bluuebunny/crossref_metadata_2025 huggingface dataset:
Night-Restricted Feeding Improves Gut Health by Synchronizing Microbe-Driven Serotonin Rhythm and Eating Activity-Driven Body Temperature Oscillations in Growing Rabbits
Authors: Wang Qiang-Jun , Guo Yao , Zhang Ke-Hao , Zhang Lei , Geng Shi-Xia , Shan Chun-Hua , Liu Peng , Zhu Meng-Qi , Jin Qiong-Yu , Liu Zhong-Ying , Wang Mei-Zhi , Li Ming-Yong , Liu Man , An Lei , Tian Jian-Hui , Wu Zhong-Hong
Published: December 2021

The circadian misalignment of the gut microbiota caused by unusual eating times in adult animals is related to disease development. However, whether the composition and diurnal rhythm of gut microbiota can be optimized by synchronizing the window period of eating with natural eating habits to reduce the risk of diarrhea remains unclear, especially in growing animals. In this study, 108 5-week-old weaned rabbits (nocturnal animals) were randomly subjected to daytime feeding (DF) and night-restricted feeding (NRF). At age 12 weeks, six rabbits were selected from each group, and caecum and cecal contents, as well as serum samples were collected at 4-h intervals during 24 h. Overall, NRF was found to reduce the risk of diarrhea in growing rabbits, improved the diurnal rhythm and abundance of beneficial microorganisms, along with the production of beneficial metabolites, whereas reduced the abundance of potential pathogens (Synergistes, Desulfovibrio, and Alistipes). Moreover, NRF improved diurnal rhythm of tryptophan hydroxylase isoform 1 and serotonin. Furthermore, NRF strengthened the diurnal amplitude of body core temperature, and promoted the diurnal expression of intestinal clock genes (BMAL1, CLOCK, REV-ERBα, and PER1), and genes related to the regulation of the intestinal barrier (CLAUDIN-1), and intestinal epithelial cell self-proliferation and renewal (BMI1). In vitro simulation experiments further revealed that synchronization of microbial-driven serotonin rhythm and eating activity-driven body temperature oscillations, which are important zeitgebers, could promote the diurnal expression of clock genes and CLAUDIN-1 in rabbit intestinal epithelial cells (RIEC), and enhance RIEC proliferation. This is the first study to reveal that NRF reprograms the diurnal rhythm of the gut microbiome, promotes the diurnal expression of clock genes and tight junction genes via synchronization of microbial-driven serotonin rhythm and eating activity-driven body temperature oscillations, thereby improving intestinal health and reducing the risk of diarrhea in growing rabbits. Collectively, these results provide a new perspective for the healthy feeding and management of growing animals.
Digital Therapeutics: Virtual Coaching Powered by Artificial Intelligence on Real-World Data
Authors: op den Akker Harm , Cabrita Miriam , Pnevmatikakis Aristodemos
Published: December 2021

An ever-increasing number of people need to cope with one or more chronic conditions for a significant portion of their life. Digital Therapeutics (DTx) focused on the prevention, management, or treatment of chronic diseases are promising in alleviating the personal socio-economic burden caused. In this paper we describe a proposed DTx methodology covering three main components: observation (which data is collected), understanding (how to acquire knowledge based on the data collected), and coaching (how to communicate the acquired knowledge to the user). We focus on an emerging form of automated virtual coaching, delivered through conversational agents allowing interaction with end-users using natural language. Our methodology will be applied in the new generation of the Healthentia platform, an eClinical solution that captures clinical outcomes from mobile, medical and Internet of Things (IoT) devices, using a patient-centric mobile application and offers Artificial Intelligence (AI) driven smart services. While we are unable to provide data to prove its effectiveness, we illustrate the potential of the proposed architecture to deliver DTx by describing how the methodology can be applied to a use-case consisting of a clinical trial for treatment of a chronic condition, combining testing of a new medication and a lifestyle intervention, which will be partly implemented and evaluated in the context of the European research project RE-SAMPLE (REal-time data monitoring for Shared, Adaptive, Multi-domain and Personalised prediction, and decision making for Long-term Pulmonary care Ecosystems).
circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation
Authors: Kong Peng , Li Chang-Lin , Dou Yong-Qing , Cao Li , Zhang Xiao-Yun , Zhang Wen-Di , Bi Ze-Qi , Peng Zu-Yi , Yan An-Qi , Han Mei
Published: December 2021

Vascular smooth muscle cell (VSMC) senescence is a major driver of neointimal formation. We have demonstrated that circ-Sirt1 derived from the SIRT1 gene suppressed VSMC inflammation and neointimal formation. However, the effect of circ-Sirt1 inhibiting inflammation on VSMC senescence during neointimal hyperplasia remains to be elucidated. Here, we showed that circ-Sirt1 was highly expressed in young and healthy arteries, which was decreased in aged arteries and neointima of humans and mice. Overexpression of circ-Sirt1 delayed Ang II-induced VSMC senescence in vitro and ameliorated neointimal hyperplasia in vivo. Mechanically, circ-Sirt1 inhibited p53 activity at the levels of transcription and post-translation modulation. In detail, circ-Sirt1, on the one hand, interacted with and held p53 to block its nuclear translocation, and on the other hand, promoted SIRT1-mediated p53 deacetylation and inactivation. In conclusion, our data suggest that circ-Sirt1 is a novel p53 repressor in response senescence-inducing stimuli, and targeting circ-Sirt1 may be a promising approach to ameliorating aging-related vascular disease.
Case Report: Leaflet Thrombosis After Transcatheter Aortic Valve Replacement With Worsening Heart Failure—A Successful Resolution Using Non-vitamin K Antagonist Oral Anti-coagulant
Authors: Liang Kae-Woei , Yu Chu-Leng , Lin Wei-Wen , Lee Wen-Lieng
Published: December 2021

Background: Transcatheter aortic valve replacement (TAVR) is indicated for treating symptomatic severe aortic valve stenosis (AS) with intermediate-to-high surgical risks. Few reports are available on managing leaflet thrombosis after TAVR with worsening heart failure.

Case Summary: A 77-year-old man with severe AS and coronary artery disease (CAD) received a successful TAVR with Edwards Sapien 3 valve. A year later, the patient developed a worsening heart failure with pulmonary edema, new-onset atrial fibrillation (Af), an increase in mean trans-aortic valve pressure gradient to 48 mmHg, worsening mitral regurgitation (MR), and pulmonary hypertension (PH). The response of the patient to intravenous diuretics and inotropic treatments was poor. Multi-slice CT (MDCT) revealed hypo-attenuated thrombus and thickened transcatheter heart valve leaflets. A non-vitamin K antagonist oral anti-coagulant (NOAC) was added to treat the new-onset Af and leaflet thrombosis on top of the con-current single antiplatelet for CAD. A series of follow-up echocardiograms showed a progressive decrease in trans-aortic valve pressure gradient to 17 mmHg and reductions in MR and PH. Three months after the NOAC treatment, MDCT revealed the resolution of hypo-attenuated thrombus and thickened leaflets. Symptoms of heart failure were also improved gradually.

Discussion: Worsening heart failure or an increase in trans-aortic valve pressure gradient after TAVR warranted further MDCT studies. Leaflet thrombosis can be resolved after using NOAC as in our present case.
Normal Ranges of Right Atrial Strain and Strain Rate by Two-Dimensional Speckle-Tracking Echocardiography: A Systematic Review and Meta-Analysis
Authors: Hosseinsabet Ali , Mahmoudian Roshanak , Jalali Arash , Mohseni-Badalabadi Reza , Davarpasand Tahereh
Published: December 2021

Background: Normal range values of right atrial (RA) phasic function markers are essential for the identification of normal and abnormal values, comparison with reference values, and the clinical meaning of obtained values. Accordingly, we aimed to define the normal range values of RA phasic function markers obtained by 2D speckle-tracking echocardiography through a meta-analysis and determine the main sources of heterogeneity among reported values.

Methods: PUBMED, SCOPUS, and EMBASE databases were searched for the following keywords: “right atrial/right atrium” and “strain/speckle/deformation” and “echocardiography.” Studies were selected that included a human healthy adult group without any cardiovascular diseases or risk factors and that were written in the English language. For the calculation of each marker of RA phasic functions, a random-effect model was used. Meta-regression was employed to define the major sources of variabilities among reported values.

Results: Fifteen studies that included 2,469 healthy subjects were selected for analysis. The normal range values for RA strain and strain rate were 42.7% (95% CI, 39.4 to 45.9%) and 2.1 s−1 (95% CI, 2.0 to 2.1 s−1) during the reservoir phase, respectively, 23.6% (95% CI, 20.7 to 26.6%) and −1.9 s−1 (95% CI, −2.2 to −1.7 s−1) during the conduit phase, correspondingly, and 16.1% (95% CI, 13.6 to 18.6%) and −1.8 s−1 (95% CI, −2.0 to −1.5 s−1) during the contraction phase, respectively. The sources of heterogeneity for the normal range of these markers were the number of participants, the type of software, the method of global value calculation, the right ventricular fractional area change, the left ventricular (LV) ejection fraction, the RA volume index, sex, the heart rate, the diastolic blood pressure, the body mass index, and the body surface area.

Conclusions: Using 2D speckle-tracking echocardiography, we defined normal values for RA phasic function markers and identified the sources of heterogeneity as demographic, anthropometric, hemodynamic, and echocardiography factors.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021236578, identifier: CRD42021236578.
Fundamentals in Covid-19-Associated Thrombosis: Molecular and Cellular Aspects
Authors: Mizurini Daniella M. , Hottz Eugenio D. , Bozza Patrícia T. , Monteiro Robson Q.
Published: December 2021

The novel coronavirus disease (COVID-19) is associated with a high incidence of coagulopathy and venous thromboembolism that may contribute to the worsening of the clinical outcome in affected patients. Marked increased D-dimer levels are the most common laboratory finding and have been repeatedly reported in critically ill COVID-19 patients. The infection caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is followed by a massive release of pro-inflammatory cytokines, which mediate the activation of endothelial cells, platelets, monocytes, and neutrophils in the vasculature. In this context, COVID-19-associated thrombosis is a complex process that seems to engage vascular cells along with soluble plasma factors, including the coagulation cascade, and complement system that contribute to the establishment of the prothrombotic state. In this review, we summarize the main findings concerning the cellular mechanisms proposed for the establishment of COVID-19-associated thrombosis.
NAP1L5 Promotes Nucleolar Hypertrophy and Is Required for Translation Activation During Cardiomyocyte Hypertrophy
Authors: Guo Ningning , Zheng Di , Sun Jiaxin , Lv Jian , Wang Shun , Fang Yu , Zhao Zhenyi , Zeng Sai , Guo Qiuxiao , Tong Jingjing , Wang Zhihua
Published: December 2021

Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocytes (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas, immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome-related pathways are remarkably enriched in the down-regulated genes. Although Nap1l5-mediated gene regulation is correlated with PRC2 and PRC1, Nap1l5 does not directly alter the levels of global histone methylations at K4, K9, K27 or K36. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to promote protein synthesis in cardiomyocyte hypertrophy. This is attributable to a direct regulation of nucleolus hypertrophy and subsequent ribosome assembly. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.
In-vitro Assessment of Silver Diamine Fluoride Effect on Natural Carious Dentin Microhardness
Authors: Prakash Meghna , Kang Yoon H. , Jain Shruti , Zandona Andrea Ferreira
Published: December 2021

This study aimed to assess the effect of silver diamine fluoride (SDF) on natural carious dentin microhardness and the correlation between tactile sensation, fluorescence, and microhardness on carious dentin. Permanent carious teeth scored ICDAS 4–6 were longitudinally sectioned into tooth slabs exposing carious dentin on one side and sound dentin on the other. Both sides were assessed for tactile sensation (soft/leathery/firm), fluorescence (red/pink/no fluorescence) with FACE technology (SiroInspect®, Dentsply Sirona, USA), and Vickers's microhardness (VMH). Samples were randomized into 3 groups based on SDF protocol (n = 30): Control/Group A- No SDF treatment; Group B- 38% SDF (Advantage Arrest™, Elevate Oral Care®, USA); Group C- SDF with potassium iodide/KI (Riva Star, SDI, Australia). After SDF application, all samples were stored for 1 week under 100% humidity at 37°C and re-assessed for tactile sensation, fluorescence, and microhardness. Change in microhardness (ΔVMH; mean ± SD), tactile sensation (ΔT), and fluorescence (ΔF) were calculated using the difference between pre-SDF and post-SDF values. Mixed ANOVA analysis showed that ΔVMH of carious and sound surfaces were statistically significantly higher for each of the experimental groups (Group B-sound: 20.22 ± 11.98 HV, carious: 19.76 ± 9.35 HV; Group C-sound: 14.26 ± 10.11 HV, carious: 22.51 ± 7.67 HV) than the control group (Group A–sound: 7.34 ± 8.28 HV, carious: 0.69 ± 3.53 HV) (p < 0.0001). There was no statistically significant difference between the experimental groups themselves for carious surfaces (p = 0.146). On sound surfaces, Group B showed a statistically significantly higher ΔVMH than Group C (p = 0.026). There was no statistically significant interaction between type of surface and ΔVMH in Group B (p = 0.809). In Group C, sound surfaces showed a statistically significantly lower ΔVMH than carious surfaces (p < 0.0001). Spearman rank-order correlation showed a statistically significant negative correlation between ΔVMH and ΔT (rs = −0.588, p < 0.0001) and between ΔVMH and ΔF (rs = −0.269, p = 0.01). There was a statistically significant positive correlation between ΔT and ΔF (rs = 0.226, p = 0.032). In conclusion, the microhardness of SDF-treated dentin surfaces increased as compared to non-SDF-treated surfaces. SDF (Advantage Arrest™) increased microhardness of carious and sound dentin to a similar extent whereas, SDF/KI (Riva Star) increased microhardness of carious dentin more than sound dentin. An increase in microhardness was correlated with a firmer tactile sensation.
Permafrost Dynamics and Degradation in Polar Arctic From Satellite Radar Observations, Yamal Peninsula
Authors: Teshebaeva Kanayim , van Huissteden Ko J. , Echtler Helmut , Puzanov Alexander V. , Balykin Dmitry N. , Sinitsky Anton I. , Kovalevskaya Nelley M. , Dolman Han A. J.
Published: December 2021

We investigate permafrost surface features revealed from satellite radar data in the Siberian arctic at the Yamal peninsula. Surface dynamics analysis based on SRTM and TanDEM-X DEMs shows up to 2 m net loss of surface relief between 2000 and 2014 indicating a highly dynamic landscape. Surface features for the past 14 years reflect an increase in small stream channels and a number of new lakes that developed, likely caused by permafrost thaw. We used Sentinel-1 SAR imagery to measure permafrost surface changes. Owing to limited observation data we analyzed only 2 years. The InSAR time-series has detected surface displacements in three distinct spatial locations during 2017 and 2018. At these three locations, 60–120 mm/yr rates of seasonal surface permafrost changes are observed. Spatial location of seasonal ground displacements aligns well with lithology. One of them is located on marine sediments and is linked to anthropogenic impact on permafrost stability. Two other areas are located within alluvial sediments and are at the top of topographic elevated zones. We discuss the influence of the geologic environment and the potential effect of local upwelling of gas. These combined analyses of InSAR time-series with analysis of geomorphic features from DEMs present an important tool for continuous process monitoring of surface dynamics as part of a global warming risk assessment.
Facilitators Improve the Learning Experience of Visitors to a Science Centre
Authors: Machado Corral Soledad , Monteiro Paulo H. Nico , Pisani Katrina , Barriault Chantal L.
Published: December 2021

We studied how interactions with interpretative science centre staff impacts the learning behaviours and engagement levels of visitors who engage with exhibits at Science North (Sudbury, Canada). This study uses the Visitor-Based Learning Framework. The tool consists of seven discrete learning-associated behaviours that visitors show when engaging with exhibits, which are grouped into three categories of engagement: Initiation, Transition, and Breakthrough. These categories reflect increasing levels of engagement and depth of the learning experience. We studied forty-seven Science North exhibits, and 4,835 visitors to analyse the impact of unstructured facilitation in a naturalistic setting. We compared visitor Engagement Levels with and without a facilitator present. We determined that the presence of staff has a statistically significant impact on the percentage of visitors that engage in Breakthrough behaviours. When a facilitator is present, more visitors reach the Breakthrough Level of Engagement (p < 0.001). In the second phase of the study, we explored what facilitators do and say through thematic analysis to uncover common patterns of facilitator actions and comments. Our findings showed that facilitators employed strategies and methods that can be grouped in four categories or Facilitation Dimensions: Comfort, Information, Reflection, and Exhibit Use. These dimensions encompass different strategies and techniques of facilitation, that are used in a variety of situations and sequences. Our study goes beyond anecdotal evidence to show that staff-visitor interactions have a positive impact on visitor engagement with exhibits and therefore, potentially on visitor learning from exhibits. Our findings can be used to inform not only training programs but also managerial decisions and considerations around resource allocation. We suggest that facilitators are a fundamental asset for institutions that prioritize visitor engagement, one that should be given top priority when considering areas for investing.
Early Initiation of Temozolomide Therapy May Improve Response in Aggressive Pituitary Adenomas
Authors: Das Liza , Gupta Nidhi , Dutta Pinaki , Walia Rama , Vaiphei Kim , Rai Ashutosh , Radotra Bishan Dass , Gupta Kirti , Sreedharanunni Sreejesh , Ahuja Chirag Kamal , Bhansali Anil , Tripathi Manjul , Sood Ridhi , Dhandapani Sivashanmugam
Published: December 2021

Introduction

Aggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. The challenge lies in their early recognition and timely management. Temozolomide is increasingly being used in patients with APAs, but evidence supporting a favorable response with early initiation is lacking.

Methods

This was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m2). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O6-methylguanine-DNA methyltransferase (MGMT), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2) was performed, and h-scores (product of the number of positive cells and staining intensity) were calculated. Response was assessed in terms of radiological response using the RECIST criteria. Patients with controlled disease (≥30% reduction in tumor volume) were classified as responders.

Results

The study comprised 35 patients (48.6% acromegaly, 37.1% prolactinomas, and 14.3% non-functioning pituitary adenomas). The median number of temozolomide (TMZ) cycles was 9 (IQR 6–14). Responders constituted 68.6% of the cohort and were more likely to have functional tumors, a lower percentage of MGMT-positive staining cells, and lower MGMT h-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 vs. 15 months, p = 0.01). ROC-derived cutoffs of 31 months for the duration between diagnosis and TMZ initiation, low-to-intermediate MGMT positivity (40% tumor cells), and MGMT h-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.

Conclusion

Early initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.
Live Birth Rate in Patients With Premature Ovarian Insufficiency During Long-Term Follow-Up Under Hormone Replacement With or Without Ovarian Stimulation
Authors: Ishizuka Bunpei , Furuya Masataka , Kimura Machiko , Kamioka Eri , Kawamura Kazuhiro
Published: December 2021

We analyzed data from 466 patients with premature ovarian insufficiency (POI) who wished to have a biological child and were followed up while undergoing hormone replacement (HR) therapy with or without ovarian stimulation (OS) between April 2014 and December 2020. OS was conducted in 6891 cycles in 429 patients (Group OS), whereas only HR (Group HR) was conducted in 1117 cycles in 37 patients. The follicle growth rate was 48.3% (207/429) per patient in Group OS and 5.4% (2/37) in Group HR (p<0.01). There were 51 live births (LBs) in 50 patients during follow-up. In Group OS, the LB rate was 5.8% (47/807) in cycles where in vitro fertilization (IVF) and embryo transfer were attempted (Group IVF), and 1.3% (3/236) in cycles where intrauterine insemination/timed intercourse was attempted (p<0.01). No pregnancies occurred in Group HR. Among the patients in Group IVF, the LB rate was significantly higher in patients aged <35 years at the initiation of follow-up than in patients who started at later ages (p<0.01). Among the cases who achieved an LB, 39 were patients with idiopathic POI (Group IVF-1, n=297) and seven were patients who had undergone surgical treatment for benign ovarian tumors (Group IVF-2, n=50); however, no LBs occurred in patients who had undergone treatment for malignancy (n=17), and only one in patients with chromosomal abnormalities (n=22). The LB rate per case in the patients in Group IVF-1 and those aged <35 years at the start of follow-up (Group IVF-1-a) was 24.1% (26/108), which was higher than those of the other age groups. The LB rate per case in the patients in Group IVF-1-a with <4 years of amenorrhea was 37.3% (19/51), and that in the patients in Group IVF-2 with <4 years of amenorrhea was 21.2% (7/33). These results suggest that infertility treatment is possible in some patients with POI, especially those that can be classified in Group IVF-1-a and Group IVF-2 with <4 years of amenorrhea. Therefore, OS combined with HR therapy should be considered for such patients before attempts at oocyte donation.
Heavy Metals in Marine Surface Sediments of Daya Bay, Southern China: Spatial Distribution, Sources Apportionment, and Ecological Risk Assessment
Authors: Wang Huijuan , Fan Zhengqiu , Kuang Zexing , Yuan Yuan , Liu Huaxue , Huang Honghui
Published: December 2021

Daya Bay, especially in the northwestern region, which is a nature reserve with larval economic fish and shrimp populations, is no longer an unpolluted marine environment due to the recent increases in anthropogenic activities. This study collected seasonal surface sediment samples from 20 sites in northwestern Daya Bay to evaluate pollution and ecological risks and to identify possible sources and transport pathways of heavy metals (Cd, Pb, Cr, Cu, Zn, Hg, As). The results showed that all the heavy metal concentrations were below the established primary standard criteria, except for concentrations of Cr in spring, as well as Cu and Zn in autumn at several sampling stations, which had excess rates of 35, 4.76, and 4.76%, respectively. The geoaccumulation index (Igeo) values of heavy metals indicated that all sites had unpolluted to moderate pollution levels. In comparison to the samples collected in autumn, those in spring experienced a higher degree of pollution, particularly Cr and As. The ecological risk indices of heavy metals in sediments ranged from 225.86 to 734.20 in spring and from 196.69 to 567.52 in autumn, suggesting that most sites had a moderate ecological risk or a considerable ecological risk, and very few a had high ecological risk. Moreover, ArcGIS10.2 software was used to visualize their spatial distribution, and the results were similar in both spring and autumn. The results of the Pearson correlation analysis and principal component analysis showed that Cu, Hg, and Pb might be affected by anthropogenic activities, and As might be derived from natural sources such as atmospheric inputs. A cluster analysis showed that heavy metals were mainly affected by the negative impacts of human beings on the environment.
The Innovative Method of Purifying Polluted Air in the Region of an Inversion Layer
Authors: Jędrzejek F. , Gryboś D. , Zyśk J. , Leszczyński J. , Szarłowicz K. , Stobiński M. , Kubica B. , Suwała W.
Published: December 2021

Formation of the inversion layer causes a lack of vertical movement of the atmosphere and the occurrence of long-lasting high concentrations of pollution. The new invention makes use of shock waves, created by explosions of a mixture of flammable gases and air. These shock waves destroy the structure of the temperature inversion layer in the atmosphere and restore natural convection. Restoring vertical movements within the atmosphere causes a reduction in air pollution at the ground level. The system was tested at full technical scale in the environment. Preliminary effects indicate an average 24% reduction in PM10 concentration in the smog layer at ground level up to 20 m, with the device operating in 11-min series consisting of 66 explosions. It was also shown that the device is able to affect a larger area, at least 4 km2.
How Does Green Technology Innovation Affect Carbon Emissions? A Spatial Econometric Analysis of China’s Provincial Panel Data
Authors: Cai Aixin , Zheng Shiyong , Cai LiangHua , Yang Hongmei , Comite Ubaldo
Published: December 2021

Due to an increasing number of issues such as climate change, sustainable development has become an important theme worldwide. Sustainable development is inseparable from technological innovation. Only by making technological breakthroughs can we ensure the overall integration of economic development and environmental protection. Here, based on China’s inter-provincial panel data from 2006 to 2019, we examine the relationship between green technological innovation and carbon dioxide (CO2) emissions in 30 provinces (excluding Hong Kong, Macao, Taiwan, and Tibet) and sub-regions (eastern, central, and western China) in China using a space panel econometric model based on the STIRPAT equation. Additionally, we use geographic information analysis methods to analyze the spatial pattern and evolution characteristics of CO2 emissions. Our major finding is that, from the perspective of the whole country, green technology innovation has a negative correlation with carbon emissions, but the effect is not obvious. In addition, from the regional sample, green technology innovation in the eastern and central regions can effectively reduce carbon emissions, while in the western region, green technology innovation can promote carbon emissions in the province. At the same time, the research results show a strong spatial spillover effect of inter-provincial carbon dioxide emissions, and the progress of green technology in neighboring provinces has a negative impact on carbon emissions in their own provinces. Therefore, cross-province policies and actions for reducing carbon emissions are necessary. Additionally, our results show that carbon-emission driving factors, such as economic development, industrial structure, energy consumption structure, and population, have a significant positive effect on carbon dioxide emissions. Based on the above research results, we put forward corresponding policy recommendations.
Downregulation of hsa_circRNA_0001400 Helps to Promote Cell Apoptosis Through Disruption of the circRNA_0001400–miR-326 Sponge in Cervical Cancer Cells
Authors: Cai Yantao , Li Chuyu , Peng Fang , Yin Shuanghong , Liang Huiyi , Su Jiyan , Li Lin , Yang Anping , Liu Hui , Yang Chuansheng , Luo Dixian , Xia Chenglai
Published: December 2021

Background: In recent years, circular RNAs (circRNAs) have been reported to serve as essential regulators in several human cancers. Nevertheless, the function and mechanism of circRNAs in cervical cancer remain elusive.

Methods: Flow cytometry assays were performed to measure cell apoptosis and cell cycle. Colony Formation and transwell chamber were performed to measure cell migration and invasion. Double luciferase reporter for gene analysis was used to detect the interaction between hsa-circRNA_0001400, miR-326, and Akt. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. Tumor Xenograft Modeling was used to evaluate the effect of hsa_circRNA_0001400_siRNA in vivo.

Results: In the present study, we showed that hsa_circRNA_0001400 was highly expressed in cervical cancer tissues relative to in matched normal tissue. We found that hsa_circRNA_0001400_siRNA significantly promoted the apoptosis of cervical cancer cells and arrested the cell cycle and migration of cervical cancer cells. We showed that hsa_circRNA_0001400_siRNA can inhibit the protein expression of Akt and that the inhibition of miR-326 could rescue the inhibition of Akt in cervical cancer cells. We found that has-miR-326 was downregulated in cervical cancer tissues and hsa_circRNA_0001400_siRNA could increase the gene expression of has-miR-326. We also observed that hsa_circRNA_0001400_siRNA inhibited the growth and angiogenesis of SiHa xenografts in nude mice.

Conclusion: In conclusion, this study provides evidence that the hsa_circRNA_0001400–miR-326–Akt network promotes cervical cancer progression. Notably, our findings demonstrate the novel antitumor effects of hsa_circRNA_0001400_siRNA in cervical cancer.
X Chromosome Inactivation Pattern and Pregnancy Outcome of Female Carriers of Pathogenic Heterozygous X-Linked Deletions
Authors: Zhao Yuanyin , Li Jia , Dai Limeng , Ma Yongyi , Bai Yun , Guo Hong
Published: December 2021

Prenatal risk assessment of carriers of heterozygous X-linked deletion is a big challenge due to the phenotypic modification induced by X chromosome inactivation (XCI). Herein, we described four Chinese pedigrees with maternal-inherited X-deletions above 1 Mb. The pathogenic evaluation revealed that all X-deletions are harmful to heterozygous carriers; however, the asymptomatic pregnant female carriers in these families tremendously complicate the prognostic assessment of the unborn heterozygous embryos. In this study, we detected the XCI pattern of 11 female carriers of heterozygous X-linked deletions and 4 non-carrier females in these families and performed the first prenatal XCI pattern analysis in a fetal female carrier of heterozygous PCDH19-deletion to make risk prediction. In an adult female who lost one copy of the terminal of X chromosome short arm (Xp), a region enriching a large number of XCI escapees, the expression level of representative XCI escape genes was also detected. Pregnancy outcomes of all families were followed up or retrospected. Our research provides clinical evidence that X-deletions above 1 Mb are indeed associated with extremely skewed XCI. The favorable skewed XCI in combination with potential compensatory upregulation of XCI escapees would protect some but not all female carriers with pathogenic X-deletion from severe clinical consequences, mainly depending on the specific genetic contents involved in the deletion region. For PCDH19-disorder, the XCI pattern is considered as the decisive factor of phenotype expression, of which prenatal XCI assay using uncultured amniocytes could be a practicable way for risk prediction of this disease. These results provide valuable information about the usage of XCI assay in the prenatal risk assessment of heterozygous X-linked deletions.
N6-methyladenosine Regulator-Mediated Immune Genes Identify Breast Cancer Immune Subtypes and Predict Immunotherapy Efficacy
Authors: Zhang Meng-Meng , Lin Yi-Lin , Zeng Wen-Feng , Li Yang , Yang Yang , Liu Miao , Ye Ying-Jiang , Jiang Ke-Wei , Wang Shu , Wang Shan
Published: December 2021

Breast cancer (BRCA) is a heterogeneous malignancy closely related to the tumor microenvironment (TME) cell infiltration. N6-methyladenosine (m6A) modification of mRNA plays a crucial regulator in regulating the immune microenvironment of BRCA. Immunotherapy represents a paradigm shift in BRCA treatment; however, lack of an appropriate approach for treatment evaluation is a significant issue in this field. In this study, we attempted to establish a prognostic signature of BRCA based on m6A-related immune genes and to investigate the potential association between prognosis and immunotherapy. We comprehensively evaluated the m6A modification patterns of BRCA tissues and non-tumor tissues from The Cancer Genome Atlas and the modification patterns with TME cell-infiltrating characteristics. Overall, 1,977 TME-related genes were identified in the literature. Based on LASSO and Cox regression analyses, the m6A-related immune score (m6A-IS) was established to characterize the TME of BRCA and predict prognosis and efficacy associated with immunotherapy. We developed an m6A-IS to effectively predict immune infiltration and the prognosis of patients with BRCA. The prognostic score model represented robust predictive performance in both the training and validation cohorts. The low-m6A-IS group was characterized by enhanced antigen presentation and improved immune checkpoint expression, further indicating sensitivity to immunotherapy. Compared with the patients in the high-score group, the overall survival rate after treatment in the low-score group was significantly higher in the testing and validation cohorts. We constructed an m6A-IS system to examine the ability of the m6A signature to predict the infiltration of immune cells of the TME in BRCA, and the m6A-IS system acted as an independent prognostic biomarker that predicts the response of patients with BRCA in immunotherapy.
A New Deep Learning Calibration Method Enhances Genome-Based Prediction of Continuous Crop Traits
Authors: Montesinos-López Osval A. , Montesinos-López Abelardo , Mosqueda-González Brandon A. , Bentley Alison R. , Lillemo Morten , Varshney Rajeev K. , Crossa José
Published: December 2021

Genomic selection (GS) has the potential to revolutionize predictive plant breeding. A reference population is phenotyped and genotyped to train a statistical model that is used to perform genome-enabled predictions of new individuals that were only genotyped. In this vein, deep neural networks, are a type of machine learning model and have been widely adopted for use in GS studies, as they are not parametric methods, making them more adept at capturing nonlinear patterns. However, the training process for deep neural networks is very challenging due to the numerous hyper-parameters that need to be tuned, especially when imperfect tuning can result in biased predictions. In this paper we propose a simple method for calibrating (adjusting) the prediction of continuous response variables resulting from deep learning applications. We evaluated the proposed deep learning calibration method (DL_M2) using four crop breeding data sets and its performance was compared with the standard deep learning method (DL_M1), as well as the standard genomic Best Linear Unbiased Predictor (GBLUP). While the GBLUP was the most accurate model overall, the proposed deep learning calibration method (DL_M2) helped increase the genome-enabled prediction performance in all data sets when compared with the traditional DL method (DL_M1). Taken together, we provide evidence for extending the use of the proposed calibration method to evaluate its potential and consistency for predicting performance in the context of GS applied to plant breeding.
Neutrophil Expression of T and B Immunomodulatory Molecules in HIV Infection
Authors: Márquez-Coello Mercedes , Ruiz-Sánchez Cristina , Martín-Aspas Andrés , Fernández Gutiérrez Del Álamo Clotilde , Illanes-Álvarez Francisco , Cuesta-Sancho Sara , Girón-González José-Antonio
Published: December 2021

Objective

Evaluate the expression of B and T cell immunomodulatory molecules in polymorphonuclear neutrophils (PMN) in HIV-infected patients.

Methods

HIV load, bacterial translocation and neutrophils’ expression of T [programmed death ligand, interleukin-10+, arginase 1+] and B [BAFF, APRIL] molecules were analyzed in different cohorts and time points: a control group of 25 healthy individuals and two groups of HIV-infected patients. Group 1 of patients included 35 untreated patients, studied at baseline and after antiretroviral therapy (ART). Group 2 was composed of 25 patients with undetectable viral load after a median of 101 months of ART prior to inclusion in the study.

Results

Compared with the control group, group 1 patients showed increased bacterial translocation and their PMN had a significantly higher expression of T and B-cell immunomodulatory molecules, both at baseline and after 12 months of ART. Group 2 patients showed reduced bacterial translocation levels when compared with group 1 patients after 12 months of treatment. PMN expression of B-cell modulators was similar between group 2 patients and healthy controls, although the expression of T-cell modulators remained increased.

Conclusion

In HIV-infected patients, the expression of B-cell stimulatory and T-cell suppressive molecules by neutrophils was increased at baseline and after a limited time of therapy. After a prolonged period of ART, only PMNs expression of T-cell immunosuppressive molecules remained elevated.
GSK3β Interacts With CRMP2 and Notch1 and Controls T-Cell Motility
Authors: Fazil Mobashar Hussain Urf Turabe , Prasannan Praseetha , Wong Brandon Han Siang , Kottaiswamy Amuthavalli , Salim Nur Syazwani Binte Mohamed , Sze Siu Kwan , Verma Navin Kumar
Published: December 2021

The trafficking of T-cells through peripheral tissues and into afferent lymphatic vessels is essential for immune surveillance and an adaptive immune response. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase and regulates numerous cell/tissue-specific functions, including cell survival, metabolism, and differentiation. Here, we report a crucial involvement of GSK3β in T-cell motility. Inhibition of GSK3β by CHIR-99021 or siRNA-mediated knockdown augmented the migratory behavior of human T-lymphocytes stimulated via an engagement of the T-cell integrin LFA-1 with its ligand ICAM-1. Proteomics and protein network analysis revealed ongoing interactions among GSK3β, the surface receptor Notch1 and the cytoskeletal regulator CRMP2. LFA-1 stimulation in T-cells reduced Notch1-dependent GSK3β activity by inducing phosphorylation at Ser9 and its nuclear translocation accompanied by the cleaved Notch1 intracellular domain and decreased GSK3β-CRMP2 association. LFA-1-induced or pharmacologic inhibition of GSK3β in T-cells diminished CRMP2 phosphorylation at Thr514. Although substantial amounts of CRMP2 were localized to the microtubule-organizing center in resting T-cells, this colocalization of CRMP2 was lost following LFA-1 stimulation. Moreover, the migratory advantage conferred by GSK3β inhibition in T-cells by CHIR-99021 was lost when CRMP2 expression was knocked-down by siRNA-induced gene silencing. We therefore conclude that GSK3β controls T-cell motility through interactions with CRMP2 and Notch1, which has important implications in adaptive immunity, T-cell mediated diseases and LFA-1-targeted therapies.
An Intranasal OMV-Based Vaccine Induces High Mucosal and Systemic Protecting Immunity Against a SARS-CoV-2 Infection
Authors: van der Ley Peter A. , Zariri Afshin , van Riet Elly , Oosterhoff Dinja , Kruiswijk Corine P.
Published: December 2021

The development of more effective, accessible, and easy to administer COVID-19 vaccines next to the currently marketed mRNA, viral vector, and whole inactivated virus vaccines is essential to curtailing the SARS-CoV-2 pandemic. A major concern is reduced vaccine-induced immune protection to emerging variants, and therefore booster vaccinations to broaden and strengthen the immune response might be required. Currently, all registered COVID-19 vaccines and the majority of COVID-19 vaccines in development are intramuscularly administered, targeting the induction of systemic immunity. Intranasal vaccines have the capacity to induce local mucosal immunity as well, thereby targeting the primary route of viral entry of SARS-CoV-2 with the potential of blocking transmission. Furthermore, intranasal vaccines offer greater practicality in terms of cost and ease of administration. Currently, only eight out of 112 vaccines in clinical development are administered intranasally. We developed an intranasal COVID-19 subunit vaccine, based on a recombinant, six-proline-stabilized, D614G spike protein (mC-Spike) of SARS-CoV-2 linked via the LPS-binding peptide sequence mCramp (mC) to outer membrane vesicles (OMVs) from Neisseria meningitidis. The spike protein was produced in CHO cells, and after linking to the OMVs, the OMV-mC-Spike vaccine was administered to mice and Syrian hamsters via intranasal or intramuscular prime-boost vaccinations. In all animals that received OMV-mC-Spike, serum-neutralizing antibodies were induced upon vaccination. Importantly, high levels of spike-binding immunoglobulin G (IgG) and A (IgA) antibodies in the nose and lungs were only detected in intranasally vaccinated animals, whereas intramuscular vaccination only induced an IgG response in the serum. Two weeks after their second vaccination, hamsters challenged with SARS-CoV-2 were protected from weight loss and viral replication in the lungs compared to the control groups vaccinated with OMV or spike alone. Histopathology showed no lesions in lungs 7 days after challenge in OMV-mC-Spike-vaccinated hamsters, whereas the control groups did show pathological lesions in the lung. The OMV-mC-Spike candidate vaccine data are very promising and support further development of this novel non-replicating, needle-free, subunit vaccine concept for clinical testing.
NK Cell Anti-Tumor Surveillance in a Myeloid Cell-Shaped Environment
Authors: Russo Eleonora , Laffranchi Mattia , Tomaipitinca Luana , Del Prete Annalisa , Santoni Angela , Sozzani Silvano , Bernardini Giovanni
Published: December 2021

NK cells are innate lymphoid cells endowed with cytotoxic capacity that play key roles in the immune surveillance of tumors. Increasing evidence indicates that NK cell anti-tumor response is shaped by bidirectional interactions with myeloid cell subsets such as dendritic cells (DCs) and macrophages. DC-NK cell crosstalk in the tumor microenvironment (TME) strongly impacts on the overall NK cell anti-tumor response as DCs can affect NK cell survival and optimal activation while, in turn, NK cells can stimulate DCs survival, maturation and tumor infiltration through the release of soluble factors. Similarly, macrophages can either shape NK cell differentiation and function by expressing activating receptor ligands and/or cytokines, or they can contribute to the establishment of an immune-suppressive microenvironment through the expression and secretion of molecules that ultimately lead to NK cell inhibition. Consequently, the exploitation of NK cell interaction with DCs or macrophages in the tumor context may result in an improvement of efficacy of immunotherapeutic approaches.
A Novel TGF-β Risk Score Predicts the Clinical Outcomes and Tumour Microenvironment Phenotypes in Bladder Cancer
Authors: Liu Zhi , Qi Tiezheng , Li Xiaowen , Yao Yiyan , Othmane Belaydi , Chen Jinbo , Zu Xiongbing , Ou Zhenyu , Hu Jiao
Published: December 2021

Background

The TGF-β pathway plays critical roles in numerous malignancies. Nevertheless, its potential role in prognosis prediction and regulating tumour microenvironment (TME) characteristics require further elucidation in bladder cancer (BLCA).

Methods

TGF-β-related genes were comprehensively summarized from several databases. The TCGA-BLCA cohort (training cohort) was downloaded from the Cancer Genome Atlas, and the independent validation cohorts were gathered from Xiangya Hospital (Xinagya cohort) and Gene Expression Omnibus. Initially, we identified differentially expressed TGF-β genes (DEGs) between cancer and normal tissues. Subsequently, univariate Cox analysis was applied to identify prognostic DEGs, which were further used to develop the TGF-β risk score by performing LASSO and multivariate Cox analyses. Then, we studied the role of the TGF-β risk score in predicting prognosis and the TME phenotypes. In addition, the role of the TGF-β risk score in guiding precision treatments for BLCA has also been assessed.

Results

We successfully constructed a TGF-β risk score with an independent prognostic prediction value. A high TGF-β risk score indicated an inflamed TME, which was supported by the positive relationships between the risk score, enrichment scores of anticancer immunity steps, and the infiltration levels of tumour-infiltrating immune cells. In addition, the risk score positively correlated with the expression of several immune checkpoints and the T cell inflamed score. Consistently, the risk score was positively related to the enrichment scores of most immunotherapy-positive pathways. In addition, the sensitivities of six common chemotherapeutic drugs were positively associated with the risk score. Furthermore, higher risk score indicated higher sensitivity to radiotherapy and EGFR-targeted therapy. On the contrary, patients with low-risk scores were more sensitive to targeted therapies, including the blockade of FGFR3 and WNT-β-catenin networks.

Conclusions

We first constructed and validated a TGF-β signature that could predict the prognosis and TME phenotypes for BLCA. More importantly, the TGF-β risk score could aid in individual precision treatment for BLCA.