bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of commercial nuclear fusion projects
Authors: Meschini Samuele , Laviano Francesco , Ledda Federico , Pettinari Davide , Testoni Raffella , Torsello Daniele , Panella Bruno
Published: June 2023

Nuclear fusion technologies have re-gained momentum in the last decade thanks to their disruptive potential in different fields, such as energy production and space propulsion, and to new technological developments, especially high temperature superconductor tapes, which allow overcoming previous performance or design limits. To date, reviews of recent nuclear fusion designs are lacking. Therefore, this paper aims at giving a comprehensive overview of nuclear fusion concepts for industrial applications with a focus on the private sector. The designs are classified according to the three leading concepts for plasma confinement, namely, magnetic confinement, inertial confinement and magneto-inertial confinement. The working principles of the main devices are described in detail to highlight strengths and weaknesses of the different designs. The importance of the public sector on private projects is discussed. The technological maturity is estimated, and the main criticalities for each project are identified. Finally, the geographical distribution of the companies (or public institutions) pursuing the design of fusion devices for commercial applications is reported.
An equilibrium analysis on the tripartite evolutionary game of garbage classification recycling
Authors: Xu Lang , Tang Hui , Liu Lin , Liu Liying
Published: June 2023

The garbage classification recycling policy is proposed to curb the waste of recyclable and land resources to reduce the environmental pollution caused by garbage. This paper establishes a tripartite evolutionary game model with governments, recycling companies, and citizens as stakeholders to discuss their corresponding strategic behaviors. Through the stability analysis, we draw a conclusion that only when governments choose to regulate the classification, while both recycling companies and citizens take an active part in the classification, can the environmental benefit be maximized. In addition, the government and recycling companies are advised to increase the rate at which the evolutionary game model converges to a steady state by reducing their own operating costs during the implementation of garbage classification. On this basis, we also recommend an appropriate increase in the benefits given to citizens, which will have a significantly positive impact on citizens and even also on the government and the recycling companies themselves.
Body condition and corticosterone stress response, as markers to investigate effects of human activities on Adélie penguins (Pygoscelis adeliae)
Authors: Marciau Coline , Raclot Thierry , Bestley Sophie , Barbraud Christophe , Delord Karine , Hindell Mark Andrew , Kato Akiko , Parenteau Charline , Poupart Timothée , Ribout Cécile , Ropert-Coudert Yan , Angelier Frédéric
Published: June 2023

Introduction

In Antarctica, there is growing concern about the potential effect of anthropogenic activities (i.e., tourism, research) on wildlife, especially since human activities are developing at an unprecedented rate. Although guidelines exist to mitigate negative impacts, fundamental data are currently lacking to reliably assess impacts. Physiological tools, such as circulating corticosterone levels, appear promising to assess the potential impact of human disturbance on Antarctic vertebrates.

Methods

In this study, we compared the body condition, and the physiological sensitivity to stress (i.e., basal and stress-induced corticosterone level) of adult and chick Adélie penguins between a disturbed and an undisturbed area (i.e., 2 colonies located in the middle of a research station exposed to intense human activities and 2 colonies located on protected islands with minimal human disturbance).

Results

We did not find any significant impact of human activities on body condition and corticosterone levels in adults (incubating adults, brooding adults). In chicks, there were significant inter-colony variations in stress-induced corticosterone levels. Specifically, the chicks from the disturbed colonies tended to have higher stress-induced corticosterone levels than the chicks from the protected areas although this difference between areas was not significant. In addition, and independently of human disturbance we also found significant differences in adult body condition, and chick corticosterone level between colonies.

Discussion

Overall, our study suggests that this species is not dramatically impacted by human activities, at least when humans and penguins have cohabited for several decades. Our results support therefore the idea that this species is likely to be tolerant to human disturbance and this corroborates with the persistence of Adélie penguin colonies in the middle of the research station. However, our results also suggest that chicks might be more sensitive to human disturbance than adults and might therefore potentially suffer from human disturbance. Our study also suggests that specific individual and environmental variables outweigh the potential minor impact of human disturbance on these variables. Combining corticosterone with complementary stress-related physiological markers, such as heart rate, may strengthen further studies examining whether human disturbance may have subtle detrimental impacts on individuals.
Altered hair root gene expression profiles highlight calcium signaling and lipid metabolism pathways to be associated with curly hair initiation and maintenance in Mangalitza pigs
Authors: Khaveh Nadia , Schachler Kathrin , Berghöfer Jan , Jung Klaus , Metzger Julia
Published: June 2023

Hair types have been under strong targeted selection in domestic animals for their impact on skin protection, thermoregulation and exterior morphology, and subsequent economic importance. In pigs, a very special hair phenotype was observed in Mangalitza, who expresses a thick coat of curly bristles and downy hair. Two breed-specific missense variants in TRPM2 and CYP4F3 were suggested to be associated with the Mangalitza pig’s hair shape due to their role in hair follicle morphogenesis reported for human and mice. However, the mechanism behind this expression of a curly hair type is still unclear and needs to be explored. In our study, hair shafts were measured and investigated for the curvature of the hair in Mangalitza and crossbreeds in comparison to straight-coated pigs. For molecular studies, hair roots underwent RNA sequencing for a differential gene expression analysis using DESeq2. The output matrix of normalized counts was then used to construct weighted gene co-expression networks. The resulting hair root gene expression profiles highlighted 454 genes to be significantly differentially expressed for initiation of curly hair phenotype in newborn Mangalitza piglets versus post-initiation in later development. Furthermore, 2,554 genes showed a significant differential gene expression in curly hair in comparison to straight hair. Neither TRPM2 nor CYP4F3 were identified as differentially expressed. Incidence of the genes in weighted co-expression networks associated with TRPM2 and CYP4F3, and prominent interactions of subsequent proteins with lipids and calcium-related pathways suggested calcium signaling and/or lipid metabolism as essential players in the induction of the curly hair as well as an ionic calcium-dependency to be a prominent factor for the maintenance of this phenotype. Subsequently, our study highlights the complex interrelations and dependencies of mutant genes TRPM2 and CYP4F3 and associated gene expression patterns, allowing the initiation of curly hair type during the development of a piglet as well as the maintenance in adult individuals.
Vasculogenic mimicry score identifies the prognosis and immune landscape of lung adenocarcinoma
Authors: Yang Weichang , Li Zhouhua , Wang Wenjun , Wu Juan , Li Jinbo , Huang Xiaotian , Zhang Xinyi , Ye Xiaoqun
Published: June 2023

Background: Lung cancer has a high incidence and mortality rate worldwide. Vasculogenic mimicry (VM) is a specific modality of tumor angiogenesis that could potentially be a new target for tumor therapy. The purpose of this study was to explore the role of VM-related genes in assessing the prognosis and immune landscape of lung cancer.

Methods: VM-related genes were obtained from previous studies, and the expression data and clinical data of lung adenocarcinoma (LUAD) patients were obtained from the TCGA database and GEO database. We performed enrichment analysis of 24 VM-related genes and screened hub genes by constructing a protein–protein interaction network and using Cytoscape software. Subsequently, we developed the VM score based on univariate Cox regression analysis and Lasso analysis and validated the VM score on the GSE72094 dataset. In addition, we constructed a nomogram based on the VM score in the TCGA cohort. Finally, we explored the correlation between the VM score and the tumor microenvironment, immune cell infiltration, immune checkpoints, and drug sensitivity.

Results: Enrichment analysis revealed that VM-related genes were associated with the HIF signaling pathway and angiogenic pathway. We developed a VM score based on 3 genes (EPHA2, LAMC2 and LOXL2) in LUAD patients. Kaplan-Meier analysis showed that the VM score was associated with poor prognosis in LUAD patients. The receiver operating characteristic curve suggested that the VM score and nomogram are valid predictors for the overall survival of LUAD patients. The VM score was significantly correlated with immune cell infiltration, such as naïve B cells, neutrophils, and eosinophils, and there was a difference in the TME between the high VM score group and the low VM score group. LUAD patients in the high VM score group were more sensitive to antitumor drugs.

Conclusion: In summary, the VM score developed in this study is a valuable indicator for evaluating the prognosis and immune landscape of LUAD patients. VM may be a potential target for antitumor therapy in lung cancer.
Metabolic reprogramming through mitochondrial biogenesis drives adenosine anti-inflammatory effects: new mechanism controlling gingival fibroblast hyper-inflammatory state
Authors: Paladines Nathalie , Dawson Shantiece , Ryan Weston , Serrano-Lopez Rogelio , Messer Regina , Huo Yuqing , Cutler Christopher W. , Ramos-Junior Erivan S. , Morandini Ana Carolina
Published: June 2023

Introduction

Fibroblasts are the dominant stromal cells in the gingival lamina propria with a well-established relevance in regulation of inflammation, and in innate immunity. This is exemplified by their hypersecretion of CXCL8, enhancing leukocyte infiltration in chronic and sustained inflammatory conditions. We have previously shown adenosine to be a key metabolic nucleoside that regulates stromal inflammation, but the underlying mechanisms linking adenosine to the metabolic status of fibroblasts and to the resultant inflammatory response are unclear. This study examined, by seahorse real-time cell metabolic analysis, the bioenergetics of the stromal fibroblast response to extracellular adenosine and IL-1β, focusing on CXCL8 secretion by primary human gingival fibroblasts (HGF).

Methods

Markers of the glycolytic pathway and mitochondrial biogenesis were tracked through immunoblot. Further, the influence of adenosine on mitochondrial accumulation was measured by uptake of MitoTracker Red fluorescent probe and assessment of the role of FCCP (a mitochondrial uncoupler) in CXCL8 secretion and mitochondrial accumulation.

Results

Our results show that the anti-inflammatory response of HGF to extracellular adenosine, typified by reduced CXCL8 secretion, is mediated by mitochondrial oxidative phosphorylation, reflected in higher oxygen consumption rate (OCR). In the presence of IL-1β, adenosine-treated cells induced higher ATP production, basal respiration and proton leak compared to IL-1β without adenosine. Surprisingly, adenosine had no additional effect on the IL-1β-induced higher glycolysis rate demonstrated by the extracellular acidification rate (ECAR). In addition, the higher OCR in adenosine-stimulated cells was not due to the mitochondrial fuel dependency or capacity, but due to an increase in mitochondrial biogenesis and accumulation in the cells with concomitant decrease in mitophagy-required p-PINK1 marker. We detected the accumulation of functional mitochondria with increased activation of the AMPK/SIRT1/PGC-1α pathway. The adenosine-induced uptake of MitoTracker was abrogated by PGC-1α inhibition with SR-12898. In addition, the adenosine effects on reduced CXCL8 were ablated by treatment with FCCP, a potent uncoupler of mitochondrial oxidative phosphorylation.

Conclusion

Our findings reveal a key role for mitochondrial bioenergetics in regulation of CXCL8-mediated inflammation by HGF through the adenosine/AMPK/SIRT1/PGC-1α axis. Therapeutically targeting this pathway in gingival fibroblasts might be a promising future strategy to modulate stromal-mediated sustained hyper-inflammatory responses.
The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation
Authors: Pille Melissa , Avila John , Sanchez Guillem Sanchez , Goetgeluk Glenn , De Munter Stijn , Jansen Hanne , Billiet Lore , Weening Karin , Xue Haipeng , Bonte Sarah , Ingels Joline , De Cock Laurenz , Pascal Eva , Deseins Lucas , Kerre Tessa , Taghon Tom , Leclercq Georges , Vermijlen David , Davis Brian , Vandekerckhove Bart
Published: June 2023

The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)+ CD4+ CD8+ double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8+ SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.
Study on the effect of mineral admixtures on working and mechanical properties of the grouting material
Authors: Shen Quanjun , Jiang Ruishuang , Cong Bori , Guo Baolin , Shang Hongfa , Ji Xiaoge
Published: June 2023

Aiming at the existing grouting material, there are a series of problems such as poor fluidity of the grouting, rapid loss of fluidity, non-compactness of the grouting after hardening, gaps or holes, and the like. In this paper, fly ash, limestone powder, and silica fume are used to replace cement, and the influence of mineral admixtures on the fluidity, rheological properties, and strength of the grouting material are systematically studied. The experiment found that: fly ash, limestone powder, and silica fume can all improve the fluidity of the grouting material, and the effect of fly ash is the best. Compared with pure cement grouting, the initial fluidity and 60 min fluidity of the grouting material mixed with 40 wt% fly ash were reduced by 35.5% and 53.8% respectively. Fly ash and limestone powder mixed into the grouting material will significantly improve the rheological properties, while silica fume will reduce the flow properties of the grouting. The addition of fly ash and limestone powder will reduce the mechanical properties of the grouting material, while silica fume can improve the mechanical properties of the grouting material. Compared with pure cement grouting, the 28 days compressive strength with 4 wt% limestone powder grouting material is reduced by 4.5%, and the flexural strength is reduced by 6%; the 28 days compressive strength with 4 wt% silica fume grouting material is increased by 6.5%, the flexural strength increased by 1%.
Molecular crosstalk between COVID-19 and Alzheimer’s disease using microarray and RNA-seq datasets: A system biology approach
Authors: Premkumar T. , Sajitha Lulu S.
Published: June 2023

Objective

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The clinical and epidemiological analysis reported the association between SARS-CoV-2 and neurological diseases. Among neurological diseases, Alzheimer’s disease (AD) has developed as a crucial comorbidity of SARS-CoV-2. This study aimed to understand the common transcriptional signatures between SARS-CoV-2 and AD.

Materials and methods

System biology approaches were used to compare the datasets of AD and COVID-19 to identify the genetic association. For this, we have integrated three human whole transcriptomic datasets for COVID-19 and five microarray datasets for AD. We have identified differentially expressed genes for all the datasets and constructed a protein–protein interaction (PPI) network. Hub genes were identified from the PPI network, and hub genes-associated regulatory molecules (transcription factors and miRNAs) were identified for further validation.

Results

A total of 9,500 differentially expressed genes (DEGs) were identified for AD and 7,000 DEGs for COVID-19. Gene ontology analysis resulted in 37 molecular functions, 79 cellular components, and 129 biological processes were found to be commonly enriched in AD and COVID-19. We identified 26 hub genes which includes AKT1, ALB, BDNF, CD4, CDH1, DLG4, EGF, EGFR, FN1, GAPDH, INS, ITGB1, ACTB, SRC, TP53, CDC42, RUNX2, HSPA8, PSMD2, GFAP, VAMP2, MAPK8, CAV1, GNB1, RBX1, and ITGA2B. Specific miRNA targets associated with Alzheimer’s disease and COVID-19 were identified through miRNA target prediction. In addition, we found hub genes-transcription factor and hub genes-drugs interaction. We also performed pathway analysis for the hub genes and found that several cell signaling pathways are enriched, such as PI3K-AKT, Neurotrophin, Rap1, Ras, and JAK–STAT.

Conclusion

Our results suggest that the identified hub genes could be diagnostic biomarkers and potential therapeutic drug targets for COVID-19 patients with AD comorbidity.
A novel hACE2 knock-in mouse model recapitulates pulmonary and intestinal SARS-CoV-2 infection
Authors: Zhou Xiaoyang , Sun Weiyang , Zhang Yu , Gu Hongjing , Wang Ruixuan , Xie Peng , Zhu Yunkai , Qiu Minyue , Ding Xiaoyan , Wang Hui , Gao Yuwei , Li Jintao
Published: June 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is responsible for the coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter the host, and the gastrointestinal tract is a potential infection site as this receptor is expressed on it. Multiple studies have indicated that an increasing number of COVID-19 patients presented with gastrointestinal symptoms that are highly associated with disease severity. Moreover, emerging evidence has demonstrated that alterations in the gut immune microenvironment induced by intestinal SARS-CoV-2 infection can regulate respiratory symptoms. Therefore, targeting the intestines may be a candidate therapeutic strategy in patients with COVID-19; however, no mouse model can serve as an appropriate infection model for the development of fatal pneumonia while mimicking intestinal infection. In this study, a novel human ACE2 knock-in (KI) mouse model (or hACE2-KI) was systemically compared with the popular K18-hACE2 mice; it showed differences in the distribution of lung and intestinal infections and pathophysiological characteristics. These newly generated hACE2-KI mice were susceptible to intranasal infection with SARS-CoV-2, and not only developed mild to severe lung injury, but also acquired intestinal infection. Consequently, this model can be a useful tool for studying intestinal SARS-CoV-2 infection and developing effective therapeutic strategies.
Differences in the composition of the bacterial element of the urinary tract microbiome in patients undergoing dialysis and patients after kidney transplantation
Authors: Jaworska Marcelina M. , Pecyna Paulina , Jaskiewicz Katarzyna , Rydzanicz Małgorzata , Kaluzna Malgorzata , Pawlaczyk Krzysztof , Ploski Rafal , Nowak-Malczewska Dorota M. , Karolak Justyna A. , Gajecka Marzena
Published: June 2023

Introduction

The development of molecular biology methods and their application in microbial research allowed the detection of many new pathogens that cause urinary tract infections (UTIs). Despite the advances of using new research techniques, the etiopathogenesis of UTIs, especially in patients undergoing dialysis and patients after kidney transplantation, is still not fully understood.

Methods

This study aimed to characterize and compare the composition of the bacterial element of the urinary tract microbiome between the groups of patients undergoing dialysis (n = 50) and patients after kidney transplantation (n = 50), with positive or negative urine culture, compared to healthy individuals (n = 50).

Results

Asymptomatic bacteriuria was observed in 30% of the urine cultures of patients undergoing dialysis and patients after kidney transplantation, with Escherichia coli as the most dominant microorganism (73%) detected with the use of classical microbiology techniques. However, differences in the bacterial composition of the urine samples between the evaluated patient groups were demonstrated using the amplicon sequencing. Finegoldia, Leptotrichia, and Corynebacterium were found to be discriminative bacteria genera in patients after dialysis and kidney transplantation compared to the control group. In addition, in all of urine samples, including those without bacteriuria in classical urine culture, many types of bacteria have been identified using 16S rRNA sequencing.

Discussion

The revealed microbial characteristics may form the basis in searching for new diagnostic markers in treatment of patients undergoing dialysis and patients after kidney transplantation.
Solvated interaction energy: from small-molecule to antibody drug design
Authors: Purisima Enrico O. , Corbeil Christopher R. , Gaudreault Francis , Wei Wanlei , Deprez Christophe , Sulea Traian
Published: June 2023

Scoring functions are ubiquitous in structure-based drug design as an aid to predicting binding modes and estimating binding affinities. Ideally, a scoring function should be broadly applicable, obviating the need to recalibrate and refit its parameters for every new target and class of ligands. Traditionally, drugs have been small molecules, but in recent years biologics, particularly antibodies, have become an increasingly important if not dominant class of therapeutics. This makes the goal of having a transferable scoring function, i.e., one that spans the range of small-molecule to protein ligands, even more challenging. One such broadly applicable scoring function is the Solvated Interaction Energy (SIE), which has been developed and applied in our lab for the last 15 years, leading to several important applications. This physics-based method arose from efforts to understand the physics governing binding events, with particular care given to the role played by solvation. SIE has been used by us and many independent labs worldwide for virtual screening and discovery of novel small-molecule binders or optimization of known drugs. Moreover, without any retraining, it is found to be transferrable to predictions of antibody-antigen relative binding affinities and as accurate as functions trained on protein-protein binding affinities. SIE has been incorporated in conjunction with other scoring functions into ADAPT (Assisted Design of Antibody and Protein Therapeutics), our platform for affinity modulation of antibodies. Application of ADAPT resulted in the optimization of several antibodies with 10-to-100-fold improvements in binding affinity. Further applications included broadening the specificity of a single-domain antibody to be cross-reactive with virus variants of both SARS-CoV-1 and SARS-CoV-2, and the design of safer antibodies by engineering of a pH switch to make them more selective towards acidic tumors while sparing normal tissues at physiological pH.
A cross-sectional study of explainable machine learning in Alzheimer’s disease: diagnostic classification using MR radiomic features
Authors: Leandrou Stephanos , Lamnisos Demetris , Bougias Haralabos , Stogiannos Nikolaos , Georgiadou Eleni , Achilleos K. G. , Pattichis Constantinos S. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Introduction

Alzheimer’s disease (AD) even nowadays remains a complex neurodegenerative disease and its diagnosis relies mainly on cognitive tests which have many limitations. On the other hand, qualitative imaging will not provide an early diagnosis because the radiologist will perceive brain atrophy on a late disease stage. Therefore, the main objective of this study is to investigate the necessity of quantitative imaging in the assessment of AD by using machine learning (ML) methods. Nowadays, ML methods are used to address high dimensional data, integrate data from different sources, model the etiological and clinical heterogeneity, and discover new biomarkers in the assessment of AD.

Methods

In this study radiomic features from both entorhinal cortex and hippocampus were extracted from 194 normal controls (NC), 284 mild cognitive impairment (MCI) and 130 AD subjects. Texture analysis evaluates statistical properties of the image intensities which might represent changes in MRI image pixel intensity due to the pathophysiology of a disease. Therefore, this quantitative method could detect smaller-scale changes of neurodegeneration. Then the radiomics signatures extracted by texture analysis and baseline neuropsychological scales, were used to build an XGBoost integrated model which has been trained and integrated.

Results

The model was explained by using the Shapley values produced by the SHAP (SHapley Additive exPlanations) method. XGBoost produced a f1-score of 0.949, 0.818, and 0.810 between NC vs. AD, MC vs. MCI, and MCI vs. AD, respectively.

Discussion

These directions have the potential to help to the earlier diagnosis and to a better manage of the disease progression and therefore, develop novel treatment strategies. This study clearly showed the importance of explainable ML approach in the assessment of AD.
Freezing of gait in Chinese patients with multiple system atrophy: prevalence and risk factors
Authors: Chen Yalan , Wang Hui , Huang Hongyan , Chen Yangmei , Xu Yanming
Published: June 2023

Objective

Freezing of gait (FOG) is common in neurodegenerative forms of atypical parkinsonism, but few studies have examined FOG in multiple system atrophy (MSA). In this study, we examined the prevalence of freezing of gait and its relationship to clinical features in a large cohort of Chinese MSA patients.

Methods

This exploratory study included 202 Chinese patients with probable MSA. FOG was defined as a score ≥ 1 on item 14 of the Unified Parkinson’s Disease Rating Scale. Patients with or without FOG were compared in terms of the Unified MSA Rating Scale (UMSARS) as well as cognitive and neuropsychiatric assessments.

Results

The frequency of FOG was 48.0, 52.1, and 38.7% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. FOG was associated with worse subscores on parts I, II and IV of the UMSARS as well as worse total UMSARS score; greater likelihood of speech difficulties, falls, gait impairment and balance disorder; more severe symptoms of anxiety and depression; and lower activities of daily living. The binary logistic regression model indicated that higher total UMSARS scores were associated with FOG in MSA, MSA-P, and MSA-C patients.

Conclusion

Freezing of gait may be common among Chinese MSA patients, FOG may correlate with severe motor symptoms, anxiety, depression and activities of daily living. Total UMSARS score may be an independent risk factor for FOG.
A grape seed and bilberry extract reduces blood pressure in individuals at risk of developing type 2 diabetes: the PRECISE study, a double-blind placebo-controlled cross-over intervention study
Authors: Grohmann Teresa , Walker Alan W. , Russell Wendy R. , Hoggard Nigel , Zhang Xuguang , Horgan Graham , de Roos Baukje
Published: June 2023

Background

Type 2 Diabetes Mellitus (T2DM) is a major risk factor for the development of cardiometabolic diseases. T2DM prevention is largely based on weight-loss and whole diet changes, but intervention with dietary plant bioactives may also improve metabolic health.

Objective

To assess whether supplementation with bilberry and grape seed extract for 12 weeks improves cardiometabolic outcomes in individuals at risk of developing T2DM, and to determine whether individual treatment response is associated with differences in gut microbiota composition and levels of phenolic metabolites in blood and feces.

Methods

In the randomized, double-blind, placebo-controlled, cross-over PRECISE intervention study, 14 participants, aged ≥45 years, with a BMI >28 kg/m2, and having an increased risk of T2DM, received a supplement containing 250 mg of bilberry plus 300 mg of grape seed extract, or 550 mg of a control extract, per day, for 12 weeks each. Blood samples were obtained for the assessment of HbA1c, fasting glucose, oral glucose tolerance tests, insulin, glucagon levels, total, LDL and HDL cholesterol, and phenolic acids. We also assessed advanced glycation end products in the skin, ambulatory 24 hours blood pressure, 7-day dietary intake by weighed food diaries, fecal levels of phenolic metabolites using LC–MS/MS and gut microbiota composition using 16S rRNA gene sequencing analysis.

Results

The combined bilberry and grape seed extract did not affect glucose and cholesterol outcomes, but it decreased systolic and diastolic ambulatory blood pressure by 4.7 (p < 0.001) and 2.3 (p = 0.0009) mmHg, respectively. Eight out of fourteen participants were identified as blood pressure ‘responders’. These responders had higher levels of phenylpropionic and phenyllactic acids in their fecal samples, and a higher proportional abundance of Fusicatenibacter-related bacteria (p < 0.01) in their baseline stool samples.

Conclusion

Long-term supplementation with bilberry and grape seed extract can improve systolic and diastolic blood pressure in individuals at risk of T2DM. Individual responsiveness was correlated with the presence of certain fecal bacterial strains, and an ability to metabolize (epi)catechin into smaller phenolic metabolites.

Clinical trial registry number: Research Registry (number 4084).
Prognostic analysis of patients with breast cancer based on tumor mutational burden and DNA damage repair genes
Authors: Teng Xu , Yang Tianshu , Yuan Baowen , Yang Yunkai , Liu Jiaxiang , Wang Xin , Wang Yong , Ma Tianyu , Yin Xin , Yu Hefen , Wang Shuang , Huang Wei
Published: June 2023

Background

Breast cancer has a high tumor-specific death rate and poor prognosis. In this study, we aimed to provide a basis for the prognostic risk in patients with breast cancer using significant gene sets selected by analyzing tumor mutational burden (TMB) and DNA damage repair (DDR).

Methods

Breast cancer genomic and transcriptomic data were obtained from The Cancer Genome Atlas (TCGA). Breast cancer samples were dichotomized into high- and low-TMB groups according to TMB values. Differentially expressed DDR genes between high- and low-TMB groups were incorporated into univariate and multivariate cox regression model to build prognosis model. Performance of the prognosis model was validated in an independently new GEO dataset and evaluated by time-dependent ROC curves.

Results

Between high- and low-TMB groups, there were 6,424 differentially expressed genes, including 67 DDR genes. Ten genes associated with prognosis were selected by univariate cox regression analysis, among which seven genes constituted a panel to predict breast cancer prognosis. The seven-gene prognostic model, as well as the gene copy numbers are closely associated with tumor-infiltrating immune cells.

Conclusion

We established a seven-gene prognostic model comprising MDC1, PARP3, PSMB1, PSMB9, PSMD2, PSMD7, and PSMD14 genes, which provides a basis for further exploration of a population-based prediction of prognosis and immunotherapy response in patients with breast cancer.
Colorectal cancer in patients of advanced age is associated with increased incidence of BRAF p.V600E mutation and mismatch repair deficiency
Authors: Christenson Eric S. , Tsai Hua-Ling , Le Dung T. , Jaffee Elizabeth M. , Dudley Jonathan , Xian Rena R. , Gocke Christopher D. , Eshleman James R. , Lin Ming-Tseh
Published: June 2023

Introduction

The highest incidence of colorectal cancer (CRC) is in patients diagnosed at 80 years or older highlighting a need for understanding the clinical and molecular features of these tumors. Methods. In this retrospective cohort study, 544 CRCs underwent next generation sequencing and mismatch repair (MMR) evaluation. Molecular and clinical features were compared between 251 patients with traditional-onset CRC (50-69 years at diagnosis) and 60 with late-onset CRC (>80 years at diagnosis).

Results

Late-onset CRC showed a significantly higher rate of right-sided tumors (82% vs 35%), MMR deficiency (35% vs. 8%) and BRAF p.V600E mutations (35% vs. 8%) and a significantly lower rate of stage IV disease (15% vs 28%) and APC mutations (52% vs. 78%). Association of these features with advanced age was supported by stratifying patients into 6 age groups (<40, 40-49, 50-59, 60-69, 70-79 and >80 years). However, the age-related rise in MMR deficient (dMMR) CRC was only seen in the female patients with an incidence of 48% (vs. 10% in the male patient) in the >80y group. In addition, BRAF p.V600E was significantly enriched in MMR deficient CRC of advanced age (67% in late-onset CRC). Categorizing CRC by mutational profiling, late-onset CRC revealed a significantly higher rate of dMMR/BRAF+APC- (18% vs. 2.0%), dMMR/BRAF-APC- (8.3% vs. 1.2%) and MMR proficient (pMMR)/BRAF+APC- (12% vs. 4.0%) as compared to traditional-onset CRC.

Discussion

In summary, there was a higher rate of dMMR and BRAF p.V600E in late-onset CRC, independently or in combination. The higher incidence of dMMR in late-onset CRC in females is most likely predominantly driven by BRAF p.V600E induced hypermethylation. Prospective studies with treatment plans designed specifically for these older patients are warranted to improve their outcomes.
Risk of venous thromboembolism with janus kinase inhibitors in inflammatory immune diseases: a systematic review and meta-analysis
Authors: Zhang Juqi , Li Wenhui , Gong Mingli , Gu Yanlun , Zhang Hanxu , Dong Bingqi , Guo Qi , Pang Xiaocong , Xiang Qian , He Xu , Cui Yimin
Published: June 2023

Objectives: This study aimed to evaluate the risk of venous thrombosis (VTE) associated with Janus kinase (JAK) inhibitors in patients diagnosed with immune-mediated inflammatory diseases.

Methods: We conducted a comprehensive search of PUBMED, Cochrane, and Embase databases for randomized controlled trials evaluating venous thromboembolic incidence after administering JAK inhibitors in patients with immune-mediated inflammatory diseases. The studies were screened according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and a meta-analysis was performed.

Results: A total of 16 studies, enrolling 17,242 participants, were included in this review. Four approved doses of JAK inhibitors were administered in the included studies. The meta-analysis revealed no significant difference in the incidence of VTE between patients receiving JAK inhibitors, a placebo, or tumor necrosis factor (TNF) inhibitors (RR 0.72, 95% CI (0.33-1.55); RR 0.94, 95%CI (0.33-2.69)). Subgroup analysis showed a lower risk of VTE with lower doses of JAK inhibitors [RR 0.56, 95%CI (0.36-0.88)]. Compared with the higher dose of tofacitinib, the lower dose was associated with a lower risk of pulmonary embolism [RR 0.37, 95%CI (0.18-0.78)].

Conclusion: Our meta-analysis of randomized controlled trials observed a potential increase in the risk of VTE in patients with immune-mediated inflammatory diseases treated with JAK inhibitors compared to placebo or tumor necrosis factor inhibitors, though statistical significance was not attained. Notably, a higher risk of pulmonary embolism was observed with high doses of tofacitinib. Our findings provide valuable insights for physicians when evaluating the use of JAK inhibitors for patients with immune-mediated inflammatory diseases.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023382544, identifier CRD42023382544
Traditional Chinese medicine residues promote the growth and quality of Salvia miltiorrhiza Bunge by improving soil health under continuous monoculture
Authors: Liu Sha , Yang Guang , Wu Faming , Ge Yang , Liu Fusong , Pu Chunjuan , Wang Zihan , Shen Ye , Zhou Xiuteng , Luo Yuzhi , Li Fengsheng , Zhang You , Chen Meilan , Huang Luqi
Published: June 2023

Continuous monoculture of crops has resulted in reduced yields and quality, as well as soil deterioration. Although traditional Chinese medicine residues (TCMRs) are known to promote plant growth and soil health, few studies have investigated their effectiveness in continuous monoculture soils. Here, we studied the impact of chemical fertilizers (CF) and four TCMRs with antibacterial activities on the growth of S. miltiorrhiza (a widely used medicinal plant in China), accumulation of active ingredients in plants, and soil health under continuous monoculture conditions. Compared with no fertilizer (CK) and CF, fermented Sophora flavescens radix residue (SFRf) and fermented and unfermented Moutan cortex residue (MCRf and MCRu, respectively) resulted in a reduction of the disease index of root rot, while CF did not. The CF and four TCMR treatments increased the accumulation of nitrogen (N) (42.8-124.6% and 17.0-101.7%), phosphorous (P) (19.8-74.7% and 8.3-27.4%), and potassium (K) (104.1-212.0% and 9.3-51.8%) in shoots and roots compared to CK. The differences in nutrient accumulation between the CF and TCMR treatments were statistically insignificant, excepted for the N accumulation in the roots. All fertilization treatments increased plant biomass compared to CK, with increases of 25.57-89.86% and 2.62-35.28% in shoots and roots, respectively. The SFRf treatment exhibited the most significant enhancement in both shoot and root biomass. CF significantly reduced the accumulation of seven active ingredients in roots by 23.90-78.95% compared to CK, whereas each TCMR increased accumulation of certain active ingredients. The TCMR treatments effectively improved the health of deteriorated soil by enhancing soil physicochemical properties, restoring the balance of the microbial community, recruiting beneficial bacteria, and reducing the relative abundance of the pathogen Fusarium. The SFRf treatment exhibited superior performance in improving soil health than other treatments. Overall, the TCMRs outperformed CF in restoring soil health and promoting the yield and quality of S. miltiorrhiza. These findings offer guidance for improving the health of continuous cropping soil and recycling TCMRs.
Enhancing heat stress tolerance in Lanzhou lily (Lilium davidii var. unicolor) with Trichokonins isolated from Trichoderma longibrachiatum SMF2
Authors: Cao Xing , Sui Juanjuan , Li Haiyan , Yue Wenxiu , Liu Tao , Hou Dong , Liang Jiahui , Wu Ze
Published: June 2023

Lanzhou lily (Lilium davidii var. unicolor) is a renowned edible crop produced in China and relatively sensitive to high temperature (HT). Trichokonins (TKs) are antimicrobial peptaibols secreted from Trichoderma longibrachiatum strain SMF2. Here, we report that TKs application improves the thermotolerance of Lanzhou lily. The activity of the antioxidant enzyme system (SOD, CAT, and POD), the level of heat-resistance-associated phytohormones (ABA, SA, and JA), the relative water content (RWC), the content of chlorophyll (Chl), and the net photosynthetic rate (Pn) were promoted by TKs treatment in Lanzhou lily plants subjected to heat stress (HS). TKs treatment also mitigated cell injury as shown by a lower accumulation of malondialdehyde (MDA) and relative electrolyte leakage (REL) under HS conditions. RNA-seq data analysis showed that more than 4.5 times differentially expressed genes (DEGs) responded to TKs treatment under HS compared to non-HS, and TKs treatment reduced protein folding and enhanced cellular repair function under HS conditions. The analyses of DEGs involved in hormone (ABA, SA and JA) synthesis and signaling pathways suggested that TKs might improve Lanzhou lily heat tolerance by promoting ABA synthesis and signal transduction. TKs highly induced DEGs of the HSF-HSP pathway under HS, in which HSFA2 accounted for most of the HSF family. Furthermore, TKs treatment resulted in the upregulation of heat-protective genes LzDREB2B, LzHsfA2a, LzMBF1c, LzHsp90, and LzHsp70 involved in HSF-HSP signal pathway after long-term HS. LzHsfA2a-1 likely plays a key role in acquisition of TKs-induced thermotolerance of Lanzhou lily as evidenced by the sustained response to HS, the enhanced response to TKs treatment under long-term HS, and the high sequence similarity to LlHsfA2a which is a key regulator for the improvement of heat tolerance in Lilium longiflorum. Our results reveal the underlying mechanisms of TKs-mediated thermotolerance in Lanzhou lily and highlight an attractive approach to protecting crop plants from damage caused by HS in a global warming future.
Four haplotype blocks linked to Ascochyta blight disease resistance in chickpea under Mediterranean conditions
Authors: Carmona Alejandro , Rubio Josefa , Millan Teresa , Gil Juan , Die Jose V. , Castro Patricia
Published: June 2023

Ascochyta blight, caused by the fungal pathogen Ascochyta blight, caused by the fungal pathogen Ascochyta rabiei, is a devastating biotic stress that poses a significant threat to chickpea cultivation worldwide. To combat this disease, breeding programs have focused on developing cultivars with resistance to Ascochyta blight. However, a comprehensive understanding of the underlying plant defense mechanism is still lacking. To identify genomic regions associated with resistance, a recombinant inbred line (RIL) population was created by crossing ILC3279 (kabuli, resistant) and WR315 (desi, susceptible), which was then phenotyped and sequenced using a tuneable genotyping-by-sequencing (tGBS) protocol to obtain single nucleotide polymorphisms (SNPs). We further validated the association of genomic regions with Ascochyta blight resistance in a second recombinant inbred line\population derived from the cross between JG62 (desi, susceptible) and ILC72 (kabuli, resistant). Our analysis identified four genomic regions associated with Ascochyta blight resistance in chromosomes 2 and 4, among which a region spanning from 3.52 to 8.20 Mb in chromosome 4 was the most robust candidate for resistance, being associated with resistance in both years and populations. A total of 30 genes from the identified regions were selected as robust candidates, and LOC101507066, which encodes a leucine-rich repeat receptor-like protein kinase, was the most robust candidate gene, as it plays critical roles in plant stress responses and immunity. Our findings have potential to accelerate marker-assisted genetic improvement and facilitate the development of integrated strategies for crop protection.
Influence of cutting time interval and season on productivity, nutrient partitioning, and forage quality of blue panicgrass (Panicum antidotale Retz.) under saline irrigation in Southern region of Morocco
Authors: El Mouttaqi Ayoub , Mnaouer Ihssane , Nilahyane Abdelaziz , Ashilenje Dennis S. , Amombo Erick , Belcaid Mohamed , Ibourki Mohamed , Lazaar Karima , Soulaimani Aziz , Devkota Krishna Prasad , Kouisni Lamfeddal , Hirich Abdelaziz
Published: June 2023

Salinity has become a major issue in various parts of the world negatively impacting agricultural activities and leading to diminished crop potential and lower yields. Such situation calls for urgent interventions such as adopting salt-tolerant crops to fill the gap in food and feed availability. Blue panicgrass (Panicum antidotale Retz.) is a promising salt-tolerant forage crop that has shown an appropriate adaptation and performance in the saline, arid, and desertic environments of southern Morocco. However, for obtaining a highest forage productivity with nutritional quality, optimization of the cutting interval is required. Thus, the objective of this study was to determine the optimal cutting time interval allowing high forage production and quality under high salinity conditions. This experiment was conducted over one entire year covering the summer and winter seasons. The effect of five cutting time intervals on selected agro-morphological traits, crop productivity, mineral nutrient accumulation, and forage quality of blue panicgrass in the region of Laayoune, southern Morocco. The finding of this study recommend that cutting blue panicgrass every 40 days maximized the annual fresh and dry forage yield as well as the protein yield, which reached 74, 22, and 2.9 t/ha, respectively. This study also revealed a significant effect of the season on both productivity and quality. However, forage yield declined during the winter and increased during the summer, while protein content increased during winter compared to summer. The mineral nutrient partitioning between shoots and roots, especially the K+/Na+ ratio, indicated that blue panicgrass has salt tolerance mechanism as it excluded sodium from the roots and compartmentalized it in the leaves. In conclusion, there is a potential of blue panicgrass on sustaining forage production under salt-affected drylands, as demonstrated by the response to two key questions: (a) a technical question to farmers for its adoption such as at which interval should blue panicgrass be harvested maximizing both forage yield and quality? And (b) a scientific question on how does blue panicgrass maintain high K+/Na+ ratio to cope with salinity stress?