bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Transient Thermal Shock on the Microstructure and Mechanical Properties of CoCrFeNiMn High-Entropy Alloy Coatings
Authors: Liu Jing-Tong , Liu Si-Wei , Zheng Hai-Lan , Huang Wen-Jing , Zhao Wei , Liao Wei-Bing
Published: December 2021

CoCrFeNiMn high-entropy alloy (HEA) has great potential for engineering application due to its good ductility and high fracture toughness at low temperature. It can be deposited on components as coatings to take advantage of its excellent properties and reduce the cost. In this study, CoCrFeNiMn HEA coatings were deposited on 316L stainless steel substrates by atmospheric plasma spraying (APS) technique, and a series of transient thermal shock tests were performed. It was found that the coatings contained two main phases: a face-centered cubic (FCC) solid solution phase and a flocculent oxides phase. The elemental contents of Co, Cr, Fe, and Ni were close to equal atomic percentage in the coating, while Mn was reduced significantly. The oxygen was mainly distributed in the dark flocculent oxides phase. After transient thermal shock tests, these two phases remained stable, but some tiny cracks appeared on the surface. Meanwhile, the microhardness of the coating after transient thermal shock tests also showed stable, ∼ 420 HV. Weibull statistics were used to analyze the reliability of the microhardness, and the Weibull modulus m was distributed from 9 to 15. The CoCrFeNiMn HEA coating exhibited high phase stability and excellent properties under transient thermal shock, making it have service advantages in extreme environments, especially in the fields of the development of future nuclear and aerospace structural materials.
Ultrastructural Analysis of Rehydrated Human Donor Corneas After Air-Drying and Dissection by Femtosecond Laser
Authors: Pedrotti Emilio , Bonacci Erika , Fasolo Adriano , De Rossi Arianna , Camposampiero Davide , Jones Gary L. A. , Bernardi Paolo , Merigo Flavia , Ponzin Diego , Marchini Giorgio , Sbarbati Andrea
Published: December 2021

Purpose: To evaluate the efficiency of femtosecond laser (FSL) incision of rehydrated human donor corneas after air-drying and its effects on corneal structure.

Methods: We compared the rehydrated and fresh-preserved corneas by microscopy following Victus-Tecnolas FSL treatment for straight-edge anterior lamellar keratoplasty (ALK). The corneas were dehydrated at room temperature under a laminar-flow hood.

Results: To obtain the horizontal cut in rehydrated corneas, we increased the FSL pulse energy to 1.2 μJ from 0.80 μJ applied for the fresh corneas and obtained a clear-cut separation of the lamellar lenticule cap from the corneal bed. Light microscopy showed regular arrangement of stromal collagen lamellae, with spaces in between the fibers in the corneal stroma in the fresh and the rehydrated corneas, but the uppermost epithelial layers in the rehydrated corneas were lost. Transmission electron microscopy (TEM) revealed no signs of thermal or mechanical damage to the corneal structure. The epithelial basal membrane and Bowman's layer maintained their integrity. The epithelial basal layer and cells were separated by large spaces due to junction alteration in the rehydrated corneas. There were gaps between the lamellar layers in the stroma, especially in the rehydrated corneas. Keratocytes displayed normal structure in the fresh corneas but were devoid of microorganules in the rehydrated corneas. Minor irregularities were observed in the vertical incision and the horizontal stroma appeared smooth on scanning electron microscopy.

Conclusion: The corneal stroma of rehydrated corneas maintained morphology and integrity, while corneal cellular components were generally altered. When corneas are intended for FSL-assisted ALK, effective stromal bed incision is best achieved at a laser power higher than that currently adopted for fresh corneas.
miRNA Combinatorics and its Role in Cell State Control—A Probabilistic Approach
Authors: Mahlab-Aviv Shelly , Linial Nathan , Linial Michal
Published: December 2021

A hallmark of cancer evolution is that the tumor may change its cell identity and improve its survival and fitness. Drastic change in microRNA (miRNA) composition and quantities accompany such dynamic processes. Cancer samples are composed of cells’ mixtures of varying stages of cancerous progress. Therefore, cell-specific molecular profiling represents cellular averaging. In this study, we consider the degree to which altering miRNAs composition shifts cell behavior. We used COMICS, an iterative framework that simulates the stochastic events of miRNA-mRNA pairing, using a probabilistic approach. COMICS simulates the likelihood that cells change their transcriptome following many iterations (100 k). Results of COMICS from the human cell line (HeLa) confirmed that most genes are resistant to miRNA regulation. However, COMICS results suggest that the composition of the abundant miRNAs dictates the nature of the cells (across three cell lines) regardless of its actual mRNA steady-state. In silico perturbations of cell lines (i.e., by overexpressing miRNAs) allowed to classify genes according to their sensitivity and resilience to any combination of miRNA perturbations. Our results expose an overlooked quantitative dimension for a set of genes and miRNA regulation in living cells. The immediate implication is that even relatively modest overexpression of specific miRNAs may shift cell identity and impact cancer evolution.
Drugging Fuzzy Complexes in Transcription
Authors: Su Bonnie G. , Henley Matthew J.
Published: December 2021

Transcription factors (TFs) are one of the most promising but underutilized classes of drug targets. The high degree of intrinsic disorder in both the structure and the interactions (i.e., “fuzziness”) of TFs is one of the most important challenges to be addressed in this context. Here, we discuss the impacts of fuzziness on transcription factor drug discovery, describing how disorder poses fundamental problems to the typical drug design, and screening approaches used for other classes of proteins such as receptors or enzymes. We then speculate on ways modern biophysical and chemical biology approaches could synergize to overcome many of these challenges by directly addressing the challenges imposed by TF disorder and fuzziness.
Smallest Chimeras Under Repulsive Interactions
Authors: Saha Suman , Dana Syamal Kumar
Published: December 2021

We present an exemplary system of three identical oscillators in a ring interacting repulsively to show up chimera patterns. The dynamics of individual oscillators is governed by the superconducting Josephson junction. Surprisingly, the repulsive interactions can only establish a symmetry of complete synchrony in the ring, which is broken with increasing repulsive interactions when the junctions pass through serials of asynchronous states (periodic and chaotic) but finally emerge into chimera states. The chimera pattern first appears in chaotic rotational motion of the three junctions when two junctions evolve coherently, while the third junction is incoherent. For larger repulsive coupling, the junctions evolve into another chimera pattern in a periodic state when two junctions remain coherent in rotational motion and one junction transits to incoherent librational motion. This chimera pattern is sensitive to initial conditions in the sense that the chimera state flips to another pattern when two junctions switch to coherent librational motion and the third junction remains in rotational motion, but incoherent. The chimera patterns are detected by using partial and global error functions of the junctions, while the librational and rotational motions are identified by a libration index. All the collective states, complete synchrony, desynchronization, and two chimera patterns are delineated in a parameter plane of the ring of junctions, where the boundaries of complete synchrony are demarcated by using the master stability function.
Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study
Authors: Dal-Bianco A. , Schranzer R. , Grabner G. , Lanzinger M. , Kolbrink S. , Pusswald G. , Altmann P. , Ponleitner M. , Weber M. , Kornek B. , Zebenholzer K. , Schmied C. , Berger T. , Lassmann H. , Trattnig S. , Hametner S. , Leutmezer F. , Rommer P.
Published: December 2021

Introduction: Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, characterized by inflammatory-driven demyelination. Symptoms in MS manifest as both physical and neuropsychological deficits. With time, inflammation is accompanied by neurodegeneration, indicated by brain volume loss on an MRI. Here, we combined clinical, imaging, and serum biomarkers in patients with iron rim lesions (IRLs), which lead to severe tissue destruction and thus contribute to the accumulation of clinical disability.

Objectives: Subcortical atrophy and ventricular enlargement using an automatic segmentation pipeline for 7 Tesla (T) MRI, serum neurofilament light chain (sNfL) levels, and neuropsychological performance in patients with MS with IRLs and non-IRLs were assessed.

Methods: In total 29 patients with MS [15 women, 24 relapsing-remitting multiple sclerosis (RRMS), and five secondary-progressive multiple sclerosis (SPMS)] aged 38 (22–69) years with an Expanded Disability Status Score of 2 (0–8) and a disease duration of 11 (5–40) years underwent neurological and neuropsychological examinations. Volumes of lesions, subcortical structures, and lateral ventricles on 7-T MRI (SWI, FLAIR, and MP2RAGE, 3D Segmentation Software) and sNfL concentrations using the Simoa SR-X Analyzer in IRL and non-IRL patients were assessed.

Results: (1) Iron rim lesions patients had a higher FLAIR lesion count (p = 0.047). Patients with higher MP2Rage lesion volume exhibited more IRLs (p <0.014) and showed poorer performance in the information processing speed tested within 1 year using the Symbol Digit Modalities Test (SDMT) (p <0.047). (2) Within 3 years, patients showed atrophy of the thalamus (p = 0.021) and putamen (p = 0.043) and enlargement of the lateral ventricles (p = 0.012). At baseline and after 3 years, thalamic volumes were lower in IRLs than in non-IRL patients (p = 0.045). (3) At baseline, IRL patients had higher sNfL concentrations (p = 0.028). Higher sNfL concentrations were associated with poorer SDMT (p = 0.004), regardless of IRL presence. (4) IRL and non-IRL patients showed no significant difference in the neuropsychological performance within 1 year.

Conclusions: Compared with non-IRL patients, IRL patients had higher FLAIR lesion counts, smaller thalamic volumes, and higher sNfL concentrations. Our pilot study combines IRL and sNfL, two biomarkers considered indicative for neurodegenerative processes. Our preliminary data underscore the reported destructive nature of IRLs.
Group-Level Ranking-Based Hubness Analysis of Human Brain Connectome Reveals Significant Interhemispheric Asymmetry and Intraparcel Heterogeneities
Authors: Hanalioglu Sahin , Bahadir Siyar , Isikay Ilkay , Celtikci Pinar , Celtikci Emrah , Yeh Fang-Cheng , Oguz Kader Karli , Khaniyev Taghi
Published: December 2021

Objective: Graph theory applications are commonly used in connectomics research to better understand connectivity architecture and characterize its role in cognition, behavior and disease conditions. One of the numerous open questions in the field is how to represent inter-individual differences with graph theoretical methods to make inferences for the population. Here, we proposed and tested a simple intuitive method that is based on finding the correlation between the rank-ordering of nodes within each connectome with respect to a given metric to quantify the differences/similarities between different connectomes.

Methods: We used the diffusion imaging data of the entire HCP-1065 dataset of the Human Connectome Project (HCP) (n = 1,065 subjects). A customized cortical subparcellation of HCP-MMP atlas (360 parcels) (yielding a total of 1,598 ROIs) was used to generate connectivity matrices. Six graph measures including degree, strength, coreness, betweenness, closeness, and an overall “hubness” measure combining all five were studied. Group-level ranking-based aggregation method (“measure-then-aggregate”) was used to investigate network properties on population level.

Results: Measure-then-aggregate technique was shown to represent population better than commonly used aggregate-then-measure technique (overall rs: 0.7 vs 0.5). Hubness measure was shown to highly correlate with all five graph measures (rs: 0.88–0.99). Minimum sample size required for optimal representation of population was found to be 50 to 100 subjects. Network analysis revealed a widely distributed set of cortical hubs on both hemispheres. Although highly-connected hub clusters had similar distribution between two hemispheres, average ranking values of homologous parcels of two hemispheres were significantly different in 71% of all cortical parcels on group-level.

Conclusion: In this study, we provided experimental evidence for the robustness, limits and applicability of a novel group-level ranking-based hubness analysis technique. Graph-based analysis of large HCP dataset using this new technique revealed striking hemispheric asymmetry and intraparcel heterogeneities in the structural connectivity of the human brain.
Association of the Polygenic Risk Score With the Probability of Prodromal Parkinson’s Disease in Older Adults
Authors: Maraki Maria I. , Hatzimanolis Alexandros , Mourtzi Niki , Stefanis Leonidas , Yannakoulia Mary , Kosmidis Mary H. , Dardiotis Efthimios , Hadjigeorgiou Georgios M. , Sakka Paraskevi , Ramirez Alfredo , Grenier-Boley Benjamin , Lambert Jean-Charles , Heilmann-Heimbach Stefanie , Stamelou Maria , Scarmeas Nikolaos , Xiromerisiou Georgia
Published: December 2021

Several studies have investigated the association of the Parkinson’s disease (PD) polygenic risk score (PRS) with several aspects of well-established PD. We sought to evaluate the association of PRS with the prodromal stage of PD. We calculated PRS in a longitudinal sample (n = 1120) of community dwelling individuals ≥ 65 years from the HELIAD (The Hellenic Longitudinal Investigation of Aging and Diet) study in order to evaluate the association of this score with the probability of prodromal PD or any of the established risk and prodromal markers in MDS research criteria, using regression multi-adjusted models. Increases in PRS estimated from GWAS summary statistics’ ninety top SNPS with p < 5 × 10–8 was associated with increased odds of having probable/possible prodromal PD (i.e., ≥ 30% probability, OR = 1.033, 95%CI: 1.009–1.057 p = 0.006). From the prodromal PD risk markers, significant association was found between PRS and global cognitive deficit exclusively (p = 0.003). To our knowledge, our study is the first population based study investigating the association between PRS scores and prodromal markers of Parkinson’s disease. Our results suggest a strong relationship between the accumulation of many common genetic variants, as measured by PRS, and cognitive deficits.
RNA Quality in Post-mortem Human Brain Tissue Is Affected by Alzheimer’s Disease
Authors: Highet Blake , Parker Remai , Faull Richard L. M. , Curtis Maurice A. , Ryan Brigid
Published: December 2021

Gene expression studies of human post-mortem brain tissue are useful for understanding the pathogenesis of neurodegenerative disease. These studies rely on the assumption that RNA quality is consistent between disease and neurologically normal cases; however, previous studies have suggested that RNA quality may be affected by neurodegenerative disease. Here, we compared RNA quality in human post-mortem brain tissue between neurologically normal cases (n = 14) and neurodegenerative disease cases (Alzheimer’s disease n = 10; Parkinson’s disease n = 11; and Huntington’s disease n = 9) in regions affected by pathology and regions that are relatively devoid of pathology. We identified a statistically significant decrease in RNA integrity number (RIN) in Alzheimer’s disease tissue relative to neurologically normal tissue (mixed effects model, p = 0.04). There were no statistically significant differences between neurologically normal cases and Parkinson’s disease or Huntington’s disease cases. Next, we investigated whether total RNA quality affected mRNA quantification, by correlating RIN with qPCR threshold cycle (CT). CT values for all six genes investigated were strongly correlated with RIN (p < 0.05, Pearson correlation); this effect was only partially mitigated by normalization to RPL30. Our results indicate that RNA quality is decreased in Alzheimer’s disease tissue. We recommend that RIN should be considered when this tissue is used in gene expression analyses.
Classification of Game Demand and the Presence of Experimental Pain Using Functional Near-Infrared Spectroscopy
Authors: Fairclough Stephen H. , Dobbins Chelsea , Stamp Kellyann
Published: December 2021

Pain tolerance can be increased by the introduction of an active distraction, such as a computer game. This effect has been found to be moderated by game demand, i.e., increased game demand = higher pain tolerance. A study was performed to classify the level of game demand and the presence of pain using implicit measures from functional Near-InfraRed Spectroscopy (fNIRS) and heart rate features from an electrocardiogram (ECG). Twenty participants played a racing game that was configured to induce low (Easy) or high (Hard) levels of demand. Both Easy and Hard levels of game demand were played with or without the presence of experimental pain using the cold pressor test protocol. Eight channels of fNIRS data were recorded from a montage of frontal and central-parietal sites located on the midline. Features were generated from these data, a subset of which were selected for classification using the RELIEFF method. Classifiers for game demand (Easy vs. Hard) and pain (pain vs. no-pain) were developed using five methods: Support Vector Machine (SVM), k-Nearest Neighbour (kNN), Naive Bayes (NB) and Random Forest (RF). These models were validated using a ten fold cross-validation procedure. The SVM approach using features derived from fNIRS was the only method that classified game demand at higher than chance levels (accuracy = 0.66, F1 = 0.68). It was not possible to classify pain vs. no-pain at higher than chance level. The results demonstrate the viability of utilising fNIRS data to classify levels of game demand and the difficulty of classifying pain when another task is present.
Insufficient Post-operative Energy Intake Is Associated With Failure of Enhanced Recovery Programs After Laparoscopic Colorectal Cancer Surgery: A Prospective Cohort Study
Authors: Liu Shuang , Zhang Sheng , Li Zike , Li Meng , Zhang Yujie , He Min , Jin Chengcheng , Gao Chun , Gong Jianping
Published: December 2021

Background: Although enhanced recovery after surgery (ERAS) has been proven to be beneficial after laparoscopic colorectal surgery, some of the patients may fail to complete the ERAS program during hospitalization. This prospective study aims to evaluate the risk factors associated with ERAS failure after laparoscopic colorectal cancer surgery.

Methods: This is a prospective study from a single tertiary referral hospital. Patients diagnosed with colorectal cancer who met the inclusion criteria were included in this study. Demographic and clinicopathological characteristics were collected. Post-operative activity time and 6-min walking distance (6MWD) were measured. Patients were divided into ERAS failure group and ERAS success according to decreased post-operative activity and 6MWD. Factors associated with ERAS failure were investigated by univariate and multivariate analysis.

Results: A total of 91 patients with colorectal cancer were included. The incidence of ERAS failure is 28.6% among all patients. Patients in ERAS failure group experienced higher rate of post-operative ileus and prolonged hospital stay (p < 0.001). Multivariate analysis revealed that older age (p = 0.006), body mass index ≥25.5 kg/m2 (p = 0.037), smoking (p = 0.002), operative time (p = 0.048), and post-operative energy intake <18.5 kcal/kg•d (p = 0.045) were independent risk factors of ERAS failure after laparoscopic colorectal surgery.

Conclusions: Our findings indicated that a proportion of patients may fail the ERAS program after laparoscopic colorectal surgery. We for the first time showed that post-operative energy intake was an independent risk factor for ERAS failure. This may provide evidence for further investigation on precise measurement of nutritional status and selected high-risk patients for enhanced nutrition support.
Priority Micronutrient Density of Foods for Complementary Feeding of Young Children (6–23 Months) in South and Southeast Asia
Authors: Ortenzi Flaminia , Beal Ty
Published: December 2021

Background: Given their high nutrient requirements and limited gastric capacity, young children during the complementary feeding period (6–23 months) should be fed nutrient-dense foods. However, complementary feeding diets in low- and middle-income countries are often inadequate in one or more essential micronutrients. In South and Southeast Asia infants' and young children's diets are commonly lacking in iron, zinc, vitamin A, folate, vitamin B12, and calcium, hereafter referred to as priority micronutrients.

Objective: This study aimed to identify the top food sources of priority micronutrients among minimally processed foods for complementary feeding of children (6–23 months) in South and Southeast Asia.

Methods: An aggregated regional food composition database for South and Southeast Asia was built, and recommended nutrient intakes (RNIs) from complementary foods were calculated for children aged 6–23 months. An approach was developed to classify foods into one of four levels of priority micronutrient density based on the calories and grams required to provide one-third (for individual micronutrients) or an average of one-third (for the aggregate score) of RNIs from complementary foods.

Results: We found that the top food sources of multiple priority micronutrients are organs, bivalves, crustaceans, fresh fish, goat, canned fish with bones, and eggs, closely followed by beef, lamb/mutton, dark green leafy vegetables, cow milk, yogurt, and cheese, and to a lesser extent, canned fish without bones.

Conclusions: This analysis provided insights into which foods to prioritize to fill common micronutrient gaps and reduce undernutrition in children aged 6–23 months in South and Southeast Asia.
Identification of Key Transcription Factors and Immune Infiltration Patterns Associated With Breast Cancer Prognosis Using WGCNA and Cox Regression Analysis
Authors: Yin Xin , Liu Jiaxiang , Wang Xin , Yang Tianshu , Li Gen , Shang Yaxin , Teng Xu , Yu Hefen , Wang Shuang , Huang Wei
Published: December 2021

Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death among women worldwide. Therefore, the need for effective breast cancer treatment is urgent. Transcription factors (TFs) directly participate in gene transcription, and their dysregulation plays a key role in breast cancer. Our study identified 459 differentially expressed TFs between tumor and normal samples from The Cancer Genome Atlas database. Based on gene expression analysis and weighted gene co-expression network analysis, the co-expression yellow module was found to be integral for breast cancer progression. A total of 121 genes in the yellow module were used for function enrichment. To further confirm prognosis-related TFs, COX regression and LASSO analyses were performed; consequently, a prognostic risk model was constructed, and its validity was verified. Ten prognosis-related TFs were identified according to their expression profile, survival probability, and target genes. COPS5, HDAC2, and NONO were recognized as hub TFs in breast cancer. These TFs were highly expressed in human breast cancer cell lines and clinical breast cancer samples; this result was consistent with the information from multiple databases. Immune infiltration analysis revealed that the proportions of resting dendritic and mast cells were greater in the low-risk group than those in the high-risk group. Thus, in this study, we identified three hub biomarkers related to breast cancer prognosis. The results provide a framework for the co-expression of TF modules and immune infiltration in breast cancer.
Prognostic Significance of NLR About NETosis and Lymphocytes Perturbations in Localized Renal Cell Carcinoma With Tumor Thrombus
Authors: Shang Bingqing , Guo Liping , Shen Rongfang , Cao Chuanzhen , Xie Ruiyang , Jiang Weixing , Wen Li , Bi Xingang , Shi Hongzhe , Zheng Shan , Li Changling , Ma Jianhui , Zhang Kaitai , Feng Lin , Shou Jianzhong
Published: December 2021

Background

Non-metastatic renal cell carcinoma (RCC) with tumor thrombus showed a greater tendency for developing metastases after surgery. Early identification of patients with high risk of poor prognosis is especially important to explore adjuvant treatment of improving outcomes. Neutrophil-to-lymphocyte ratio (NLR) was a systemic inflammation marker and outcome predictor in RCC, reflecting the chaos in systemic immune status in cancer as myeloid cell expansion and lymphatic cell suppression. Neutrophil extracellular traps (NET) formation (NETosis) is the process of neutrophils generating an extracellular DNA net-like structure. NETosis in tumor was demonstrated to conduce to the subsequent metastases of tumor. However, the role of NLR for systemic immune status and tumor local immune infiltration, especially for neutrophil-associated NETs, in non-metastatic RCC with thrombus remains unclear.

Patients and Methods

In our clinical cohort, we enrolled the clinical, pathologic, and preoperative laboratory parameters of 214 RCC patients with tumor thrombus who were treated surgically. The clinical endpoint was defined as cancer-specific survival (CSS). In our basic research cohort, RNA-seq, TCR-seq, and scRNA-seq data were analyzed. Patients who reached the endpoint as recurrence-free survival (RFS) were defined as the “High-risk” group. Otherwise, they were separated into the “Low-risk” group.

Results

In the clinical cohort, NLR≥4 was an independent risk factor for 203 localized RCC with tumor thrombus. In the basic research cohort, tumor thrombi were separated into NETosis-thrombi belonging to the “High-risk” group and non-NETosis-thrombi to the “Low-risk” group. NETs induced by tumor-derived G-CSF in tumor thrombus has a mechanistic role in unfavorable prognosis. Besides, NETs-score from single sample GSEA (ssGSEA) algorithm was an independent prognostic factor validated in the TCGA data. Apart from the neutrophils-associated NETosis, systemic immune perturbations of lymphocytes occurred in the “High-risk” group, represented with decreased TCR diversity and increasingly high proportion of CD4-positive effector memory T (Tem) cells, which indirectly represented the state of lymphopenia.

Conclusions

Our findings firstly demonstrated that neutrophils-associated NETosis and systemic lymphocytes perturbations were considered as tumor progression in patients of localized RCC with tumor thrombus, which reflected NLR≥4 as an independent risk factor for patients.
A Clinical–Radiomics Model for Predicting Axillary Pathologic Complete Response in Breast Cancer With Axillary Lymph Node Metastases
Authors: Gan Liangyu , Ma Mingming , Liu Yinhua , Liu Qian , Xin Ling , Cheng Yuanjia , Xu Ling , Qin Naishan , Jiang Yuan , Zhang Xiaodong , Wang Xiaoying , Ye Jingming
Published: December 2021

Purpose

To develop a clinical–radiomics model based on radiomics features extracted from MRI and clinicopathologic factors for predicting the axillary pathologic complete response (apCR) in breast cancer (BC) patients with axillary lymph node (ALN) metastases.

Materials and Methods

The MR images and clinicopathologic data of 248 eligible invasive BC patients at the Peking University First Hospital from January 2013 to December 2020 were included in this study. All patients received neoadjuvant chemotherapy (NAC), and the presence of ALN metastases was confirmed through cytology pre-NAC. The data from January 2013 to December 2018 were randomly divided into the training and validation sets in a ratio of 7:3, and the data from January 2019 to December 2020 served as the independent testing set. The following three types of prediction models were investigated in this study. 1) A clinical model: the model was built by independently predicting clinicopathologic factors through logistic regression. 2) Radiomics models: we used an automatic segmentation model based on deep learning to segment the axillary areas, visible ALNs, and breast tumors on post-NAC dynamic contrast-enhanced MRI. Radiomics features were then extracted from the region of interest (ROI). Radiomics models were built based on different ROIs or their combination. 3) A clinical–radiomics model: it was built by integrating radiomics signature and independent predictive clinical factors by logistic regression. All models were assessed using a receiver operating characteristic curve analysis and by calculating the area under the curve (AUC).

Results

The clinical model yielded AUC values of 0.759, 0.787, and 0.771 in the training, validation, and testing sets, respectively. The radiomics model based on the combination of MRI features of breast tumors and visible ALNs yielded the best AUC values of 0.894, 0.811, and 0.806 in the training, validation, and testing sets, respectively. The clinical–radiomics model yielded AUC values of 0.924, 0.851, and 0.878 in the training, validation, and testing sets, respectively, for predicting apCR.

Conclusion

We developed a clinical–radiomics model by integrating radiomics signature and clinical factors to predict apCR in BC patients with ALN metastases post-NAC. It may help the clinicians to screen out apCR patients to avoid lymph node dissection.
Deep Learning Enables Prostate MRI Segmentation: A Large Cohort Evaluation With Inter-Rater Variability Analysis
Authors: Liu Yongkai , Miao Qi , Surawech Chuthaporn , Zheng Haoxin , Nguyen Dan , Yang Guang , Raman Steven S. , Sung Kyunghyun
Published: December 2021

Whole-prostate gland (WPG) segmentation plays a significant role in prostate volume measurement, treatment, and biopsy planning. This study evaluated a previously developed automatic WPG segmentation, deep attentive neural network (DANN), on a large, continuous patient cohort to test its feasibility in a clinical setting. With IRB approval and HIPAA compliance, the study cohort included 3,698 3T MRI scans acquired between 2016 and 2020. In total, 335 MRI scans were used to train the model, and 3,210 and 100 were used to conduct the qualitative and quantitative evaluation of the model. In addition, the DANN-enabled prostate volume estimation was evaluated by using 50 MRI scans in comparison with manual prostate volume estimation. For qualitative evaluation, visual grading was used to evaluate the performance of WPG segmentation by two abdominal radiologists, and DANN demonstrated either acceptable or excellent performance in over 96% of the testing cohort on the WPG or each prostate sub-portion (apex, midgland, or base). Two radiologists reached a substantial agreement on WPG and midgland segmentation (κ = 0.75 and 0.63) and moderate agreement on apex and base segmentation (κ = 0.56 and 0.60). For quantitative evaluation, DANN demonstrated a dice similarity coefficient of 0.93 ± 0.02, significantly higher than other baseline methods, such as DeepLab v3+ and UNet (both p values < 0.05). For the volume measurement, 96% of the evaluation cohort achieved differences between the DANN-enabled and manual volume measurement within 95% limits of agreement. In conclusion, the study showed that the DANN achieved sufficient and consistent WPG segmentation on a large, continuous study cohort, demonstrating its great potential to serve as a tool to measure prostate volume.
Cyclin-Dependent Kinase Inhibitors and Their Therapeutic Potential in Colorectal Cancer Treatment
Authors: Thoma Oana-Maria , Neurath Markus F. , Waldner Maximilian J.
Published: December 2021

Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation. So far, more than ten CDKs have been described. Their direct interaction with cyclins allow progression through G1 phase, transitions to S and G2 phase and finally through mitosis (M). While CDK activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells. Dysregulations in CDK pathways are often encountered in various types of cancer, including all gastrointestinal (GI) tract tumors. This prompted the development of CDK inhibitors as novel therapies for cancer. Currently, CDK inhibitors such as CDK4/6 inhibitors are used in pre-clinical studies for cancer treatment. In this review, we will focus on the therapeutic role of various CDK inhibitors in colorectal cancer, with a special focus on the CDK4/6 inhibitors.
First-Line ICI Monotherapies for Advanced Non-small-cell Lung Cancer Patients With PD-L1 of at Least 50%: A Cost-Effectiveness Analysis
Authors: Liu Qiao , Zhou Zhen , Luo Xia , Yi Lidan , Peng Liubao , Wan Xiaomin , Tan Chongqing , Zeng Xiaohui
Published: December 2021

Objective:Three immune checkpoint inhibitors (ICIs), pembrolizumab, atezolizumab and cemiplimab, have been successively approved as first-line treatments for advanced non-small-cell lung cancer (NSCLC) patients with programmed cell death ligand 1(PD-L1) expression of at least 50%. This study was designed to compare the cost-effectiveness of these three novel therapies in this patient population.

Material and Methods:Using Markov model and network meta-analysis, we conducted separate cost-effectiveness analyses for cemiplimab, pembrolizumab and atezolizumab among advanced NSCLC patients with PD-L1 of at least 50% from the United States health care sector perspective. Health states included progression-free survival, progressive disease, end-stage disease, and death. Clinical efficacy and safety data were derived from phase III clinical trials and health state utilities and costs data were collected from published resources. Two scenario analyses were conducted to assess the impact of varying subsequent anticancer therapies on the cost-effectiveness of these 3 ICIs and cost-effectiveness of pembrolizumab combined with chemotherapy versus these 3 first-line ICI monotherapies.

Results:In base case analysis, cemiplimab compared with pembrolizumab was associated with a gain of 0.44 quality-adjusted life-years (QALYs) and an increased cost of $23,084, resulting in an incremental cost-effectiveness ratio (ICER) of $52,998/QALY; cemiplimab compared with atezolizumab was associated with a gain of 0.13 QALYs and a decreased cost of $104,642, resulting in its dominance of atezolizumab. The first scenario analysis yielded similar results as our base case analysis. The second scenario analysis founded the ICERs for pembrolizumab plus chemotherapy were $393,359/QALY, $190,994/QALY and $33,230/QALY, respectively, compared with cemiplimab, pembrolizumab and atezolizumab.

Conclusion:For advanced NSCLC patients with PD-L1 of at least 50%, cemiplimab was a cost-effective option compared with pembrolizumab and a dominant alternative against atezolizumab. Our scenario analysis results supported the cemiplimab plus chemotherapy as a second-line therapy and suggested an extended QALY but overwhelming cost linking to pembrolizumab plus chemotherapy.
Lacosamide Inhibition of NaV1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore
Authors: Labau Julie I. R. , Alsaloum Matthew , Estacion Mark , Tanaka Brian , Dib-Hajj Fadia B. , Lauria Giuseppe , Smeets Hubert J. M. , Faber Catharina G. , Dib-Hajj Sulayman , Waxman Stephen G.
Published: December 2021

Lacosamide, developed as an anti-epileptic drug, has been used for the treatment of pain. Unlike typical anticonvulsants and local anesthetics which enhance fast-inactivation and bind within the pore of sodium channels, lacosamide enhances slow-inactivation of these channels, suggesting different binding mechanisms and mode of action. It has been reported that lacosamide’s effect on NaV1.5 is sensitive to a mutation in the local anesthetic binding site, and that it binds with slow kinetics to the fast-inactivated state of NaV1.7. We recently showed that the NaV1.7-W1538R mutation in the voltage-sensing domain 4 completely abolishes NaV1.7 inhibition by clinically-achievable concentration of lacosamide. Our molecular docking analysis suggests a role for W1538 and pore residues as high affinity binding sites for lacosamide. Aryl sulfonamide sodium channel blockers are also sensitive to substitutions of the W1538 residue but not of pore residues. To elucidate the mechanism by which lacosamide exerts its effects, we used voltage-clamp recordings and show that lacosamide requires an intact local anesthetic binding site to inhibit NaV1.7 channels. Additionally, the W1538R mutation does not abrogate local anesthetic lidocaine-induced blockade. We also show that the naturally occurring arginine in NaV1.3 (NaV1.3-R1560), which corresponds to NaV1.7-W1538R, is not sufficient to explain the resistance of NaV1.3 to clinically-relevant concentrations of lacosamide. However, the NaV1.7-W1538R mutation conferred sensitivity to the NaV1.3-selective aryl-sulfonamide blocker ICA-121431. Together, the W1538 residue and an intact local anesthetic site are required for lacosamide’s block of NaV1.7 at a clinically-achievable concentration. Moreover, the contribution of W1538 to lacosamide inhibitory effects appears to be isoform-specific.
Effects of Replacement of Dietary Fishmeal by Cottonseed Protein Concentrate on Growth Performance, Liver Health, and Intestinal Histology of Largemouth Bass (Micropterus salmoides)
Authors: Liu Yulong , Lu Qisheng , Xi Longwei , Gong Yulong , Su Jingzhi , Han Dong , Zhang Zhimin , Liu Haokun , Jin Junyan , Yang Yunxia , Zhu Xiaoming , Xie Shouqi
Published: December 2021

An 8-week feeding trial was conducted to explore the effects of replacement of dietary fishmeal by cottonseed protein concentrate (CPC) on growth performance, liver health, and intestine histology of largemouth bass. Four isoproteic and isolipidic diets were formulated to include 0, 111, 222, and 333 g/kg of CPC, corresponding to replace 0% (D1), 25% (D2), 50% (D3), and 75% (D4) of fishmeal. Two hundred and forty largemouth bass (15.11 ± 0.02 g) were randomly divided into four groups with three replicates per group. During the experiment, fish were fed to apparent satiation twice daily. Results indicated that CPC could replace up to 50% fishmeal in a diet for largemouth bass without significant adverse effects on growth performance. However, weight gain rate (WGR), specific growth rate (SGR), feed efficiency (FE), and condition factor (K) of the largemouth bass were significantly decreased when 75% of dietary fishmeal that was replaced by CPC. The whole body lipid content was increased with the increasing of dietary CPC levels. Oil red O staining results indicated that fish fed the D4 diet showed an aggravated fat deposition in the liver. Hepatocytes exhibited serious degeneration, volume shrinkage, and inflammatory cells infiltration in the D4 group. Intestinal villi appeared shorter and sparse with severe epithelial damage in the D4 group. The transcription levels of anti-inflammatory cytokines, such as transforming growth factor β (tgf-β), interleukin 10 (il-10), and interleukin 11 β (il-11β), were downregulated in the D4 group. The lipid metabolism-related genes carnitine palmitoyl transferase 1 (cpt1), peroxisome proliferator-activated receptor α (pparα), and target of rapamycin (TOR) pathway were also significantly downregulated in the D4 group. It was concluded that suitable replacement of fishmeal by less than 222 g CPC/kg diet had a positive effect on growth performance of fish, but an excessive substitution of 75% fishmeal by CPC would lead to the suppressed growth, liver inflammation, and intestinal damage of largemouth bass.
A Breakthrough in Understanding the Pathogenesis of Molar Hypomineralisation: The Mineralisation-Poisoning Model
Authors: Hubbard Michael J. , Mangum Jonathan E. , Perez Vidal A. , Williams Rebecca
Published: December 2021

Popularly known as “chalky teeth”, molar hypomineralisation (MH) affects over 1-in-5 children worldwide, triggering massive amounts of suffering from toothache and rapid decay. MH stems from childhood illness and so offers a medical-prevention avenue for improving oral and paediatric health. With a cross-sector translational research and education network (The D3 Group;thed3group.org) now highlighting this global health opportunity, aetiological understanding is urgently needed to enable better awareness, management and eventual prevention of MH. Causation and pathogenesis of “chalky enamel spots” (i.e., demarcated opacities, the defining pathology of MH) remain unclear despite 100 years of investigation. However, recent biochemical studies provided a pathomechanistic breakthrough by explaining several hallmarks of chalky opacities for the first time. This article outlines these findings in context of previous understanding and provides a working model for future investigations. The proposed pathomechanism, termed “mineralisation poisoning”, involves localised exposure of immature enamel to serum albumin. Albumin binds to enamel-mineral crystals and blocks their growth, leading to chalky opacities with distinct borders. Being centred on extracellular fluid rather than enamel-forming cells as held by dogma, this localising pathomechanism invokes a new type of connection with childhood illness. These advances open a novel direction for research into pathogenesis and causation of MH, and offer prospects for better clinical management. Future research will require wide-ranging inputs that ideally should be coordinated through a worldwide translational network. We hope this breakthrough will ultimately lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay.
Tracheid and Pit Dimensions Hardly Vary in the Xylem of Pinus sylvestris Under Contrasting Growing Conditions
Authors: Held Magdalena , Ganthaler Andrea , Lintunen Anna , Oberhuber Walter , Mayr Stefan
Published: December 2021

Maintaining sufficient water transport via the xylem is crucial for tree survival under variable environmental conditions. Both efficiency and safety of the water transport are based on the anatomical structure of conduits and their connections, the pits. Yet, the plasticity of the xylem anatomy, particularly that of the pit structures, remains unclear. Also, trees adjust conduit dimensions to the water transport distance (i.e., tree size), but knowledge on respective adjustments in pit dimensions is scarce. We compared tracheid traits [mean tracheid diameter d, mean hydraulic diameter dh, cell wall reinforcement (t/b)2], pit dimensions (diameters of pit aperture Da, torus Dt, margo Dm, and pit border Dp), and pit functional properties (margo flexibility F, absolute overlap Oa, torus overlap O, and valve effect Vef) of two Scots pine (Pinus sylvestris L.) stands of similar tree heights but contrasting growth rates. Furthermore, we analyzed the trends of these xylem anatomical parameters across tree rings. Tracheid traits and pit dimensions were similar on both sites, whereas Oa, O, and F were higher at the site with a lower growth rate. On the lower growth rate site, dh and pit dimensions increased across tree rings from pith to bark, and in trees from both sites, dh scaled with pit dimensions. Adjusted pit functional properties indicate slightly higher hydraulic safety in trees with a lower growth rate, although a lack of major differences in measured traits indicated overall low plasticity of the tracheid and pit architecture. Mean hydraulic diameter and pit dimension are well coordinated to increase the hydraulic efficiency toward the outer tree rings and thus with increasing tree height. Our results contribute to a better understanding of tree hydraulics under variable environmental conditions.
Personal Perspectives on Plant Ribosomal RNA Genes Research: From Precursor-rRNA to Molecular Evolution
Authors: Hemleben Vera , Grierson Donald , Borisjuk Nikolai , Volkov Roman A. , Kovarik Ales
Published: December 2021

The history of rDNA research started almost 90 years ago when the geneticist, Barbara McClintock observed that in interphase nuclei of maize the nucleolus was formed in association with a specific region normally located near the end of a chromosome, which she called the nucleolar organizer region (NOR). Cytologists in the twentieth century recognized the nucleolus as a common structure in all eukaryotic cells, using both light and electron microscopy and biochemical and genetic studies identified ribosomes as the subcellular sites of protein synthesis. In the mid- to late 1960s, the synthesis of nuclear-encoded rRNA was the only system in multicellular organisms where transcripts of known function could be isolated, and their synthesis and processing could be studied. Cytogenetic observations of NOR regions with altered structure in plant interspecific hybrids and detailed knowledge of structure and function of rDNA were prerequisites for studies of nucleolar dominance, epistatic interactions of rDNA loci, and epigenetic silencing. In this article, we focus on the early rDNA research in plants, performed mainly at the dawn of molecular biology in the 60 to 80-ties of the last century which presented a prequel to the modern genomic era. We discuss – from a personal view – the topics such as synthesis of rRNA precursor (35S pre-rRNA in plants), processing, and the organization of 35S and 5S rDNA. Cloning and sequencing led to the observation that the transcribed and processed regions of the rRNA genes vary enormously, even between populations and species, in comparison with the more conserved regions coding for the mature rRNAs. Epigenetic phenomena and the impact of hybridization and allopolyploidy on rDNA expression and homogenization are discussed. This historical view of scientific progress and achievements sets the scene for the other articles highlighting the immense progress in rDNA research published in this special issue of Frontiers in Plant Science on “Molecular organization, evolution, and function of ribosomal DNA.”
Constraint-Based Sound-Motion Objects in Music Performance
Authors: Godøy Rolf Inge
Published: December 2021

The aim of this paper is to present principles of constraint-based sound-motion objects in music performance.Sound-motion objectsare multimodal fragments of combined sound and sound-producing body motion, usually in the duration range of just a few seconds, and conceived, produced, and perceived as intrinsically coherent units. Sound-motion objects have a privileged role as building blocks in music because of their duration, coherence, and salient features and emerge from combined instrumental, biomechanical, and motor control constraints at work in performance. Exploring these constraints and the crucial role of the sound-motion objects can enhance our understanding of generative processes in music and have practical applications in performance, improvisation, and composition.