bluuebunny/crossref_metadata_2025 huggingface dataset:
Atomic-Level Investigation of Reactant Recognition Mechanism and Thermodynamic Property in Glucosamine 6-Phosphate Deaminase Catalysis
Authors: Zhang Xiao , Liu Xiaoyuan , Zhang Zhiyang , Zhao Yuan , Wang Chaojie
Published: August 2021

Glucosamine 6-phosphate deaminase (NagB) influences the direction of N-acetylglucosamine (GlcNAc) metabolism, facilitating the conversion of D-glucosamine 6-phosphate (GlcN6P) to D-fructose 6-phosphate (Fru6P) with the release of ammonia. Here, extensive molecular dynamics simulations combined with various techniques were performed to study the recognition and delivery process of GlcN6P by SmuNagB, due to its guidance of subsequent enzymatic reaction. The key residues Lys194, His130, Arg127, Thr38, and Ser37 stabilize GlcN6P in the active site by hydrogen bond interactions, therein electrostatic and polar solvent effects provide the primary traction. Four delivery channels were identified, with GlcN6P most likely to enter the active site of NagB through a “door” comprising residues 6–10, 122–136, and 222–233. The corresponding mechanism and thermodynamic properties were investigated. An exothermic recognition and delivery process were detected, accompanied by the flipping of GlcN6P and changes in key direct and indirect hydrogen bond interactions, which provide the driving force for the chemical reaction to occur. Furthermore, “the lid motif” was identified that remain open in alkaline condition with different extent of opening at each stage of transfer that induced GlcN6P to move the active site of NagB. The work will assist in the elucidation of the catalytic mechanism of action of NagB, allowing inhibitors to be designed with superior dynamic behavior.
Integrative Longitudinal Analysis of Metabolic Phenotype and Microbiota Changes During the Development of Obesity
Authors: Higgins Keah V. , Woodie Lauren N. , Hallowell Haley , Greene Michael W. , Schwartz Elizabeth Hiltbold
Published: August 2021

Obesity has increased at an alarming rate over the past two decades in the United States. In addition to increased body mass, obesity is often accompanied by comorbidities such as Type II Diabetes Mellitus and metabolic dysfunction-associated fatty liver disease, with serious impacts on public health. Our understanding of the role the intestinal microbiota in obesity has rapidly advanced in recent years, especially with respect to the bacterial constituents. However, we know little of when changes in these microbial populations occur as obesity develops. Further, we know little about how other domains of the microbiota, namely bacteriophage populations, are affected during the progression of obesity. Our goal in this study was to monitor changes in the intestinal microbiome and metabolic phenotype following western diet feeding. We accomplished this by collecting metabolic data and fecal samples for shotgun metagenomic sequencing in a mouse model of diet-induced obesity. We found that after two weeks of consuming a western diet (WD), the animals weighed significantly more and were less metabolically stable than their chow fed counterparts. The western diet induced rapid changes in the intestinal microbiome with the most pronounced dissimilarity at 12 weeks. Our study highlights the dynamic nature of microbiota composition following WD feeding and puts these events in the context of the metabolic status of the mammalian host.
Week 3–4 Prediction of Wintertime CONUS Temperature Using Machine Learning Techniques
Authors: Buchmann Paul , DelSole Timothy
Published: August 2021

This paper shows that skillful week 3–4 predictions of a large-scale pattern of 2 m temperature over the US can be made based on the Nino3.4 index alone, where skillful is defined to be better than climatology. To find more skillful regression models, this paper explores various machine learning strategies (e.g., ridge regression and lasso), including those trained on observations and on climate model output. It is found that regression models trained on climate model output yield more skillful predictions than regression models trained on observations, presumably because of the larger training sample. Nevertheless, the skill of the best machine learning models are only modestly better than ordinary least squares based on the Nino3.4 index. Importantly, this fact is difficult to infer from the parameters of the machine learning model because very different parameter sets can produce virtually identical predictions. For this reason, attempts to interpret the source of predictability from the machine learning model can be very misleading. The skill of machine learning models also are compared to those of a fully coupled dynamical model, CFSv2. The results depend on the skill measure: for mean square error, the dynamical model is slightly worse than the machine learning models; for correlation skill, the dynamical model is only modestly better than machine learning models or the Nino3.4 index. In summary, the best predictions of the large-scale pattern come from machine learning models trained on long climate simulations, but the skill is only modestly better than predictions based on the Nino3.4 index alone.
Integrated Care in the Era of COVID-19: Turning Vision Into Reality With Digital Health
Authors: Kouroubali Angelina , Kondylakis Haridimos , Katehakis Dimitrios G.
Published: August 2021

The lives of millions of people have been affected during the coronavirus pandemic that spread throughout the world in 2020. Society is changing establishing new norms for healthcare education, social life, and business. Digital health has seen an accelerated implementation throughout the world in response to the pandemic challenges. In this perspective paper, the authors highlight the features that digital platforms are important to have in order to support integrated care during a pandemic. The features of the digital platform Safe in COVID-19 are used as an example. Integrated care can only be supported when healthcare data is available and can be sharable and reusable. Healthcare data is essential to support effective prevention, prediction, and disease management. Data available in personal health apps can be sharable and reusable when apps follow interoperability guidelines for semantics and data management. The authors also highlight that not only technical but also political and social barriers need to be addressed in order to achieve integrated care in practice.
Zirconia Based Dental Biomaterials: Structure, Mechanical Properties, Biocompatibility, Surface Modification, and Applications as Implant
Authors: Lin Hua , Yin Cuilan , Mo Anchun
Published: August 2021

Zirconia, with its excellent mechanical properties, chemical stability, biocompatibility, and negligible thermal conductivity, is ideal for dental and orthopedic applications. In addition, the biocompatibility of zirconia has been studied in vivo, and no adverse reactions were observed when zirconia samples were inserted into bone. However, their use is controversial among dentists and researchers, especially when compared with mature implants made of titanium alloy. The advantages and limitations of zirconia as biomaterials, such as implant materials, need to be carefully studied, and the design, manufacture, and clinical operation guidelines are urgently required. In this review, the special components, microstructure, mechanical strength, biocompatibility, and the application of zirconia ceramics in biomaterials are detailly introduced. The review highlights discussions on how to implement innovative strategies to design the physical and chemical properties of zirconia so that the treated zirconia can provide better osteointegration after implantation.
LPSlow-Macrophages Alleviate the Outcome of Graft-Versus-Host Disease Without Aggravating Lymphoma Growth in Mice
Authors: Jeljeli Mohamed , Chêne Charlotte , Chouzenoux Sandrine , Thomas Marine , Segain Benjamin , Doridot Ludivine , Nicco Carole , Batteux Frédéric
Published: August 2021

Despite significant therapeutic advances, graft-versus-host disease (GvHD) remains the main life-threatening complication following allogeneic hematopoietic stem cell transplantation. The pathogenesis of GvHD is dominated by a dysregulated allogeneic immune response that drives fibrosis and autoimmunity in chronic forms. A multitude of cell therapy approaches, including infusion of myeloid cells, has been proposed to prevent GvHD through tolerance induction but yielded variable results. Myeloid cells like macrophages can be reprogrammed to develop adaptive-like features following antigenic challenge to reinforce or inhibit a subsequent immune response; a phenomenon termed ‘trained immunity’. Here we report that, whereas LPSlow-trained macrophages elicit a suppressor effect on allogeneic T cell proliferation and functionin vitroin an IL-10-dependent manner, Bacille Calmette et Guérin (BCG)-trained macrophages exert an opposite effect. In a murine model of sclerodermatous chronic GvHD, LPSlow-trained macrophages attenuate clinical signs of GvHD with significant effects on T cell phenotype and function, autoantibodies production, and tissue fibrosis. Furthermore, infusion of LPSlow-macrophages significantly improves survival in mice with acute GvHD. Importantly, we also provide evidence that LPSlow-macrophages do not accelerate A20-lymphoma tumor growth, which is significantly reduced upon transfer of BCG-macrophages. Collectively, these data indicate that macrophages can be trained to significantly inhibitin vitroandin vivoallo-reactive T cell proliferation without exhibiting pro-tumoral effect, thereby opening the way to promising clinical applications.
Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma
Authors: Ma Ming , Li Guoyang , Qi Minghui , Jiang Wei , Zhou Rongbin
Published: August 2021

Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1β in alveolar macrophages (AMs). Using Nlrp3-mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.
Comprehensive Characterization of RNA Processing Factors in Gastric Cancer Identifies a Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses
Authors: Lou Shenghan , Meng Fanzheng , Yin Xin , Zhang Yao , Han Bangling , Xue Yingwei
Published: August 2021

RNA processing converts primary transcript RNA into mature RNA. Altered RNA processing drives tumor initiation and maintenance, and may generate novel therapeutic opportunities. However, the role of RNA processing factors in gastric cancer (GC) has not been clearly elucidated. This study presents a comprehensive analysis exploring the clinical, molecular, immune, and drug response features underlying the RNA processing factors in GC. This study included 1079 GC cases from The Cancer Genome Atlas (TCGA, training set), our hospital cohort, and two other external validation sets (GSE15459, GSE62254). We developed an RNA processing-related prognostic signature using Cox regression with the least absolute shrinkage and selection operator (LASSO) penalty. The prognostic value of the signature was evaluated using a multiple-method approach. The genetic variants, pathway activation, immune heterogeneity, drug response, and splicing features associated with the risk signature were explored using bioinformatics methods. Among the tested 819 RNA processing genes, we identified five distinct RNA processing patterns with specific clinical outcomes and biological features. A 10-gene RNA processing-related prognostic signature, involving ZBTB7A, METTL2B, CACTIN, TRUB2, POLDIP3, TSEN54, SUGP1, RBMS1, TGFB1, and PWP2, was further identified. The signature was a powerful and robust prognosis factor in both the training and validation datasets. Notably, it could stratify the survival of patients with GC in specific tumor-node-metastasis (TNM) classification subgroups. We constructed a composite prognostic nomogram to facilitate clinical practice by integrating this signature with other clinical variables (TNM stage, age). Patients with low-risk scores were characterized with good clinical outcomes, proliferation, and metabolism hallmarks. Conversely, poor clinical outcome, invasion, and metastasis hallmarks were enriched in the high-risk group. The RNA processing signature was also involved in tumor microenvironment reprogramming and regulating alternative splicing, causing different drug response features between the two risk groups. The low-risk subgroup was characterized by high genomic instability, high alternative splicing and might benefit from the immunotherapy. Our findings highlight the prognostic value of RNA processing factors for patients with GC and provide insights into the specific clinical and molecular features underlying the RNA processing-related signature, which may be important for patient management and targeting treatment.
Blue Carbon Ecosystem Services Through a Vulnerability Lens: Opportunities to Reduce Social Vulnerability in Fishing Communities
Authors: Quiros T. E. Angela L. , Sudo Kenji , Ramilo Reynante V. , Garay Helbert G. , Soniega Muammar Princess G. , Baloloy Alvin , Blanco Ariel , Tamondong Ayin , Nadaoka Kazuo , Nakaoka Masahiro
Published: August 2021

Ecosystem services (ES) are benefits nature provides to humans; these services change in space and time and are largely dependent on context. Coastal habitat that provides key ES are blue carbon ecosystems, namely seagrass and mangroves. One important ES they provide is the provisioning of seafood, which benefits coastal populations with livelihoods and food security. We employed a social-ecological approach that draws from the vulnerability literature for social, ecological, and economic criteria to map ES provision in ten communities on Busuanga Island, Palawan Province, Philippines. We assess the spatial dynamics of ES provision for small-scale fisheries in seagrass and mangroves, in relation to local beneficiaries. Using a mixed-methods approach with ecological assessments of seagrass beds, spatial analysis, landing surveys, household and key informant interviews, we overlaid biophysical variables on social data, mapping sensitivities and adaptive capacities to compare communities’ social vulnerabilities. Spatial analysis revealed healthy blue carbon ecosystems in ten local communities (barangays) as measured by proportion of coastline covered, low patchiness and high continuity along the coastline, and the presence of adjacent habitat. We found seagrass ecosystems were more vulnerable than mangroves. Rural barangays had less exposure and lower sensitivity to blue carbon ecosystem loss than urban barangays. Blue carbon ecosystem fisheries are highly sensitive fisheries, due to their catch composition and low catch per unit effort, with mangrove fisheries having a slightly lower sensitivity than seagrass fisheries due to greater catch per unit effort. Diversified livelihoods and the presence of NGOs and People’s Organizations (POs) increased adaptive capacity and reduced overall vulnerability. We aim to highlight a coastal human community’s relationship with blue carbon ecosystems using context-specific vulnerability criteria. Our site-specific social vulnerability assessment may be adapted for use in other coastal communities within the coral triangle. This work suggests opportunities for conservation interventions to manage local communities’ sensitivities and adaptive capacity around the use of blue carbon ecosystems.
Clinical Value of Fecal Calprotectin in Predicting Mucosal Healing in Patients With Ulcerative Colitis
Authors: Chen Fang , Hu Yue , Fan Yi-Hong , Lv Bin
Published: August 2021

Aim: This study aimed to evaluate the clinical significance of fecal calprotectin (FC) in assessment of ulcerative colitis (UC) patients' endoscopic patterns and clinical manifestation.

Methods: A total of 143 UC patients who received colonoscopy and 108 controls were included. After providing stool samples, patients underwent total colonoscopy. FC was measured by an enzyme-linked immunosorbent assay (ELISA). Clinical activity was based on the Mayo score. Endoscopic findings was scored by the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Correlation analysis and receiver-operator characteristic (ROC) analysis were carried out to determine the significance of measurements.

Results: The median (interquartile range, IQR) of FC levels was 211 (43–990) μg/g in UC and 87.5 (40.50~181) μg/g in the control group. Fecal calprotectin correlated significantly with both Mayo and UCEIS scores (Spearman's r 0.670 and 0.592, P < 0.01). With a cut-off value of 164 μg/g for fecal calprotectin concentration, the area under the curve (AUC) in receiver operator characteristic analysis was 0.830, sensitivity was 85.42%, specificity was 73.68%, positive predictive value (PPV) was 62.12%, and negative predictive value (NPV) was 9.10% in predicting clinical active disease. Similarly, the power of FC to predict mucosal healing (MH) was modest. With a cut-off value of 154.5 μg/g, the AUC was 0.839, sensitivity was 72.34%, and specificity was 85.71%.

Conclusion: For evaluating the disease activity of UC, FC is a clinically relevant biomarker for both clinically active disease and MH in patients with UC. But the cut-off value still needs large and multicenter studies for confirmation.
Efficient Hydrogen Delivery for Microbial Electrosynthesis via 3D-Printed Cathodes
Authors: Kracke Frauke , Deutzmann Jörg S. , Jayathilake Buddhinie S. , Pang Simon H. , Chandrasekaran Swetha , Baker Sarah E. , Spormann Alfred M.
Published: August 2021

The efficient delivery of electrochemically in situ produced H2 can be a key advantage of microbial electrosynthesis over traditional gas fermentation. However, the technical details of how to supply large amounts of electric current per volume in a biocompatible manner remain unresolved. Here, we explored for the first time the flexibility of complex 3D-printed custom electrodes to fine tune H2 delivery during microbial electrosynthesis. Using a model system for H2-mediated electromethanogenesis comprised of 3D fabricated carbon aerogel cathodes plated with nickel-molybdenum and Methanococcus maripaludis, we showed that novel 3D-printed cathodes facilitated sustained and efficient electromethanogenesis from electricity and CO2 at an unprecedented volumetric production rate of 2.2 LCH4 /Lcatholyte/day and at a coulombic efficiency of 99%. Importantly, our experiments revealed that the efficiency of this process strongly depends on the current density. At identical total current supplied, larger surface area cathodes enabled higher methane production and minimized escape of H2. Specifically, low current density (<1 mA/cm2) enabled by high surface area cathodes was found to be critical for fast start-up times of the microbial culture, stable steady state performance, and high coulombic efficiencies. Our data demonstrate that 3D-printing of electrodes presents a promising design tool to mitigate effects of bubble formation and local pH gradients within the boundary layer and, thus, resolve key critical limitations for in situ electron delivery in microbial electrosynthesis.
Amble Gait EEG Points at Complementary Cortical Networks Underlying Stereotypic Multi-Limb Co-ordination
Authors: Weersink Joyce B. , Maurits Natasha M. , de Jong Bauke M.
Published: August 2021

Background

Walking is characterized by stable antiphase relations between upper and lower limb movements. Such bilateral rhythmic movement patterns are neuronally generated at levels of the spinal cord and brain stem, that are strongly interconnected with cortical circuitries, including the Supplementary Motor Area (SMA).

Objective

To explore cerebral activity associated with multi-limb phase relations in human gait by manipulating mutual attunement of the upper and lower limb antiphase patterns.

Methods

Cortical activity and gait were assessed by ambulant EEG, accelerometers and videorecordings in 35 healthy participants walking normally and 19 healthy participants walking in amble gait, where upper limbs moved in-phase with the lower limbs. Power changes across the EEG frequency spectrum were assessed by Event Related Spectral Perturbation analysis and gait analysis was performed.

Results

Amble gait was associated with enhanced Event Related Desynchronization (ERD) prior to and during especially the left swing phase and reduced Event Related Synchronization (ERS) at final swing phases. ERD enhancement was most pronounced over the putative right premotor, right primary motor and right parietal cortex, indicating involvement of higher-order organization and somatosensory guidance in the production of this more complex gait pattern, with an apparent right hemisphere dominance. The diminished within-step ERD/ERS pattern in amble gait, also over the SMA, suggests that this gait pattern is more stride driven instead of step driven.

Conclusion

Increased four-limb phase complexity recruits distributed networks upstream of the primary motor cortex, primarily lateralized in the right hemisphere. Similar parietal-premotor involvement has been described to compensate impaired SMA function in Parkinson’s disease bimanual antiphase movement, indicating a role as cortical support regions.
Suppression of miR-130a-3p Attenuates Oxygen–Glucose Deprivation/Reoxygenation-Induced Dendritic Spine Loss by Promoting APP
Authors: Zhu Liang , Zhu Lei , Tan Jinyun , Chen Kui , Yu Bo
Published: August 2021

Background

Cerebral stroke induces neuronal dysfunction as a consequence of neuronal morphology changes. Emerging evidence suggests that microRNAs (miRNAs) may play an important role in regulating dysfunction in stroke, yet there are still few studies examining the association between whole blood miRNAs and neuronal morphology. The present study aimed to ascertain the potential roles and mechanisms of action of miR-130a-3p in ischemic stroke.

Methods

The miRNA datasets of peripheral serum in the GEO database and the mRNA datasets of the human brain after ischemia were analyzed to identify differentially expressed RNAs, and their functions were verified in cultured neurons in vitro. Furthermore, the target gene was validated by dual-luciferase reporter assay, RT-PCR, Western blot, and immunofluorescence experiments. The identified miRNA was further verified by the OGD test to restore neuronal changes after ischemia through APP.

Results

The expression of whole blood miR-130a-3p was found significantly lower in participants with ischemic stroke than in controls by analyzing expression profiling datasets of cerebral ischemia stroke obtained from the Gene Expression Omnibus (GEO) DataSets portal, which was confirmed in the MCAO model in mice. Furthermore, GO analysis showed that miR-130a-3p might directly affect neuronal function. Indeed, we demonstrated that miR-130a-3p played a central role in the inhibition of dendritic morphogenesis and in the growth of dendritic spines in vitro. We also confirmed that miR-130a-3p could regulate the expression of APP by luciferase reporter assay, RT-PCR, Western blot, and immunofluorescence experiments, which were consistent with the bioinformatic analysis. Last but not least, we also demonstrated that reducing miR-130a-3p expression partially rescued neuronal morphological changes after OGD in vitro.

Conclusion

miR-130a-3p is a potential biomarker of cerebral stroke, can affect neuronal morphology through APP, and promote the repair of neurons by promoting APP expression after cerebral ischemia.
CREB3L2 Modulates Nerve Growth Factor-Induced Cell Differentiation
Authors: Sampieri Luciana , Funes Chabán Macarena , Di Giusto Pablo , Rozés-Salvador Victoria , Alvarez Cecilia
Published: August 2021

Nerve growth factor (NGF) stimulates numerous cellular physiological processes, including growth, differentiation, and survival, and maintains the phenotype of several neuronal types. Most of these NGF-induced processes require adaptation of the secretory pathway since they involve extensive remodeling of membranes and protein redistribution along newly formed neuritic processes. CREB3 transcription factors have emerged as signaling hubs for the regulation of numerous genes involved in the secretory pathway and Golgi homeostasis, integrating stimuli from multiple sources to control secretion, posttranslational modifications and trafficking of proteins. Although recent studies have focused on their role in the central nervous system, little is known about their participation in cell differentiation. Therefore, we aimed to analyze the expression and signaling mechanism of CREB3 transcription factor family members, using the NGF-induced PC12 cell differentiation model. Results show that NGF treatment causes Golgi enlargement and a parallel increased expression of proteins and mRNAs encoding for proteins required for membrane transport (transport factors). Additionally, a significant increase in CREB3L2 protein and mRNA levels is detected in response to NGF. Both MAPK and cAMP signaling pathways are required for this response. Interestingly, CREB3L2 overexpression hampers the NGF-induced neurite outgrowth while its inhibition enhances the morphological changes driven by NGF. In agreement, CREB3L2 overexpressing cells display higher immunofluorescence intensity of Rab5 GTPase (a negative regulator of PC12 differentiation) than control cells. Also, Rab5 immunofluorescence levels decrease in CREB3L2-depleted cells. Taken together, our findings imply that CREB3L2 is an important downstream effector of NGF-activated pathways, leading to neuronal differentiation.
Various Kinds of Functional Digestive Tract Reconstruction Methods After Proximal Gastrectomy
Authors: Lu Shuaibing , Ma Fei , Zhang Zhandong , Peng Liangqun , Yang Wei , Chai Junhui , Liu Chen , Ge Fusheng , Ji Sheqing , Luo Suxia , Chen Xiaobing , Hua Yawei
Published: August 2021

The incidence of proximal gastric cancer has shown a rising trend in recent years. Surgery is still the main way to cure proximal gastric cancer. Total gastrectomy with D2 lymph node dissection was considered to be the standard procedure for proximal gastric cancer in the past several decades. However, in recent years, many studies have confirmed that proximal gastrectomy can preserve part of the stomach function and can result in a better quality of life of the patient than total gastrectomy. Therefore, proximal gastrectomy is increasingly used in patients with proximal gastric cancer. Unfortunately, there are some concerns after proximal gastrectomy with traditional esophagogastrostomy. For example, the incidence of reflux esophagitis in patients who underwent proximal gastrectomy with traditional esophagogastrostomy is significantly higher than those patients who underwent total gastrectomy. To solve those problems, various functional digestive tract reconstruction methods after proximal gastrectomy have been proposed gradually. In order to provide some help for clinical treatment, in this article, we reviewed relevant literature and new clinical developments to compare various kinds of functional digestive tract reconstruction methods after proximal gastrectomy mainly from perioperative outcomes, postoperative quality of life and survival outcomes aspects. After comparison and discussion, we drew the conclusion that various functional reconstruction methods have their own advantages and disadvantages; large scale high-level clinical studies are needed to choose an ideal reconstruction method in the future. Besides, in clinical practice, surgeons should consider the condition of the patient for individualized selection of the most appropriate reconstruction method.
Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients
Authors: Rothé Françoise , Lambertini Matteo , Goldrat Oranite , Maetens Marion , Bareche Yacine , Blanc Jeremy , Rouas Ghizlane , Larsimont Denis , Sotiriou Christos , Ignatiadis Michail , Demeestere Isabelle
Published: August 2021

Background

Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite this is a widely adopted protocol, the safety of let-COS on breast cancer outcomes has been poorly investigated and its use remains off-label. We assessed the safety of let-COS in breast cancer patients using circulating tumor DNA (ctDNA) as a surrogate biomarker of disease recurrence.

Methods

BROVALE is an interventional non-randomized prospective study designed to evaluate the efficacy and safety of let-COS for fertility preservation in early breast cancer patients before starting (neo)adjuvant chemotherapy. Letrozole was administered throughout the COS cycle, until ovulation triggering. Safety was a secondary endpoint. Data on oncological outcomes were collected during the follow-up as well as plasma and whole blood for evaluation of ctDNA levels at the time of enrollment (i.e. before starting let-COS) and oocyte retrieval (i.e. 48 hours after the last administration of letrozole). Targeted gene sequencing on the primary tumor samples was performed to identify specific mutations used for ctDNA analysis by digital PCR. DNA extracted from whole blood samples was used to discriminate between somatic and germline mutations.

Results

From April 2014 to May 2017, 29 young early breast cancer patients enrolled in the BROVALE study who had available tissue samples participated to the ctDNA substudy. Among them, 15 had at least one validated somatic mutation. ctDNA was undetectable neither before nor after let-COS in 9 of them. Six patients had detectable ctDNA in the plasma samples collected before Let-COS. No change in ctDNA level after let-COS was observed in 3 patients and the level decreased (fold-change ≤ 0.5) in two women. One patient experienced an increased (fold-change ≥ 2) in ctDNA level but without disease relapse 34 months after diagnosis.

Conclusions

No increase in ctDNA level was observed in 93% (14/15) of the patients receiving let-COS supporting its use as a safe strategy for young women with early breast cancer interested in fertility preservation before chemotherapy.
The Influence of miRNAs on Radiotherapy Treatment in Prostate Cancer – A Systematic Review
Authors: Soares Sílvia , Guerreiro Susana G. , Cruz-Martins Natália , Faria Isabel , Baylina Pilar , Sales Maria Goreti , Correa-Duarte Miguel A. , Fernandes Rúben
Published: August 2021

In the last years, extensive investigation on miRNomics have shown to have great advantages in cancer personalized medicine regarding diagnosis, treatment and even clinical outcomes. Prostate cancer (PCa) is the second most common male cancer and about 50% of all PCa patients received radiotherapy (RT), despite some of them develop radioresistance. Here, we aim to provide an overview on the mechanisms of miRNA biogenesis and to discuss the functional impact of miRNAs on PCa under radiation response. As main findings, 23 miRNAs were already identified as being involved in genetic regulation of PCa cell response to RT. The mechanisms of radioresistance are still poorly understood, despite it has been suggested that miRNAs play an important role in cell signaling pathways. Identification of miRNAs panel can be thus considered an upcoming and potentially useful strategy in PCa diagnosis, given that radioresistance biomarkers, in both prognosis and therapy still remains a challenge.
Can Elevated Pretreatment Serum Carcinoembryonic Antigen Levels Serve as a Potential Biomarker Guiding Adjuvant Chemotherapy in Rectal Cancer Patients With ypTis-3N0 After Neoadjuvant Radiotherapy and Surgery?
Authors: Huang Chi , Jiang Mingkun , Li Yan , Tang Chaoyang , Ma Xiang , Huan Xiangkun
Published: August 2021

Survival benefit of adjuvant chemotherapy (ACT) remained controversial in patients with stage II/III rectal cancer (RC) who received neoadjuvant therapy and surgery. This study aimed to investigate the guiding role of elevated pretreatment serum carcinoembryonic antigen (CEA) levels for receiving ACT in yield pathological Tis-3N0 (ypTis-3N0) RC patients after neoadjuvant radiotherapy and surgery. Between 2004 and 2015, 10,973 RC patients with ypTis-3N0 who received neoadjuvant radiotherapy and radical surgery were retrospectively analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Compared with CEA-normal group, elevated-CEA patients had worse 5-year CSS rate (90.1 vs 83.5%). The 5-year CSS rates were 86.3 and 87.4% for ypTis-3N0M0 patients with or without ACT, respectively. Patients receiving ACT had a comparable 5-year CSS rate compared to those who did not regardless of CEA levels in ypTis-3N0M0 RC patients (CEA elevation group: 76.4 vs. 83.5%, P = 0.305; CEA normal group: 90.0 vs. 90.1%, P = 0.943). Intriguingly, ypT3N0M0 RC patients with elevated CEA levels may benefit from ACT (5-year CSS: 69.1 vs. 82.9%, P = 0.045), while those with normal CEA levels did not (5-year CSS: 89.3 vs. 89.3%, P = 0.885). Multivariate Cox analysis demonstrated that ACT tended to be a protective factor in elevated-CEA ypT3N0M0 RC patients (HR = 0.633, 95% CI = 0.344–1.164, P = 0.141), while ACT was not associated with improved CSS in normal-CEA ypT3N0M0 RC patients (HR = 1.035, 95% CI = 0.487–2.202, P = 0.928). Elevated pretreatment serum CEA levels may serve as a promising biomarker guiding ACT in rectal cancer patients with ypT3N0M0.
Amplitude Integrated Electroencephalography and Continuous Electroencephalography Monitoring Is Crucial in High-Risk Infants and Their Findings Correlate With Neurodevelopmental Outcomes
Authors: Lee Inn-Chi , Hong Syuan-Yu , Weng Yi-Ho , Chen Yi-Ting
Published: August 2021

Background: To evaluate seizure diagnosis in sick infants in the neonatal intensive care unit (NICU) based on electroencephalography (EEG) monitoring combined with amplitude integrated electroencephalography (aEEG).

Methods: We retrospectively reviewed EEG and aEEG findings and determined their correlations with neurodevelopmental outcomes at the age of >1 year in 65 patients with diagnosed seizures, encephalopathy, or both.

Results: Seizure identification rate was 43.1%. The rate in nonstructural groups (hypocalcemic, hypoglycemic, and genetic seizures) was 71.4%, which was higher (p < 0.05) than the rate of 35.3% of structural brain lesion group [hypoxic–ischemic encephalopathy (HIE) and congenital brain structural malformation]. The aEEG background correlating with neurodevelopmental outcomes had 70.0% positive prediction value (PPV), 65.5%% negative prediction value (NPV), 67.7% specificity, and 67.9% sensitivity (p < 0.005). The aEEG background strongly (PPV, 93.8%; p < 0.005) correlated with the outcomes in HIE. For genetic seizures, the detected rate was high. The ictal recordings for the nonstructural seizures revealed downflected on the aEEG background initially, which differed from the structural lesion.

Conclusions: EEG monitoring combined with aEEG can detect seizures, facilitating early treatment. EEG changes during seizures could exhibit delta-theta waves with or without clinical seizures in patients with brain lesions. In non-structural etiologies (hypocalcemic and KCNQ2 seizures), aEEG initially exhibited lower background during seizures that could aid in differentiating these EEG changes from those of other etiologies. The aEEG background was correlated with neurodevelopmental outcome and exhibited high PPV but not NPV in neonatal HIE.
Ginkgo Biloba Extract Is Comparable With Donepezil in Improving Functional Recovery in Alzheimer’s Disease: Results From a Multilevel Characterized Study Based on Clinical Features and Resting-State Functional Magnetic Resonance Imaging
Authors: Zheng Yu , Xie Yi , Qi Ming , Zhang Ling , Wang Wei , Zhang Wanrong , Sha Liju , Wu Jiawen , Li Wanting , Wu Ting
Published: August 2021

Background: Ginkgo biloba extract (GBE) and donepezil have been reported to be effective in patients with Alzheimer’s disease (AD). Nonetheless, how these drugs impact spontaneous brain activities and how they consequently improve functional recovery are currently unclear.

Objectives: This study was to explore the efficacy of GBE vs. donepezil and their add-on efficacy on functional recovery and the adaption of spontaneous brain activities following pharmacologic treatment in patients with AD.

Methods: Patients with AD were enrolled and assigned to the GBE group (n = 50), the donepezil group (n = 50), or the combined group (n = 50). Neuropsychological assessments, including minimum mental state examination (MMSE), Alzheimer’s disease assessment scale-cognition (ADAS-Cog), instrumental activity of daily living (IADL), geriatric depression scale (GDS), neuropsychiatric inventory (NPI), and quality of life in Alzheimer’s disease (QOL-AD), were conducted at baseline, 1 month, 3 months, and 6 months. Resting-state functional magnetic resonance imaging (rs-fMRI) was collected to compare the amplitude of low-frequency fluctuation (ALFF), percent amplitude of fluctuation (PerAF), regional homogeneity (ReHo), and degree centrality (DC) at baseline and 6 months.

Results: No major significant differences were detected in all comparisons between groups across all follow-up time points. For intragroup comparison, MMSE and ADAS-Cog scores differed significantly across all follow-ups in three groups. The combined group showed significant improvement of GDS scores between baseline and 6 months (p = 0.007). The GBE group (p = 0.044) and donepezil group (p = 0.012) demonstrated significant improvement of NPI scores between baseline and 6 months. Significant correlations were observed between IADL and ALFF in the right gyrus rectus (p = 0.03) and in the left superior cerebellum gyrus (p = 0.01), between GDS and ALFF in the right middle temporal gyrus (p = 0.01), between NPI and PerAF in the left fusiform gyrus (p = 0.03), and between MMSE and ReHo in right superior frontal gyrus (p = 0.04).

Conclusion: GBE was comparable with donepezil in the improvement of functional recovery in patients with AD while the combined application of GBE and donepezil seems unnecessary. GBE-mediated improvement of functional recovery was characterized by decreased ALFF values in the right gyrus rectus and decreased PerAF values in the left fusiform gyrus. These featured variations of imaging metrics in specific brain regions may serve as biomarkers in the monitoring of the therapeutic efficacy of GBE.
Classical Limit of Quantum Mechanics for Damped Driven Oscillatory Systems: Quantum–Classical Correspondence
Authors: Choi Jeong Ryeol
Published: August 2021

The investigation of quantum–classical correspondence may lead to gaining a deeper understanding of the classical limit of quantum theory. I have developed a quantum formalism on the basis of a linear invariant theorem, which gives an exact quantum–classical correspondence for damped oscillatory systems perturbed by an arbitrary force. Within my formalism, the quantum trajectory and expectation values of quantum observables precisely coincide with their classical counterparts in the case where the global quantum constant ℏ has been removed from their quantum results. In particular, I have illustrated the correspondence of the quantum energy with the classical one in detail.
Fine Structure and Olfactory Reception of the Labial Palps of Spodoptera frugiperda
Authors: Chen Qiuyan , Liu Xiaolan , Cao Song , Ma Baiwei , Guo Mengbo , Shen Jie , Wang Guirong
Published: August 2021

The olfactory system of insects is essential in many crucial behaviors, such as host seeking, mate recognition, and locating oviposition sites. Lepidopteran moths possess two main olfactory organs, including antennae and labial palps. Compared to antennae, the labial palps are relatively specific and worthy of further investigation due to the labial-palp pit organ (LPO), which contains a large number of sensilla located on the tip segment. The fall armyworm, Spodoptera frugiperda, is a worldwide lepidopteran pest, which can damage more than 350 plants and cause significant economic losses. In this study, we surveyed the structure of the labial palps and LPO of S. frugiperda using a super-high magnification lens zoom 3D microscope. Then, the distribution and fine structure of sensilla located in the LPO of S. frugiperda were investigated using scanning electron microscopy. Subsequently, the electrophysiological responses of labial palps to CO2 and 29 plant volatiles were recorded by using electrolabialpalpography. Our results showed the fine structure of labial palps, the LPO, and the sensilla located in the LPO of S. frugiperda. Moreover, we demonstrated that the labial palps are olfactory organs that respond to both CO2 and other volatile compounds. Our work established a foundation for further study of the roles of labial palps in insect olfactory related behaviors. Further investigations on the function of labial palps and their biological roles together with CO2 and volatile compound responses in S. frugiperda are necessary, as they may provide better insect behavioral regulators for controlling this pest.
Effect of Post-mortem Interval and Perfusion on the Biophysical Properties of ex vivo Liver Tissue Investigated Longitudinally by MRE and DWI
Authors: Garczyńska Karolina , Tzschätzsch Heiko , Assili Sanam , Kühl Anja A. , Häckel Akvile , Schellenberger Eyk , Berndt Nikolaus , Holzhütter Hermann-Georg , Braun Jürgen , Sack Ingolf , Guo Jing
Published: August 2021

Structural changes of soft tissues on the cellular level can be characterized by histopathology, but not longitudinally in the same tissue. Alterations of cellular structures and tissue matrix are associated with changes in biophysical properties which can be monitored longitudinally by quantitative diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE). In this work, DWI and MRE examinations were performed in a 0.5-Tesla compact scanner to investigate longitudinal changes in water diffusivity, stiffness and viscosity of ex-vivo rat livers for up to 20 h post-mortem (pm). The effect of blood on biophysical parameters was examined in 13 non-perfused livers (containing blood, NPLs) and 14 perfused livers (blood washed out, PLs). Changes in cell shape, cell packing and cell wall integrity were characterized histologically. In all acquisitions, NPLs presented with higher shear-wave speed(c), higher shear-wave penetration rate(a)and smaller apparent-diffusion-coefficients (ADCs) than PL. Time-resolved analysis revealed three distinct phases: (i) an initial phase (up to 2 h pm) with markedly increased c and a and reduced ADCs; (ii) an extended phase with relatively stable values; and (iii) a degradation phase characterized by significant increases ina(10 h pm in NPLs and PLs) and ADCs (10 h pm in NPLs, 13 h pm in PLs). Histology revealed changes in cell shape and packing along with decreased cell wall integrity, indicating tissue degradation in NPLs and PLs 10 h pm. Taken together, our results demonstrate that the biophysical properties of fresh liver tissue rapidly change within 2 h pm, which seems to be an effect of both cytotoxic edema and vascular blood content. Several hours later, disruption of cell walls resulted in higher water diffusivity and wave penetration. These results reveal the individual contributions of vascular components and cellular integrity to liver elastography and provide a biophysical, imaging-based fingerprint of liver tissue degradation.
The Effect of a Pace Training Session on Internal Load and Neuromuscular Parameters in Taekwondo Athletes
Authors: Sant' Ana Jader , Sakugawa Raphael Luiz , Diefenthaeler Fernando
Published: August 2021

This study aimed to verify the effect of a pace training session at an intensity corresponding to the kick frequency at the anaerobic threshold (KFAT) on the internal load response and motor response performance of the roundhouse kick. Twelve black belt taekwondo athletes underwent two evaluation sessions: (1) performed the progressive specific test for taekwondo (PSTT) to identify the heart rate deflection point (HRDP) and the KFAT; (2) performed three 2-min rounds with a 1-min interval. Heart rate (HR) throughout each round and motor response performance before and after sessions were measured. The Student's T-test or Wilcoxon test was used, and p < 0.05 was adopted. During round 1, a lower internal load was observed (167 ± 10 bpm) compared with HRDP (179 ± 8 bpm; p = 0.035). During rounds 2 (178 ± 10 bpm; p = 0.745) and 3 (179 ± 8 bpm; p = 1), no differences were observed for an internal load and HRDP. Motor response performance showed no differences. However, a potentiation in the post countermovement jump test compared with rounds 1 (p = 0.012) and 2 (p = 0.028) was observed. The internal load (HR) observed at the intensity corresponding to KFAT can be considered in the prescription of training when the aim is to control the internal load responses without inducing fatigue.
RETRACTED: Abnormal Mitochondria-Endoplasmic Reticulum Communication Promotes Myocardial Infarction
Authors: Cheng Degang , Zheng Jia , Hu Fang , Lv Wei , Lu Chengzhi
Published: August 2021

Myocardial infarction is characterized by cardiomyocyte death, and can be exacerbated by mitochondrial damage and endoplasmic reticulum injury. In the present study, we investigated whether communication between mitochondria and the endoplasmic reticulum contributes to cardiomyocyte death after myocardial infarction. Our data demonstrated that hypoxia treatment (mimicking myocardial infarction) promoted cardiomyocyte death by inducing the c-Jun N-terminal kinase (JNK) pathway. The activation of JNK under hypoxic conditions was dependent on overproduction of mitochondrial reactive oxygen species (mtROS) in cardiomyocytes, and mitochondrial division was identified as the upstream inducer of mtROS overproduction. Silencing mitochondrial division activators, such as B cell receptor associated protein 31 (BAP31) and mitochondrial fission 1 (Fis1), repressed mitochondrial division, thereby inhibiting mtROS overproduction and preventing JNK-induced cardiomyocyte death under hypoxic conditions. These data revealed that a novel death-inducing mechanism involving the BAP31/Fis1/mtROS/JNK axis promotes hypoxia-induced cardiomyocyte damage. Considering that BAP31 is localized within the endoplasmic reticulum and Fis1 is localized in mitochondria, abnormal mitochondria-endoplasmic reticulum communication may be a useful therapeutic target after myocardial infarction.
A Physio-Logging Journey: Heart Rates of the Emperor Penguin and Blue Whale
Authors: Ponganis Paul J.
Published: August 2021

Physio-logging has the potential to explore the processes that underlie the dive behavior and ecology of marine mammals and seabirds, as well as evaluate their adaptability to environmental change and other stressors. Regulation of heart rate lies at the core of the physiological processes that determine dive capacity and performance. The bio-logging of heart rate in unrestrained animals diving at sea was infeasible, even unimaginable in the mid-1970s. To provide a historical perspective, I review my 40-year experience in the development of heart rate physio-loggers and the evolution of a digital electrocardiogram (ECG) recorder that is still in use today. I highlight documentation of the ECG and the interpretation of heart rate profiles in the largest of avian and mammalian divers, the emperor penguin and blue whale.