2 is associated with increased genome alteration; and alteration in CHEK2 and JAK2 is linked to preferential deletion or amplification of cancer-related genes. Thus, our findings not only reveal a novel JAK2-CHK2 signaling axis that maintains genome integrity through SAC but also highlight the potential impact on genomic stability with clinical JAK2 inhibition.
The role of N6-methyladenosine-modified non-coding RNAs in the pathological process of human cancer
Authors: Luo Lin , Zhen Yingwei , Peng Dazhao , Wei Cheng , Zhang Xiaoyang , Liu Xianzhi , Han Lei , Zhang Zhenyu
Published: July 2022

Non-coding RNAs (ncRNAs) account for the majority of the widespread transcripts of mammalian genomes. They rarely encode proteins and peptides, but their regulatory role is crucial in numerous physiological and pathological processes. The m6A (N6-methyladenosine) modification is one of the most common internal RNA modifications in eukaryotes and is associated with all aspects of RNA metabolism. Accumulating researches have indicated a close association between m6A modification and ncRNAs, and suggested m6A-modified ncRNAs played a crucial role in tumor progression. The correlation between m6A modification and ncRNAs offers a novel perspective for investigating the potential mechanisms of cancer pathological processes, which suggests that both m6A modification and ncRNAs are critical prognostic markers and therapeutic targets in numerous malignancies. In the present report, we summarized the interaction between m6A modification and ncRNA, emphasizing how their interaction regulates pathological processes in cancer.
Orexin neurons inhibit sleep to promote arousal
Authors: De Luca Roberto , Nardone Stefano , Grace Kevin P. , Venner Anne , Cristofolini Michela , Bandaru Sathyajit S. , Sohn Lauren T. , Kong Dong , Mochizuki Takatoshi , Viberti Bianca , Zhu Lin , Zito Antonino , Scammell Thomas E. , Saper Clifford B. , Lowell Bradford B. , Fuller Patrick M. , Arrigoni Elda
Published: July 2022

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.
N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis
Authors: Ma Xiaojie , Cao Jie , Zhou Ziyu , Lu Yunkun , Li Qin , Jin Yan , Chen Guo , Wang Weiyun , Ge Wenyan , Chen Xi , Hu Zhensheng , Shu Xiao , Deng Qian , Pu Jiaqi , Liang Chengzhen , Fu Junfen , Liu Jianzhao , Zhu Saiyong
Published: July 2022

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.
People infer communicative action through an expectation for efficient communication
Authors: Royka Amanda , Chen Annie , Aboody Rosie , Huanca Tomas , Jara-Ettinger Julian
Published: July 2022

Humans often communicate using body movements like winks, waves, and nods. However, it is unclear how we identify when someone’s physical actions are communicative. Given people’s propensity to interpret each other’s behavior as aimed to produce changes in the world, we hypothesize that people expect communicative actions to efficiently reveal that they lack an external goal. Using computational models of goal inference, we predict that movements that are unlikely to be produced when acting towards the world and, in particular, repetitive ought to be seen as communicative. We find support for our account across a variety of paradigms, including graded acceptability tasks, forced-choice tasks, indirect prompts, and open-ended explanation tasks, in both market-integrated and non-market-integrated communities. Our work shows that the recognition of communicative action is grounded in an inferential process that stems from fundamental computations shared across different forms of action interpretation.
In situ atomic-scale observation of dislocation climb and grain boundary evolution in nanostructured metal
Authors: Chu Shufen , Liu Pan , Zhang Yin , Wang Xiaodong , Song Shuangxi , Zhu Ting , Zhang Ze , Han Xiaodong , Sun Baode , Chen Mingwei
Published: July 2022

Non-conservative dislocation climb plays a unique role in the plastic deformation and creep of crystalline materials. Nevertheless, the underlying atomic-scale mechanisms of dislocation climb have not been explored by direct experimental observations. Here, we report atomic-scale observations of grain boundary (GB) dislocation climb in nanostructured Au during in situ straining at room temperature. The climb of a edge dislocation is found to occur by stress-induced reconstruction of two neighboring atomic columns at the edge of an extra half atomic plane in the dislocation core. This is different from the conventional belief of dislocation climb by destruction or construction of a single atomic column at the dislocation core. The atomic route of the dislocation climb we proposed is demonstrated to be energetically favorable by Monte Carlo simulations. Our in situ observations also reveal GB evolution through dislocation climb at room temperature, which suggests a means of controlling microstructures and properties of nanostructured metals.
Efficient use of cement and concrete to reduce reliance on supply-side technologies for net-zero emissions
Authors: Watari Takuma , Cao Zhi , Hata Sho , Nansai Keisuke
Published: July 2022

Decarbonization strategies for the cement and concrete sector have relied heavily on supply-side technologies, including carbon capture and storage (CCS), masking opportunities for demand-side intervention. Here we show that cross-cutting strategies involving both the supply and demand sides can achieve net-zero emissions by 2050 across the entire Japanese cement and concrete cycle without resorting to mass deployment of CCS. Our analysis shows that a series of mitigation efforts on the supply side can reduce 2050 CO2 emissions by up to 80% from baseline levels and that the remaining 20% mitigation gap can be fully bridged by the efficient use of cement and concrete in the built environment. However, this decarbonization pathway is dependent on how CO2 uptake by carbonation and carbon capture and utilization is accounted for in the inventory. Our analysis underscores the importance of including demand-side interventions at the heart of decarbonization strategies and highlights the urgent need to discuss how to account for CO2 uptake in national inventories under the Paris Agreement.
Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children
Authors: Chan Jo-Anne , Loughland Jessica R. , de la Parte Lauren , Okano Satomi , Ssewanyana Isaac , Nalubega Mayimuna , Nankya Felistas , Musinguzi Kenneth , Rek John , Arinaitwe Emmanuel , Tipping Peta , Bourke Peter , Andrew Dean , Dooley Nicholas , SheelaNair Arya , Wines Bruce D. , Hogarth P. Mark , Beeson James G. , Greenhouse Bryan , Dorsey Grant , Kamya Moses , Hartel Gunter , Minigo Gabriela , Feeney Margaret , Jagannathan Prasanna , Boyle Michelle J.
Published: July 2022

T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies are boosted in children with current infection, and are higher in females. The children with the very highest antibody levels have increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.
Low-defect-density WS2 by hydroxide vapor phase deposition
Authors: Wan Yi , Li En , Yu Zhihao , Huang Jing-Kai , Li Ming-Yang , Chou Ang-Sheng , Lee Yi-Te , Lee Chien-Ju , Hsu Hung-Chang , Zhan Qin , Aljarb Areej , Fu Jui-Han , Chiu Shao-Pin , Wang Xinran , Lin Juhn-Jong , Chiu Ya-Ping , Chang Wen-Hao , Wang Han , Shi Yumeng , Lin Nian , Cheng Yingchun , Tung Vincent , Li Lain-Jong
Published: July 2022

Two-dimensional (2D) semiconducting monolayers such as transition metal dichalcogenides (TMDs) are promising channel materials to extend Moore’s Law in advanced electronics. Synthetic TMD layers from chemical vapor deposition (CVD) are scalable for fabrication but notorious for their high defect densities. Therefore, innovative endeavors on growth reaction to enhance their quality are urgently needed. Here, we report that the hydroxide W species, an extremely pure vapor phase metal precursor form, is very efficient for sulfurization, leading to about one order of magnitude lower defect density compared to those from conventional CVD methods. The field-effect transistor (FET) devices based on the proposed growth reach a peak electron mobility ~200 cm2/Vs (~800 cm2/Vs) at room temperature (15 K), comparable to those from exfoliated flakes. The FET device with a channel length of 100 nm displays a high on-state current of ~400 µA/µm, encouraging the industrialization of 2D materials.
Immune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults
Authors: Kared Hassen , Wolf Asia-Sophia , Alirezaylavasani Amin , Ravussin Anthony , Solum Guri , Tran Trung The , Lund-Johansen Fridtjof , Vaage John Torgils , Nissen-Meyer Lise Sofie , Nygaard Unni C. , Hungnes Olav , Robertson Anna H. , Næss Lisbeth Meyer , Trogstad Lill , Magnus Per , Munthe Ludvig A. , Mjaaland Siri
Published: July 2022

The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.
Actuating compact wearable augmented reality devices by multifunctional artificial muscle
Authors: Kim Dongjin , Kim Baekgyeom , Shin Bongsu , Shin Dongwook , Lee Chang-Kun , Chung Jae-Seung , Seo Juwon , Kim Yun-Tae , Sung Geeyoung , Seo Wontaek , Kim Sunil , Hong Sunghoon , Hwang Sungwoo , Han Seungyong , Kang Daeshik , Lee Hong-Seok , Koh Je-Sung
Published: July 2022

An artificial muscle actuator resolves practical engineering problems in compact wearable devices, which are limited to conventional actuators such as electromagnetic actuators. Abstracting the fundamental advantages of an artificial muscle actuator provides a small-scale, high-power actuating system with a sensing capability for developing varifocal augmented reality glasses and naturally fit haptic gloves. Here, we design a shape memory alloy-based lightweight and high-power artificial muscle actuator, the so-called compliant amplified shape memory alloy actuator. Despite its light weight (0.22 g), the actuator has a high power density of 1.7 kW/kg, an actuation strain of 300% under 80 g of external payload. We show how the actuator enables image depth control and an immersive tactile response in the form of augmented reality glasses and two-way communication haptic gloves whose thin form factor and high power density can hardly be achieved by conventional actuators.
Paracrine-mediated rejuvenation of aged mesenchymal stem cells is associated with downregulation of the autophagy-lysosomal pathway
Authors: Hung George , Ashvetiya Tamara , Leszczynska Aleksandra , Yang Wanjun , Hwang Chao-Wei , Gerstenblith Gary , Barth Andreas S. , Johnston Peter V.
Published: July 2022

Age-related differences in stem-cell potency contribute to variable outcomes in clinical stem cell trials. To help understand the effect of age on stem cell potency, bone marrow-derived mesenchymal stem cells (MSCs) were isolated from young (6 weeks) and old (18–24 months) mice. HUVEC tubule formation (TF) induced by the old and young MSCs and ELISA of conditioned media were compared to one another, and to old MSCs after 7 d in indirect co-culture with young MSCs. Old MSCs induced less TF than did young (1.56 ± 0.11 vs 2.38 ± 0.17, p = 0.0003) and released lower amounts of VEGF (p = 0.009) and IGF1 (p = 0.037). After 7 d in co-culture with young MSCs, TF by the old MSCs significantly improved (to 2.09 ± 0.18 from 1.56 ± 0.11; p = 0.013), and was no longer different compared to TF from young MSCs (2.09 ± 0.18 vs 2.38 ± 0.17; p = 0.27). RNA seq of old MSCs, young MSCs, and old MSCs following co-culture with young MSCs revealed that the age-related differences were broadly modified by co-culture, with the most significant changes associated with lysosomal pathways. These results indicate that the age-associated decreased paracrine-mediated effects of old MSCs are improved following indirect co-culture with young MSC. The observed effect is associated with broad transcriptional modification, suggesting potential targets to both assess and improve the therapeutic potency of stem cells from older patients.
Flexible microfluidic nanoplasmonic sensors for refreshable and portable recognition of sweat biochemical fingerprint
Authors: He Xuecheng , Fan Chuan , Luo Yong , Xu Tailin , Zhang Xueji
Published: July 2022

Wearable sweat sensors with various sensing systems can provide noninvasive medical diagnostics and healthcare monitoring. Here, we demonstrate a wearable microfluidic nanoplasmonic sensor capable of refreshable and portable recognition fingerprint information of targeted biomarkers including urea, lactate, and pH in sweat. A miniature, thin plasmonic metasurface with homogeneous mushroom-shaped hot spots and high surface-enhanced Raman scattering (SERS) activity is designed and integrated into a microfluidics platform. Compared to conventional wearable SERS platforms with the risk of mixed effect between new and old sweat, the microfluidic SERS system allows sweat administration in a controllable and high temporal-resolution fashion, providing refreshable SERS analysis. We use a portable and customized Raman analyzer with a friendly human-machine interface for portable recognition of the spectroscopic signatures of sweat biomarkers. This study integrates epidermal microfluidics with portable SERS molecular recognition, presenting a controllable, handy, and dynamical biofluid sensing system for personalized medicine.
Early detection and surveillance of SARS-CoV-2 genomic variants in wastewater using COJAC
Authors: Jahn Katharina , Dreifuss David , Topolsky Ivan , Kull Anina , Ganesanandamoorthy Pravin , Fernandez-Cassi Xavier , Bänziger Carola , Devaux Alexander J. , Stachler Elyse , Caduff Lea , Cariti Federica , Corzón Alex Tuñas , Fuhrmann Lara , Chen Chaoran , Jablonski Kim Philipp , Nadeau Sarah , Feldkamp Mirjam , Beisel Christian , Aquino Catharine , Stadler Tanja , Ort Christoph , Kohn Tamar , Julian Timothy R. , Beerenwinkel Niko
Published: July 2022

The continuing emergence of SARS-CoV-2 variants of concern and variants of interest emphasizes the need for early detection and epidemiological surveillance of novel variants. We used genomic sequencing of 122 wastewater samples from three locations in Switzerland to monitor the local spread of B.1.1.7 (Alpha), B.1.351 (Beta) and P.1 (Gamma) variants of SARS-CoV-2 at a population level. We devised a bioinformatics method named COJAC (Co-Occurrence adJusted Analysis and Calling) that uses read pairs carrying multiple variant-specific signature mutations as a robust indicator of low-frequency variants. Application of COJAC revealed that a local outbreak of the Alpha variant in two Swiss cities was observable in wastewater up to 13 d before being first reported in clinical samples. We further confirmed the ability of COJAC to detect emerging variants early for the Delta variant by analysing an additional 1,339 wastewater samples. While sequencing data of single wastewater samples provide limited precision for the quantification of relative prevalence of a variant, we show that replicate and close-meshed longitudinal sequencing allow for robust estimation not only of the local prevalence but also of the transmission fitness advantage of any variant. We conclude that genomic sequencing and our computational analysis can provide population-level estimates of prevalence and fitness of emerging variants from wastewater samples earlier and on the basis of substantially fewer samples than from clinical samples. Our framework is being routinely used in large national projects in Switzerland and the UK.
Reference genome assemblies reveal the origin and evolution of allohexaploid oat
Authors: Peng Yuanying , Yan Honghai , Guo Laichun , Deng Cao , Wang Chunlong , Wang Yubo , Kang Lipeng , Zhou Pingping , Yu Kaiquan , Dong Xiaolong , Liu Xiaomeng , Sun Zongyi , Peng Yun , Zhao Jun , Deng Di , Xu Yinghong , Li Ying , Jiang Qiantao , Li Yan , Wei Liming , Wang Jirui , Ma Jian , Hao Ming , Li Wei , Kang Houyang , Peng Zhengsong , Liu Dengcai , Jia Jizeng , Zheng Youliang , Ma Tao , Wei Yuming , Lu Fei , Ren Changzhong
Published: July 2022

Common oat (Avena sativa) is an important cereal crop serving as a valuable source of forage and human food. Although reference genomes of many important crops have been generated, such work in oat has lagged behind, primarily owing to its large, repeat-rich polyploid genome. Here, using Oxford Nanopore ultralong sequencing and Hi-C technologies, we have generated a reference-quality genome assembly of hulless common oat, comprising 21 pseudomolecules with a total length of 10.76 Gb and contig N50 of 75.27 Mb. We also produced genome assemblies for diploid and tetraploid Avena ancestors, which enabled the identification of oat subgenomes and provided insights into oat chromosomal evolution. The origin of hexaploid oat is inferred from whole-genome sequencing, chloroplast genomes and transcriptome assemblies of different Avena species. These findings and the high-quality reference genomes presented here will facilitate the full use of crop genetic resources to accelerate oat improvement.
A randomized, placebo-controlled clinical trial evaluating of a mouthwash containing Sambucus williamsii var. coreana extract for prevention of gingivitits
Authors: Kim Yu-Rin , Nam Seoul-Hee
Published: July 2022

The purpose of this study is to verify the clinical applicability by applying a mouthwash containing Sambucus williamsii var. coreana extract for preventing periodontal disease. A randomized, double-blind, placebo-controlled study was conducted on 64 patients, excluding those with insufficient data, who visited M dental clinic located in Busan, Korea. Thirty-two people were assigned respectively to the saline solution gargle group and the Sambucus williamsii var. coreana extract gargle group to conduct the O'Leary index, plaque index (PI), gingival index (GI), and subgingival plaques. For the homogeneity of the two groups, scaling was carried out one week before the experiment, and the participants were taught for oral care to conduct during the study period. SPSS 24.0 for Windows (IBM Corp., Armonk, NY, USA) was used to compare the saline solution gargle group and the Sambucus williamsii var. coreana extract gargle group as well as to analyze Baseline (before gargle application), Treatment (immediately after gargle application), and After 5 Days (5 days after gargle application). There was a significant difference in the O'Leary index, PI, GI and subgingival plaques after Treatment and After 5 days (p < 0.05). Also, the periodontal-related indexes improved as the application time increased in the Sambucus williamsii var. coreana extract gargle group. The antibacterial effect was also shown for gram-positive bacteria and gram-negative bacteria in subgingival plaques as the application time increased. The use of the mouthwash containing Sambucus williamsii var. coreana extract was found to be effective for oral periodontal-related indicators and bacteria causing periodontal disease. Therefore, using a mouthwash containing Sambucus williamsii var. coreana extract, a natural drug, will possibly maintain healthy periodontal health by inhibiting and preventing the progression of periodontal disease.
An integrated framework for breast mass classification and diagnosis using stacked ensemble of residual neural networks
Authors: Baccouche Asma , Garcia-Zapirain Begonya , Elmaghraby Adel S.
Published: July 2022

A computer-aided diagnosis (CAD) system requires automated stages of tumor detection, segmentation, and classification that are integrated sequentially into one framework to assist the radiologists with a final diagnosis decision. In this paper, we introduce the final step of breast mass classification and diagnosis using a stacked ensemble of residual neural network (ResNet) models (i.e. ResNet50V2, ResNet101V2, and ResNet152V2). The work presents the task of classifying the detected and segmented breast masses into malignant or benign, and diagnosing the Breast Imaging Reporting and Data System (BI-RADS) assessment category with a score from 2 to 6 and the shape as oval, round, lobulated, or irregular. The proposed methodology was evaluated on two publicly available datasets, the Curated Breast Imaging Subset of Digital Database for Screening Mammography (CBIS-DDSM) and INbreast, and additionally on a private dataset. Comparative experiments were conducted on the individual models and an average ensemble of models with an XGBoost classifier. Qualitative and quantitative results show that the proposed model achieved better performance for (1) Pathology classification with an accuracy of 95.13%, 99.20%, and 95.88%; (2) BI-RADS category classification with an accuracy of 85.38%, 99%, and 96.08% respectively on CBIS-DDSM, INbreast, and the private dataset; and (3) shape classification with 90.02% on the CBIS-DDSM dataset. Our results demonstrate that our proposed integrated framework could benefit from all automated stages to outperform the latest deep learning methodologies.
Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment
Authors: Salman Ibrahim M. , Ameer Omar Z. , McMurray Sheridan , Hassan Sarah F. , Sridhar Arun , Lewis Stephen J. , Hsieh Yee-Hsee
Published: July 2022

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.
COVID-19 symptom severity predicts neutralizing antibody activity in a community-based serological study
Authors: Sancilio Amelia , Schrock Joshua M. , Demonbreun Alexis R. , D’Aquila Richard T. , Mustanski Brian , Vaught Lauren A. , Reiser Nina L. , Velez Matt P. , Hsieh Ryan R. , Ryan Daniel T. , Saber Rana , McNally Elizabeth M. , McDade Thomas W.
Published: July 2022

Serological testing for SARS-CoV-2 IgG antibodies is used to assess their presence in blood samples from exposed individuals and provides a measure of the magnitude of immune response to infection. The measurement of neutralizing antibodies (NAbs) in particular provides information about the severity of prior infection and level of protective immunity against re-infection. Much of the work investigating the association between prior infection severity and NAb levels has been conducted among clinical populations, and less is known about this relationship in the general population. Accordingly, we utilize data from a large (n = 790) community-based cohort of unvaccinated, seropositive participants. We analyzed the association between NAb response, measured via surrogate virus neutralization assay, with patterns of symptoms and household exposure. Our results indicate no detectable NAb activity in 63.8% of the seropositive participants (n = 504). Those with detectable NAb levels demonstrated a positive relationship between NAb activity and both self-reported previous symptom severity and household exposure. These findings are significant in light of recent concerns about degree of protective immunity conferred by prior infection or vaccination, and we highlight the value of community-based research for investigating variation in immune response.
Critical structural elements for the antigenicity of wheat allergen LTP1 (Tri a 14) revealed by site-directed mutagenesis
Authors: Mameri Hamza , Gaudin Jean-Charles , Lollier Virginie , Tranquet Olivier , Brossard Chantal , Pietri Manon , Marion Didier , Codreanu-Morel Fanny , Beaudouin Etienne , Wien Frank , Gohon Yann , Briozzo Pierre , Denery-Papini Sandra
Published: July 2022

Lipid transfer proteins (LTPs) were identified as allergens in a large variety of pollens and foods, including cereals. LTPs belong to the prolamin superfamily and display an α-helical fold, with a bundle of four α-helices held together by four disulfide bonds. Wheat LTP1 is involved in allergic reactions to food. To identify critical structural elements of antibody binding to wheat LTP1, we used site-directed mutagenesis on wheat recombinant LTP1 to target: (i) sequence conservation and/or structure flexibility or (ii) each disulfide bond. We evaluated the modifications induced by these mutations on LTP1 secondary structure by synchrotron radiation circular dichroism and on its antigenicity with patient’s sera and with mouse monoclonal antibodies. Disruption of the C28–C73 disulfide bond significantly affected IgE-binding and caused protein denaturation, while removing C13–C27 bond decreased LTP1 antigenicity and slightly modified LTP1 overall folding. In addition, we showed Lys72 to be a key residue; the K72A mutation did not affect global folding but modified the local 3D structure of LTP1 and strongly reduced IgE-binding. This work revealed a cluster of residues (C13, C27, C28, C73 and K72), four of which embedded in disulfide bonds, which play a critical role in LTP1 antigenicity.
Dynamical stochastic simulation of complex electrical behavior in neuromorphic networks of metallic nanojunctions
Authors: Mambretti F. , Mirigliano M. , Tentori E. , Pedrani N. , Martini G. , Milani P. , Galli D. E.
Published: July 2022

Nanostructured Au films fabricated by the assembling of nanoparticles produced in the gas phase have shown properties suitable for neuromorphic computing applications: they are characterized by a non-linear and non-local electrical behavior, featuring switches of the electric resistance whose activation is typically triggered by an applied voltage over a certain threshold. These systems can be considered as complex networks of metallic nanojunctions where thermal effects at the nanoscale cause the continuous rearrangement of regions with low and high electrical resistance. In order to gain a deeper understanding of the electrical properties of this nano granular system, we developed a model based on a large three dimensional regular resistor network with non-linear conduction mechanisms and stochastic updates of conductances. Remarkably, by increasing enough the number of nodes in the network, the features experimentally observed in the electrical conduction properties of nanostructured gold films are qualitatively reproduced in the dynamical behavior of the system. In the activated non-linear conduction regime, our model reproduces also the growing trend, as a function of the subsystem size, of quantities like Mutual and Integrated Information, which have been extracted from the experimental resistance series data via an information theoretic analysis. This indicates that nanostructured Au films (and our model) possess a certain degree of activated interconnection among different areas which, in principle, could be exploited for neuromorphic computing applications.
Geographic social inequalities in information-seeking response to the COVID-19 pandemic in China: longitudinal analysis of Baidu Index
Authors: Wang Zhicheng , Xiao Hong , Lin Leesa , Tang Kun , Unger Joseph M.
Published: July 2022

The outbreak of the COVID-19 pandemic alarmed the public and initiated the uptake of preventive measures. However, the manner in which the public responded to these announcements, and whether individuals from different provinces responded similarly during the COVID-19 pandemic in China, remains largely unknown. We used an interrupted time-series analysis to examine the change in Baidu Search Index of selected COVID-19 related terms associated with the COVID-19 derived exposure variables. We analyzed the daily search index in Mainland China using segmented log-normal regressions with data from Jan 2017 to Mar 2021. In this longitudinal study of nearly one billion internet users, we found synchronous increases in COVID-19 related searches during the first wave of the COVID-19 pandemic and subsequent local outbreaks, irrespective of the location and severity of each outbreak. The most precipitous increase occurred in the week when most provinces activated their highest level of response to public health emergencies. Search interests increased more as Human Development Index (HDI) -an area level measure of socioeconomic status—increased. Searches on the index began to decline nationwide after the initiation of mass-scale lockdowns, but statistically significant increases continued to occur in conjunction with the report of major sporadic local outbreaks. The intense interest in COVID-19 related information at virtually the same time across different provinces indicates that the Chinese government utilizes multiple channels to keep the public informed of the pandemic. Regional socioeconomic status influenced search patterns.
Multi-parametric analyses to investigate dependencies of normal left atrial strain by cardiovascular magnetic resonance feature tracking
Authors: Eckstein Jan , Körperich Hermann , Paluszkiewicz Lech , Burchert Wolfgang , Piran Misagh
Published: July 2022

Left-atrial (LA) strain is the result of complex hemodynamics, which may be better characterized using a multiparametric approach. Cardiovascular magnetic resonance (CMR) feature tracking was used to perform a comprehensive LA strain assessment of 183 enrolled healthy volunteers (11–70 years, 97 females, median 32.9 ± 28.3 years). Novel strain dependencies were assessed using multi-parametric regression (MPR) analyses. LA volumetric data, left ventricular strain, transmitral and pulmonary venous blood flow parameters were utilized to create clusters for MPR of all subjects and a heart rate controlled subgroup (pulse: 60–75/min, N = 106). The LA reservoir(r) and conduit(c) strains of the total cohort were significantly elevated (p ≤ 0.001) in women (r: 49.7 ± 12.9%, c: 32.0 ± 11.0%) compared to men (r: 42.9 ± 11.4%, c: 26.1 IQ 10.5%). In contrast, there were no gender-specific differences (p > 0.05) for subgroup LA reservoir, conduit and booster(b) strains (all, r: 47.3 ± 12.7%; c: 29.0 IQ 15.5%; b: 17.6 ± 5.4%) and strain rates (all, 2.1 IQ 1.0 s−1; − 2.9 IQ 1.5 s−1; − 2.3 IQ 1.0 s−1). MPR found large effect sizes (|R2|≥ 0.26) for correlations between strain and various cardiac functional parameters. Largest effect size was found for the association between LA conduit strain and LA indexed booster volume, LA total ejection fraction, left ventricular global radial strain and E-wave (|R2|= 0.437). In addition to providing normal values for sex-dependent LA strain and strain rate, no gender differences were found with modified heart rate. MPR analyses of LA strain/strain rate and various cardiac functional parameters revealed that heart rate control improved goodness-of-fit for the overall model.
Fluid structure interaction study of non-Newtonian Casson fluid in a bifurcated channel having stenosis with elastic walls
Authors: Shahzad Hasan , Wang Xinhua , Ghaffari Abuzar , Iqbal Kaleem , Hafeez Muhammad Bilal , Krawczuk Marek , Wojnicz Wiktoria
Published: July 2022

Fluid–structure interaction (FSI) gained a huge attention of scientists and researchers due to its applications in biomedical and mechanical engineering. One of the most important applications of FSI is to study the elastic wall behavior of stenotic arteries. Blood is the suspension of various cells characterized by shear thinning, yield stress, and viscoelastic qualities that can be assessed by using non-Newtonian models. In this study we explored non-Newtonian, incompressible Casson fluid flow in a bifurcated artery with a stenosis. The two-dimensional Casson model is used to study the hemodynamics of the flow. The walls of the artery are supposed to be elastic and the stenosis region is constructed in both walls. Suitable scales are used to transform the nonlinear differential equations into a dimensionless form. The problem is formulated and discretized using Arbitrary Lagrangian–Eulerian (ALE) approach. The finite element method (FEM) technique is used to solve the system of equations, together with appropriate boundary conditions. The analysis is carried out for the Bingham number, Hartmann number, and Reynolds number. The graphical results of pressure field, velocity profile, and load on the walls are assessed and used to study the influence of hemodynamic effects on stenotic arteries, bifurcation region, and elastic walls. This study shows that there is an increase in wall shear stresses (WSS) with increasing values of Bingham number and Hartmann number. Also, for different values of the Bingham number, the load on the upper wall is computed against the Hartmann number. The result indicate that load at the walls increases as the values of Bingham number and Hartmann number increase.
Relationship between sprint, jump, dynamic balance with the change of direction on young soccer players' performance
Authors: Falces-Prieto Moisés , González-Fernández Francisco Tomás , García-Delgado Gabriel , Silva Rui , Nobari Hadi , Clemente Filipe Manuel
Published: July 2022

The aim of the present paper was to determine the relationship between linear sprinting and jump performance, dynamic balance and change of direction on young soccer players. Ninety-four healthy young highly trained male soccer players belonging to the same high-performance academy agreed to participate in the study [twenty-seven soccer players U16 (14.8 ± 0.4 years; height: 170.6 ± 5.6 cm; body mass 64.7 ± 8.4 kg)] and [sixty-seven soccer players U19 (16.6 ± 1.3 years; height: 173.7 ± 7.2 cm; body mass 66.7 ± 8.0 kg)]. Participants completed 3 testing sessions, 7 days apart. Data from a CMJ, Crossover Hop Test, 10-m sprint test, 505 COD tests and the 90° COD test were collected. Moderate correlations were found in some of the cases (r values were between 0.2 and 0.5 in all cases, beingp < 0.05), indicating that linear sprinting, jumping performance and dynamic balance are influential factors in agility but are not the main limiting factor. The highest correlation was found between the cross-over hop test and the 505 COD test (r = 0.44;p < 0.001). The main evidence from the current study suggested that linear sprinting, jumping performance and dynamics balance are determinants of COD, namely explaining the variations in such a skill. The current study revealed that short-distance sprint and jumping performance significantly explain the variations of COD performance on young soccer players.
Identifying and characterising sources of variability in digital outcome measures in Parkinson’s disease
Authors: Roussos George , Herrero Teresa Ruiz , Hill Derek L. , Dowling Ariel V. , L. T. M. Müller Martijn , Evers Luc J. W. , Burton Jackson , Derungs Adrian , Fisher Katherine , Kilambi Krishna Praneeth , Mehrotra Nitin , Bhatnagar Roopal , Sardar Sakshi , Stephenson Diane , Adams Jamie L. , Ray Dorsey E. , Cosman Josh
Published: July 2022

Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson’s disease. Yet, only limited progress has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD. This paper introduces a conceptual framework to assist clinical research teams investigating a specific Concept of Interest within a particular Context of Use, to identify, characterise, and when possible, mitigate the influence of SoVs. We illustrate how this conceptual framework can be applied in practice through specific examples, including two data-driven case studies.
Learning plastic matching of robot dynamics in closed-loop central pattern generators
Authors: Ruppert Felix , Badri-Spröwitz Alexander
Published: July 2022

Animals achieve agile locomotion performance with reduced control effort and energy efficiency by leveraging compliance in their muscles and tendons. However, it is not known how biological locomotion controllers learn to leverage the intelligence embodied in their leg mechanics. Here we present a framework to match control patterns and mechanics based on the concept of short-term elasticity and long-term plasticity. Inspired by animals, we design a robot, Morti, with passive elastic legs. The quadruped robot Morti is controlled by a bioinspired closed-loop central pattern generator that is designed to elastically mitigate short-term perturbations using sparse contact feedback. By minimizing the amount of corrective feedback on the long term, Morti learns to match the controller to its mechanics and learns to walk within 1 h. By leveraging the advantages of its mechanics, Morti improves its energy efficiency by 42% without explicit minimization in the cost function.