bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial Protein kinase D1 is a major regulator of post-traumatic hyperinflammation
Authors: Schönfelder Jonathan , Seibold Tanja , Morawe Mareen , Sroka Robert , Schneider Nora , Cai Jierui , Golomejic Josip , Schütte Lena , Armacki Milena , Huber-Lang Markus , Kalbitz Miriam , Seufferlein Thomas , Eiseler Tim 
Published: March 2023

Trauma is a major cause of death worldwide. The post-traumatic immune response culminates in the release of pro-inflammatory mediators, translating in the infiltration of neutrophils (PMNs) at injury sites. The extent of this inflammation is determined by multiple factors, such as PMN adhesion to the endothelium, transendothelial migration, endothelial barrier integrity as well as PMN swarming, mass infiltration and activation. This process is initiated by secondary lipid mediators, such as leukotriene B4 (LTB4). We here provide evidence that Protein kinase D1 (PRKD1) in endothelial cells is implicated in all these processes. Endothelial PRKD1 is activated by pro-inflammatory stimuli and amplifies PMN-mediated inflammation by upregulation of cytokine and chemokines as well as adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin. This induces enhanced PMN adhesion and trans-migration. PRKD1 activation also destabilizes endothelial VE-cadherin adhesion complexes and thus the endothelial barrier, fostering PMN infiltration. We even describe a yet unrecognized PRKD1-dependant mechanism to induce biosynthesis of the PMN-swarming mediator LTB4 directed via intercellular communication through small extracellular vesicles (sEVs) and enhanced CXCL8 secretion from activated endothelial cells. These endothelial sEVs transfer the LTB4 biosynthesis enzyme LTA4 hydrolase (LTA4H) to prime PMNs, while initiating biosynthesis also requires additional signals, like CXCL8. We further demonstrate the respective LTA4H-positive sEVs in the serum of polytrauma patients, peaking 12 h post injury. Therefore, PRKD1 is a key regulator in the coordinated communication of the endothelium with PMNs and a vital signaling node during post-traumatic inflammation.
Integrated analysis from multicentre studies identities m7G-related lncRNA-derived molecular subtypes and risk stratification systems for gastric cancer
Authors: Ma Mingwei , Li Jie , Zeng Ziyang , Zheng Zicheng , Kang Weiming 
Published: March 2023

IntroductionGastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the lack of effective chemotherapy methods for advanced gastric cancer and poor prognosis, the emergence of immunotherapy has brought new hope to gastric cancer. Further research is needed to improve the response rate to immunotherapy and identify the populations with potential benefits of immunotherapy. It is unclear whether m7G-related lncRNAs influence tumour immunity and the prognosis of immunotherapy.MethodsThis study evaluated 29 types of immune cells and immune functions in gastric cancer patients, and m7G-related lncRNAs and their molecular subtypes were identified. In addition, we also studied the biological function characteristics of m7G-related lncRNA molecular subtypes. Finally, the patient's risk score was calculated based on m7G-related lncRNAs, and a nomogram of staging and risk groups was established to predict the prognosis. For experimental verification, RT–qPCR were preformed from the native cohort.ResultsAfter identifying m7G-related lncRNAs and their molecular subtypes, we found three molecular subtypes, the B subtype had the highest level of infiltration, and the B subtype may benefit more from immunotherapy. We divided GC patients into two regulator subtypes based on biological function. The two subtypes have significant immunological differences and can be used to judge ICI treatment. We established a risk score formula based on five lncRNAs, including LINC00924, LINC00944, LINC00865, LINC00702, and ZFAS1. Patients with poor prognoses were closely related to patients in the high-risk group. After comprehensive analysis of different risk groups, the efficacy of the high-risk group on bleomycin, cisplatin, docetaxel, doxorubicin and etoposide was better than that of the low-risk group, suggesting that risk subgroups based on risk scores play a guiding role in chemotherapy and that the high-risk group may benefit more from immunotherapy. RT–qPCR results showed that LINC00924, LINC00944, and LINC00865 were highly expressed in tumour tissues, while LINC00702 and ZFAS1 were expressed at low levels in tumour tissues.DiscussionIn conclusion, we were the first to discover that m7G-related lncRNAs play a vital role in the tumour immune microenvironment of gastric cancer, and a risk prediction model was established to identify patients with potential benefits from immunotherapy and predict the prognosis of GC patients.
Skeletal myotube-derived extracellular vesicles enhance itaconate production and attenuate inflammatory responses of macrophages
Authors: Yamaguchi Atomu , Maeshige Noriaki , Yan Jiawei , Ma Xiaoqi , Uemura Mikiko , Matsuda Mami , Nishimura Yuya , Hasunuma Tomohisa , Kondo Hiroyo , Fujino Hidemi , Yuan Zhi-Min 
Published: March 2023

IntroductionMacrophages play an important role in the innate immunity. While macrophage inflammation is necessary for biological defense, it must be appropriately controlled. Extracellular vesicles (EVs) are small vesicles released from all types of cells and play a central role in intercellular communication. Skeletal muscle has been suggested to release anti-inflammatory factors, but the effect of myotube-derived EVs on macrophages is unknown. As an anti-inflammatory mechanism of macrophages, the immune responsive gene 1 (IRG1)-itaconate pathway is essential. In this study, we show that skeletal muscle-derived EVs suppress macrophage inflammatory responses, upregulating the IRG1-itaconate pathway.MethodsC2C12 myoblasts were differentiated into myotubes and EVs were extracted by ultracentrifugation. Skeletal myotube-derived EVs were administered to mouse bone marrow-derived macrophages, then lipopolysaccharide (LPS) stimulation was performed and inflammatory cytokine expression was measured by RT-qPCR. Metabolite abundance in macrophages after addition of EVs was measured by CE/MS, and IRG1 expression was measured by RT-PCR. Furthermore, RNA-seq analysis was performed on macrophages after EV treatment.ResultsEVs attenuated the expression of LPS-induced pro-inflammatory factors in macrophages. Itaconate abundance and IRG1 expression were significantly increased in the EV-treated group. RNA-seq analysis revealed activation of the PI3K-Akt and JAK-STAT pathways in macrophages after EV treatment. The most abundant miRNA in myotube EVs was miR-206-3p, followed by miR-378a-3p, miR-30d-5p, and miR-21a-5p.DiscussionSkeletal myotube EVs are supposed to increase the production of itaconate via upregulation of IRG1 expression and exhibited an anti-inflammatory effect in macrophages. This anti-inflammatory effect was suggested to involve the PI3K-Akt and JAK-STAT pathways. The miRNA profiles within EVs implied that miR-206-3p, miR-378a-3p, miR-30d-5p, and miR-21a-5p may be responsible for the anti-inflammatory effects of the EVs. In summary, in this study we showed that myotube-derived EVs prevent macrophage inflammatory responses by activating the IRG1-itaconate pathway.
CAR-iNKT cells targeting clonal TCRVβ chains as a precise strategy to treat T cell lymphoma
Authors: Rowan Aileen G. , Ponnusamy Kanagaraju , Ren Hongwei , Taylor Graham P. , Cook Lucy B. M. , Karadimitris Anastasios 
Published: March 2023

IntroductionMost T cell receptor (TCR)Vβ chain-expressing T cell lymphomas (TCL) including those caused by Human T cell leukaemia virus type-1 (HTLV-1) have poor prognosis. We hypothesised that chimeric antigen receptor (CAR)-mediated targeting of the clonal, lymphoma-associated TCRβ chains would comprise an effective cell therapy for TCL that would minimally impact the physiological TCR repertoire.MethodsAs proof of concept, we generated CAR constructs to target four TCRVβ subunits. Efficacy of the CAR constructs was tested using conventional T cells as effectors (CAR-T). Since invariant NKT (iNKT) cell do not incite acute graft-versus-host disease and are suitable for ‘off-the-shelf’ immunotherapy, we generated anti-TCRVβ CAR-iNKT cells.ResultsWe show that anti-TCRVβ CAR-T cells selectively kill their cognate tumour targets while leaving &gt;90% of the physiological TCR repertoire intact. CAR-iNKT cells inhibited the growth of TCL in vivo, and were also selectively active against malignant cells from Adult T cell leukaemia/lymphoma patients without activating expression of HTLV-1.DiscussionThus we provide proof-of-concept for effective and selective anti-TCRVβ CAR-T and -iNKT cell-based therapy of TCL with the latter providing the option for ‘off-the-shelf’ immunotherapy.
Systematic integration of machine learning algorithms to develop immune escape-related signatures to improve clinical outcomes in lung adenocarcinoma patients
Authors: Wang Ting , Huang Lin , Zhou Jie , Li Lu 
Published: March 2023

BackgroundImmune escape has recently emerged as one of the barriers to the efficacy of immunotherapy in lung adenocarcinoma (LUAD). However, the clinical significance and function of immune escape markers in LUAD have largely not been clarified.MethodsIn this study, we constructed a stable and accurate immune escape score (IERS) by systematically integrating 10 machine learning algorithms. We further investigated the clinical significance, functional status, TME interactions, and genomic alterations of different IERS subtypes to explore potential mechanisms. In addition, we validated the most important variable in the model through cellular experiments.ResultsThe IERS is an independent risk factor for overall survival, superior to traditional clinical variables and published molecular signatures. IERS-based risk stratification can be well applied to LUAD patients. In addition, high IERS is associated with stronger tumor proliferation and immunosuppression. Low IERS exhibited abundant lymphocyte infiltration and active immune activity. Finally, high IERS is more sensitive to first-line chemotherapy for LUAD, while low IERS is more sensitive to immunotherapy.ConclusionIn conclusion, IERS may serve as a promising clinical tool to improve risk stratification and clinical management of individual LUAD patients and may enhance the understanding of immune escape.
Blood count derangements after sepsis and association with post-hospital outcomes
Authors: Denstaedt Scott J. , Cano Jennifer , Wang Xiao Qing , Donnelly John P. , Seelye Sarah , Prescott Hallie C. 
Published: March 2023

RationalePredicting long-term outcomes in sepsis survivors remains a difficult task. Persistent inflammation post-sepsis is associated with increased risk for rehospitalization and death. As surrogate markers of inflammation, complete blood count parameters measured at hospital discharge may have prognostic value for sepsis survivors.ObjectiveTo determine the incremental value of complete blood count parameters over clinical characteristics for predicting 90-day outcomes in sepsis survivors.MethodsElectronic health record data was used to identify sepsis hospitalizations at United States Veterans Affairs hospitals with live discharge and relevant laboratory data (2013 to 2018). We measured the association of eight complete blood count parameters with 90-day outcomes (mortality, rehospitalization, cause-specific rehospitalizations) using multivariable logistic regression models.Measurements and main resultsWe identified 155,988 eligible hospitalizations for sepsis. Anemia (93.6%, N=142,162) and lymphopenia (28.1%, N=29,365) were the most common blood count abnormalities at discharge. In multivariable models, all parameters were associated with the primary outcome of 90-day mortality or rehospitalization and improved model discrimination above clinical characteristics alone (likelihood ratio test, p&lt;0.02 for all). A model including all eight parameters significantly improved discrimination (AUROC, 0.6929 v. 0.6756) and reduced calibration error for the primary outcome. Hemoglobin had the greatest prognostic separation with a 1.5 fold increased incidence of the primary outcome in the lowest quintile (7.2-8.9 g/dL) versus highest quintile (12.70-15.80 g/dL). Hemoglobin and neutrophil lymphocyte ratio provided the most added value in predicting the primary outcome and 90-day mortality alone, respectively. Absolute lymphocyte count added little value in predicting 90-day outcomes.ConclusionsThe incorporation of discharge complete blood count parameters into prognostic scoring systems could improve prediction of 90-day outcomes. Hemoglobin had the greatest prognostic value for the primary composite outcome of 90-day rehospitalization or mortality. Absolute lymphocyte count provided little added value in multivariable model comparisons, including for infection- or sepsis-related rehospitalization.
Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling
Authors: Waad Sadiq Zeinab , Brioli Annamaria , Al-Abdulla Ruba , Çetin Gonca , Schütt Jacqueline , Murua Escobar Hugo , Krüger Elke , Ebstein Frédéric 
Published: March 2023

IntroductionProteasome inhibition is first line therapy in multiple myeloma (MM). The immunological potential of cell death triggered by defects of the ubiquitin-proteasome system (UPS) and subsequent perturbations of protein homeostasis is, however, less well defined.MethodsIn this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD).ResultsOur data show that while BTZ treatment triggers sterile type I interferon (IFN) responses, exposure of the cells to ONX0914 or RA190 was mostly immunologically silent. Interestingly, inhibition of protein de-ubiquitination by PR619 was associated with the acquisition of a strong type I IFN gene signature which relied on key components of the unfolded protein and integrated stress responses including inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR) and general control nonderepressible 2 (GCN2). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms.ConclusionAltogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.
The effectiveness of vaginal progesterone in reducing preterm birth in high-risk patients diagnosed with short cervical length after 24 weeks: A retrospective cohort study
Authors: Luxenbourg Danielle , Porat Shay , Romero Roberto , Raif Nesher Dror , Haj Yahya Rani , Sompolinsky Yishai , Hochler Hila , Ezra Yossef , Kabiri Doron 
Published: March 2023

ObjectiveTo assess the impact of progesterone treatment on maternal and neonatal outcomes in women with a history of preterm birth and short cervical length diagnosed after 24 weeks of gestation.MethodsA retrospective cohort study included women with a history of preterm birth and a transvaginal sonographic cervical length measurement of ≤ 25 mm, diagnosed between 24+0 and 33+6 weeks of gestation. Exclusion criteria included prior progesterone treatment, cervical cerclage, or pessary. The study population was divided into the progesterone treatment group and the non-treatment group.ResultsThe study included 104 women, with 46.2% (48/104) receiving progesterone treatment and 53.8% (56/104) not receiving treatment. The rate of spontaneous preterm birth before 37 weeks of gestation was 43% (24/56) in the non-treatment group and 31% (15/48) in the progesterone treatment group (P = 0.14); the rate of spontaneous preterm birth before 34 weeks was 7% (4/56) in the non-treatment group and 0% (0/48) in the progesterone treatment group (P = 0.05). Progesterone treatment was associated with a significant decrease in neonatal intensive care unit admissions (OR 0.20, 95% CI 0.05–0.74) and in the neonatal hospitalization period (mean difference in days 2.43, 95% CI 0.44–4.42). The risk of recurrent spontaneous preterm birth was highest (71%) among women with two or more previous preterm deliveries who did not receive progesterone treatment, and lowest (24%) among women with one previous preterm delivery who received progesterone treatment.ConclusionProgesterone treatment was associated with a reduction in rates of spontaneous preterm birth before 34 weeks of gestation, neonatal intensive care unit admission, and neonatal length of stay in high-risk patients, even when initiated after 24 weeks of gestation.
Flexibility in the ambrosia symbiosis of Xyleborus bispinatus
Authors: Menocal Octavio , Cruz Luisa F. , Kendra Paul E. , Berto Marielle , Carrillo Daniel 
Published: March 2023

IntroductionAmbrosia beetles maintain strict associations with specific lineages of fungi. However, anthropogenic introductions of ambrosia beetles into new ecosystems can result in the lateral transfer of their symbionts to other ambrosia beetles. The ability of a Florida endemic ambrosia beetle,Xyleborus bispinatus, to feed and establish persistent associations with two of its known symbionts (Raffaelea subfuscaandRaffaelea arxii) and two other fungi (Harringtonia lauricolaandFusariumsp. nov.), which are primary symbionts of invasive ambrosia beetles, was investigated.MethodsThe stability of these mutualisms and their effect on the beetle’s fitness were monitored over five consecutive generations. Surface-disinfested pupae with non-developed mycangia were reared separately on one of the four fungal symbionts. Non-treated beetles (i.e., lab colony) with previously colonized mycangia were used as a control group.ResultsXyleborus bispinatuscould exchange its fungal symbionts, survive, and reproduce on different fungal diets, including known fungal associates and phylogenetically distant fungi, which are plant pathogens and primary symbionts of other invasive ambrosia beetles. These changes in fungal diets resulted in persistent mutualisms, and some symbionts even increased the beetle’s reproduction. Females that developed onFusariumsp. nov. had a significantly greater number of female offspring than non-treated beetles. Females that fed solely onHarringtoniaorRaffaeleasymbionts produced fewer female offspring.DiscussionEven though some ambrosia beetles likeX. bispinatuscan partner with different ambrosia fungi, their symbiosis under natural conditions is modulated by their mycangium and possibly other environmental factors. However, exposure to symbionts of invasive beetles can result in stable partnerships with these fungi and affect the population dynamics of ambrosia beetles and their symbionts.
Enhancing response of a protein conformational switch by using two disordered ligand binding domains
Authors: Sekhon Harsimranjit , Ha Jeung-Hoi , Loh Stewart N. 
Published: March 2023

Introduction: Protein conformational switches are often constructed by fusing an input domain, which recognizes a target ligand, to an output domain that establishes a biological response. Prior designs have employed binding-induced folding of the input domain to drive a conformational change in the output domain. Adding a second input domain can in principle harvest additional binding energy for performing useful work. It is not obvious, however, how to fuse two binding domains to a single output domain such that folding of both binding domains combine to effect conformational change in the output domain.Methods: Here, we converted the ribonuclease barnase (Bn) to a switchable enzyme by duplicating a C-terminal portion of its sequence and appending it to its N-terminus, thereby establishing a native fold (OFF state) and a circularly permuted fold (ON state) that competed for the shared core in a mutually exclusive fashion. Two copies of FK506 binding protein (FKBP), both made unstable by the V24A mutation and one that had been circularly permuted, were inserted into the engineered barnase at the junctions between the shared and duplicated sequences.Results: Rapamycin-induced folding of FK506 binding protein stretched and unfolded the native fold of barnase via the mutually exclusive folding effect, and rapamycin-induced folding of permuted FK506 binding protein stabilized the permuted fold of barnase by the loop-closure entropy principle. These folding events complemented each other to turn on RNase function. The cytotoxic switching mechanism was validated in yeast and human cells, and in vitro with purified protein.Discussion: Thermodynamic modeling and experimental results revealed that the dual action of loop-closure entropy and mutually exclusive folding is analogous to an engine transmission in which loop-closure entropy acts as the low gear, providing efficient switching at low ligand concentrations, and mutually exclusive folding acts as the high gear to allow the switch to reach its maximum response at high ligand concentrations.
Clinical outcomes of increased focal amyloid uptake in individuals with subthreshold global amyloid levels
Authors: Kim Jaeho , Choe Yeong Sim , Park Yuhyun , Kim Yeshin , Kim Jun Pyo , Jang Hyemin , Kim Hee Jin , Na Duk L. , Cho Soo-Jin , Moon Seung Hwan , Seo Sang Won 
Published: March 2023

BackgroundAlthough the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased β-amyloid (Aβ) uptake and global Aβ status.MethodsWe recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach.ResultsA total of 62 (6.4%) subjects showed increased focal Aβ uptake with subthreshold global Aβ status [global (−) and focal (+) Aβ group, G(−)F(+) group]. The G(−)F(+) group showed worse performance in memory impairment (p &lt; 0.001), global cognition (p = 0.009), greater hippocampal atrophy (p = 0.045), compared to those in the G(−)F(−). Participants with widespread Aβ involvement in the whole region [G(+)] showed worse neuropsychological (p &lt; 0.001) and neuroimaging features (p &lt; 0.001) than those with focal Aβ involvement G(−)F(+).ConclusionOur findings suggest that individuals show distinctive clinical outcomes according to focally increased Aβ uptake and global Aβ status. Thus, researchers and clinicians should pay more attention to focal increased Aβ uptake in addition to global Aβ status.