bluuebunny/crossref_metadata_2025 huggingface dataset:
A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
Authors: Jafari Khamirani Hossein , Palicharla Vivek Reddy , Dastgheib Seyed Alireza , Dianatpour Mehdi , Imanieh Mohammad Hadi , Tabei Seyed Sajjad , Besse Whitney , Mukhopadhyay Saikat , Liem Karel F.
Published: October 2022

Patient variants in Tubby Like Protein-3 (TULP3) have recently been associated with progressive fibrocystic disease in tissues and organs. TULP3 is a ciliary trafficking protein that links membrane-associated proteins to the intraflagellar transport complex A. In mice, mutations in Tulp3 drive phenotypes consistent with ciliary dysfunction which include renal cystic disease, as part of a ciliopathic spectrum. Here we report two sisters from consanguineous parents with fibrocystic renal and hepatic disease harboring a homozygous missense mutation in TULP3 (NM_003324.5: c.1144C>T, p.Arg382Trp). The R382W patient mutation resides within the C-terminal Tubby domain, a conserved domain required for TULP3 to associate with phosphoinositides. We show that inner medullary collecting duct-3 cells expressing the TULP3 R382W patient variant have a severely reduced ability to localize the membrane-associated proteins ARL13b, INPP5E, and GPR161 to the cilium, consistent with a loss of TULP3 function. These studies establish Arginine 382 as a critical residue in the Tubby domain, which is essential for TULP3-mediated protein trafficking within the cilium, and expand the phenotypic spectrum known to result from recessive deleterious mutations in TULP3.
Utilizing genomics and historical data to optimize gene pools for new breeding programs: A case study in winter wheat
Authors: Ballén-Taborda Carolina , Lyerly Jeanette , Smith Jared , Howell Kimberly , Brown-Guedira Gina , Babar Md. Ali , Harrison Stephen A. , Mason Richard E. , Mergoum Mohamed , Murphy J. Paul , Sutton Russell , Griffey Carl A. , Boyles Richard E.
Published: October 2022

With the rapid generation and preservation of both genomic and phenotypic information for many genotypes within crops and across locations, emerging breeding programs have a valuable opportunity to leverage these resources to 1) establish the most appropriate genetic foundation at program inception and 2) implement robust genomic prediction platforms that can effectively select future breeding lines. Integrating genomics-enabled1 breeding into cultivar development can save costs and allow resources to be reallocated towards advanced (i.e., later) stages of field evaluation, which can facilitate an increased number of testing locations and replicates within locations. In this context, a reestablished winter wheat breeding program was used as a case study to understand best practices to leverage and tailor existing genomic and phenotypic resources to determine optimal genetics for a specific target population of environments. First, historical multi-environment phenotype data, representing 1,285 advanced breeding lines, were compiled from multi-institutional testing as part of the SunGrains cooperative and used to produce GGE biplots and PCA for yield. Locations were clustered based on highly correlated line performance among the target population of environments into 22 subsets. For each of the subsets generated, EMMs and BLUPs were calculated using linear models with the ‘lme4’ R package. Second, for each subset, TPs representative of the new SC breeding lines were determined based on genetic relatedness using the ‘STPGA’ R package. Third, for each TP, phenotypic values and SNP data were incorporated into the ‘rrBLUP’ mixed models for generation of GEBVs of YLD, TW, HD and PH. Using a five-fold cross-validation strategy, an average accuracy of r = 0.42 was obtained for yield between all TPs. The validation performed with 58 SC elite breeding lines resulted in an accuracy of r = 0.62 when the TP included complete historical data. Lastly, QTL-by-environment interaction for 18 major effect genes across three geographic regions was examined. Lines harboring major QTL in the absence of disease could potentially underperform (e.g., Fhb1 R-gene), whereas it is advantageous to express a major QTL under biotic pressure (e.g., stripe rust R-gene). This study highlights the importance of genomics-enabled breeding and multi-institutional partnerships to accelerate cultivar development.
Investigation of the biomarkers involved in ectopic ossification: The shared mechanism in ossification of the spinal ligament
Authors: Liu Jiachen , Chen Yunxia , Shan Xiuqi , Wang Huan
Published: October 2022

Background: Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) are multifactor diseases characterized by progressively ectopic ossification in the spinal ligament. However, the shared ossification mechanism of OPLL and OLF remains to be elucidated. The study aims to investigate the common biomarkers related to ectopic ossification and the potential molecular regulatory mechanism.

Methods: Microarray and RNA-seq datasets were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) from OPLL and OLF were identified to construct the protein-protein interaction (PPI) network. Furthermore, the hub intersection genes were screened and the diagnostic performance was assessed in the external OLF and OPLL cohorts. We also depicted the landscape of immune cell infiltration and m6A modification meanwhile further estimating the relationship with BMP4.

Results: A total of nine up-regulated DEGs and 11 down-regulated DEGs were identified to construct the PPI networks. The integrative bioinformatic analysis defined five hub genes (BMP4, ADAMTS4, HBEGF, IL11, and HAS2) as the common risk biomarkers. Among them, BMP4 was the core target. ROC analysis demonstrated a high diagnostic value of the hub genes. Moreover, activated B cells were recognized as shared differential immune infiltrating cells and significantly associated with BMP4 in OPLL and OLF. Meanwhile, a strong correlation was detected between the expression pattern of the m6A regulator METTL3 and BMP4.

Conclusion: This study first identified BMP4 as the shared core biomarker in the development of OPLL and OLF. Activated B cells and m6A writer METTL3 might be involved in the osteogenesis process mediated by BMP4. Our findings provide insights into the pathogenesis in the ossification of the spinal ligament and unveil the potential therapeutic targets.
Intergenomic and epistatic interactions control free radical mediated pancreatic β-cell damage
Authors: Chen Jing , Li Renhua , Knapp Sarah , Zhu Guizhi , Whitener Robert L. , Leiter Edward H. , Mathews Clayton E.
Published: October 2022

Alloxan (AL)-generated Reactive Oxygen Species (ROS) selectively destroy insulin-producing pancreatic β-cells. A previous genome-wide scan (GWS) using a cohort of 296 F2 hybrids between NOD (AL-sensitive) and ALR (AL-resistant) mice identified linkages contributing to β-cell susceptibility or resistance to AL-induced diabetes on Chromosomes (Chr) 2, 3, 8, and a single nucleotide polymorphism in mt-Nd2 of the mitochondrial genome (mtDNA). AL treatment of congenic and consomic NOD mouse stocks confirmed resistance linked to both the mtDNA and the Chr 8 locus from ALR [NOD.mtALR.ALR-(D8Mit293-D8Mit137)]. To identify possible epistatic interactions, the GWS analysis was expanded to 678 F2 mice. ALR-derived diabetes-resistance linkages on Chr 8 as well as the mt-Nd2a allele were confirmed and novel additional linkages on Chr 4, 5, 6, 7, and 13 were identified. Epistasis was observed between the linkages on Chr 8 and 2 and Chr 8 and 6. Furthermore, the mt-Nd2 genotype affected the epistatic interactions between Chr 8 and 2. These results demonstrate that a combination of nuclear-cytoplasmic genome interactions regulates β-cell sensitivity to ROS-mediated ALD.
B7-H3-targeting Fc-optimized antibody for induction of NK cell reactivity against sarcoma
Authors: Hagelstein Ilona , Engel Monika , Hinterleitner Clemens , Manz Timo , Märklin Melanie , Jung Gundram , Salih Helmut R. , Zekri Latifa
Published: October 2022

Natural killer (NK) cells largely contribute to antibody-dependent cellular cytotoxicity (ADCC), a central factor for success of monoclonal antibodies (mAbs) treatment of cancer. The B7 family member B7-H3 (CD276) recently receives intense interest as a novel promising target antigen for immunotherapy. B7-H3 is highly expressed in many tumor entities, whereas expression on healthy tissues is rather limited. We here studied expression of B7-H3 in sarcoma, and found substantial levels to be expressed in various bone and soft-tissue sarcoma subtypes. To date, only few immunotherapeutic options for treatment of sarcomas that are limited to a minority of patients are available. We here used a B7-H3 mAb to generate chimeric mAbs containing either a wildtype Fc-part (8H8_WT) or a variant Fc part with amino-acid substitutions (S239D/I332E) to increase affinity for CD16 expressing NK cells (8H8_SDIE). In comparative studies we found that 8H8_SDIE triggers profound NK cell functions such as activation, degranulation, secretion of IFNγ and release of NK effector molecules, resulting in potent lysis of different sarcoma cells and primary sarcoma cells derived from patients. Our findings emphasize the potential of 8H8_SDIE as novel compound for treatment of sarcomas, particularly since B7-H3 is expressed in bone and soft-tissue sarcoma independent of their subtype.
Regulatory T-cells and GARP expression are decreased in exercise-associated chikungunya viral arthritis flares
Authors: Dobbs John E. , Tritsch Sarah R. , Encinales Liliana , Cadena Andres , Suchowiecki Karol , Simon Gary , Mores Christopher , Insignares Silvana , Orozco Vierys Patricia Villamil , Ospino Mirna , Echavez Lil Avendano , Gomez Carlos Andres Herrera , Crespo Yerlenis Galvis , Amdur Richard , Jimenez Alberto David Cabana , Hernandez Carlos Alberto Perez , Zapata Jennifer Carolina Martinez , Hernandez Alfonso Sucerquia , Silvera Paula Bruges , Rosales Wendy , Mendoza Evelyn , Osorio-Llanes Estefanie , Castellar Jairo , Jimenez Dennys , Cooper Dan M. , Firestein Gary S. , Martins Karen , Chang Aileen Y.
Published: October 2022

Objective

Chikungunya virus (CHIKV) causes persistent arthritis, and our prior study showed that approximately one third of CHIKV arthritis patients had exacerbated arthritis associated with exercise. The underlying mechanism of exercise-associated chikungunya arthritis flare (EACAF) is unknown, and this analysis aimed to examine the regulatory T-cell immune response related to CHIKV arthritis flares.

Methods

In our study, 124 Colombian patients with a history of CHIKV infection four years prior were enrolled and 113 cases with serologically confirmed CHIKV IgG were used in this analysis. Patient information was gathered via questionnaires, and blood samples were taken to identify total live peripheral blood mononuclear cells, CD4+ cells, T regulatory cells, and their immune markers. We compared outcomes in CHIKV patients with (n = 38) vs. without (n = 75) EACAF using t-tests to assess means and the Fisher’s exact test, chi-squared to evaluate categorical variables, and Kruskal-Wallis tests in the setting of skewed distributions (SAS 9.3).

Results

33.6% of CHIKV cases reported worsening arthritis with exercise. EACAF patients reported higher global assessments of arthritis disease ranging from 0-100 (71.2 ± 19.7 vs. 59.9 ± 28.0, p=0.03). EACAF patients had lower ratios of T regulatory (Treg)/CD4+ T-cells (1.95 ± 0.73 vs. 2.4 ± 1.29, p = 0.04) and lower percentage of GARP (glycoprotein-A repetitions predominant) expression per Treg (0.13 ± 0.0.33 vs. 0.16 ± 0.24 p= 0.020).

Conclusion

These findings suggest relative decreases in GARP expression may indicate a decreased level of immune suppression. Treg populations in patients with CHIKV arthritis may contribute to arthritis flares during exercise, though current research is conflicting.
Inducible general knockout of Runx3 profoundly reduces pulmonary cytotoxic CD8+ T cells with minimal effect on outcomes in mice following influenza infection
Authors: Hao Qin , Kundu Suman , Shetty Sreerama , Tucker Torry A. , Idell Steven , Tang Hua
Published: October 2022

Respiratory viruses pose a continuing and substantive threat to human health globally. Host innate and adaptive immune responses are the critical antiviral defense mechanisms to control viral replication and spread. The present study is designed to determine the role of transcription factor Runx3 in the host immune response to influenza A virus (IAV) infection. As Runx3 is required for embryonic development, we generated an inducibleRunx3global knockout (KO) mouse model and found thatRunx3KO in adult C57BL/6 mice minimally affected thymic function under normal conditions and survival was at least 250 days postRunx3deletion. We applied the mouse model to IAV infection and found thatRunx3KO resulted in a huge reduction (>85%) in numbers of total and antigen-specific pulmonary CD8+cytotoxic T cells during IAV infection, while it had a minor effect on pulmonary generation of CD4+T cells. To our surprise, this general KO ofRunx3did not significantly alter viral clearance and animal survival following IAV infection. Interestingly, we found thatRunx3KO significantly increased the numbers of pulmonary innate immune cells such as macrophages and neutrophils and the production of pro-inflammatory cytokines during IAV infection. We further found that Runx3 was strongly detected in CCR2+immune cells in IAV-infected mouse lungs and was induced in activated macrophages and dendritic cells (DCs). As pulmonary CD8+cytotoxic T cells play a central role in the clearance of IAV, our findings suggest thatRunx3KO may enhance host innate immunity to compensate for the loss of pulmonary CD8+cytotoxic T cells during IAV infection.
Lipidomic insights into the immune response and pearl formation in transplanted pearl oyster Pinctada fucata martensii
Authors: Wu Hailing , Yang Chuangye , Hao Ruijuan , Liao Yongshan , Wang Qingheng , Deng Yuewen
Published: October 2022

During pearl culture, the excess immune responses may induce nucleus rejection and death of pearl oysters after transplantation. To better understand the immune response and pearl formation, lipidomic analysis was applied to investigate changes in the serum lipid profile of pearl oyster Pinctada fucata martensii following transplantation. In total, 296 lipid species were identified by absolute quantitation. During wound healing, the content of TG and DG initially increased and then decreased after 3 days of transplantation with no significant differences, while the level of C22:6 decreased significantly on days 1 and 3. In the early stages of transplantation, sphingosine was upregulated, whereas PC and PUFAs were downregulated in transplanted pearl oyster. PI was upregulated during pearl sac development stages. GP and LC-PUFA levels were upregulated during pearl formation stage. In order to identify enriched metabolic pathways, pathway enrichment analysis was conducted. Five metabolic pathways were found significantly enriched, namely glycosylphosphatidylinositol-anchor biosynthesis, glycerophospholipid metabolism, alpha-linolenic acid metabolism, linoleic acid metabolism and arachidonic acid metabolism. Herein, results suggested that the lipids involved in immune response, pearl sac maturation, and pearl formation in the host pearl oyster after transplantation, which might lead to an improvement in the survival rate and pearl quality of transplanted pearl oyster.
Epstein-Barr virus, interleukin-10 and multiple sclerosis: A ménage à trois
Authors: Schönrich Günther , Abdelaziz Mohammed O. , Raftery Martin J.
Published: October 2022

Multiple Sclerosis (MS) is an autoimmune disease that is characterized by inflammation and demyelination of nerve cells. There is strong evidence that Epstein-Barr virus (EBV), a human herpesvirus infecting B cells, greatly increases the risk of subsequent MS. Intriguingly, EBV not only induces human interleukin-10 but also encodes a homologue of this molecule, which is a key anti-inflammatory cytokine of the immune system. Although EBV-encoded IL-10 (ebvIL-10) has a high amino acid identity with its cellular counterpart (cIL-10), it shows more restricted and partially weaker functionality. We propose that both EBV-induced cIL-10 and ebvIL-10 act in a temporally and functionally coordinated manner helping the pathogen to establish latency in B cells and, at the same time, to balance the function of antiviral T cells. As a result, the EBV load persisting in the immune system is kept at a constant but individually different level (set point). During this immunological tug of war between virus and host, however, MS can be induced as collateral damage if the set point is too high. Here, we discuss a possible role of ebvIL-10 and EBV-induced cIL-10 in EBV-driven pathogenesis of MS.
Inflammatory profile of convalescent plasma to treat COVID: Impact of amotosalen/UVA pathogen reduction technology
Authors: Cognasse Fabrice , Hamzeh-Cognasse Hind , Duchez Anne-Claire , Shurko Natalia , Eyraud Marie-Ange , Arthaud Charles-Antoine , Prier Amélie , Heestermans Marco , Hequet Olivier , Bonneaudeau Brigitte , Rochette-Eribon Sandrine , Teyssier Françoise , Barlet-Excoffier Valérie , Chavarin Patricia , Legrand Dominique , Richard Pascale , Morel Pascal , Mooney Nuala , Tiberghien Pierre
Published: October 2022

Blood products in therapeutic transfusion are now commonly acknowledged to contain biologically active constituents during the processes of preparation. In the midst of a worldwide COVID-19 pandemic, preliminary evidence suggests that convalescent plasma may lessen the severity of COVID-19 if administered early in the disease, particularly in patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms. This study examined the influence of photochemical Pathogen Reduction Treatment (PRT) using amotosalen‐HCl and UVA light in comparison with untreated control convalescent plasma (n= 72 – paired samples) - cFFP, regarding soluble inflammatory factors: sCD40L, IFN-alpha, IFN-beta, IFN-gamma, IL-1 beta, IL-6, IL-8, IL-10, IL-18, TNF-alpha and ex-vivo inflammatory bioactivity on endothelial cells. We didn’t observe significant modulation of the majority of inflammatory soluble factors (8 of 10 molecules tested) pre- or post-PRT. We noted that IL-8 concentrations were significantly decreased in cFFP with PRT, whereas the IL-18 concentration was increased by PRT. In contrast, endothelial cell release of IL-6 was similar whether cFFP was pre-treated with or without PRT. Expression of CD54 and CD31 in the presence of cFFP were similar to control levels, and both were significant decreased in when cFFP had been pre-treated by PRT. It will be interesting to continue investigations of IL-18 and IL-8, and the physiopathological effect of PRT- treated convalescent plasma and in clinical trials. But overall, it appears that cFFP post-PRT were not excessively pro-inflammatory. Further research, including a careful clinical evaluation of CCP-treated patients, will be required to thoroughly define the clinical relevance of these findings.
Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma
Authors: Lin Lanlan , Lin Guofu , Lin Hai , Chen Luyang , Chen Xiaohui , Lin Qinhui , Xu Yuan , Zeng Yiming
Published: October 2022

Background

DERL3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, the correlation of DERL3 expression with the malignant phenotype of lung adenocarcinoma (LUAD) cells is unclear and remains to be elucidated. Herein, we investigated the interaction between the DERL3 and LUAD pathological process.

Methods

The Cancer Genome Atlas (TCGA) database was utilized to determine the genetic alteration of DERL3 in stage I LUAD. Clinical LUAD samples including carcinoma and adjacent tissues were obtained and were further extracted to detect DERL3 mRNA expression via RT-qPCR. Immunohistochemistry was performed to evaluate the protein expression of DERL3 in LUAD tissues. The GEPIA and TIMER website were used to evaluate the correlation between DERL3 and immune cell infiltration. We further used the t-SNE map to visualize the distribution of DERL3 in various clusters at the single-cell level via TISCH database. The potential mechanisms of the biological process mediated by DERL3 in LUAD were conducted via KEGG and GSEA.

Results

It was indicated that DERL3 was predominantly elevated in carcinoma compared with adjacent tissues in multiple kinds of tumors from the TCGA database, especially in LUAD. Immunohistochemistry validated that DERL3 was also upregulated in LUAD tissues compared with adjacent tissues from individuals. DERL3 was preliminarily found to be associated with immune infiltration via the TIMER database. Further, the t-SNE map revealed that DERL3 was predominantly enriched in plasma cells of the B cell population. It was demonstrated that DERL3 high-expressed patients presented significantly worse response to chemotherapy and immunotherapy. GSEA and KEGG results indicated that DERL3 was positively correlated with B cell activation and unfolded protein response (UPR).

Conclusion

Our findings indicated that DERL3 might play an essential role in the endoplasmic reticulum-associated degradation (ERAD) process in LUAD. Moreover, DERL3 may act as a promising immune biomarker, which could predict the efficacy of immunotherapy in LUAD.
Resolvin D1 shows osseous-protection via RANK reduction on monocytes during orthodontic tooth movement
Authors: Klein Yehuda , Levin-Talmor Offir , Berkstein Jaime Garber , Wald Sharon , Meirow Yaron , Maimon Avi , Leibovich Avi , Barenholz Yechezkel , Polak David , Chaushu Stella
Published: October 2022

The study aimed to investigate the role of RvD1 in acute and prolonged sterile inflammation and bone remodeling. A mouse model of sterile inflammation that involves bone resorption was used to examine endogenous RvD1 kinetics during inflammation. Application of exogenous RvD1 significantly inhibited bone remodeling via osteoclast reduction, alongside an anti-inflammatory secretome shift, increased macrophages recruitment and reduction of T-cytotoxic cells. In vitro and in vivo, RvD1 led to significant reduction in RANK expression which reduce osteoclastogenesis in a dose-dependent manner. Taken together, the data shows a dual role for RvD1, as a potent immunoresolvent agent alongside an osteoresolvent role, showing a potential therapeutic agent in bone resorption associated inflammatory conditions.
Postoperative neutrophil-lymphocyte ratio predicts unfavorable outcome of acute ischemic stroke patients who achieve complete reperfusion after thrombectomy
Authors: Feng Yao , Bai Xuesong , Li Wei , Cao Wenbo , Xu Xin , Yu Fan , Fu Zhaolin , Tian Qiuyue , Guo Xiaofan , Wang Tao , Sha Arman , Chen Yanfei , Gao Peng , Wang Yabing , Chen Jian , Ma Yan , Chen Fei , Dmytriw Adam A. , Regenhardt Robert W. , Lu Jie , Ma Qingfeng , Yang Bin , Jiao Liqun
Published: October 2022

Purpose

Only approximately half of anterior circulation large vessel occlusion (LVO) patients receiving endovascular treatment (EVT) have a favorable outcome. The aim of this study was to explore the association of dynamic inflammatory markers (i.e., neutrophil to lymphocyte ratios, NLR, measured at different times after EVT) as well as other potential influencing factors with unfavorable outcome among acute ischemic stroke (AIS) patients who achieved complete reperfusion after EVT.

Methods

Patients treated with EVT for LVO between January 2019 to December 2021 were prospectively enrolled. Complete reperfusion was defined as modified thrombolysis in cerebral infarction (mTICI) grade 3. A modified Rankin scale at 90 days (mRS90) of 3–6 was defined as unfavorable outcome (i.e., futile reperfusion). A logistic regression analysis was performed with unfavorable outcome as a dependent variable. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were then used to determine the diagnostic values of NLR and other relevant factors.

Results

170 patients with complete reperfusion (mTICI 3) were included in this study. Unfavorable outcome was observed in 70 (41.2%). Higher NLR within 24h (p=0.017) and at 3-7d (p=0.008) after EVT were an independent risk factors for unfavorable outcome at 3 months. In addition, older age, higher NIHSS scores, poor collaterals, and general anesthesia were independent predictors of unfavorable outcomes. When accounting for NLR, the diagnostic efficiency improved compared to conventional characteristics.

Conclusion

Our findings suggest that advanced age, increased stroke severity, poor collaterals, general anesthesia, and NLR are independent predictors for an unfavorable clinical outcome following complete reperfusion after EVT. Neuroinflammation may merit particular attention in future studies.
The C1q-ApoE complex: A new hallmark pathology of viral hepatitis and nonalcoholic fatty liver disease
Authors: Habenicht Livia K. L. , Wang Zhihua , Zhang Xi , Li Yuanfang , Mogler Carolin , Huspenina Julia Slotta , Schmid Roland M. , Weber Christian , Mohanta Sarajo K. , Ma Zhe , Yin Changjun
Published: October 2022

We recently identified a high-affinity C1q-ApoE complex in human artery atherosclerotic intima lesions and in human amyloid plaques of Alzheimer’s Disease brains defining a common pathogenetic pathway of two diverse diseases, i.e. atherosclerosis and dementia. C1q is the initiating and controlling protein of the classical complement cascade (CCC), which occupies a key role in multiple acute and chronic inflammatory tissue responses. C1q is largely produced by myeloid cells including Kupffer cells (KCs) and subsequently secreted into the circulation as an inactive preprotein. Its binding partner, Apolipoprotein E (ApoE), is produced by KCs and hepatocytes and it is also secreted into the circulation, where it regulates essential steps of lipid transport. In addition to its major source, ApoE can be produced by non-liver cells including immune cells and multiple other cells depending on local tissue contexts. To initiate the CCC cascade, C1q must be activated by molecules as varied as oxidized lipids, amyloid fibrils, and immune complexes. However, ApoE is mute towards inactive C1q but binds at high-affinity to its activated form. Specifically, our studies revealed that ApoE is a CCC-specific checkpoint inhibitor via the formation of the C1q-ApoE complex. We proposed that it may arise in multiple if not all CCC-associated diseases and that its presence indicates ongoing CCC activity. Here, we turned to the liver to examine C1q-ApoE complexes in human B- and C-viral hepatitis and nonalcoholic fatty liver disease (NAFLD). In addition, we used multidrug-resistance-2 gene-knockout (Mdr2-KO) mice as a model for inflammatory liver disease and hepatocellular carcinoma (HCC) pathogenesis. In normal murine and human livers, KCs were the major C1q-producing cell type while hepatocytes were the primary ApoE-forming cell type though the C1q-ApoE complex was rare or nonexistent. However, significant numbers of C1q-ApoE complexes formed in both Mdr2-KO, human viral hepatitis, and NAFLD around portal triads where immune cells had infiltrated the liver. Additionally, high numbers of C1q-ApoE complexes emerged in human livers in areas of extracellular lipid droplets across the entire liver parenchyma in NAFLD-affected patients. Thus, the C1q-ApoE complex is a new pathological hallmark of viral hepatitis B and C and NAFLD.
TP53I13 promotes metastasis in glioma via macrophages, neutrophils, and fibroblasts and is a potential prognostic biomarker
Authors: Ge Xinqi , Xu Manyu , Cheng Tong , Hu Nan , Sun Pingping , Lu Bing , Wang Ziheng , Li Jian
Published: October 2022

Background

TP53I13 is a protein coding tumor suppression gene encoded by the tumor protein p53. Overexpression of TP53I13 impedes tumor cell proliferation. Nevertheless, TP53I13 role and expression in the emergence and progression of glioma (low-grade glioma and glioblastoma) are yet to be identified. Thus, we aim to use comprehensive bioinformatics analyses to investigate TP53I13 and its prognostic value in gliomas.

Methods

Multiple databases were consulted to evaluate and assess the expression of TP53I13, such as the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GeneMANIA, and Gene Expression Profiling Interactive. TP53I13 expression was further explored using immunohistochemistry (IHC) and multiplex immunohistochemistry (mIHC). Through Gene Set Enrichment Analysis (GSEA), the biological functions of TP53I13 and metastatic processes associated with it were studied.

Results

The expression of TP53I13 was higher in tumor samples compared to normal samples. In samples retrieved from the TCGA and CGGA databases, high TP53I13 expression was associated with poor survival outcomes. The analysis of multivariate Cox showed that TP53I13 might be an independent prognostic marker of glioma. It was also found that increased expression of TP53I13 was significantly correlated with PRS type, status, 1p/19q codeletion status, IDH mutation status, chemotherapy, age, and tumor grade. According to CIBERSORT (Cell-type Identification by Estimating Relative Subsets of RNA Transcript), the expression of TP53I13 correlates with macrophages, neutrophils, and dendritic cells. GSEA shows a close correlation between TP53I13 and p53 signaling pathways, DNA replication, and the pentose phosphate pathway.

Conclusion

Our results reveal a close correlation between TP53I13 and gliomas. Further, TP53I13 expression could affect the survival outcomes in glioma patients. In addition, TP53I13 was an independent marker that was crucial in regulating the infiltration of immune cells into tumors. As a result of these findings, TP53I13 might represent a new biomarker of immune infiltration and prognosis in patients with gliomas.
Chronovaccination: Harnessing circadian rhythms to optimize immunisation strategies
Authors: Otasowie Claire O. , Tanner Rachel , Ray David W. , Austyn Jonathan M. , Coventry Brendon J.
Published: October 2022

Vaccination, as a public health measure, offers effective protection of populations against infectious diseases. Optimising vaccination efficacy, particularly for higher-risk individuals, like the elderly whose immunocompromised state can prevent the development of robust vaccine responses, is vital. It is now clear that 24-hour circadian rhythms, which govern virtually all aspects of physiology, can generate oscillations in immunological responses. Consequently, vaccine efficacy may depend critically on the time of day of administration(s), including for Covid-19, current vaccines, and any future diseases or pandemics. Published clinical vaccine trials exploring diurnal immune variations suggest this approach could represent a powerful adjunct strategy for optimising immunisation, but important questions remain to be addressed. This review explores the latest insights into diurnal immune variation and the outcomes of circadian timing of vaccination or ‘chronovaccination’.
A novel hypoxia- and lactate metabolism-related signature to predict prognosis and immunotherapy responses for breast cancer by integrating machine learning and bioinformatic analyses
Authors: Li Jia , Qiao Hao , Wu Fei , Sun Shiyu , Feng Cong , Li Chaofan , Yan Wanjun , Lv Wei , Wu Huizi , Liu Mengjie , Chen Xi , Liu Xuan , Wang Weiwei , Cai Yifan , Zhang Yu , Zhou Zhangjian , Zhang Yinbin , Zhang Shuqun
Published: October 2022

Background

Breast cancer is the most common cancer worldwide. Hypoxia and lactate metabolism are hallmarks of cancer. This study aimed to construct a novel hypoxia- and lactate metabolism-related gene signature to predict the survival, immune microenvironment, and treatment response of breast cancer patients.

Methods

RNA-seq and clinical data of breast cancer from The Cancer Genome Atlas database and Gene Expression Omnibus were downloaded. Hypoxia- and lactate metabolism-related genes were collected from publicly available data sources. The differentially expressed genes were identified using the “edgeR” R package. Univariate Cox regression, random survival forest (RSF), and stepwise multivariate Cox regression analyses were performed to construct the hypoxia-lactate metabolism-related prognostic model (HLMRPM). Further analyses, including functional enrichment, ESTIMATE, CIBERSORTx, Immune Cell Abundance Identifier (ImmuCellAI), TIDE, immunophenoscore (IPS), pRRophetic, and CellMiner, were performed to analyze immune status and treatment responses.

Results

We identified 181 differentially expressed hypoxia-lactate metabolism-related genes (HLMRGs), 24 of which were valuable prognostic genes. Using RSF and stepwise multivariate Cox regression analysis, five HLMRGs were included to establish the HLMRPM. According to the medium-risk score, patients were divided into high- and low-risk groups. Patients in the high-risk group had a worse prognosis than those in the low-risk group (P < 0.05). A nomogram was further built to predict overall survival (OS). Functional enrichment analyses showed that the low-risk group was enriched with immune-related pathways, such as antigen processing and presentation and cytokine-cytokine receptor interaction, whereas the high-risk group was enriched in mTOR and Wnt signaling pathways. CIBERSORTx and ImmuCellAI showed that the low-risk group had abundant anti-tumor immune cells, whereas in the high-risk group, immunosuppressive cells were dominant. Independent immunotherapy datasets (IMvigor210 and GSE78220), TIDE, IPS and pRRophetic analyses revealed that the low-risk group responded better to common immunotherapy and chemotherapy drugs.

Conclusions

We constructed a novel prognostic signature combining lactate metabolism and hypoxia to predict OS, immune status, and treatment response of patients with breast cancer, providing a viewpoint for individualized treatment.
Mechanisms of unconventional CD8 Tc2 lymphocyte induction in allergic contact dermatitis: Role of H3/H4 histamine receptors
Authors: Alcain Julieta , Infante Cruz Alejandra del Pilar , Barrientos Gabriela , Vanzulli Silvia , Salamone Gabriela , Vermeulen Mónica
Published: October 2022

Histamine (HA) is a potent mediator that plays a central role in inflammation and allergy, acting through four G-protein-coupled receptors (i.e. H1–H4). HA is an accepted promoter of type 2 immunity in CD4+T cells during hypersensitivity. Previously, we demonstrated that HA can promote antigen cross-presentation, inducing the activation of antigen-specific CD8+T cells in an asthmatic murine model. Non-classical CD8+ T-cell profiles, such as Tc2 or Tc17, are associated with allergic disease persistence and chronicity. In this paper, we focus on the role of the H3receptor (H3R) and the H4receptor (H4R) in the development of allergic contact dermatitis. We were able to show that induction of the type 2 profiles associated with interleukin 13 production, both by CD4 and CD8 lymphocytes, depend on the interaction of HA with H3R and H4R. Blocking both receptors using the selective H3/H4receptor antagonist thioperamide or the selective H4R ligand JNJ777120 reduces the inflammatory response, inducing an immunosuppressive profile associated with the increased proportion of FOXp3+regulatory T lymphocytes and CD11b+Gr-1+myeloid suppressor cells. Interestingly, in dendritic cells, only H4R blockade, and not H3R blockade, is capable of modulating most of the inflammatory effects observed in our model.
Simulations of sea fog case impacted by air–sea interaction over South China Sea
Authors: Han Liguo , Zhang Shuqin , Xu Feng , Lü Jingjing , Lu Zebin , Ye Guiling , Chen Siqi , Xu Jianjun , Du Jiaming
Published: October 2022

A sea fog event in the South China Sea was simulated using a coupled ocean–atmosphere model (WRF for the atmosphere and ROMS for the ocean). Offshore and onshore visibility, liquid water content, air temperature, humidity, and wind speed observations and MICAPS data were utilized to validate the model results. The results of the coupled model were also compared with those of the uncoupled atmosphere model. Sea fog duration in the coupled model was closer to offshore and onshore observations, but the uncoupled model emptily forecasted offshore fog, and underreported onshore fog. Air–sea temperature difference played an important role in regulating the formation and dissipation of sea fog. The decrease of sea surface temperature in the coupled model cooled the low-level atmosphere, promoted the condensation of low-level water vapor, and increased the low-level water vapor. The decrease of air–sea temperature difference strengthened the low-level stable stratification, which weakened the horizontal wind speed and favored the formation and development of sea fog. Rising wind speed was the major driver of fog dissipation.
First observations of seasonal bottom water deoxygenation off the Gironde estuary (Bay of Biscay, North East Atlantic)
Authors: Dubosq Nicolas , Schmidt Sabine , Sudre Joël , Rigaud Sylvain , Lamarque Bastien , Danilo Martin , Grémare Antoine , Deflandre Bruno
Published: October 2022

Although not systematically considered as oxygen minimum zones, River-dominated Ocean Margins are sensitive to oxygen depletions. For example, the continental shelf off the Gironde, which flows into the Bay of Biscay, had not yet been studied from this perspective although recent simulations suggested that this area should already have experienced deoxygenations in recent decades. To fill this gap, profiles of temperature, salinity and dissolved oxygen were performed in the water column of the continental shelf off the Gironde during seven cruises distributed over the different seasons between 2016 and 2021. Turbidity, chlorophyll-a and pH were also measured during some of these cruises. In winter, the water column was slightly stratified due to high river flows. Then, a seasonal thermal stratification was present from spring to autumn. Similarly, dissolved oxygen showed a seasonal dynamic with: a well-oxygenated water column in winter, an oxygen oversaturation in the first 20 meters during the spring bloom, and then a progressive oxygen depletion in bottom waters until reaching an oxygen saturation minimum down to 45% in autumn. These deoxygenations are explained by the seasonal stratification that isolates the bottom waters from spring to autumn, and are likely enhanced by the advection of deoxygenated waters from the north of the Bay of Biscay and the settling of the organic matter produced in surface waters. A better understanding of these processes in the context of global warming undoubtedly requires better documentation of dissolved oxygen variability through the implementation of a long-term and continuous in situ monitoring.
An ecosystem-based system of variables to enhance marine species and habitat monitoring and conservation: The Adriatic Natura 2000 case study
Authors: Manea Elisabetta , Bergami Caterina , Pugnetti Alessandra , Gianni Fabrizio , Oggioni Alessandro , Bandelj Vinko , Cataletto Bruno , Pleslić Grgur , Bongiorni Lucia
Published: October 2022

Implementing effective marine monitoring to detect and track ecosystem shifts, biodiversity alteration, and habitat loss is one of the most crucial challenges to meet the objectives set out by the Post-2020 Biodiversity Framework and by the United Nations Sustainable Development Goals. The lack of coordinated and harmonized monitoring frameworks at different spatial scales and their weakness in accounting for ecological processes, due to incomplete sets of monitoring variables, strongly hinder the achievement of conservation objectives. Here, we propose an approach to build a coherent ecosystem-based system of monitoring variables for target marine species and habitats. The approach is designed to integrate the existing monitoring frameworks set up by the Water and the Marine Strategy Framework directives, and the Essential Ocean and Biodiversity Variables, with the aim to contribute to their harmonization and implementation. Furthermore, by embracing a holistic vision, it aims to incorporate ecological processes and socio-ecological aspects, considering the benefits of public engagement through citizen science, and of the ecosystem services approach for policies’ implementation. The study stems from the Ecological Observing System of the Adriatic Sea (ECOAdS), which was developed in the framework of the Interreg Italy-Croatia project ECOSS, using as exemplary monitoring test cases two relevant conservation targets for Natura 2000 sites of the Adriatic Sea, the common bottlenose dolphin and seagrass meadows. We test the potential of this approach in guiding the prioritization of monitoring variables under ecosystem-based criteria, and provide insights into the benefits delivered by an integrated system of observatories’ networks and monitoring frameworks to support marine conservation at both local and regional scales. The proposed approach can be transferred to other contexts and scales to help build a common knowledge and monitoring framework for conservation and management strategies, saving costs by relying on available resources and on consolidated and long-lasting approaches that might converge towards global initiatives.
Advances in coral immunity ‘omics in response to disease outbreaks
Authors: Traylor-Knowles Nikki , Baker Andrew C. , Beavers Kelsey M. , Garg Neha , Guyon Jeffrey R. , Hawthorn Aine , MacKnight Nicholas J. , Medina Mónica , Mydlarz Laura D. , Peters Esther C. , Stewart Julia Marie , Studivan Michael S. , Voss Joshua D.
Published: October 2022

Coral disease has progressively become one of the most pressing issues affecting coral reef survival. In the last 50 years, several reefs throughout the Caribbean have been severely impacted by increased frequency and intensity of disease outbreaks leading to coral death. A recent example of this is stony coral tissue loss disease which has quickly spread throughout the Caribbean, devastating coral reef ecosystems. Emerging from these disease outbreaks has been a coordinated research response that often integrates ‘omics techniques to better understand the coral immune system. ‘Omics techniques encompass a wide range of technologies used to identify large scale gene, DNA, metabolite, and protein expression. In this review, we discuss what is known about coral immunity and coral disease from an ‘omics perspective. We reflect on the development of biomarkers and discuss ways in which coral disease experiments to test immunity can be improved. Lastly, we consider how existing data can be better leveraged to combat future coral disease outbreaks.
A non-traditional crystal-based compound screening method targeting the ATP binding site of Plasmodium falciparum GRP78 for identification of novel nucleoside analogues
Authors: Mrozek Alexander , Antoshchenko Tetyana , Chen Yun , Zepeda-Velázquez Carlos , Smil David , Kumar Nirbhay , Lu Hua , Park Hee-Won
Published: October 2022

Drug resistance to front-line malarial treatments represents an ongoing threat to control malaria, a vector borne infectious disease. The malarial parasite, Plasmodium falciparum has developed genetic variants, conferring resistance to the current standard therapeutic artemisinin and its derivatives commonly referred to as artemisinin-combination therapies (ACTs). Emergence of multi-drug resistance parasite genotypes is a warning of potential treatment failure, reaffirming the urgent and critical need to find and validate alternate drug targets to prevent the spread of disease. An attractive and novel drug target includes glucose-regulated protein 78 kDa (GRP78, or BiP), an essential molecular chaperone protein involved in the unfolded protein response that is upregulated in ACT treated P. falciparum parasites. We have shown that both sequence and structure are closely related to human GRP78 (hGRP78), a chaperone belonging to the HSP70 class of ATPase proteins, which is often upregulated in cellular stress responses and cancer. By screening a library of nucleoside analogues, we identified eight ‘hit’ compounds binding at the active site of the ATP binding domain of P. falciparum GRP78 using a high-throughput ligand soaking screen using x-ray crystallography. These compounds were further evaluated using protein thermal shift assays to assess target binding activity. The nucleoside analogues identified from our screen provide a starting point for the development of more potent and selective antimalarial inhibitors. In addition, we have established a well-defined, high-throughput crystal-based screening approach that can be applied to many crystallizable P. falciparum proteins for generating anti-Plasmodium specific compounds.
Role of mitochondria-associated endoplasmic reticulum membranes in insulin sensitivity, energy metabolism, and contraction of skeletal muscle
Authors: Nieblas Bianca , Pérez-Treviño Perla , García Noemí
Published: October 2022

Skeletal muscle has a critical role in the regulation of the energy balance of the organism, particularly as the principal tissue responsible for insulin-stimulated glucose disposal and as the major site of peripheral insulin resistance (IR), which has been related to accumulation of lipid intermediates, reduced oxidative capacity of mitochondria and endoplasmic reticulum (ER) stress. These organelles form contact sites, known as mitochondria-associated ER membranes (MAMs). This interconnection seems to be involved in various cellular processes, including Ca2+ transport and energy metabolism; therefore, MAMs could play an important role in maintaining cellular homeostasis. Evidence suggests that alterations in MAMs may contribute to IR. However, the evidence does not refer to a specific subcellular location, which is of interest due to the fact that skeletal muscle is constituted by oxidative and glycolytic fibers as well as different mitochondrial populations that appear to respond differently to stimuli and pathological conditions. In this review, we show the available evidence of possible differential responses in the formation of MAMs in skeletal muscle as well as its role in insulin signaling and the beneficial effect it could have in the regulation of energetic metabolism and muscular contraction.
Attenuation of neural responses in subthalamic nucleus during internally guided voluntary movements in Parkinson’s disease
Authors: Filyushkina Veronika , Belova Elena , Usova Svetlana , Tomskiy Alexey , Sedov Alexey
Published: October 2022

The proposed models of segregated functional loops describe the organization of motor control over externally triggered (ET) and internally guided (IG) movements. The dopamine deficiency in Parkinson’s disease (PD) is considered to cause a disturbance in the functional loop regulating IG movements. At the same time, the neural mechanisms of movement performance and the role of basal ganglia in motor control remain unclear.The aim of this study was to compare neuronal responses in the subthalamic nucleus (STN) during ET and IG movements in PD. We found and analyzed 26 sensitive neurons in 12 PD patients who underwent surgery for implantation of electrodes for deep brain stimulation. We also analyzed the local field potentials (LFP) of the STN of six patients during the postoperative period. Patients were asked to perform voluntary movements (clenching and unclenching the fist) evoked by verbal command (ET) or self-initiated (IG). We showed heterogeneity of neuronal responses and did not find sensitive neurons associated with only one type of movement. Most cells were characterized by leading responses, indicating that the STN has an important role in movement initiation. At the same time, we found attenuation of motor responses during IG movement vs. stable responses during ET movements. LFP analysis also showed attenuation of beta desynchronization during multiple IG movements.We propose that stable neuronal response to ET movements is associated with the reboot of the motor program for each movement, while attenuation of responses to IG movement is associated with single motor program launching for multiple movements.