bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of a startle-based warning, age, sex, and secondary task on takeover actions in critical autonomous driving scenarios
Authors: Griffith M. , Akkem R. , Maheshwari J. , Seacrist T. , Arbogast K. B. , Graci V.
Published: March 2023

Introduction: In highly autonomous driving scenarios, it is critical to identify strategies to accelerate reaction times since drivers may take too long to take over control of the vehicle. Previous studies reported that an Acoustic Startling Pre-Stimulus (ASPS, i.e., a loud warning preceding an action) accelerated reaction times in simple ankle flexion exercises.

Methods: In this study, we examined if an ASPS warning leads to shorter takeover reaction times in a sled-simulated evasive swerving maneuver. Twenty-eight participants (seven male adults, seven male teenagers, seven female adults, and seven female teenagers) were instructed to align a marker on the steering wheel with a marker on a lateral post as fast as they could as soon as the lateral sled perturbation (0.75 g) started. Four conditions were examined: with and without an ASPS (105 dB, played 250 ms before sled perturbation for 40 ms), and with and without a secondary task (i.e., texting). A catch trial (ASPS only) was used to minimize anticipation. Human kinematics were captured with an 8-camera 3D motion capture system.

Results: Results showed that the drivers’ hands lifted towards the steering wheel more quickly with the ASPS (169 ± 55 ms) than without (194 ± 46 ms; p = 0.01), and that adult drivers touched the steering wheel quicker with the ASPS (435 ± 54 ms) than without (470 ± 33 ms; p = 0.01). Similar findings were not observed for the teen drivers. Additionally, female drivers were found to lift their hands towards the steering wheel faster than male drivers (166 ± 58 ms vs. 199 ± 36 ms; p = 0.009).

Discussion: Our findings suggest that the ASPS may be beneficial to accelerate driver reaction times during the initiation of a correction maneuver, and that autonomous vehicle warnings may need to be tailored to the age and sex of the driver.
Cell-specific occupancy dynamics between the pioneer-like factor Opa/ZIC and Ocelliless/OTX regulate early head development in embryos
Authors: Fenelon Kelli D. , Gao Fan , Borad Priyanshi , Abbasi Shiva , Pachter Lior , Koromila Theodora
Published: March 2023

During development, embryonic patterning systems direct a set of initially uncommitted pluripotent cells to differentiate into a variety of cell types and tissues. A core network of transcription factors, such as Zelda/POU5F1, Odd-paired (Opa)/ZIC3 and Ocelliless (Oc)/OTX2, are conserved across animals. While Opa is essential for a second wave of zygotic activation after Zelda, it is unclear whether Opa drives head cell specification, in the Drosophila embryo. Our hypothesis is that Opa and Oc are interacting with distinct cis-regulatory regions for shaping cell fates in the embryonic head. Super-resolution microscopy and meta-analysis of single-cell RNAseq datasets show that opa’s and oc’s overlapping expression domains are dynamic in the head region, with both factors being simultaneously transcribed at the blastula stage. Additionally, analysis of single-embryo RNAseq data reveals a subgroup of Opa-bound genes to be Opa-independent in the cellularized embryo. Interrogation of these genes against Oc ChIPseq combined with in situ data, suggests that Opa is competing with Oc for the regulation of a subgroup of genes later in gastrulation. Specifically, we find that Oc binds to late, head-specific enhancers independently and activates them in a head-specific wave of zygotic transcription, suggesting distinct roles for Oc in the blastula and gastrula stages.
An immunoresponsive three-dimensional urine-tolerant human urothelial model to study urinary tract infection
Authors: Jafari Nazila V. , Rohn Jennifer L.
Published: March 2023

Introduction

Murine models of urinary tract infection (UTI) have improved our understanding of host-pathogen interactions. However, given differences between rodent and human bladders which may modulate host and bacterial response, including certain biomarkers, urothelial thickness and the concentration of urine, the development of new human-based models is important to complement mouse studies and to provide a more complete picture of UTI in patients.

Methods

We originally developed a human urothelial three-dimensional (3D) model which was urine tolerant and demonstrated several urothelial biomarkers, but it only achieved human thickness in heterogenous, multi-layered zones and did not demonstrate the comprehensive differentiation status needed to achieve barrier function. We optimised this model by altering a variety of conditions and validated it with microscopy, flow cytometry, transepithelial electrical resistance and FITC-dextran permeability assays to confirm tissue architecture, barrier integrity and response to bacterial infection.

Results

We achieved an improved 3D urine-tolerant human urothelial model (3D-UHU), which after 18-20 days of growth, stratified uniformly to 7-8 layers comprised of the three expected, distinct human cell types. The apical surface differentiated into large, CD227+ umbrella-like cells expressing uroplakin-1A, II, III, and cytokeratin 20, all of which are important terminal differentiation markers, and a glycosaminoglycan layer. Below this layer, several layers of intermediate cells were present, with a single underlying layer of CD271+ basal cells. The apical surface also expressed E-cadherin, ZO-1, claudin-1 and -3, and the model possessed good barrier function. Infection with both Gram-negative and Gram-positive bacterial classes elicited elevated levels of pro-inflammatory cytokines and chemokines characteristic of urinary tract infection in humans and caused a decrease in barrier function.

Discussion

Taken together, 3D-UHU holds promise for studying host-pathogen interactions and host urothelial immune response.
3D seismic simulation analysis of the Longtoushan Town Basin during the 2014 Ludian earthquake, Yunnan province
Authors: Li Chengcheng , Liu Peng , Liu Zhongxian , Yuan Xiaoming , Tian Yuan , Zhang Hai , Cao Zhenzhong
Published: March 2023

On 3 August 2014, a magnitude Ms 6.5 earthquake struck Ludian County, Zhaotong City, Yunnan Province, causing grave losses of life and property in the Longtoushan Town Basin near the fault. In this study, a three-dimensional model of the Longtoushan Town Basin and the velocity structure of the surrounding area, and the Spectral Elements in Elastic Dynamics code, which combines the discontinuous Galerkin technique and the spectral element method (SEM) are used to simulate and study the entire seismic wave propagation process. The results show that due to the variations in the basin geometry and the impedance ratio of the media inside and outside the basin, the seismic waves incident on the basin edge are refracted and diffracted, further prolonging the ground motion holding time within the basin. In the bedrock outside the basin, the velocity peaks are higher at higher elevations; viceversa within the basin, the locally depressed basement produces an obvious amplification effect. The amplitude of the ground motion is not the greatest in the thickest sedimentary layers in the basin, and it is closely related to the degree of undulation at the base of the sedimentary layers, the overburden thickness, and the basin geometry. The peak ground accelerations (PGAs) of approximately 8 m/s2 in the east–west (E–W) direction and 3 m/s2 in the north–south (N–S) direction are influenced by the rupture directivity effect (the ruptured surface is the Baogunao–Xiaohe fault that is oriented in the N–W direction). The peak ground velocity with a sedimentary model is 2.6 and 1.6 times that of the non-sedimentary model in the E–W and N–S directions, respectively. The maximum amplification factor for PGA in the E–W direction is 2.8 and that in the N–S direction is approximately 2.3. The results are in agreement with the actual observed seismic station data in terms of the waveforms and peaks, and the intensity distribution map matches the actual damage distribution. This proves the accuracy and rationality of the method used in this study. The results are useful for the seismic zoning of cities, and they can help engineers predict ground motions for future large earthquakes.
Mosaicking Andean morphostructure and seismic cycle crustal deformation patterns using GNSS velocities and machine learning
Authors: Yáñez-Cuadra Vicente , Moreno Marcos , Ortega-Culaciati Francisco , Donoso Felipe , Báez Juan Carlos , Tassara Andrés
Published: March 2023

We use unsupervised machine learning techniques to analyze continental-scale crustal motions in areas affected by the seismic cycle of large subduction earthquakes along the Chilean Trench. Specifically, we use the agglomerative clustering algorithm as an exploratory tool to investigate spatial patterns in GNSS regional velocities without the complexity of modeling a physical source. We present a continental-scale velocity field including all available GNSS data for two-time windows (pre-2014, 2018–2021) that represents two periods with different deformation patterns of the seismic cycle. We test two different pre-processing methodologies for the design of machine learning features from the GNSS-derived velocities. The first method uses the direction and magnitude of the secular rates as input features to the clustering algorithm. These results show a clustering spatially related to seismic cycle deformation, separating latitudinal segments with different velocities in the fore-arc and back-arc, as well as regions affected by postseismic relaxation. Thus, highlighting the effectiveness of this method for mapping first-order patterns of active deformation in a subduction zone, that are particularly related to variations on interplate coupling and postseismic transient deformation. In a more sophisticated approach, we use surface strain and rotational rates from GNSS velocities as features in the second methodology. Here, we develop a novel methodology to estimate strain and rotation rates accounting for the spatial heterogeneity of the GNSS-network. We determine the spatial scale at which these features are estimated by least squares inversions, by using a Bayesian model class selection method. The distribution of stations allows to identify heterogeneities in strain and rotation rates at spatial scales larger than 50 km, being particularly notorious the main features of regional deformation at scales > 100 km. Interestingly, the results show a spatial correlation between seismic segmentation in the fore-arc and geologic and structural domains in the arc and back-arc. Our results demonstrate the ability of the combination of inverse and machine learning methods to efficiently identify active deformation patterns and their relationship to the subduction seismic cycle and regional-scale geological structures. Furthermore, our analysis suggests that Andean geological structures influence the observed deformation field.
Automated detection and classification of acute vertebral body fractures using a convolutional neural network on computed tomography
Authors: Zhang Jianlun , Liu Feng , Xu Jingxu , Zhao Qingqing , Huang Chencui , Yu Yizhou , Yuan Huishu
Published: March 2023

Background

Acute vertebral fracture is usually caused by low-energy injury with osteoporosis and high-energy trauma. The AOSpine thoracolumbar spine injury classification system (AO classification) plays an important role in the diagnosis and treatment of the disease. The diagnosis and description of vertebral fractures according to the classification scheme requires a great deal of time and energy for radiologists.

Purpose

To design and validate a multistage deep learning system (multistage AO system) for the automatic detection, localization and classification of acute thoracolumbar vertebral body fractures according to AO classification on computed tomography.

Materials and Methods

The CT images of 1,217 patients who came to our hospital from January 2015 to December 2019 were collected retrospectively. The fractures were marked and classified by 2 junior radiology residents according to the type A standard in the AO classification. Marked fracture sites included the upper endplate, lower endplate and posterior wall. When there were inconsistent opinions on classification labels, the final result was determined by a director radiologist. We integrated different networks into different stages of the overall framework. U-net and a graph convolutional neural network (U-GCN) are used to realize the location and classification of the thoracolumbar spine. Next, a classification network is used to detect whether the thoracolumbar spine has a fracture. In the third stage, we detect fractures in different parts of the thoracolumbar spine by using a multibranch output network and finally obtain the AO types.

Results

The mean age of the patients was 61.87 years with a standard deviation of 17.04 years, consisting of 760 female patients and 457 male patients. On vertebrae level, sensitivity for fracture detection was 95.23% in test dataset, with an accuracy of 97.93% and a specificity of 98.35%. For the classification of vertebral body fractures, the balanced accuracy was 79.56%, with an AUC of 0.904 for type A1, 0.945 for type A2, 0.878 for type A3 and 0.942 for type A4.

Conclusion

The multistage AO system can automatically detect and classify acute vertebral body fractures in the thoracolumbar spine on CT images according to AO classification with high accuracy.
Crafting a prognostic nomogram for the overall survival rate of cutaneous verrucous carcinoma using the surveillance, epidemiology, and end results database
Authors: Chong Siomui , Huang Liying , Yu Hai , Huang Hui , Ming Wai-kit , Ip Cheong Cheong , Mu Hsin-Hua , Li Kexin , Zhang Xiaoxi , Lyu Jun , Deng Liehua
Published: March 2023

Background

The aim of this study was to establish and verify a predictive nomogram for patients with cutaneous verrucous carcinoma (CVC) who will eventually survive and to determine the accuracy of the nomogram relative to the conventional American Joint Committee on Cancer (AJCC) staging system.

Methods

Assessments were performed on 1125 patients with CVC between 2004 and 2015, and the results of those examinations were recorded in the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided at a ratio of 7:3 into the training (n = 787) and validation (n = 338) cohorts. Predictors were identified using stepwise regression analysis in the COX regression model for create a nomogram to predict overall survival of CVC patients at 3-, 5-, and 8-years post-diagnosis. We compared the performance of our model with that of the AJCC prognosis model using several evaluation metrics, including C-index, NRI, IDI, AUC, calibration plots, and DCAs.

Results

Multivariate risk factors including sex, age at diagnosis, marital status, AJCC stage, radiation status, and surgery status were employed to determine the overall survival (OS) rate (P<0.05). The C-index nomogram performed better than the AJCC staging system variable for both the training (0.737 versus 0.582) and validation cohorts (0.735 versus 0.573), which AUC (> 0.7) revealed that the nomogram exhibited significant discriminative ability. The statistically significant NRI and IDI values at 3-, 5-, and 8-year predictions for overall survival (OS) in the validation cohort (55.72%, 63.71%, and 78.23%, respectively and 13.65%, 20.52%, and 23.73%, respectively) demonstrate that the established nomogram outperforms the AJCC staging system (P < 0.01) in predicting OS for patients with cutaneous verrucous carcinoma (CVC). The calibration plots indicate good performance of the nomogram, while decision curve analyses (DCAs) show that the predictive model could have a favorable clinical impact.

Conclusion

This study constructed and validated a nomogram for predicting the prognosis of patients with CVC in the SEER database and assessed it using several variables. This nomogram model can assist clinical staff in making more-accurate predictions than the AJCC staging method about the 3-, 5-, and 8-year OS probabilities of patients with CVC.
How to maximize the therapeutic effect of exosomes on skin wounds in diabetes mellitus: Review and discussion
Authors: Dong Jia , Wu Bin , Tian Weidong
Published: March 2023

Chronic skin wound healing, especially in diabetes mellitus, is still unsolved. Although many efforts have been made to treat diabetic skin wounds, current strategies have achieved limited effectiveness. Nowadays, a great number of studies have shown that exosomes might be a promising approach for treating diabetic wounds. Many studies and reviews have focused on investigating and discussing the effectiveness and mechanism of exosomes. However, maximizing its value in treating skin wounds in diabetes mellitus requires further consideration. In this review, we reviewed and discussed the aspects that could be further improved in this process, including finding a better source of exosomes, engineering exosomes, adjusting dosage and frequency, and combining more efficient delivery methods. This review provided an overview and idea of what we can do to improve the therapeutic effect of exosomes on skin wounds in diabetes mellitus. Only by combining all the factors that affect the effectiveness of exosomes in diabetic wound healing can we further promote their clinical usefulness.
Estimating direct and indirect effects of habitat structure on nesting field sparrows (Spizella pusilla) using structural equation models
Authors: Glass Alex , Eichholz Michael W.
Published: March 2023

Due to consistent population declines across the continent, grassland birds have become a guild of high conservation and management interest. Despite a large number of studies investigating grassland bird habitat associations, we know relatively little about the mechanisms through which habitat characteristics may impact grassland birds, as these mechanisms are often assumed rather than directly tested. For this study, we estimated whether the effects of habitat structure on breeding Field Sparrows are mediated through changes in predator (snake and raccoon) abundance, alternative prey availability, or arthropod biomass using structural equation models. We found no evidence of nest survival or nest density of Field Sparrows being directly influenced by nest predator abundance, alternative prey, or arthropod biomass, although habitat characteristics associated with increased nest survival were also associated with greater arthropod biomass and reduced predator abundance. We suggest that habitat structure in our study area primarily impacts breeding Field Sparrows through direct means, such as influencing nest concealment or foraging efficiency. Our results also suggest that nest success and nest density are decoupled in our study area, so Field Sparrows may be preferentially selecting nest sites with structural characteristics that do not increase nest survival. Ultimately, our findings from this study indicate that while predator avoidance and food provisioning likely play an important role in determining nest survival for grassland birds, predator abundance and arthropod biomass may not necessarily predict predation risk and foraging efficiency to the extent that is often assumed.
Data-driven quality assessment of cycling networks
Authors: Weikl Simone , Mayer Patricia
Published: March 2023

Most planning guidelines for bicycle networks define a consistent set of qualitative criteria. All relevant destinations should be reached by bike in a safe, coherent (i.e., continuous bicycle facilities), direct (i.e., minimal detours), comfortable and attractive way. For transportation planners, few information exist on the degree to which these qualitative criteria are (still) fulfilled for already existing bicycle networks. However, these information are essential for the definition and prioritization of appropriate bicycle infrastructure measures under limited budget. Until now, no standardized methodology for the purely data-driven quantitative assessment of all of these five (and potentially more) qualitative bicycle network criteria exists. This paper develops a data-driven quality assessment methodology for bicycle networks. Based on an extensive literature review of existing guidelines, design manuals and literature on bicycle network planning, a comprehensible set of relevant qualitative criteria for bicycle networks including sub-criteria are defined in detail. For each sub-criterion, possible measurable indicators and data sources are identified as well. Indicators are translated into precise and transparent evaluation scales with a strong foundation. They are based on widely used guidelines and design manuals for bicycle traffic in European countries, especially the ones of pioneer countries for cycling such as the Netherlands. The work differentiates between local indicators of single bicycle facilities (edge-based, e.g., surface quality), route-wide indicators (e.g., travel time ratio) and network-wide indicators (e.g., network density) and integrates these into an overall framework. A methodology is developed that combines and weights several sub-criteria to consolidated scores for each criterion as well as one final overall score for bicycle network quality. Finally, the applicability of the approach is shown within a case study for the city of Munich, Germany. The key findings for Munich’s cycling network are as follows. The cycling network has a medium level of quality, indicating clear potential for improvement. The analysis of sub-criteria revealed that the city of Munich should focus primarily on expanding the main cycling network, on decreasing the number of conflict points and on decreasing the travel time of cyclists.
Identification of disease-related genes and construction of a gene co-expression database in non-alcoholic fatty liver disease
Authors: Ye Hua , Sun Mengxia , Su Mingli , Chen Dahua , Liu Huiwei , Ma Yanyan , Luo Wenjing , Li Hong , Xu Feng
Published: March 2023

Background: The mechanism of NAFLD progression remains incompletely understood. Current gene-centric analysis methods lack reproducibility in transcriptomic studies.

Methods: A compendium of NAFLD tissue transcriptome datasets was analyzed. Gene co-expression modules were identified in the RNA-seq dataset GSE135251. Module genes were analyzed in the R gProfiler package for functional annotation. Module stability was assessed by sampling. Module reproducibility was analyzed by the ModulePreservation function in the WGCNA package. Analysis of variance (ANOVA) and Student’s t-test was used to identify differential modules. The receiver operating characteristic (ROC) curve was used to illustrate the classification performance of modules. Connectivity Map was used to mine potential drugs for NAFLD treatment.

Results: Sixteen gene co-expression modules were identified in NAFLD. These modules were associated with multiple functions such as nucleus, translation, transcription factors, vesicle, immune response, mitochondrion, collagen, and sterol biosynthesis. These modules were stable and reproducible in the other 10 datasets. Two modules were positively associated with steatosis and fibrosis and were differentially expressed between non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver (NAFL). Three modules can efficiently separate control and NAFL. Four modules can separate NAFL and NASH. Two endoplasmic reticulum related modules were both upregulated in NAFL and NASH compared to normal control. Proportions of fibroblasts and M1 macrophages are positively correlated with fibrosis. Two hub genes Aebp1 and Fdft1 may play important roles in fibrosis and steatosis. m6A genes were strongly correlated with the expression of modules. Eight candidate drugs for NAFLD treatment were proposed. Finally, an easy-to-use NAFLD gene co-expression database was developed (available at https://nafld.shinyapps.io/shiny/).

Conclusion: Two gene modules show good performance in stratifying NAFLD patients. The modules and hub genes may provide targets for disease treatment.
Small RNA sequencing identified miR-3180 as a potential prognostic biomarker for Chinese hepatocellular carcinoma patients
Authors: Sun Libo , Zhou Hansheng , Zhao Xiaofei , Zhang Haitao , Wang Yan , Li Guangming
Published: March 2023

MicroRNAs (miRNAs) and their target genes are aberrantly expressed in many cancers and are linked to carcinogenesis and metastasis, especially among hepatocellular carcinoma (HCC) patients. This study sought to identify new biomarkers related to HCC prognosis using small RNA sequencing from the tumor and matched normal adjacent tissue of 32 patients with HCC. Eight miRNAs were downregulated and 61 were upregulated more than twofold. Of these, five miRNAs, hsa-miR-3180, hsa-miR-5589-5p, hsa-miR-490-5p, hsa-miR-137, and hsa-miR-378i, were significantly associated with 5-year overall survival (OS) rates. Differential upregulation of hsa-miR-3180 and downregulation of hsa-miR-378i in tumor samples supported the finding that low and high concentrations of hsa-miR-3180 (p = 0.029) and hsa-miR-378i (p = 0.047), respectively, were associated with higher 5-year OS. Cox regression analyses indicated that hsa-miR-3180 (HR = 0.08; p = 0.013) and hsa-miR-378i (HR = 18.34; p = 0.045) were independent prognostic factors of poor survival. However, high hsa-miR-3180 expression obtained larger AUCs for OS and progression-free survival (PFS) and had better nomogram prediction than hsa-miR-378i. These findings indicate that hsa-miR-3180 may be associated with HCC progression and could serve as a potential biomarker for this disease.
Development of a risk model to predict prognosis in breast cancer based on cGAS-STING-related genes
Authors: Chen Chen , Wang Junxiao , Dong Chao , Lim David , Feng Zhihui
Published: March 2023

Background: Breast cancer (BRCA) is regarded as a lethal and aggressive cancer with increasing morbidity and mortality worldwide. cGAS-STING signaling regulates the crosstalk between tumor cells and immune cells in the tumor microenvironment (TME), emerging as an important DNA-damage mechanism. However, cGAS-STING-related genes (CSRGs) have rarely been investigated for their prognostic value in breast cancer patients.

Methods: Our study aimed to construct a risk model to predict the survival and prognosis of breast cancer patients. We obtained 1087 breast cancer samples and 179 normal breast tissue samples from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEX) database, 35 immune-related differentially expression genes (DEGs) from cGAS-STING-related genes were systematically assessed. The Cox regression was applied for further selection, and 11 prognostic-related DEGs were used to develop a machine learning-based risk assessment and prognostic model.

Results: We successfully developed a risk model to predict the prognostic value of breast cancer patients and its performance acquired effective validation. The results derived from Kaplan-Meier analysis revealed that the low-risk score patients had better overall survival (OS). The nomogram that integrated the risk score and clinical information was established and had good validity in predicting the overall survival of breast cancer patients. Significant correlations were observed between the risk score and tumor-infiltrating immune cells, immune checkpoints and the response to immunotherapy. The cGAS-STING-related genes risk score was also relevant to a series of clinic prognostic indicators such as tumor staging, molecular subtype, tumor recurrence, and drug therapeutic sensibility in breast cancer patients.

Conclusion: cGAS-STING-related genes risk model provides a new credible risk stratification method to improve the clinical prognostic assessment for breast cancer.
The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus
Authors: Banos Aggelos , Thomas Konstantinos , Garantziotis Panagiotis , Filia Anastasia , Malissovas Nikolaos , Pieta Antigone , Nikolakis Dimitrios , Panagiotopoulos Alexandros G. , Chalkia Aglaia , Petras Dimitrios , Bertsias George , Boumpas Dimitrios T. , Vassilopoulos Dimitrios
Published: March 2023

Introduction

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).

Methods

We performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.

Results

We report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.

Discussion

We conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy.
Molecular subtype identification and signature construction based on Golgi apparatus-related genes for better prediction prognosis and immunotherapy response in hepatocellular carcinoma
Authors: Sun Liang , Liu Zitao , Wu Zhengyi , Ning Ke , Hu Junwen , Chen Zhendong , Wu Zhipeng , Yin Xiangbao
Published: March 2023

Introduction

The Golgi apparatus (GA) is the center of protein and lipid synthesis and modification in normal cells and is involved in regulating various cellular process as a signaling hub, the dysfunction of which can lead to the development of various pathological conditions, including tumors. Mutations in Golgi apparatus-related genes (GARGs) are prevalent in most tumors, and their mutations can make them pro-tumor metastatic. The aim of this study was to analyze the predictive role of GARGs in the prognosis and immunotherapeutic outcome of hepatocellular carcinoma.

Methods

We used TCGA, GEO and ICGC databases to classify hepatocellular carcinoma samples into two molecular subtypes based on the expression of GARGs. Signature construction was then performed using GARGs, and signature genes were selected for expression validation and tumor phenotype experiments to determine the role of GARGs in the prognosis of hepatocellular carcinoma.

Results

Using the TCGA, GEO and ICGC databases, two major subtypes of molecular heterogeneity among hepatocellular carcinoma tumors were identified based on the expression of GARGs, C1 as a high-risk subtype (low survival) and C2 as a low-risk subtype (high survival). The high-risk subtype had lower StromalScore, ImmuneScore, ESTIMATEScore and higher TumorPurity, indicating poorer treatment outcome for ICI. Meanwhile, we constructed a new risk assessment profile for hepatocellular carcinoma based on GARGs, and we found that the high-risk group had a worse prognosis, a higher risk of immune escape, and a higher TP53 mutation rate. Meanwhile, TME analysis showed higher tumor purity TumorPurity and lower ESTIMATEScore, ImmuneScore and StromalScore in the high-risk group. We also found that the high-risk group responded more strongly to a variety of anticancer drugs, which is useful for guiding clinical drug use. Meanwhile, the expression of BSG was experimentally found to be associated with poor prognosis of HCC. After interfering with the expression of BSG in HCC cells SMMC-7721, the proliferation and migration ability of HCC cells were significantly restricted.

Discussion

The signature we constructed using GARGs can well predict the prognosis and immunotherapy effect of hepatocellular carcinoma, providing new ideas and strategies for the treatment of hepatocellular carcinoma.
Perfluorocarbon nanodrug induced oxygen self-enriching sonodynamic therapy improves cancer immunotherapy after insufficient radiofrequency ablation
Authors: Huang Tongyi , Wu Wenxin , Wu Jiancong , Tan Yang , Zhang Minru , Long Haiyi , Guo Huanling , Zhang Xiaoer , Zhou Wenwen , Zhang Qi , Xie Xiaoyan , Xu Ming , Zhang Chunyang
Published: March 2023

Residual lesions and undetectable metastasis after insufficient radiofrequency ablation (iRFA) are associated with earlier new metastases and poor survival in cancer patients, for induced aggressive tumor phenotype and immunosuppression. Programmed cell death protein 1(PD-1) blockade has been reported to enhance the radiofrequency ablation-elicited antitumor immunity, but its ability to eliminate incompletely ablated residual lesions has been questioned. Here, we report a combined treatment modality post iRFA based on integrating an oxygen self-enriching nanodrug PFH-Ce6 liposome@O2 nanodroplets (PCL@O2)-augmented noninvasive sonodynamic therapy (SDT) with PD-1 blockade. PCL@O2 containing Ce6 as the sonosensitizer and PFH as O2 reservoir, was synthesized as an augmented SDT nanoplatform and showed increased ROS generation to raise effective apoptosis of tumor cells, which also exposed more calreticulin to induce stronger immunogenic cell death (ICD). Combining with PD-1 blockade post iRFA, this optimized SDT induced a better anti-tumor response in MC38 tumor bearing mouse model, which not only arrested residual primary tumor progression, but also inhibited the growth of distant tumor, therefore prolonging the survival. Profiling of immune populations within the tumor draining lymph nodes and tumors further revealed that combination therapy effectively induced ICD, and promoted the maturation of dendritic cells, tumor infiltration of T cells, as well as activation of cytotoxic T lymphocytes. While iRFA alone could result in an increase of regulatory T cells (Tregs) in the residual tumors, SDT plus PD-1 blockade post iRFA reduced the number of Tregs in both primary and distant tumors. Moreover, the combined treatment could significantly initiate long-term immune memory, manifesting as elevated levels of CD8+ and CD4+ central memory cells. Therefore, this study establishes the preclinical proof of concept to apply oxygen self-enriching SDT to augment cancer immunotherapy after iRFA.
Case report: Heterogenous SMARCA4-deficient thoracic non-small cell lung carcinoma with various responses to nivolumab
Authors: Lin Yun-Tzu , Li Chien-Feng , Wu Hung-Chang , Jan Yi-Hua , Kuo Yu-Hsuan
Published: March 2023

SMARCA4-deficient non-small cell carcinoma is an aggressive neoplasm with poor outcome. Several studies have highlighted its immunochemistry, pathophysiology, and underlying mechanisms, but studies of its definite treatment are few. Here, we report on a 69-year-old male with heterogenous pathological presentations of SMARCA4-deficient non-small cell carcinoma. He initially presented with neck lymphadenopathies. Immunohistochemistry staining and genomic profiling confirmed the diagnosis of SMARCA4-deficient non-small cell carcinoma. The patient responded well to immune checkpoint inhibitors with nivolumab. However, new lesions with various pathological presentations and various responses to nivolumab appeared during the treatment course. The patient survived more than 3 years from the initial diagnosis. This case shows the efficacy of nivolumab to treat SMARCA4-deficient non-small cell lung carcinoma.
Relative expression of receptors in uterine natural killer cells compared to peripheral blood natural killer cells
Authors: Ismail Nurul Izza
Published: March 2023

One would expect maternal immune cells to attack the invading trophoblast as the placenta is semi-allogenic. However, they appear to cooperate with the trophoblast in disrupting the arterial wall which has been determined in several studies. uNK cells are a particular type of immune cell that appears to play a role in pregnancy. As in pregnancy, the key contributors to trophoblast invasion appear to be a unique combination of genes, which appear to regulate multiple components of the interactions between placental and maternal cells, called HLA class 1b genes. The HLA class 1b genes have few alleles, which makes them unlikely to be recognized as foreign by the maternal cells. The low polymorphic properties of these particular HLAs may aid trophoblasts in actively avoiding immune attacks. This review gives a complete description of the mechanisms of interaction between HLAs and maternal uNK cells in humans.
Influence of water content on elastohydrodynamic friction and film thickness of water-containing polyalkylene glycols
Authors: Hofmann Stefan , Lohner Thomas , Stahl Karsten
Published: March 2023

Lubricants with a functional water portion have demonstrated a drastic reduction in friction under elastohydrodynamic lubrication conditions. With water-containing polyalkylene glycols, superlubricity with coefficients of friction <0.01 have been measured in model and gear contacts. In addition to the low friction, their calorimetric properties make them particularly interesting for application in electrified vehicles because the liquid can simultaneously serve as lubricant for the gearbox and coolant for the electric motors and the power electronics. In this study, the influence of water content between 8 wt% and 40 wt% of water-soluble polyalkylene glycols on friction and film thickness in elastohydrodynamically lubricated rolling-sliding contacts such as in gears and bearings is investigated. A polyalphaolefine oil is used as a reference. Friction has been measured on a ball-on-disk tribometer and film thickness on an optical tribometer. For a water content of 40 wt%, superlubricity with coefficients of friction down to 0.004 are found. The decrease in friction is up to 95% compared to the polyalphaolefine reference. The measured film thickness decreases with increasing water content. For a water content of 8 wt%, the film thickness is similar to that of the polyalphaolefine reference while at the same time friction is still reduced by 81%. Depending on the friction and film thickness requirements of a specific tribosystem, the water content of a water-containing polyalkylene glycol can be chosen accordingly.
Research trends of omics in ulcerative colitis: A bibliometric analysis
Authors: Zhang He , Ni Yuanyuan , Ji Hangyu , Liu Hongliang , Liu Shaoneng
Published: March 2023

Background

Omics has emerged as a promising biological science to shed light on the etiology, pathogenesis, and treatment of ulcerative colitis (UC). At present, although research on the omics of UC has drawn global attention, there is still a lack of bibliometric analysis in this field. This study aimed to access the trends and hotspots of omics in UC research.

Method

Publications related to omics in UC from 1 January 2000 to 15 October 2022 were retrieved from the Web of Science Core Collection database. VOSviewer, CiteSpace, and the online bibliometric analysis platform “Bibliometrix” were adopted to extract and visualize information.

Results

A total of 385 publications were finally included and the annual number of publications fluctuated. The trend in publications increased rapidly after 2019. The United States showed its dominant position in several publications, total citations, and international collaborations. The top five research organizations for publications on the research of omics in UC were Harvard Medical School, the Icahn School of Medicine at Mount Sinai, Karolinska Institutet, the Brigham and Women's Hospital, and the Massachusetts General Hospital. Ashwin Ananthakrishnan from the Massachusetts General Hospital was the most productive author, and Séverine Vermeire from the Catholic University of Leuven was co-cited most often. Inflammatory bowel disease was the most popular and co-cited journal in this field. The reference with citation bursts and trend topics showed that “ulcerative colitis,” “inflammatory bowel disease,” “microbiome,” “transcriptomics,” “genomics,” “metabolomics,” “proteomics,” “dysbiosis,” “biomarkers,” “loci,” and “therapy” are currently research hotspots.

Conclusion

Our study presents several important insights into the research trends and developments in the field of omics in UC, which will provide key information for further research.
Molecular signature of methotrexate response among rheumatoid arthritis patients
Authors: Brynedal Boel , Yoosuf Niyaz , Ulfarsdottir Tinna Bjorg , Ziemek Daniel , Maciejewski Mateusz , Folkersen Lasse , Westerlind Helga , Müller Malin , Sahlström Peter , Jelinsky Scott A. , Hensvold Aase , Padyukov Leonid , Pomiano Nancy Vivar , Catrina Anca , Klareskog Lars , Berg Louise
Published: March 2023

Background

Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but failure of satisfying treatment response occurs in a significant proportion of patients. Here we present a longitudinal multi-omics study aimed at detecting molecular and cellular processes in peripheral blood associated with a successful methotrexate treatment of rheumatoid arthritis.

Methods

Eighty newly diagnosed patients with RA underwent clinical assessment and donated blood before initiation of MTX, and 3 months into treatment. Flow cytometry was used to describe cell types and presence of activation markers in peripheral blood, the expression of 51 proteins was measured in serum or plasma, and RNA sequencing was performed in peripheral blood mononuclear cells (PBMC). Response to treatment after 3 months was determined using the EULAR response criteria. We assessed the changes in biological phenotypes during treatment, and whether these changes differed between responders and non-responders with regression analysis. By using measurements from baseline, we also tried to find biomarkers of future MTX response or, alternatively, to predict MTX response.

Results

Among the MTX responders, (Good or Moderate according to EULAR treatment response classification,n= 60, 75%), we observed changes in 29 partly overlapping cell types proportions, levels of 13 proteins and expression of 38 genes during treatment. These changes were in most cases suppressions that were stronger among responders compared to non-responders. Within responders to treatment, we observed a suppression of FOXP3 gene expression, reduction of immunoglobulin gene expression and suppression of genes involved in cell proliferation. The proportion of many HLA-DR expressing T-cell populations were suppressed in all patients irrespective of clinical response, and the proportion of many IL21R+ T-cells were reduced exclusively in non-responders. Using only the baseline measurements we could not detect any biomarkers or prediction models that could predict response to MTX.

Conclusion

We conclude that a deep molecular and cellular phenotyping of peripheral blood cells in RA patients treated with methotrexate can reveal previously not recognized differences between responders and non-responders during 3 months of treatment with MTX. This may contribute to the understanding of MTX mode of action and explain non-responsiveness to MTX therapy.
Progress in 7SK ribonucleoprotein structural biology
Authors: Camara Momodou B. , Sobeh Amr M. , Eichhorn Catherine D.
Published: March 2023

The 7SK ribonucleoprotein (RNP) is a dynamic and multifunctional regulator of RNA Polymerase II (RNAPII) transcription in metazoa. Comprised of the non-coding 7SK RNA, core proteins, and numerous accessory proteins, the most well-known 7SK RNP function is the sequestration and inactivation of the positive transcription elongation factor b (P-TEFb). More recently, 7SK RNP has been shown to regulate RNAPII transcription through P-TEFb-independent pathways. Due to its fundamental role in cellular function, dysregulation has been linked with human diseases including cancers, heart disease, developmental disorders, and viral infection. Significant advances in 7SK RNP structural biology have improved our understanding of 7SK RNP assembly and function. Here, we review progress in understanding the structural basis of 7SK RNA folding, biogenesis, and RNP assembly.
Endoscopic endonasal surgery for non-invasive pituitary neuroendocrinology tumors with incomplete pseudocapsule
Authors: Zhang Gang , Wang Pan , Wang Junwei , Zou Dewei , Yao Hui , Liu Jie , Tang Chao , Jiang Haotian , Tan Xiaorong , Wu Nan
Published: March 2023

Background

Pituitary neuroendocrinology tumors (PitNETs) with pseudocapsule can be effectively removed by the pseudocapsule-based extracapsular resection technique. In the areas without pseudocapsule, the tumor cells can spread into the adjacent tissues at the cellular level, which brings a great challenge to achieving total tumor resection.

Methods

Our surgical strategy for PitNETs with an incomplete pseudocapsule is to combine the pseudocapsule-based extracapsular resection technique with the intensive excision technique for the removal of the tumor. Specifically, the pseudocapsule-based extracapsular resection technique is applied in the areas with pseudocapsule, while in the areas without pseudocapsule, the intensive excision technique bounded by adjacent normal structures is adopted. Moreover, a pathological examination was performed to determine the situations of pseudocapsule and tumor cell remnant.

Results

All growth hormone-secreting PitNETs achieved biochemical remission after surgery. There was no deterioration of pituitary functions postoperatively, and the preoperative hypopituitarism had improved in all patients postoperatively. In total, two cases suffered a transient diabetes insipidus, and intraoperative cerebrospinal fluid leakage was observed in two cases but no postoperative cerebrospinal fluid leakage in all cases. There was no recurrence during the follow-up. The fragmental pseudocapsule and small tumor remnants were found in the majority of suspicious tissues by histological staining.

Conclusion

The effectiveness and safety of the surgical strategy were preliminarily explored for removing PitNETs without incomplete pseudocapsules. In overview, the pseudocapsule-based extracapsular resection technique is applied in areas with pseudocapsule, while the intensive excision bounded by adjacent normal structures is adopted in other areas.