bluuebunny/crossref_metadata_2025 huggingface dataset:
Multifidelity Ensemble Kalman Filtering Using Surrogate Models Defined by Theory-Guided Autoencoders
Authors: Popov Andrey A. , Sandu Adrian
Published: June 2022

Data assimilation is a Bayesian inference process that obtains an enhanced understanding of a physical system of interest by fusing information from an inexact physics-based model, and from noisy sparse observations of reality. The multifidelity ensemble Kalman filter (MFEnKF) recently developed by the authors combines a full-order physical model and a hierarchy of reduced order surrogate models in order to increase the computational efficiency of data assimilation. The standard MFEnKF uses linear couplings between models, and is statistically optimal in case of Gaussian probability densities. This work extends the MFEnKF into to make use of a broader class of surrogate model such as those based on machine learning methods such as autoencoders non-linear couplings in between the model hierarchies. We identify the right-invertibility property for autoencoders as being a key predictor of success in the forecasting power of autoencoder-based reduced order models. We propose a methodology that allows us to construct reduced order surrogate models that are more accurate than the ones obtained via conventional linear methods. Numerical experiments with the canonical Lorenz'96 model illustrate that nonlinear surrogates perform better than linear projection-based ones in the context of multifidelity ensemble Kalman filtering. We additionality show a large-scale proof-of-concept result with the quasi-geostrophic equations, showing the competitiveness of the method with a traditional reduced order model-based MFEnKF.
An Algorithm for Accurate Marker-Based Gait Event Detection in Healthy and Pathological Populations During Complex Motor Tasks
Authors: Bonci Tecla , Salis Francesca , Scott Kirsty , Alcock Lisa , Becker Clemens , Bertuletti Stefano , Buckley Ellen , Caruso Marco , Cereatti Andrea , Del Din Silvia , Gazit Eran , Hansen Clint , Hausdorff Jeffrey M. , Maetzler Walter , Palmerini Luca , Rochester Lynn , Schwickert Lars , Sharrack Basil , Vogiatzis Ioannis , Mazzà Claudia
Published: June 2022

There is growing interest in the quantification of gait as part of complex motor tasks. This requires gait events (GEs) to be detected under conditions different from straight walking. This study aimed to propose and validate a new marker-based GE detection method, which is also suitable for curvilinear walking and step negotiation. The method was first tested against existing algorithms using data from healthy young adults (YA, n = 20) and then assessed in data from 10 individuals from the following five cohorts: older adults, chronic obstructive pulmonary disease, multiple sclerosis, Parkinson’s disease, and proximal femur fracture. The propagation of the errors associated with GE detection on the calculation of stride length, duration, speed, and stance/swing durations was investigated. All participants performed a variety of motor tasks including curvilinear walking and step negotiation, while reference GEs were identified using a validated methodology exploiting pressure insole signals. Sensitivity, positive predictive values (PPV), F1-score, bias, precision, and accuracy were calculated. Absolute agreement [intraclass correlation coefficient (ICC2,1)] between marker-based and pressure insole stride parameters was also tested. In the YA cohort, the proposed method outperformed the existing ones, with sensitivity, PPV, and F1 scores ≥ 99% for both GEs and conditions, with a virtually null bias (<10 ms). Overall, temporal inaccuracies minimally impacted stride duration, length, and speed (median absolute errors ≤1%). Similar algorithm performances were obtained for all the other five cohorts in GE detection and propagation to the stride parameters, where an excellent absolute agreement with the pressure insoles was also found (ICC2,1=0.817− 0.999). In conclusion, the proposed method accurately detects GE from marker data under different walking conditions and for a variety of gait impairments.
Identification of Type 2 Diabetes Biomarkers From Mixed Single-Cell Sequencing Data With Feature Selection Methods
Authors: Li Zhandong , Pan Xiaoyong , Cai Yu-Dong
Published: June 2022

Diabetes is the most common disease and a major threat to human health. Type 2 diabetes (T2D) makes up about 90% of all cases. With the development of high-throughput sequencing technologies, more and more fundamental pathogenesis of T2D at genetic and transcriptomic levels has been revealed. The recent single-cell sequencing can further reveal the cellular heterogenicity of complex diseases in an unprecedented way. With the expectation on the molecular essence of T2D across multiple cell types, we investigated the expression profiling of more than 1,600 single cells (949 cells from T2D patients and 651 cells from normal controls) and identified the differential expression profiling and characteristics at the transcriptomics level that can distinguish such two groups of cells at the single-cell level. The expression profile was analyzed by several machine learning algorithms, including Monte Carlo feature selection, support vector machine, and repeated incremental pruning to produce error reduction (RIPPER). On one hand, some T2D-associated genes (MTND4P24, MTND2P28, and LOC100128906) were discovered. On the other hand, we revealed novel potential pathogenic mechanisms in a rule manner. They are induced by newly recognized genes and neglected by traditional bulk sequencing techniques. Particularly, the newly identified T2D genes were shown to follow specific quantitative rules with diabetes prediction potentials, and such rules further indicated several potential functional crosstalks involved in T2D.
Gut Microbiota Signatures in Tumor, Para-Cancerous, Normal Mucosa, and Feces in Colorectal Cancer Patients
Authors: Li Yanmin , Cao Hong , Fei Bojian , Gao Qizhong , Yi Wanya , Han Weifeng , Bao Chuanqing , Xu Jianmin , Zhao Wei , Zhang Feng
Published: June 2022

Background: Association studies have linked microbiome alterations with colorectal cancer (CRC). However, differences in tumor, para-cancerous, normal mucosal, and fecal microbiota remain to be strengthened.

Methods: We performed a study on the ecologically rich and taxonomically diverse of gut microbiota using three types of colorectal mucosa (tumor mucosa, para-cancerous mucosa, normal mucosa) and feces from 98 CRC patients. Additionally, we profiled the microbiota in the fecal occult blood test (FOBT) positive and negative groups at different sampling sites.

Results: We found striking variations between tumor mucosal microbiota and normal mucosal microbiota. However, there was no significant difference between tumor and para-cancerous mucosal microbiota, as well as between para-cancerous and normal mucosal microbiota, revealing that the para-cancerous mucosal microbiota was a transitional state between the tumor and normal mucosal microbiota. And the substantial shifts in the fecal microbiota compared to mucosal microbiota indicated the risk of using fecal microbiota to define mucosal microbiota. A strong correlation between FOBT positive and Fusobacterium was discovered, indicating this adherent-invasive genus was closely related to intestinal bleeding. Furthermore, we identified six key genera, including Fusobacterium, Gemella, Campylobacter, Peptostreptococcus, Alloprevotella, and Parvimonas, which appear to be consistently over-represented in tumor mucosa compared to normal mucosa and/or in mucosa compared to feces.

Conclusion: Compositional alterations in the microbiota existed in three types of colorectal mucosa and feces in CRC patients. Six key genera may contribute to the topographic variances in the microbiota of tumor-bearing colorectum.
Altered Gut Microbiota and Short-Chain Fatty Acids After Vonoprazan-Amoxicillin Dual Therapy for Helicobacter pylori Eradication
Authors: Hu Yi , Xu Xin , Ouyang Yao-Bin , He Cong , Li Nian-Shuang , Xie Chuan , Peng Chao , Zhu Zhen-Hua , Shu Xu , Xie Yong , Lu Nong-Hua , Zhu Yin
Published: June 2022

The combination of vonoprazan (VPZ) and amoxicillin (VA therapy) has been shown to achieve acceptable eradication rates for Helicobacter pylori (H. pylori). Herein, our aim was to explore the short-term effect of VA therapy on the gut microbiota and short-chain fatty acids (SCFAs) using human fecal samples. A total of 119 H. pylori-positive patients were randomized into low- or high-dose VA therapy (i.e., amoxicillin 1 g b.i.d. or t.i.d. and VPZ 20 mg b.i.d.) for 7 or 10 days. Thirteen H. pylori-negative patients served as controls. Fecal samples were collected from H. pylori-positive and H. pylori-negative patients. The gut microbiota and SCFAs were analyzed using 16S rRNA gene sequencing and gas chromatography–mass spectrometry, respectively. The gut microbiota in H. pylori-positive patients exhibited increased richness, diversity, and better evenness than matched patients. Fifty-three patients studied before and after H. pylori eradication were divided into low (L-VA) and high (H-VA) amoxicillin dose groups. The diversity and composition of the gut microbiota among L-VA patients exhibited no differences at the three time points. However, among H-VA patients, diversity was decreased, and the microbial composition was altered immediately after H-VA eradication but was restored by the confirmation time point. The decreased abundance of Anaerostipes, Dialister, and Lachnospira induced by H-VA was associated with altered SCFA levels. VA dual therapy for H. pylori eradication has minimal negative effects on gut microbiota and SCFAs.
Preoperative Iron Deficiency Is Associated With Increased Blood Transfusion in Infants Undergoing Cardiac Surgery
Authors: Gao Peng , Wang Xu , Zhang Peiyao , Jin Yu , Bai Liting , Wang Wenting , Li Yixuan , Liu Jinping
Published: June 2022

Background

Iron deficiency (ID) is common in patients undergoing cardiac surgery, which is associated with adverse outcomes. However, the relevance of ID in congenital heart disease is still unclear. This study aimed to investigate the characteristics of preoperative ID and its association with clinical outcomes in infants undergoing cardiac surgery with cardiopulmonary bypass.

Methods

In this retrospective study, 314 patients undergoing cardiac surgery were assigned into three groups according to their preoperative ID status. Absolute ID was defined by serum ferritin <12 μg/L, and functional ID was defined by serum ferritin level at 12–30 μg/L and transferrin saturation <20%. Baseline characteristics were compared between groups and multiple logistic regression was used to identify predictors for ID. The association between ID and clinical outcomes, including allogenic blood transfusion requirements, was also evaluated.

Results

Among the 314 patients included, 32.5% were absolute ID and 28.7% were functional ID. Patients with absolute ID were more often of higher weight, cyanotic heart disease, and anemia. The presence of absolute ID was associated with an increase in postoperative blood transfusion (OR 1.837, 95% CI 1.016–3.321, p = 0.044). There was no significant difference in postoperative morbidity, mortality, and the length of hospital stay.

Conclusions

Absolute ID was associated with preoperative anemia and cyanotic heart disease, and was an independent risk factor for postoperative blood transfusion. Further research should better explore the definition of ID and its impact on outcomes in pediatric cardiac surgery.
Investigation of Retinal Metabolic Function in Type 1 Diabetic Akita Mice
Authors: Shosha Esraa , Qin Luke , Lemtalsi Tahira , Zaidi Syed A. H. , Rojas Modesto , Xu Zhimin , Caldwell Robert William , Caldwell Ruth B. , Fouda Abdelrahman Y.
Published: June 2022

Diabetic retinopathy (DR) is the leading cause of vision loss in working age adults. Understanding the retinal metabolic response to circulating high glucose levels in diabetic patients is critical for development of new therapeutics to treat DR. Measuring retinal metabolic function using the Seahorse analyzer is a promising technique to investigate the effect of hyperglycemia on retinal glycolysis and mitochondrial respiration. Here, we analyzed the retinal metabolic function in young and old diabetic and control mice. We also compared the expression of key glycolytic enzymes between the two groups. The Seahorse XF analyzer was used to measure the metabolic function of retina explants from young and old type 1 diabetic Akita (Ins2Akita) mice and their control littermates. Rate-limiting glycolytic enzymes were analyzed in retina lysates from the two age groups by Western blotting. Retinas from young adult Akita mice showed a decreased glycolytic response as compared to control littermates. However, this was not observed in the older mice. Western blotting analysis showed decreased expression of the glycolytic enzyme PFKFB3 in the young Akita mice retinas. Measurement of the oxygen consumption rate showed no difference in retinal mitochondrial respiration between Akita and WT littermates under normal glucose conditions ex vivo despite mitochondrial fragmentation in the Akita retinas as examined by electron microscopy. However, Akita mice retinas showed decreased mitochondrial respiration under glucose-free conditions. In conclusion, diabetic retinas display a decreased glycolytic response during the early course of diabetes which is accompanied by a reduction in PFKFB3. Diabetic retinas exhibit decreased mitochondrial respiration under glucose deprivation.
A Tryptophan Metabolite of the Microbiota Improves Neovascularization in Diabetic Limb Ischemia
Authors: Ma Xiurui , Yang Jinjing , Yang Guanrui , Li Lei , Hao Xiaojun , Wang Guoqin , An Jian , Wang Fei
Published: June 2022

Diabetes mellitus (DM) is accompanied by a series of macrovascular and microvascular injuries. Critical limb ischemia is the most severe manifestation of peripheral artery disease (PAD) caused by DM and is almost incurable. Therapeutic modulation of angiogenesis holds promise for the prevention of limb ischemia in diabetic patients with PAD. However, no small-molecule drugs are capable of promoting diabetic angiogenesis. An endogenous tryptophan metabolite, indole-3-aldehyde (3-IAld), has been found to have proangiogenic activity in endothelial cells. Nevertheless, the role of 3-IAld in diabetic angiogenesis remains unknown. Here, we found that 3-IAld ameliorated high glucose-induced mitochondrial dysfunction, decreasing oxidative stress and apoptosis and thus improving neovascularization.
So Volcanoes Created the Dinosaurs? A Quantitative Characterization of the Early Evolution of Terrestrial Pan-Aves
Authors: Langer Max Cardoso , Godoy Pedro L.
Published: June 2022

The early Mesozoic is marked by several global-scale environmental events, including the emplacement of large igneous provinces, such as the Siberian Traps, Wrangellia, and Central Atlantic Magmatic Province (CAMP). These have been hypothesised as drivers of the successful diversification of Pan-Aves, the lineage of archosaurs closer to birds than to crocodiles. We characterize here the diversification and body size evolution of terrestrial pan-avians (excluding pterosaurs) along the Triassic and Early Jurassic, using phylogenetic- and occurrence-based approaches, in an attempt to test the influence of such drivers. As diversity metrics, we quantified raw species richness and phylogenetic diversity (using time-calibrated phylogenetic trees), and net diversification rates were estimated with PyRate and the episodic fossilized-birth-death model. We have also characterised through-time patterns of body size (femoral length) and estimated body size evolutionary rates. Our results indicate that macroevolutionary shifts estimated from occurrence data are placed more recently in time than those from phylogenetic-based approaches, as shown by the higher diversity increase, diversification rates, and body size disparity of terrestrial Pan-Aves in the Carnian. This is consistent with hypotheses suggesting that the Carnian Pluvial Episode (CPE) was crucial for the early radiation of the group. Yet, phylogeny-based results show higher diversity/diversification rates for the Ladinian and Norian, suggesting a minor effect for the Carnian Pluvial Episode (CPE). We also found no meaningful shifts in diversity, diversification, or size-related metrics across the Triassic-Jurassic boundary. Even if the end-Triassic mass extinction possibly emptied ecospace, allowing dinosaur diversity to increase during the Jurassic, our results suggest that this expansion did not occur fast and homogeneously for the entire group. In fact, a sustained reduction in diversity and sub-zero net diversification rates are seen after the extinction, but macroevolutionary patterns here should be interpreted with care towards the end of the Early Jurassic, as they may be biased by an “edge effect.” Overall, few macroevolutionary shifts were consistently identified across all results, suggesting that the early diversification of terrestrial pan-avians was more nuanced and complex than anticipated.
RJX Improves Wound Healing in Diabetic Rats
Authors: Uckun Fatih M. , Orhan Cemal , Tuzcu Mehmet , Durmus Ali Said , Ozercan Ibrahim H. , Volk Michael , Sahin Kazim
Published: June 2022

Background

We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). The primary objective of the present study was to examine the effects of GMP-grade RJX on wound and burn injury healing in diabetic rats.

Methods

In the present study, a rat model of T2DM was used that employs HFD in combination with a single injection of STZ intraperitoneally (i.p) at a moderate dose level (45 mg/kg). Anesthetized diabetic rats underwent full-thickness skin excision on the back or were subjected to burn injury via a heated brass probe and then started on treatments with normal saline (NS = vehicle) or RJX administered via intraperitoneal injections for three weeks.

Findings

Notably, diabetic rats treated with the 1.25 mL/kg or 2.5 mL/kg RJX (DM+RJX groups) rapidly healed their wounds as fast as non-diabetic control rats. Inflammatory cell infiltration in the dermis along with fibrin and cell debris on the epithelial layer persisted for up to 14 days in the DM+NS group but not in RJX-treated groups. The histopathological score of wound healing on days 7 and 14 was better in diabetic rats treated with RJX than diabetic rats treated with NS and comparable to the scores for non-diabetic healthy rats consistent with an accelerated healing process. The residual wound area of RJX-treated rats was significantly smaller than that of NS-treated diabetic rats at each evaluation time point (P<0.001). The accelerating effect of RJX on diabetic wound healing was dose-dependent. We obtained similar results in the burn injury model. Our results demonstrate that RJX – at a dose level >10-fold lower than its clinical maximum tolerated dose (MTD) – accelerates the healing of excision wounds as well burn injury in diabetic rats.
Appearance Fault Diagnosis of a Transformer Based on Data Set Optimization and Heterogeneous Model Ensemble
Authors: Xuan Yi , Fan Libo , Tu Yongwei , Sun Zhiqing , Han Rongjie , Jiang Jian , Chen Yifang , Lai Yibo , Huang Jiabin
Published: June 2022

Prosumers refer to the integration of production and consumption. Due to a large number of access to distributed power sources, electric vehicles, etc., which have a certain impact on power transformers, and increasing potential failures, transformers need to be monitored. In recent years, image recognition technology based on deep learning has been widely used in intelligent inspection image analysis. Aiming at the problem that the accuracy of appearance fault diagnosis in intelligent inspection images is limited by image quantity and quality, an image data set optimization method based on a seamless cloning algorithm and image cleaning is proposed. First, a sample generation method based on the seamless fusion algorithm is proposed, which seamlessly fuses the corroded texture of other power equipment into the transformer image to generate the rust transformer image. On this basis, an image quality evaluation and screening method based on the XGBoost algorithm is proposed to evaluate the image quality of the data set and clean the low-quality images. In addition, aiming at the limitation of a single diagnosis algorithm, an appearance diagnosis method based on heterogeneous model ensemble learning is proposed. By constructing multiple learning models and using a weighted voting strategy to fuse model outputs as final outputs, the accuracy of fault diagnosis is improved.
Hydrochemical Characteristics and Groundwater Quality Assessment Using an Integrated Approach of the PCA, SOM, and Fuzzy c-Means Clustering: A Case Study in the Northern Sichuan Basin
Authors: Yao Rongwen , Yan Yuting , Wei Changli , Luo Ming , Xiao Yong , Zhang Yunhui
Published: June 2022

Groundwater is a precious resource that is vital for human life. Widespread human activities occur in the Sichuan basin due to befitting climate and geological conditions, inducing a series of groundwater contamination. In this article, hydrochemical analysis, principal component analysis (PCA), self-organizing map (SOM), and fuzzy c-means clustering (FCM) were integrated to reveal the hydrochemical process and assess groundwater quality in the northern part of the Sichuan Basin based on a collection of 203 groundwater samples. The groundwater hydrochemical types were dominated by the HCO3-Ca type. The PCA results show both natural and anthropogenic factors contributed to the hydrochemical compositions. The combination of the SOM and FCM classifies neurons into two categories: the first category where NO2− and NH4+ are most similar, perhaps as anthropogenic sources of pollution, which pose serious threats to human health; and the second category, where the total dissolved solids, Ca2+, Na+, Cl−, SO42, Mg2+, and K+ are most similar, explained as the influence of natural factors. The ion source was determined by water–rock interactions: Na+ mainly comes from the dissolution of silicate rocks, while Ca2+, Mg2+, and HCO3− from the dissolution of calcite and dolomite. Cation exchange was recognized in the water–rock interactions. The achievements would provide a significant reference for groundwater protection in the Sichuan Basin.
How Does Social Embeddedness Affect Farmers’ Adoption Behavior of Low-Carbon Agricultural Technology? Evidence From Jiangsu Province, China
Authors: Zheng Huawei , Ma Jing , Yao Zhaoyu , Hu Feng
Published: June 2022

Agricultural carbon emissions, which are the second largest source of greenhouse gas emissions in China, not only place great pressure on emission reduction but also seriously affect food security and sustainable development of agriculture. As farmers are the direct users of cultivated land and the main adopters of agricultural technology, their adoption behavior of low-carbon agricultural technology directly determines its promotion and subsequent emissions reduction. It is of great theoretical and practical significance to analyze farmers’ adoption behavior of low-carbon agricultural technology and their influencing factors. Based on social embeddedness theory and the survey data of 688 farmers in Jiangsu Province, this study applied a logistic model to analyze the impact of government support, farmers’ cognition, social capital, personal characteristics, and family characteristics on farmers’ adoption behavior of low-carbon agricultural technology. The results showed that (1) only 58.72% of farmers have adopted such a technology, which needs to be further improved; (2) government support and farmers’ cognition had significantly positive influences on farmers’ adoption behavior; (3) social capital is an important factor affecting farmers’ adoption decisions, where social trust, networks, and norms play a significant role in promoting the adoption of low-carbon agricultural technology; and (4) party membership and household-contracted farmland area also had positive influences on farmers’ adoption behavior of low-carbon technology. Therefore, to continue developing low-carbon agriculture, it is recommended to further strengthen government support, raise the price of low-carbon agricultural products, strengthen environmental supervision, and build a social embedded environment according to local conditions, and further improve farmers’ social trust, enrich social networks, improve social norms, and give full play to the guiding and exemplary role of social capital. Additionally, it is also recommended to reinforce education and training to raise farmers’ awareness regarding low-carbon agricultural technology, thereby guiding them to actively adopt these technologies.
Increased Frequency of Indels in Hypervariable Regions of SARS-CoV-2 Proteins—A Possible Signature of Adaptive Selection
Authors: Alisoltani Arghavan , Jaroszewski Lukasz , Iyer Mallika , Iranzadeh Arash , Godzik Adam
Published: June 2022

Most attention in the surveillance of evolving SARS-CoV-2 genome has been centered on nucleotide substitutions in the spike glycoprotein. We show that, as the pandemic extends into its second year, the numbers and ratio of genomes with in-frame insertions and deletions (indels) increases significantly, especially among the variants of concern (VOCs). Monitoring of the SARS-CoV-2 genome evolution shows that co-occurrence (i.e., highly correlated presence) of indels, especially deletions on spike N-terminal domain and non-structural protein 6 (NSP6) is a shared feature in several VOCs such as Alpha, Beta, Delta, and Omicron. Indels distribution is correlated with spike mutations associated with immune escape and growth in the number of genomes with indels coincides with the increasing population resistance due to vaccination and previous infections. Indels occur most frequently in the spike, but also in other proteins, especially those involved in interactions with the host immune system. We also showed that indels concentrate in regions of individual SARS-CoV-2 proteins known as hypervariable regions (HVRs) that are mostly located in specific loop regions. Structural analysis suggests that indels remodel viral proteins’ surfaces at common epitopes and interaction interfaces, affecting the virus’ interactions with host proteins. We hypothesize that the increased frequency of indels, the non-random distribution of them and their independent co-occurrence in several VOCs is another mechanism of response to elevated global population immunity.
Integrative Analysis Identifies a TNFα-Derived Gene Signature for Predicting Prognosis, Tumor Immunity, and Treatment Sensitivity in Gastric Cancer
Authors: Wang Ke , Qi Lina , Sun Hua , Diao Min , Yang Lin
Published: June 2022

Objective: TNF-α is an essential pro-inflammatory cytokine in the tumor microenvironment of gastric cancer (GC), possessing a key biological and clinical impact. Here, we conducted an integrative analysis of the role of TNFα-derived genes in GC prognosis and precision medicine.

Methods: We pooled transcriptome and clinical features of GC patients from TCGA and GSE15459 projects. TNFα signaling was quantified through the ssGSEA algorithm, and TNFα-derived genes were screened with WGCNA. Thereafter, a LASSO model was established. The somatic mutation was analyzed across GC specimens. Immune cell infiltrations were inferred through ESTIMATE and ssGSEA algorithms, followed by measuring the immune checkpoint expression. AKR1B1, CPVL, and CTSL expressions were measured in gastric mucosal cells GES-1 and GC cells (HGC-27, MKN-28, and AGS) through RT-qPCR and Western blotting.

Results: A TNFα-derived gene signature (containing AKR1B1, CPVL, and CTSL) was developed for GC. A high-risk score indicated more undesirable OS, DFS, DSS, and PFS outcomes. Time-independent ROC curves and multivariate cox regression models confirmed that the signature reliably and independently predicted GC prognosis. Additionally, risk scores displayed significant correlations to more severe histological grades and pathological stages. A low-risk score was characterized by increased somatic mutation, while a high-risk score was characterized by immune and stromal activation, enhanced immune cell infiltrations, and increased expression of immune checkpoint molecules. Experimental results confirmed the significant upregulation of AKR1B1, CPVL, and CTSL in GC cells.

Conclusion: Collectively, stratification based on the TNFα-derived gene signature might enable GC patients to predict prognosis, benefit from immunotherapy, and assist in formulating novel therapeutic regimens.
Biotechnological Approaches for Host Plant Resistance to Insect Pests
Authors: Kumari Pritam , Jasrotia Poonam , Kumar Deepak , Kashyap Prem Lal , Kumar Satish , Mishra Chandra Nath , Kumar Sudheer , Singh Gyanendra Pratap
Published: June 2022

Annually, the cost of insect pest control in agriculture crosses billions of dollars around the world. Until recently, broad-spectrum synthetic pesticides were considered as the most effective means of pest control in agriculture. However, over the years, the overreliance on pesticides has caused adverse effects on beneficial insects, human health and the environment, and has led to the development of pesticide resistant insects. There is a critical need for the development of alternative pest management strategies aiming for minimum use of pesticides and conservation of natural enemies for maintaining the ecological balance of the environment. Host plant resistance plays a vital role in integrated pest management but the development of insect-resistant varieties through conventional ways of host plant resistance takes time, and is challenging as it involves many quantitative traits positioned at various loci. Biotechnological approaches such as gene editing, gene transformation, marker-assisted selection etc. in this direction have recently opened up a new era of insect control options. These could contribute towards about exploring a much wider array of novel insecticidal genes that would otherwise be beyond the scope of conventional breeding. Biotechnological interventions can alter the gene expression level and pattern as well as the development of transgenic varieties with insecticidal genes and can improve pest management by providing access to novel molecules. This review will discuss the emerging biotechnological tools available to develop insect-resistant engineered crop genotypes with a better ability to resist the attack of insect pests.
Neoadjuvant Pembrolizumab and Chemotherapy in Resectable Esophageal Cancer: An Open-Label, Single-Arm Study (PEN-ICE)
Authors: Duan Hongtao , Shao Changjian , Pan Minghong , Liu Honggang , Dong Xiaoping , Zhang Yong , Tong Liping , Feng Yingtong , Wang Yuanyuan , Wang Lu , Newman Neil B. , Sarkaria Inderpal S. , Reynolds John V. , De Cobelli Francesco , Ma Zhiqiang , Jiang Tao , Yan Xiaolong
Published: June 2022

Background

In this single-arm study, the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy were evaluated in patients with resectable esophageal squamous cell carcinoma (ESCC).

Methods

This study included patients with ESCC of clinical stages II–IVA who underwent surgery within 4 to 6 weeks after completing treatment with pembrolizumab (200 mg) combined with a conventional chemotherapy regimen (3 cycles). The safety and efficacy of this combination treatment were evaluated as primary endpoints of the study.

Results

From April 2019 to August 2020, a total of 18 patients (including 14 men) were enrolled, of whom 13 patients progressed to surgery. Postoperative pathology revealed a major pathological response (MPR) in 9 cases (9/13, 69.2%) and a pathological complete response (pCR) in 6 cases (6/13, 46.2%). Five patients (5/18, 27.8%) experienced serious treatment-related adverse events (AEs) of grades 3–4. At the time of data cutoff (Mar 25, 2022), the shortest duration of follow-up was 17.8 months. Programmed death-ligand 1 (PD-L1) expression in pretreatment specimens was not significantly associated with the percentage of residual viable tumor (RVT) (r=−0.55, P=0.08). Changes in counts of CD68+ macrophage between pre- and post-treatment specimens were weakly correlated with RVT (r=0.71; P=0.07), while a positive correlation was observed between postoperative forkhead box P3-positive (Foxp3)+T cells/CD4+Tcells ratios and RVT (r=0.84, P=0.03).

Conclusions

The combination of neoadjuvant immunotherapy and chemotherapy for ESCC is associated with a high pathological response and immunologic effects in the tumor microenvironment (TME). It has acceptable toxicity and great efficacy, suggesting a strong rationale for its further evaluation in randomized clinical trials (RCTs).

Trial Registration

ChiCTR2100048917.
mRNA or ChAd0x1 COVID-19 Vaccination of Adolescents Induces Robust Antibody and Cellular Responses With Continued Recognition of Omicron Following mRNA-1273
Authors: Dowell Alexander C. , Powell Annabel A. , Davis Chris , Scott Sam , Logan Nicola , Willett Brian J. , Bruton Rachel , Ayodele Morenike , Jinks Elizabeth , Gunn Juliet , Spalkova Eliska , Sylla Panagiota , Nicol Samantha M. , Zuo Jianmin , Ireland Georgina , Okike Ifeanyichukwu , Baawuah Frances , Beckmann Joanne , Ahmad Shazaad , Garstang Joanna , Brent Andrew J. , Brent Bernadette , White Marie , Collins Aedin , Davis Francesca , Lim Ming , Cohen Jonathan , Kenny Julia , Linley Ezra , Poh John , Amirthalingam Gayatri , Brown Kevin , Ramsay Mary E. , Azad Rafaq , Wright John , Waiblinger Dagmar , Moss Paul , Ladhani Shamez N.
Published: June 2022

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.
Next Generation Natural Killer Cells for Cancer Immunotherapy
Authors: Rossi Fiorella , Fredericks Nathaniel , Snowden Andrew , Allegrezza Michael J. , Moreno-Nieves Uriel Y.
Published: June 2022

In recent years, immunotherapy for cancer has become mainstream with several products now authorized for therapeutic use in the clinic and are becoming the standard of care for some malignancies. Chimeric antigen receptor (CAR)-T cell therapies have demonstrated substantial efficacy for the treatment of hematological malignancies; however, they are complex and currently expensive to manufacture, and they can generate life-threatening adverse events such as cytokine release syndrome (CRS). The limitations of current CAR-T cells therapies have spurred an interest in alternative immunotherapy approaches with safer risk profiles and with less restrictive manufacturing constraints. Natural killer (NK) cells are a population of immune effector cells with potent anti-viral and anti-tumor activity; they have the capacity to swiftly recognize and kill cancer cells without the need of prior stimulation. Although NK cells are naturally equipped with cytotoxic potential, a growing body of evidence shows the added benefit of engineering them to better target tumor cells, persist longer in the host, and be fitter to resist the hostile tumor microenvironment (TME). NK-cell-based immunotherapies allow for the development of allogeneic off-the-shelf products, which have the potential to be less expensive and readily available for patients in need. In this review, we will focus on the advances in the development of engineering of NK cells for cancer immunotherapy. We will discuss the sourcing of NK cells, the technologies available to engineer NK cells, current clinical trials utilizing engineered NK cells, advances on the engineering of receptors adapted for NK cells, and stealth approaches to avoid recipient immune responses. We will conclude with comments regarding the next generation of NK cell products, i.e., armored NK cells with enhanced functionality, fitness, tumor-infiltration potential, and with the ability to overcome tumor heterogeneity and immune evasion.
Cryptococcus neoformans Csn1201 Is Associated With Pulmonary Immune Responses and Disseminated Infection
Authors: Yang Ya-li , Fan Yi-bin , Gao Lei , Zhang Chao , Gu Ju-lin , Pan Wei-hua , Fang Wei
Published: June 2022

Cryptococcus neoformans is a major etiological agent of fungal meningoencephalitis. The outcome of cryptococcosis depends on the complex interactions between the pathogenic fungus and host immunity. The understanding of how C. neoformans manipulates the host immune response through its pathogenic factors remains incomplete. In this study, we defined the roles of a previously uncharacterized protein, Csn1201, in cryptococcal fitness and host immunity. Use of both inhalational and intravenous mouse models demonstrated that the CSN1201 deletion significantly blocked the pulmonary infection and extrapulmonary dissemination of C. neoformans. The in vivo hypovirulent phenotype of the csn1201Δ mutant was attributed to a combination of multiple factors, including preferential dendritic cell accumulation, enhanced Th1 and Th17 immune responses, decreased intracellular survival inside macrophages, and attenuated blood–brain barrier transcytosis rather than exclusively to pathogenic fitness. The csn1201Δ mutant exhibited decreased tolerance to various stressors in vitro, along with reduced capsule production and enhanced cell wall thickness under host-relevant conditions, indicating that the CSN1201 deletion might promote the exposure of cell wall components and thus induce a protective immune response. Taken together, our results strongly support the importance of cryptococcal Csn1201 in pulmonary immune responses and disseminated infection.
A Japanese Herbal Formula, Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial Profiles and Enhancing Group 3 Innate Lymphoid Cells
Authors: Shi Zhengzheng , Takeuchi Tadashi , Nakanishi Yumiko , Kato Tamotsu , Beck Katharina , Nagata Ritsu , Kageyama Tomoko , Ito Ayumi , Ohno Hiroshi , Satoh-Takayama Naoko
Published: June 2022

Daikenchuto (DKT) is one of the most widely used Japanese herbal formulae for various gastrointestinal disorders. It consists of Zanthoxylum Fructus (Japanese pepper), Zingiberis Siccatum Rhizoma (processed ginger), Ginseng radix, and maltose powder. However, the use of DKT in clinical settings is still controversial due to the limited molecular evidence and largely unknown therapeutic effects. Here, we investigated the anti-inflammatory actions of DKT in the dextran sodium sulfate (DSS)-induced colitis model in mice. We observed that DKT remarkably attenuated the severity of experimental colitis while maintaining the members of the symbiotic microbiota such as family Lactobacillaceae and increasing levels of propionate, an immunomodulatory microbial metabolite, in the colon. DKT also protected colonic epithelial integrity by upregulating the fucosyltransferase gene Fut2 and the antimicrobial peptide gene Reg3g. More remarkably, DKT restored the reduced colonic group 3 innate lymphoid cells (ILC3s), mainly RORγthigh-ILC3s, in DSS-induced colitis. We further demonstrated that ILC3-deficient mice showed increased mortality during experimental colitis, suggesting that ILC3s play a protective function on colonic inflammation. These findings demonstrate that DKT possesses anti-inflammatory activity, partly via ILC3 function, to maintain the colonic microenvironment. Our study also provides insights into the molecular basis of herbal medicine effects, promotes more profound mechanistic studies towards herbal formulae and contributes to future drug development.
High Mobility Group Proteins in Sepsis
Authors: Liang Guibin , He Zhihui
Published: June 2022

Sepsis, a systemic inflammatory response disease, is the most severe complication of infection and a deadly disease. High mobility group proteins (HMGs) are non-histone nuclear proteins binding nucleosomes and regulate chromosome architecture and gene transcription, which act as a potent pro-inflammatory cytokine involved in the delayed endotoxin lethality and systemic inflammatory response. HMGs increase in serum and tissues during infection, especially in sepsis. A growing number of studies have demonstrated HMGs are not only cytokines which can mediate inflammation, but also potential therapeutic targets in sepsis. To reduce sepsis-related mortality, a better understanding of HMGs is essential. In this review, we described the structure and function of HMGs, summarized the definition, epidemiology and pathophysiology of sepsis, and discussed the HMGs-related mechanisms in sepsis from the perspectives of non-coding RNAs (microRNA, long non-coding RNA, circular RNA), programmed cell death (apoptosis, necroptosis and pyroptosis), drugs and other pathophysiological aspects to provide new targets and ideas for the diagnosis and treatment of sepsis.
Recent Advancements in Poor Graft Function Following Hematopoietic Stem Cell Transplantation
Authors: Man Yan , Lu Zhixiang , Yao Xiangmei , Gong Yuemin , Yang Tonghua , Wang Yajie
Published: June 2022

Poor graft function (PGF) is a life-threatening complication that occurs after transplantation and has a poor prognosis. With the rapid development of haploidentical hematopoietic stem cell transplantation, the pathogenesis of PGF has become an important issue. Studies of the pathogenesis of PGF have resulted in some success in CD34+-selected stem cell boosting. Mesenchymal stem cells, N-acetyl-l-cysteine, and eltrombopag have also been investigated as therapeutic strategies for PGF. However, predicting and preventing PGF remains challenging. Here, we propose that the seed, soil, and insect theories of aplastic anemia also apply to PGF; CD34+ cells are compared to seeds; the bone marrow microenvironment to soil; and virus infection, iron overload, and donor-specific anti-human leukocyte antigen antibodies to insects. From this perspective, we summarize the available information on the common risk factors of PGF, focusing on its potential mechanism. In addition, the safety and efficacy of new strategies for treating PGF are discussed to provide a foundation for preventing and treating this complex clinical problem.
Correlation Analysis Between Trace Elements and Colorectal Cancer Metabolism by Integrated Serum Proteome and Metabolome
Authors: Zheng Zhi , Wei Qingfeng , Wan Xianghui , Zhong Xiaoming , Liu Lijuan , Zeng Jiquan , Mao Lihua , Han Xiaojian , Tou Fangfang , Rao Jun
Published: June 2022

Colorectal cancer (CRC) is currently the third most common cancer with a high mortality rate. The underlying molecular mechanism of CRC, especially advanced CRC, remains poorly understood, resulting in few available therapeutic plans. To expand our knowledge of the molecular characteristics of advanced CRC and explore possible new therapeutic strategies, we herein conducted integrated proteomics and metabolomics analyses of 40 serum samples collected from 20 advanced CRC patients before and after treatment. The mass spectrometry-based proteomics analysis was performed under data-independent acquisition (DIA), and the metabolomics analysis was performed by ultra-performance liquid chromatography coupled with time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS). Trace elements including Mg, Zn, and Fe were measured by inductively coupled plasma spectrometry (ICP-MS) analysis. Four of the 20 patients had progressive disease (PD) after treatment, and clinical test results indicated that they all had impaired liver functions. In the proteomics analysis, 64 proteins were discovered to be significantly altered after treatment. These proteins were enriched in cancer-related pathways and pathways participating immune responses, such as MAPK signaling pathway and complement/coagulation cascades. In the metabolomics analysis, 128 metabolites were found to be significantly changed after treatment, and most of them are enriched in pathways associated with lipid metabolism. The cholesterol metabolism pathway was significantly enriched in both the proteomics and metabolomics pathway enrichment analyses. The concentrations of Mg in the serums of CRC patients were significantly lower than those in healthy individuals, which returned to the normal range after treatment. Correlation analysis linked key lipids, proteins, and Mg as immune modulators in the development of advanced CRC. The results of this study not only extended our knowledge on the molecular basis of advanced CRC but also provided potential novel therapeutic targets for CRC treatment.
Interesting Probiotic Bacteria Other Than the More Widely Used Lactic Acid Bacteria and Bacilli in Finfish
Authors: Ringø Einar , Li Xuemei , Doan Hien van , Ghosh Koushik
Published: June 2022

Growing demands stimulate the intensification of production and create the need for practices that are both economically viable and environmentally sustainable. As European Union banned the use of antibiotics in production in 2003, several alternative treatments have been suggested, including probiotics. The first probiotic study in aquaculture was published in 1986, and since then probiotics have been considered as a beneficial tool in this industry. Today current evidence suggests that administration of certain probiotic strains might be able to enhance growth rate, improve the welfare of different fish species by modulating gut microbiota, improve physiological functions, such as metabolism, digestion, immunity, stress tolerance, intestinal histology, and disease resistance. Even though lactic acid bacteria and Bacillus spp. are the most frequently used probiotics in aquaculture, numerous studies have been published on other interesting probiotics. Therefore, the purpose of this paper is to summarize, comment, and discuss the current knowledge related to the effects of Aeromonas, Aliivibrio, Alteromonas, Arthrobacter, Bifidobacterium, Brochothrix, Clostridium, Enterovibrio, Kocuria, Microbacterium, Micrococcus, Paenibacillus, Phaeobacter, Pseudoalteromonas, Pseudomonas, Rhodococcus, Rhodopseudomonas, Rhodosporidium, Roseobacter, Shewanella and Vibrio as probiotics in finfish aquaculture, and present general information on their presence in the gastrointestinal tract of finfish. Moreover, some considerations for future studies are also indicated.