bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis
Authors: Zhang Pengpeng , Li Hao , Peng Bo , Zhang Yu , Liu Kai , Cheng Ke , Ming Yingzi
Published: February 2023

Background

Alcoholic and hepatitis B virus (HBV)-related liver cirrhosis has placed a tremendous burden on the healthcare system with limited treatment options. This study explored the differences in the immune status of alcoholic and HBV-related liver cirrhosis.

Methods

A total of 15 human liver samples from the Third Xiangya Hospital of Central South University, including five healthy controls (HC group), five alcoholic cirrhosis patients (ALC group), and five HBV-related cirrhosis patients (HBV group) were used. Of these, eight samples, including 3 HC group, 2 ALC group and 3 HBV group, were randomly collected to do single-cell RNA sequencing (scRNA-seq). The degree of steatosis was assessed by H&E staining and the presence of intrahepatic immune cells was evaluated by immunochemistry (IHC).

Results

The immune status of alcoholic and HBV-related liver cirrhosis differed significantly. ScRNA-seq analysis identified a higher ratio of intrahepatic monocyte/macrophages and an obvious decreased ratio of T cells and B cells in the ALC group than in the HBV group. IHC staining of intrahepatic monocyte/macrophages, T and B cell exhibited similar results with scRNA-seq analysis. CD5L+ Kupffer cells, a cell type involved in lipid metabolism, were the major monocyte/macrophage subset in ALC liver tissue. H&E staining indicated that the level of steatosis was more severe in the ALC than in the HBV group. Ligand/receptor analysis showed that the T cell exhaustion observed in the ALC liver may be related to the expression of Galectin-9 on Kupffer cells. Fewer B cells were also found in the ALC group and most had higher lipid metabolism, reduced ribosomal activity, and a dysregulated mitochondrial oxidative phosphorylation system. Moreover, scRNA-seq showed a significantly lower ratio of plasma B cells, indicating that the humoral immune response in the ALC liver was similarly dysfunctional. Ligand/receptor analysis also discovered that Galectin-9 expressed on Kupffer cells may inhibit humoral immunity.

Conclusion

Patients with ALC have different immune characteristics than those with HBV-induced cirrhosis, including an increased ratio of intrahepatic monocyte/macrophages and a dysfunctional adaptive immune response in the liver. Galectin-9 could serve as a potential therapeutic target for ALC treatment.
Radar echo simulation of dynamically rotating wind turbine blades based on 3D scattering center
Authors: Tang Bo , Xie Huanghai , Liu Gang , Zhang Longbin , Shang Zhiyu
Published: February 2023

Introduction: High-fidelity simulation of the radar echo from the wind turbine (WT) for accurate acquisition of Doppler features, is the key issue in addressing radiation interference from the wind farm on the nearby radar station. In view of the limitation of the conventional scattering center-based equivalent model to reflect the complex surface of blades, it is difficult to simulate the rotating blades’echo accurately with the existing algorithm. Therefore, we proposed a simulation method based on a 3D scattering center extraction to deal with it.

Methods: Therefore, we proposed a simulation method based on a 3D scattering center extraction to deal with it. First, the method of scattering center equivalence to blade scattering is used in order to reduce the modelling as well as the solution of electromagnetic scattering from the multi-space attitude of the blade, which is different from the existing algorithm. Since the geometry affects the parameters of the scattering center, an orthogonal matching pursuit greedy algorithm is used to extract the parameter of the 3D scattering center model.

Results: Therefore, the temporal correspondence between the scattering center and the blade motion characteristics is established, resulting in a reconstruction of the scattered field data of the rotating blades. Consequently, the real-time simulation and Doppler characteristic of blades echoes are achieved using the Short Time Fourier Transform (STFT).

Discussion: A comparison of the results with the data obtained from the GTD scattering center model verififies the accuracy of the proposed method.
Pro-environmental behavior, green HRM practices, and green psychological climate: Examining the underlying mechanism in Pakistan
Authors: Li Mingxing , ul Abidin Rana Zain , Qammar Rabia , Qadri Syed Usman , Khan Muhammad Kaleem , Ma Zhiqiang , Qadri Safwan , Ahmed Haseeb , Khan Hira Salah ud din , Mahmood Shahid
Published: February 2023

The success of an organization’s environmental sustainability objectives is contingent on the environmental behavior of its personnel. The present study was conducted to observe how the green human resource management (GHRM) practice improves environmental performance (EP) through psychological green climate (PGC) and pro-environmental behavior (PEB). It also evaluates the moderating role of the individual green value (IGV). Data were collected from HR professionals and health officers directly engaged in human resource practices in private hospitals in Sialkot, Pakistan. To gather the responses, questionnaires were distributed and PLS analysis was used to analyze the data. The findings showed that GHRM explains that the PGC stimulates employees to perform pro-environmental behaviors for better environmental performance. Furthermore, the individual green value moderates the employee’s behavior for better environmental performance. This research paper gives vital practical implications to the top management and regulators in assuring employee engagement in applying green human resource management practices.
Tropical savanna small mammals respond to loss of cover following disturbance: A global review of field studies
Authors: Bergstrom Bradley J. , Scruggs Samuel B. , Vieira Emerson M.
Published: February 2023

Small-mammal faunas of tropical savannas consist of endemic assemblages of murid rodents, small marsupials, and insectivores on four continents. Small mammals in tropical savannas are understudied compared to other tropical habitats and other taxonomic groups (e.g., Afrotropical megafauna or Neotropical rainforest mammals). Their importance as prey, ecosystem engineers, disease reservoirs, and declining members of endemic biodiversity in tropical savannas compels us to understand the factors that regulate their abundance and diversity. We reviewed field studies published in the last 35 years that examined, mostly experimentally, the effects of varying three primary endogenous disturbances in tropical savanna ecosystems—fire, large mammalian herbivory (LMH), and drought—on abundance and diversity of non-volant small mammals. These disturbances are most likely to affect habitat structure (cover or concealment), food availability, or both, for ground-dwelling small mammalian herbivores, omnivores, and insectivores. Of 63 studies (included in 55 published papers) meeting these criteria from the Afrotropics, Neotropics, and northern Australia (none was found from southern Asia), 29 studies concluded that small mammals responded (mostly negatively) to a loss of cover (mostly from LMH and fire); four found evidence of increased predation on small mammals in lower-cover treatments (e.g., grazed or burned). Eighteen studies concluded a combination of food- and cover-limitation explained small-mammal responses to endogenous disturbances. Only two studies concluded small-mammal declines in response to habitat-altering disturbance were caused by food limitation and not related to cover reduction. Evidence to date indicates that abundance and richness of small savanna mammals, in general (with important exceptions), is enhanced by vegetative cover (especially tall grass, but sometimes shrub cover) as refugia for these prey species amid a “landscape of fear,” particularly for diurnal, non-cursorial, and non-fossorial species. These species have been called “decreasers” in response to cover reduction, whereas a minority of small-mammal species have been shown to be “increasers” or disturbance-tolerant. Complex relationships between endogenous disturbances and small-mammal food resources are important secondary factors, but only six studies manipulated or measured food resources simultaneous to habitat manipulations. While more such studies are needed, designing effective ones for cryptic consumer communities of omnivorous dietary opportunists is a significant challenge.
Mapping seagrass habitats of potential suitability using a hybrid machine learning model
Authors: He Bohao , Zhao Yanghe , Liu Siyu , Ahmad Shahid , Mao Wei
Published: February 2023

Seagrass meadows provide essential ecosystem services globally in the context of climate change. However, seagrass is being degraded at an accelerated rate globally due to ocean warming, ocean acidification, aquaculture, and human activities. The need for more information on seagrasses’ spatial distribution and health status is a serious impediment to their conservation and management. Therefore, we propose a new hybrid machine learning model (RF-SWOA) that integrates the sinusoidal chaos map whale optimization algorithm (SWOA) with a random forest (RF) model to accurately model the suitable habitat of potential seagrasses. This study combines in situ sampling data with multivariate remote sensing data to train and validate hybrid machine learning models. It shows that RF-SWOA can predict potential seagrass habitat suitability more accurately and efficiently than RF. It also shows that the two most important factors affecting the potential seagrass habitat suitability on Hainan Island in China are distance to land (38.2%) and depth to sea (25.9%). This paper not only demonstrates the effectiveness of a hybrid machine learning model but also provides a more accurate machine learning model approach for predicting the potential suitability distribution of seagrasses. This research can help identify seagrass suitability distribution areas and thus develop conservation strategies to restore healthy seagrass ecosystems.
CRISPR/Cas9 mediated gene editing in non-model nematode Panagrolaimus sp. PS1159
Authors: Hellekes Viktoria , Claus Denise , Seiler Johanna , Illner Felix , Schiffer Philipp H. , Kroiher Michael
Published: February 2023

The phylum Nematoda harbors a huge diversity of species in a broad range of ecosystems and habitats. Nematodes share a largely conserved Bauplan but major differences have been found in early developmental processes. The development of the nematode model organism Caenorhabditis elegans has been studied in great detail for decades. These efforts have provided the community with a large number of protocols and methods. Unfortunately, many of these tools are not easily applicable in non-Caenorhabditis nematodes. In recent years it has become clear that many crucial genes in the C. elegans developmental toolkit are absent in other nematode species. It is thus necessary to study the developmental program of other nematode species in detail to understand evolutionary conservation and novelty in the phylum. Panagrolaimus sp. PS1159 is a non-parasitic nematode exhibiting parthenogenetic reproduction and we are establishing the species to comparatively study evolution, biodiversity, and alternative reproduction and survival strategies. Here, we demonstrate the first successful application of the CRISPR/Cas9 system for genome editing in Panagrolaimus sp. PS1159 and the closely related hermaphroditic species Propanagrolaimus sp. JU765 applying the non-homologous end joining and the homology-directed repair (HDR) mechanisms. Using microinjections and modifying published protocols from C. elegans and P. pacificus we induced mutations in the orthologue of unc-22. This resulted in a visible uncoordinated twitching phenotype. We also compared the HDR efficiency following the delivery of different single-stranded oligodeoxynucleotides (ssODNs). Our work will expand the applicability for a wide range of non-model nematodes from across the tree and facilitate functional analysis into the evolution of parthenogenesis, changes in the developmental program of Nematoda, and cryptobiosis.
Genomic epidemiology of Mycobacterium avium subsp. paratuberculosis isolates from Canadian dairy herds provides evidence for multiple infection events
Authors: Byrne Alexander , Ollier Séverine , Tahlan Kapil , Biet Franck , Bissonnette Nathalie
Published: February 2023

Mycobacterium aviumsubsp.paratuberculosis(MAP) is the pathogen responsible for paratuberculosis or Johne’s Disease (JD) in ruminants, which is responsible for substantial economic losses worldwide. MAP transmission primarily occurs through the fecal-oral route, and the introduction of an MAP infected animal into a herd is an important transmission route. In the current study, we characterized MAP isolates from 67 cows identified in 20 herds from the provinces of Quebec and Ontario, Canada. Whole genome sequencing (WGS) was performed and an average genome coverage (relative to K-10) of ∼14.9 fold was achieved. The total number of SNPs present in each isolate varied from 51 to 132 and differed significantly between herds. Isolates with the highest genetic variability were generally present in herds from Quebec. The isolates were broadly separated into two main clades and this distinction was not influenced by the province from which they originated. Analysis of 8 MIRU-VNTR loci and 11 SSR loci was performed on the 67 isolates from the 20 dairy herds and publicly available references, notably major genetic lineages and six isolates from the province of Newfoundland and Labrador. All 67 field isolates were phylogenetically classified as Type II (C-type) and according to MIRU-VNTR, the predominant type was INMV 2 (76.1%) among four distinct patterns. Multilocus SSR typing identified 49 distinct INMV SSR patterns. The discriminatory index of the multilocus SSR typing was 0.9846, which was much higher than MIRU-VNTR typing (0.3740). Although multilocus SSR analysis provides good discriminatory power, the resolution was not informative enough to determine inter-herd transmission. In select cases, SNP-based analysis was the only approach able to document disease transmission between herds, further validated by animal movement data. The presence of SNPs in several virulence genes, notably for PE, PPE, mce and mmpL, is expected to explain differential antigenic or pathogenetic host responses. SNP-based studies will provide insight into how MAP genetic variation may impact host-pathogen interactions. Our study highlights the informative power of WGS which is now recommended for epidemiological studies and to document mixed genotypes infections.
Identification of two near-identical novel HIV-1 unique recombinant forms (CRF01_AE/B) among men who have sex with men in baoding, hebei, China
Authors: Zhang Binbin , Chen Sisi , Meng Juan , Su Miaomiao , Fan Weiguang , An Weina , Lu Xinli
Published: February 2023

Men who have sex with men (MSM) are the most frequent infection route of the human immunodeficiency virus (HIV) in Baoding, China, creating chances for the occurrence of unique recombinant forms (URFs) of the virus, i.e., recombination of different subtypes caused by co-circulation of multiple subtypes. In this report, two near-identical URFs (BDD002A and BDD069A) isolated from MSM in Baoding were identified. Phylogenetic tree analysis based on nearly full-length genomes (NFLGs) revealed that the two URFs formed a distinct monophyletic cluster with a bootstrap value of 100%. Recombinant breakpoints analysis identified that the NFLGs of BDD002A and BDD069A were both composed of CRF01_AE and subtype B, with six subtype B mosaic segments inserted into the CRF01_AE backbone. The CRF01_AE segments of the URFs clustered closely with the CRF01_AE reference sequences, and the B subregions clustered with the B reference sequences. The recombinant breakpoints of the two URFs were almost identical. These results suggest that effective interventions are urgently needed to prevent the formation of complex HIV-1 recombinant forms in Baoding, China.
Identification of immune related gene signature for predicting prognosis of cholangiocarcinoma patients
Authors: Zhang Zi-jian , Huang Yun-peng , Liu Zhong-tao , Wang Yong-xiang , Zhou Hui , Hou Ke-xiong , Tang Ji-wang , Xiong Li , Wen Yu , Huang Sheng-fu
Published: February 2023

Objective

To identify the gene subtypes related to immune cells of cholangiocarcinoma and construct an immune score model to predict the immunotherapy efficacy and prognosis for cholangiocarcinoma.

Methods

Based on principal component analysis (PCA) algorithm, The Cancer Genome Atlas (TCGA)-cholangiocarcinoma, GSE107943 and E-MTAB-6389 datasets were combined as Joint data. Immune genes were downloaded from ImmPort. Univariate Cox survival analysis filtered prognostically associated immune genes, which would identify immune-related subtypes of cholangiocarcinoma. Least absolute shrinkage and selection operator (LASSO) further screened immune genes with prognosis values, and tumor immune score was calculated for patients with cholangiocarcinoma after the combination of the three datasets. Kaplan-Meier curve analysis determined the optimal cut-off value, which was applied for dividing cholangiocarcinoma patients into low and high immune score group. To explore the differences in tumor microenvironment and immunotherapy between immune cell-related subtypes and immune score groups of cholangiocarcinoma.

Results

34 prognostic immune genes and three immunocell-related subtypes with statistically significant prognosis (IC1, IC2 and IC3) were identified. Among them, IC1 and IC3 showed higher immune cell infiltration, and IC3 may be more suitable for immunotherapy and chemotherapy. 10 immune genes with prognostic significance were screened by LASSO regression analysis, and a tumor immune score model was constructed. Kaplan-Meier (KM) and receiver operating characteristic (ROC) analysis showed that RiskScore had excellent prognostic prediction ability. Immunohistochemical analysis showed that 6 gene (NLRX1, AKT1, CSRP1, LEP, MUC4 and SEMA4B) of 10 genes were abnormal expressions between cancer and paracancer tissue. Immune cells infiltration in high immune score group was generally increased, and it was more suitable for chemotherapy. In GSE112366-Crohn’s disease dataset, 6 of 10 immune genes had expression differences between Crohn’s disease and healthy control. The area under ROC obtained 0.671 based on 10-immune gene signature. Moreover, the model had a sound performance in Crohn’s disease.

Conclusion

The prediction of tumor immune score model in predicting immune microenvironment, immunotherapy and chemotherapy in patients with cholangiocarcinoma has shown its potential for indicating the effect of immunotherapy on patients with cholangiocarcinoma.
Caveolin-1 regulates OMV-induced macrophage pro-inflammatory activation and multiple Toll-like receptors
Authors: Sivanantham Ayyanar , Alktaish Ward , Murugeasan Selvakumar , Gong Bin , Lee Heedoo , Jin Yang
Published: February 2023

Macrophages (MФ), the primary cell of the innate immune system, serves as the first line of defense. During bacterial infection, Gram-negative (G-) bacteria release nanosized outer membrane vesicles (OMVs), facilitating the crosstalk between the microbe and the host. The underlying mechanisms by which OMVs induced pro-inflammatory (M1) activation are still unknown. Our study shows that OMVs caused M1 activation via modulating various toll-like receptor (TLR) expressions as they contain LPS, LTA, bacterial DNAs, and flagellins. Also, we found that caveolin-1 (cav-1), a 21-kDa scaffolding protein of caveolae and lipid rafts, plays a significant role in OMV-induced pro-inflammatory response in regulating various TLR signaling pathways. Specifically, cav-1 deletion increased the expression of OMV-induced TLRs, pro-inflammatory cytokine secretions (TNF-α and IL-1β), and the reactive oxygen species (ROS) production in MФs. Further, we examined the interaction between Cav-1 and TLR4 by immunoprecipitation, colocalization, and computational models, providing future direction to explore the role of cav-1 in OMV-induced other TLR signaling. Altogether, Cav-1 is a key regulator in OMV-induced multiple TLRs response. This study promotes future research to develop drugs by targeting the specific motif of cav-1 or TLRs against bacterial infection and macrophage-mediated inflammation.
Persistence of spike-specific immune responses in BNT162b2-vaccinated donors and generation of rapid ex-vivo T cells expansion protocol for adoptive immunotherapy: A pilot study
Authors: Mestiri Sarra , Merhi Maysaloun , Inchakalody Varghese P. , Taib Nassiba , Smatti Maria K. , Ahmad Fareed , Raza Afsheen , Ali Fatma H. , Hydrose Shereena , Fernandes Queenie , Ansari Abdul W. , Sahir Fairooz , Al-Zaidan Lobna , Jalis Munir , Ghoul Mokhtar , Allahverdi Niloofar , Al Homsi Mohammed U. , Uddin Shahab , Jeremijenko Andrew Martin , Nimir Mai , Abu-Raddad Laith J. , Abid Fatma Ben , Zaqout Ahmed , Alfheid Sameer R. , Saqr Hassan Mohamed Hassan , Omrani Ali S. , Hssain Ali Ait , Al Maslamani Muna , Yassine Hadi M. , Dermime Said
Published: February 2023

Introduction

The BNT162b2 mRNA-based vaccine has shown high efficacy in preventing COVID-19 infection but there are limited data on the types and persistence of the humoral and T cell responses to such a vaccine.

Methods

Here, we dissect the vaccine-induced humoral and cellular responses in a cohort of six healthy recipients of two doses of this vaccine.

Results and discussion

Overall, there was heterogeneity in the spike-specific humoral and cellular responses among vaccinated individuals. Interestingly, we demonstrated that anti-spike antibody levels detected by a novel simple automated assay (Jess) were strongly correlated (r=0.863, P<0.0001) with neutralizing activity; thus, providing a potential surrogate for neutralizing cell-based assays. The spike-specific T cell response was measured with a newly modified T-spot assay in which the high-homology peptide-sequences cross-reactive with other coronaviruses were removed. This response was induced in 4/6 participants after the first dose, and all six participants after the second dose, and remained detectable in 4/6 participants five months post-vaccination. We have also shown for the first time, that BNT162b2 vaccine enhanced T cell responses also against known human common viruses. In addition, we demonstrated the efficacy of a rapid ex-vivo T cell expansion protocol for spike-specific T cell expansion to be potentially used for adoptive-cell therapy in severe COVID-19, immunocompromised individuals, and other high-risk groups. There was a 9 to 13.7-fold increase in the number of expanded T cells with a significant increase of anti-spike specific response showing higher frequencies of both activation and cytotoxic markers. Interestingly, effector memory T cells were dominant in all four participants’ CD8+ expanded memory T cells; CD4+ T cells were dominated by effector memory in 2/4 participants and by central memory in the remaining two participants. Moreover, we found that high frequencies of CD4+ terminally differentiated memory T cells were associated with a greater reduction of spike-specific activated CD4+ T cells. Finally, we showed that participants who had a CD4+ central memory T cell dominance expressed a high CD69 activation marker in the CD4+ activated T cells.
IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma
Authors: Swan Sheridan L. , Mehta Nalini , Ilich Ekaterina , Shen Steven H. , Wilkinson Daniel S. , Anderson Alexa R. , Segura Tatiana , Sanchez-Perez Luis , Sampson John H. , Bellamkonda Ravi V.
Published: February 2023

Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.
Targeted modulation of gut microbiota by traditional Chinese medicine and natural products for liver disease therapy
Authors: Zhu Li-Ran , Li Shan-Shan , Zheng Wan-Qun , Ni Wei-Jian , Cai Ming , Liu Hai-Peng
Published: February 2023

The gut microbiota not only constitutes intestinal microenvironment homeostasis and human health but also exerts indispensable roles in the occurrence and progression of multiple liver diseases, including alcohol-related liver disease, nonalcoholic fatty liver disease, autoimmune liver disease and liver cancer. Given the therapeutic status of these diseases, their prevention and early therapy are crucial, and the detailed mechanism of gut microbiota in liver disease urgently needs to be explored. Meanwhile, multiple studies have shown that various traditional Chinese medicines, such as Si Miao Formula, Jiangzhi Granules, Liushen Capsules, Chaihu-Shugan Power, Cassiae Semen and Gynostemma, as well as some natural products, including Costunolide, Coprinus comatus polysaccharide, Antarctic krill oil, Oridonin and Berberine, can repair liver injury, improve fatty liver, regulate liver immunity, and even inhibit liver cancer through multiple targets, links, and pathways. Intriguingly, the aforementioned effects demonstrated by these traditional Chinese medicines and natural products have been shown to be closely related to the gut microbiota, directly driving the strategy of traditional Chinese medicines and natural products to regulate the gut microbiota as one of the breakthroughs in the treatment of liver diseases. Based on this, this review comprehensively summarizes and discusses the characteristics, functions and potential mechanisms of these medicines targeting gut microbiota during liver disease treatment. Research on the potential effects on gut microbiota and the regulatory mechanisms of traditional Chinese medicine and natural products provides novel insights and significant references for developing liver disease treatment strategies. In parallel, such explorations will enhance the comprehension of traditional Chinese medicine and natural products modulating gut microbiota during disease treatment, thus facilitating their clinical investigation and application.
IL-17A expression by both T cells and non-T cells contribute to HSV-IL-2-induced CNS demyelination
Authors: Hirose Satoshi , Wang Shaohui , Jaggi Ujjaldeep , Matundan Harry H. , Kato Mihoko , Song Xue-Ying , Molesworth-Kenyon Sara J. , Lausch Robert N. , Ghiasi Homayon
Published: February 2023

Previously we reported that a recombinant HSV-1 expressing murine IL-2 (HSV-IL-2) causes CNS demyelination in different strains of mice and in a T cell-dependent manner. Since TH17 cells have been implicated in CNS pathology, in the present study, we looked into the effects of IL-17A-/- and three of its receptors on HSV-IL-2-induced CNS demyelination. IL-17A-/- mice did not develop CNS demyelination, while IL-17RA-/-, IL-17RC-/-, IL-17RD-/- and IL-17RA-/-RC-/- mice developed CNS demyelination. Adoptive transfer of T cells from wild-type (WT) mice to IL-17A-/- mice or T cells from IL-17A-/- mice to Rag-/- mice induced CNS demyelination in infected mice. Adoptive T cell experiments suggest that both T cells and non-T cells expressing IL-17A contribute to HSV-IL-2-induced CNS demyelination with no difference in the severity of demyelination between the two groups of IL-17A producing cells. IL-6, IL-10, or TGFβ did not contribute to CNS demyelination in infected mice. Transcriptome analysis between IL-17A-/- brain and spinal cord of infected mice with and without T cell transfer from WT mice revealed that “neuron projection extension involved in neuron projection guidance” and “ensheathment of neurons” pathways were associated with CNS demyelination. Collectively, the results indicate the importance of IL-17A in CNS demyelination and the possible involvement of more than three of IL-17 receptors in CNS demyelination.
Intralymphatic glutamic acid decarboxylase administration in type 1 diabetes patients induced a distinctive early immune response in patients with DR3DQ2 haplotype
Authors: Puente-Marin Sara , Dietrich Fabrícia , Achenbach Peter , Barcenilla Hugo , Ludvigsson Johnny , Casas Rosaura
Published: February 2023

GAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compared the immunomodulatory effect of GAD-alum administered into lymph nodes of patients with T1D versus placebo with focus on patients with DR3DQ2 haplotype.

Methods

GAD autoantibodies, GADA subclasses, GAD65-induced cytokine secretion (Luminex panel) and proliferation of peripheral mononuclear cells were analyzed in T1D patients (n=109) who received either three intra-lymphatic injections (one month apart) with 4 µg GAD-alum and oral vitamin D supplementation (2000 IE daily for 120 days), or placebo.

Results

Higher GADA, GADA subclasses, GAD65-induced proliferation and cytokine secretion was observed in actively treated patients after the second injection of GAD-alum compared to the placebo group. Following the second injection of GAD-alum, actively treated subjects with DR3DQ2 haplotype had higher GAD65-induced secretion of several cytokine (IL4, IL5, IL7, IL10, IL13, IFNγ, GM-CSF and MIP1β) and proliferation compared to treated individuals without DR3DQ2. Stratification of samples from GAD-alum treated patients according to C-peptide preservation at 15 months revealed that “good responder” individuals with better preservation of C-peptide secretion, independently of the HLA haplotype, had increased GAD65-induced proliferation and IL13 secretion at 3 months, and a 2,5-fold increase of IL5 and IL10 as compared to “poor responders”. The second dose of GAD-alum also induced a more pronounced cytokine secretion in “good responders” with DR3DQ2, compared to few “good responders” without DR3DQ2 haplotype.

Conclusion

Patients with DR3DQ2 haplotype had a distinct early cellular immune response to GAD-alum injections into the lymph node, and predominant GAD65-induced IL13 secretion and proliferation that seems to be associated with a better clinical outcome. If confirmed in the ongoing larger randomized double-blind placebo-controlled clinical trial (DIAGNODE-3), including only patients carrying DR3DQ2 haplotype, these results might be used as early surrogate markers for clinical efficacy.
IFN regulatory factor 3 of golden pompano and its NLS domain are involved in antibacterial innate immunity and regulate the expression of type I interferon (IFNa3)
Authors: Sun Yun , Cao Zhenjie , Zhang Panpan , Wei Caoying , Li Jianlong , Wu Ying , Zhou Yongcan
Published: February 2023

Introduction

The transcription factor interferon regulatory factor 3 (IRF3) plays an important role in host defence against viral infections. However, its role during bacterial infection in teleosts remains unclear. In the present study, we evaluated the antibacterial effects of Trachinotus ovatus IRF3 (TroIRF3) and how it regulates type I interferon (IFN).

Methods

Subcellular localisation experiments, overexpression, and quantitative real-time PCR (qRT-PCR) were performed to examine the nuclear localisation signal (NLS) of TroIRF3 and its role in the antibacterial regulatory function of TroIRF3. We assessed the binding activity of TroIRF3 to the IFNa3 promoter by luciferase reporter assay.

Results and Discussion

The results showed that TroIRF3 was constitutively expressed at high levels in the gill and liver. TroIRF3 was significantly upregulated and transferred from the cytoplasm to the nucleus after Vibrio harveyi infection. By overexpressing TroIRF3, the fish were able to inhibit the replication of V. harveyi, whereas knocking it down increased bacterial replication. Moreover, the overexpression of TroIRF3 increased type I interferon (IFNa3) production and the IFN signalling molecules. The NLS, which is from the 64–127 amino acids of TroIRF3, contains the basic amino acids KR74/75 and RK82/84. The results proved that NLS is required for the efficient nuclear import of TroIRF3 and that the NLS domain of TroIRF3 consists of the key amino acids KR74/75 and RK82/84. The findings also showed that NLS plays a key role in the antibacterial immunity and upregulation of TroIFNa3 induced by TroIRF3. Moreover, TroIRF3 induces TroIFNa3 promoter activity, whereas these effects are inhibited when the NLS domain is deficient. Overall, our results suggested that TroIRF3 is involved in the antibacterial immunity and regulation of type I IFN in T. ovatus and that the NLS of TroIRF3 is vital for IRF3-mediated antibacterial responses, which will aid in understanding the immune role of fish IRF3.
Agonistic and antagonistic targeting of immune checkpoint molecules differentially regulate osteoclastogenesis
Authors: Brom Victoria C. , Strauss Andreas C. , Sieberath Alexander , Salber Jochen , Burger Christof , Wirtz Dieter C. , Schildberg Frank A.
Published: February 2023

Introduction

Immune checkpoint inhibitors are used in the treatment of various cancers and have been extensively researched with regard to inflammatory and autoimmune diseases. However, this revolutionary therapeutic strategy often provokes critical auto-inflammatory adverse events, such as inflammatory reactions affecting the cardiovascular, gastrointestinal, nervous, and skeletal systems. Because the function of these immunomodulatory co-receptors is highly cell-type specific and the role of macrophages as osteoclast precursors is widely published, we aimed to analyze the effect of immune checkpoint inhibitors on these bone-resorbing cells.

Methods

We established an in vitro model of osteoclastogenesis using human peripheral blood mononuclear cells, to which various immune checkpoints and corresponding antagonistic antibodies were administered. Formation of osteoclasts was quantified and cell morphology was analyzed via immunofluorescence staining, cell size measurements, and calculation of cell numbers in a multitude of samples.

Results

These methodical approaches for osteoclast research achieved objective, comparable, and reproducible results despite the great heterogeneity in the form, size, and number of osteoclasts. In addition to the standardization of experimental analyses involving osteoclasts, our study has revealed the substantial effects of agonistic and antagonistic checkpoint modulation on osteoclastogenesis, confirming the importance of immune checkpoints in bone homeostasis.

Discussion

Our work will enable more robust and reproducible investigations into the use of immune checkpoint inhibitors in conditions with diminished bone density such as osteoporosis, aseptic loosening of endoprostheses, cancer, as well as the side effects of cancer therapy, and might even pave the way for novel individualized diagnostic and therapeutic strategies.
Analysis on the dynamic mechanism of Acetes aggregation near a nuclear power cooling water system based on the Lagrangian flow network
Authors: Lou Qi , Zhang Xueqing , Xiang Xusheng , Yu Fan , Xiong Ying , Li Zhengyan
Published: February 2023

The outbreak of nuclear power cooling water system (NPCS) disaster-causing organisms has become more frequent, causing huge economic losses. Therefore, it is necessary to understand the aggregation mechanism of disaster-causing organisms for the risk prevention and control of NPCS. Hence, this study applied the Lagrangian flow network (LFN) to analyze the aggregation mechanism of Acetes near NPCS, as such a complex network can describe the interconnections between massive nodes and has already been used for modeling complex nonlinear systems, revealing how the mechanisms of such novel processes emerge. In this study, the degree and probability paths in the network were used to reveal the transport pathway and aggregation area of Acetes. The experimental results highlighted that the sea area of the nuclear power plant is the key node with a large in-degree of the LFN, where the material easily accumulated. The Acetes near the NPCS mainly originated from the east along two critical paths. Overall, this study demonstrates that the LFN is a feasible approach to predicting the transport and the accumulation of the NPCS disaster-causing plankton.
Assessing differences in acoustic characteristics from impact and vibratory pile installation and their potential effects on the large yellow croaker (Pseudosciaena crocea)
Authors: Niu Fuqiang , Xie Jiarui , Zhang Xuexin , Xue Ruichao , Chen Benqing , Liu Zhenwen , Yang Yanming
Published: February 2023

Underwater noise from anthropogenic activities can have negative behavioral and physical effects on marine life, including physical changes, injuries, and death. Impact pile driving and vibratory pile driving are generally used for the construction of ocean-based foundations. Based on the field data under the same marine engineering and marine environment, this paper addresses the characteristics of underwater noise from impact and vibratory pile driving, their differences, and the effects of noise on populations of the large yellow croaker (Pseudosciaena crocea). The impact pile driving pulse had a median peak-to-peak sound pressure source level (SPLpp) of 244.7 dB re 1 μPa at 1 m and a median sound exposure source level (SELss) of 208.1 dB re 1 μPa2s at 1 m by linear regression. The waveform of vibratory pile driving appears to be continuous with a low SPLpp, but the cumulative SEL (SELcum) in 1 min is very high, reaching 207.5 dB re 1 μPa2s at 1 m. The range of behavioral response for adult large yellow croaker (20–23 cm) is predicted to be 4,798 m for impact pile driving and 1,779 m for vibratory pile driving. The study provides evidence of the comparative potential effects of vibratory and impact pile driving on the large yellow croaker and reference for the conservation of croaker.
Reconstruction of horizontal tidal current fields in a shallow water with model-oriented coastal acoustic tomography
Authors: Taniguchi Naokazu , Mutsuda Hidemi , Arai Masazumi , Sakuno Yuji , Hamada Kunihiro , Takahashi Toshiyuki , Yoshiki Kengo , Yamamoto Hironori
Published: February 2023

Reciprocal acoustic transmission and coastal acoustic tomography (CAT) is a powerful tool for measuring tidal currents in shallow coastal water, especially if data assimilation is employed. In previous CAT data assimilation studies, the ensemble Kalman filter (EnKF) has been implemented to assimilate observed path-averaged velocity, but ad-hoc procedures called localization and inflation, which compensate for issues associated with using ensemble approximation, were not always implemented. In this study, EnKF is applied to assimilate the path-averaged currents obtained from a reciprocal acoustic transmission experiment conducted at Mihara-Seto in the Seto Inland Sea, Japan, with four acoustic stations in 2020 to reconstruct spatiotemporal variations of tidal currents at the observation site. We executed EnKF with several combinations of different values of the inflation, localization, and the number of ensemble members. The resulting data assimilated velocity reconstructions are compared with acoustic Doppler current profiling (ADCP) results. The results show that data assimilation with EnKF improved the velocity reproduction compared with the model prediction and that implementing covariance inflation contributed to additional improvements. The covariance localization did not improve the results in our case. The best result in terms of fractional error variance (FEV) between the ADCP velocity was obtained from the case with 980 ensemble members with a covariance inflation of 1.01; the FEV was 7.9%. The case of 98 ensemble members with a covariance inflation of 1.01 resulted in similar performance; the FEV value was 8.2%. Thus, with the covariance inflation, the number of ensemble member used in previous CAT studies are reasonable. In the study, we also clarified the reason for the high-frequency variation in the observed path-averaged currents in a preliminary experiment; the path-averaged currents had captured the spatiotemporal variation of vortex generation associated with island wakes. The reciprocal acoustic transmission with EnKF can capture short-period variation over a long period; thus, it can be used in studies of coastal physical processes with various time scales.
Simulating the giant magnetocaloric effect-from mean-field theory to microscopic models
Authors: Amaral J. S. , Amaral V. S.
Published: February 2023

Magnetocaloric materials are recognized as one of the major classes of magnetic materials for energy applications, and can be either employed as refrigerants in heat-pumping devices, or in thermomagnetic generators for energy conversion/harvesting. For both applications, having a material that presents a first-order magnetic phase transition is advantageous, as this typically leads to enhanced values of magnetization change in temperature (relevant to energy conversion) and of the magnetocaloric effect (relevant to heat-pumping). We present a brief overview of selected models applied to the simulation of applied magnetic field and temperature-dependent magnetization and magnetic entropy change of first-order magnetic phase transition systems, covering mean-field models such as the Landau theory of phase transitions and the Bean-Rodbell model, up to more recent developments using a Ising-like microscopic model with magnetovolume coupling effects. We highlight the fundamental and practical limitations of employing these models and compare predicted thermodynamic properties.
Fracture mechanism and failure strain of TA31 titanium alloy for deep-sea pressure hulls based on continuum damage mechanics
Authors: Zhang Bowen , Wan Zhengquan
Published: February 2023

Titanium alloys has high fatigue resistance, high corrosion resistance, high temperature resistance, and other excellent properties, and have been widely used in deep-sea equipment and aviation industries. In this paper, the fracture mechanism and failure strain of TA31 titanium alloy, which has been widely used in deep-sea equipment, were studied experimentally and numerically in different stress states. Considering the pressure sensitivity, the Modified Johnson-Cook (MJC) model and the Bonora damage model were used to study the fracture behavior. In order to obtain the parameters of models, four types of specimens under different stress triaxiality were conducted, and a hybrid experimental-numerical approach was employed in this paper. Then, the coupled constitutive elastic–plastic-damage model was developed and implemented in ABAQUS explicit finite element analysis (FEA) code. Finally, to validate the suggested model, FEA simulation was carried out and compared with the experimental results. The comparison revealed that the Bonora model with constant parameters was not enough to predict the failure strain. The damage parameters were sensitive to the stress triaxiality. In addition, the fracture morphology was observed by scanning electron microscope (SEM), which revealed the micro-mechanism of failure for TA31 titanium alloy. It is concluded that a higher stress triaxiality and shear mechanism lead to lower plastic deformation, and will inhibit the void growth on the damage evolution.
Commercial and business aspects of alpha radioligand therapeutics
Authors: Ostuni Emanuele , Taylor Martin R. G.
Published: February 2023

Radioligand therapy (RLT) is gaining traction as a safe and effective targeted approach for the treatment of many cancer types, reflected by a substantial and growing commercial market (valued at $7.78 billion in 2021, with a projected value of $13.07 billion by 2030). Beta-emitting RLTs have a long history of clinical success dating back to the approval of Zevalin and Bexxar in the early 2000s, later followed by Lutathera and Pluvicto. Alpha radioligand therapeutics (ARTs) offer the potential for even greater success. Driven by ground-breaking clinical results in early trials, improved isotope availability, and better understanding of isotope and disease characteristics, the global market for alpha emitters was estimated at $672.3 million for the year 2020, with projected growth to $5.2 billion by 2027. New company formations, promising clinical trial data, and progression for many radioligand therapy products, as well as an inflow of investor capital, are contributing to this expanding field. Future growth will be fueled by further efficacy and safety data from ART clinical trials and real-world results, but challenges remain. Radionuclide supply, manufacturing, and distribution are key obstacles for growth of the field. New models of delivery are needed, along with cross-disciplinary training of specialized practitioners, to ensure patient access and avoid challenges faced by early RLT candidates such as Zevalin and Bexxar. Understanding of the history of radiation medicine is critical to inform what may be important to the success of ART–most past projections were inaccurate and it is important to analyze the reasons for this. Practical considerations in how radiation medicine is delivered and administered are important to understand in order to inform future approaches.
Neuroanatomical and neurocognitive changes associated with subjective cognitive decline
Authors: Rivas-Fernández Miguel Ángel , Lindín Mónica , Zurrón Montserrat , Díaz Fernando , Lojo-Seoane Cristina , Pereiro Arturo X. , Galdo-Álvarez Santiago
Published: February 2023

Introduction

Subjective Cognitive Decline (SCD) can progress to mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia and thus may represent a preclinical stage of the AD continuum. However, evidence about structural changes observed in the brain during SCD remains inconsistent.

Materials and methods

This cross-sectional study aimed to evaluate, in subjects recruited from the CompAS project, neurocognitive and neurostructural differences between a group of forty-nine control subjects and forty-nine individuals who met the diagnostic criteria for SCD and exhibited high levels of subjective cognitive complaints (SCCs). Structural magnetic resonance imaging was used to compare neuroanatomical differences in brain volume and cortical thickness between both groups.

Results

Relative to the control group, the SCD group displayed structural changes involving frontal, parietal, and medial temporal lobe regions of critical importance in AD etiology and functionally related to several cognitive domains, including executive control, attention, memory, and language.

Conclusion

Despite the absence of clinical deficits, SCD may constitute a preclinical entity with a similar (although subtle) pattern of neuroanatomical changes to that observed in individuals with amnestic MCI or AD dementia.