bluuebunny/crossref_metadata_2025 huggingface dataset:
How supervisors provide and students react to EAL thesis supervision: Voices from Sweden and Indonesia
Authors: Nangimah Musrifatun , Walldén Robert
Published: March 2023

Introduction

Thesis supervision is a critical part of students’ academic literacy development. Previous research has shown different dimensions of this development with limited attention to cross-cultural aspects. In particular, there has been little research on how students and supervisors negotiate supervision practices in non-anglophone contexts. This study aimed to explore students’ and supervisors’ reported priorities and experiences regarding the provision and reception of feedback in English as an Additional Language thesis supervision.

Method

We conducted a qualitative case study to illuminate supervisor’s and students’ experiences of supervision in Sweden and Indonesia. It involved 39 participants (14 supervisors and 25 students) from one Swedish and three Indonesian universities. One-on-one semi-structured interviews were conducted and analyzed thematically using Biesta’s functions of education, Habermas’ communicative action theory, and perspectives on academic literacy.

Findings

Firstly, we found that Swedish and Indonesian supervisors had different feedback provision priorities. Swedish supervisors described prioritizing content-focused feedback to facilitate students’ socialization into academic writing. Conversely, most Indonesian supervisors expressed balancing content- and form-focused feedback with a greater emphasis on qualifying as English teachers. Despite these differences, supervisors in both contexts tended to isolate academic language use from discipline-specific values and practices. Secondly, students in both contexts largely expressed an instrumental orientation to achieving their goals and were frustrated by supervisors phrasing feedback as questions. Many students expressed unfamiliarity with necessary methodologies and theoretical frameworks, which made supervisors’ feedback difficult to decode.

Discussion

Since only a few of the students viewed the feedback as a support for their process of learning, this study calls for a clear communication about the academic socialization intention through supervision. However, academic socialization cannot solely be the responsibility of supervisors but must be embedded in the curriculum courses.
Associations of serum amino acids related to urea cycle with risk of chronic kidney disease in Chinese with type 2 diabetes
Authors: Zhang Wei , Zheng Jun , Zhang Jikun , Li Ninghua , Yang Xilin , Fang Zhong-Ze , Zhang Qiang
Published: March 2023

Objective

Serum levels of amino acids related to urea cycle are associated with risk of type 2 diabetes mellitus (T2DM). Our study aimed to explore whether serum levels of amino acids related to urea cycle, i.e., arginine, citrulline, and ornithine, are also associated with increased risk of chronic kidney disease (CKD) in T2DM.

Methods

We extracted medical records of 1032 consecutive patients with T2DM from the Electronic Administrative System of Liaoning Medical University First Affiliated Hospital (LMUFAH) system from May 2015 to August 2016. Of them, 855 patients with completed data available were used in the analysis. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Serum amino acids were measured by mass spectrometry (MS) technology. Binary logistic regression was performed to obtain odds ratios (ORs) and their 95% confidence intervals (CIs).

Results

52.3% of the 855 T2DM patients were male, and 143 had CKD. In univariable analysis, high serum citrulline, high ratio of arginine to ornithine, and low ratio of ornithine to citrulline were associated with markedly increased risk of CKD (OR of top vs. bottom tertile: 2.87, 95%CI, 1.79-4.62 & 1.98, 95%CI,1.25-3.14 & 2.56, 95%CI, 1.61-4.07, respectively). In multivariable analysis, the ORs of citrulline and ornithine/citrulline ratio for CKD remained significant (OR of top vs. bottom tertile: 2.22, 95%CI, 1.29-3.82 & 2.24, 1.29-3.87, respectively).

Conclusions

In Chinese patients with T2DM, high citrulline and low ornithine/citrulline ratio were associated with increased risk of CKD.
Subcutaneous transplantation of human embryonic stem cells-derived pituitary organoids
Authors: Sasaki Hiroo , Suga Hidetaka , Takeuchi Kazuhito , Nagata Yuichi , Harada Hideyuki , Kondo Tatsuma , Ito Eiji , Maeda Sachi , Sakakibara Mayu , Soen Mika , Miwata Tsutomu , Asano Tomoyoshi , Ozaki Hajime , Taga Shiori , Kuwahara Atsushi , Nakano Tokushige , Arima Hiroshi , Saito Ryuta
Published: March 2023

Introduction

The pituitary gland, regulating various hormones, is central in the endocrine system. As spontaneous recovery from hypopituitarism is rare, and exogenous-hormone substitution is clumsy, pituitary replacement via regenerative medicine, using pluripotent stem cells, is desirable. We have developed a differentiation method that in mice yields pituitary organoids (POs) derived from human embryonic stem cells (hESC). Efficacy of these POs, transplanted subcutaneously into hypopituitary mice, in reversing hypopituitarism was studied.

Methods

hESC-derived POs were transplanted into inguinal subcutaneous white adipose tissue (ISWAT) and beneath dorsal skin, a relatively avascular region (AR), of hypophysectomized severe combined immunodeficient (SCID) mice. Pituitary function was evaluated thereafter for ¾ 6mo, assaying basal plasma ACTH and ACTH response to corticotropin-releasing hormone (CRH) stimulation. Histopathologic examination of organoids 150d after transplantation assessed engraftment. Some mice received an inhibitor of vascular endothelial growth factor (VEGF) to permit assessment of how angiogenesis contributed to subcutaneous engraftment.

Results

During follow-up, both basal and CRH-stimulated plasma ACTH levels were significantly higher in the ISWAT group (p < 0.001 – 0.05 and 0.001 – 0.005, respectively) than in a sham-operated group. ACTH secretion also was higher in the ISWAT group than in the AR group. Histopathologic study found ACTH-producing human pituitary-cell clusters in both groups of allografts, which had acquired a microvasculature. POs qPCR showed expression of angiogenetic factors. Plasma ACTH levels decreased with VEGF-inhibitor administration.

Conclusions

Subcutaneous transplantation of hESC-derived POs into hypopituitary SCID mice efficaciously renders recipients ACTH-sufficient.
Meteorin-like levels are associated with active brown adipose tissue in early infancy
Authors: Garcia-Beltran Cristina , Navarro-Gascon Artur , López-Bermejo Abel , Quesada-López Tania , de Zegher Francis , Ibáñez Lourdes , Villarroya Francesc
Published: March 2023

Introduction

Meteorin-like (METRNL) is a hormonal factor released by several tissues, including thermogenically active brown and beige adipose tissues. It exerts multiple beneficial effects on metabolic and cardiovascular systems in experimental models. However, the potential role of METRNL as brown adipokine in humans has not been investigated previously, particularly in relation to the metabolic adaptations taking place in early life, when brown adipose tissue (BAT) is particularly abundant.

Methods and materials

METRNL levels, as well as body composition (DXA) and circulating endocrine-metabolic variables, were assessed longitudinally in a cohort of infants at birth, and at ages 4 and 12 months. BAT activity was measured by infrared thermography at age 12 months. METRNL levels were also determined cross-sectionally in adults; METRNL gene expression (qRT-PCR) was assessed in BAT and liver samples from neonates, and in adipose tissue and liver samples form adults. Simpson-Golabi-Behmel Syndrome (SGBS) adipose cells were thermogenically activated using cAMP, and METRNL gene expression and METRNL protein released were analysed.

Results

Serum METRNL levels were high at birth and declined across the first year of life albeit remaining higher than in adulthood. At age 4 and 12 months, METRNL levels correlated positively with circulating C-X-C motif chemokine ligand 14 (CXCL14), a chemokine released by thermogenically active BAT, but not with parameters of adiposity or metabolic status. METRNL levels also correlated positively with infrared thermography-estimated posterior-cervical BAT activity in girls aged 12 months. Gene expression analysis indicated high levels of METRNL mRNA in neonatal BAT. Thermogenic stimulus of brown/beige adipocytes led to a significant increase of METRNL gene expression and METRN protein release to the cell culture medium.

Conclusion

Circulating METRNL levels are high in the first year of life and correlate with indices of BAT activity and with levels of an established brown adipokine such as CXCL14. These data, in addition with the high expression of METRNL in neonatal BAT and in thermogenically-stimulated brown/beige adipocytes, suggest that METRNL is actively secreted by BAT and may be a circulating biomarker of BAT activity in early life.
Consensus control for distributed power tracking by device-level digital twin agents
Authors: Wang Yanan , Guo Zhimin , Pang Yuhang , Gao Kaiqiang , Zhao Jian
Published: March 2023

Abstract: The development of electronics and software has resulted in the ability of twin agents to act as digital counterparts for the optimization, control, and monitoring of real power grids. When increasing regulation resources are connected to the power grid, is challenging for independent system operators to use a centralized controller to achieve power tracking and balance. Therefore, the present study applied device-level-based digital twins to monitor physical signals for computer-aided design for power tracking. Moreover, a consensus control-based distributed power tracking system is proposed for the physical-model simulation of the power grid. A communication network was also designed for realistic signal exchange. The combination of the proposed distributed power tracking method and communication network can accelerate computational efficiency and protect the privacy of the regulation resources. Finally, the performance of the proposed distributed power tracking method is validated in a simulation system with 10 regulation resources.
Assessment of groundwater quality in a highly urbanized coastal city using water quality index model and bayesian model averaging
Authors: Wang Xin , Tian Yong , Liu Chongxuan
Published: March 2023

Prediction and assessment of water quality are important aspects of water resource management. To date, several water quality index (WQI) models have been developed and improved for effective water quality assessment and management. However, the application of these models is limited because of their inherent uncertainty. To improve the reliability of the WQI model and quantify its uncertainty, we developed a WQI-Bayesian model averaging (BMA) model based on the BMA method to merge different WQI models for comprehensive groundwater quality assessment. This model comprised two stages: i) WQI model stage, four traditional WQI models were used to calculate WQI values, and ii) BMA model stage for integrating the results from multiple WQI models to determine the final groundwater quality status. In this study, a machine learning method, namely, the extreme gradient boosting algorithm was also adopted to systematically assign weights to the sub-index functions and calculate the aggregation function. It can avoid time consumption and computational effort required to find the most effective parameters. The results showed that the groundwater quality status in the study area was mainly maintained in the fair and good categories. The WQI values ranged from 35.01 to 98.45 based on the BMA prediction in the study area. Temporally, the groundwater quality category in the study area exhibited seasonal fluctuations from 2015 to 2020, with the highest percentage in the fair category and lowest percentage in the marginal category. Spatially, most sites fell under the fair-to-good category, with a few scattered areas falling under the marginal category, indicating that groundwater quality of the study area has been well maintained. The WQI-BMA model developed in this study is relatively easy to implement and interpret, which has significant implications for regional groundwater management.
Restoration of bighorn sheep: History, successes, and remaining conservation issues
Authors: Whiting Jericho C. , Bleich Vernon C. , Bowyer R. Terry , Epps Clinton W.
Published: March 2023

Mammals are imperiled worldwide, primarily from habitat loss or modification, and exhibit downward trends in their populations and distributions. Likewise, large-bodied herbivores have undergone a collapse in numbers and are at the highest extinction risk of all mammals. Bighorn sheep (Ovis canadensis) are among those large-bodied herbivores that possess a slow-paced life history, suffer from debilitating diseases, and have experienced range contractions across their historical distribution since the late 1800s. Translocations and reintroductions of these mountain ungulates are key aspects of restoration and often are used to re-establish populations in historical habitat or to supplement declining herds. Millions of US dollars and much effort by state and federal natural resource agencies, as well as public and private organizations, have been expended to restore bighorn sheep. Despite those efforts, translocated populations of bighorn sheep have not always been successful. We assessed restoration of bighorn sheep to provide insights in the context of conservation of populations of bighorn sheep, because this management tool is a frequently used to re-establish populations. We focused briefly on past efforts to restore bighorn sheep populations and followed with updates on the value of habitat enhancements, genetic issues, the importance of ecotypic or phenotypic adaptations when restoring populations, predation, and disease transmission. We also raised issues and posed questions that have potential to affect future decisions regarding the restoration of bighorn sheep. This information will help conservationists improve the success of conserving these iconic large mammals.
Quantitative assessment of the degree of harmony between humanity and nature for national parks in China: A case study of the Three-River-Source National Park
Authors: Guo Yanming , Liu Xiaojie , Liu Xiaohuang , Zhang Jiahong , Zhang Haiyan , Fan Jiangwen , Khan Nawab , Ma Jiliang
Published: March 2023

Introduction

National parks, defined as the mainstay of the nature reserve system in China, pursue to achieve scientific protection and rational utilization of natural resources. However, eco-environmental and socioeconomic benefits are rarely considered together. Hereby, how to quantitatively express the relationship between humanity and nature in national parks needs further exploration. We selected the Three-River-Source National Park (TRSNP), China's largest national park by area and the world's highest altitude national park, as a representative case to construct an evaluation model for the degree of harmony between humanity and the nature of the national alpine ecological park.

Methods

Based on the field survey data, the meteorological data, the remote sensing data, and the socioeconomic data, the study used the model inversion and the spatial analysis methods to quantitatively evaluate the degree of harmony consisting of 12 indexes from a fresh perspective of a combination of the ecological environment and social economy. Considering the TRSNP establishment in 2016 as the time node, we assessed and compared the degree of harmony between humanity and nature during the dynamic baseline period (2011–2015) and the evaluation period (2016–2020).

Results

The results show that the degree of harmony between humanity and nature showed a gradual upward trend from the northwest to the southeast in the TRSNP. Compared with the dynamic baseline period, the eco-environmental and socioeconomic levels of the evaluation period were increased by 34.48 and 5.46%, respectively. Overall, the degree of harmony between humanity and nature visibly increased by 23.38%.

Discussion

This study has developed a novel comprehensive method for evaluating national parks at the regional scale for the win-win goal of both protection and development, and it provides a theoretical basis for effective planning and management policies for national parks.
Climate change and maple syrup: Producer observations, perceptions, knowledge, and adaptation strategies
Authors: Ahmed Selena , Lutz David , Rapp Joshua , Huish Ryan , Dufour Boris , Brunelle Autumn , Morelli Toni Lyn , Stinson Kristina , Warne Teresa
Published: March 2023

Introduction

Climate change is impacting forest-based agricultural systems with implications for producer decision-making and livelihoods. This article presents a case study on the observations, perceptions, knowledge, and adaptation strategies of maple syrup producers in the United States to climate change.

Methods

We carried out two semi-structured surveys with maple producers on: (1) climate change and its impacts on the maple system (n = 106 participants); and (2) responses to climate adaptation scenarios (n = 98 participants). Additionally, we carried out two focus groups and key informant interviews (n = 70+) to understand barriers and opportunities for climate adaptation. One of these focus groups and follow up key informant interviews was with tribally affiliated community members with the intention to acknowledge Indigenous Peoples’ voices, history, and relationships to the land.

Results

Findings highlight that most of the surveyed producers (89%) have experienced the negative impacts of climate on maple syrup production. While 40% of participants feel concerned regarding the future of the maple system, 39% feel hopeful, with significant differences based on the age of the surveyed producers. The majority of producers have adapted their harvesting practices to climate effects. Producers shared knowledge of multiple adaptation strategies in response to climate scenarios comprised of: (1) stand management practices such as diversification of sap species tapped; (2) harvesting practices such as changing the type and number of taps; (3) sap processing practices focused on the integration of technology such as the use of an evaporator and reverse osmosis; and (4) marketing practices such as innovation of products and marketing different maple syrup characteristics. Responses shared by tribally affiliated producers highlight knowledge of multiple adaptation strategies that focus on long-term ecological management of forests rather than technological solutions.

Discussion

Overall, findings emphasize the importance of cooperation and diversification at every level and dimension of the maple system for its long-term resilience.
DNA methylation patterns associated with breast cancer prognosis that are specific to tumor subtype and menopausal status
Authors: Kim Do Hyun , Binder Alexandra M. , Zhou Hua , Jung Su Yon
Published: March 2023

Tumor subtype and menopausal status are strong predictors of breast cancer (BC) prognosis. We aimed to find and validate subtype- or menopausal-status-specific changes in tumor DNA methylation (DNAm) associated with all-cause mortality or BC progression. Associations between site-specific tumor DNAm and BC prognosis were estimated among The Cancer Genome Atlas participants (n = 692) with Illumina Infinium HumanMethylation450 BeadChip array data. All-cause mortality and BC progression were modeled using Cox proportional hazards models stratified by tumor subtypes, adjusting for age, race, stage, menopausal status, tumor purity, and cell type proportion. Effect measure modification by subtype and menopausal status were evaluated by incorporating a product term with DNAm. Site-specific inference was used to identify subtype- or menopausal-status-specific differentially methylated regions (DMRs) and functional pathways. The validation of the results was carried out on an independent dataset (GSE72308; n = 180). We identified a total of fifteen unique CpG probes that were significantly associated (P≤1×10−7 with survival outcomes in subtype- or menopausal-status-specific manner. Seven probes were associated with overall survival (OS) or progression-free interval (PFI) for women with luminal A subtype, and four probes were associated with PFI for women with luminal B subtype. Five probes were associated with PFI for post-menopausal women. A majority of significant probes showed a lower risk of OS or BC progression with higher DNAm. We identified subtype- or menopausal-status-specific DMRs and functional pathways of which top associated pathways differed across subtypes or menopausal status. None of significant probes from site-specific analyses met genome-wide significant level in validation analyses while directions and magnitudes of coefficients showed consistent pattern. We have identified subtype- or menopausal-status-specific DNAm biomarkers, DMRs and functional pathways associated with all-cause mortality or BC progression, albeit with limited validation. Future studies with larger independent cohort of non-post-menopausal women with non-luminal A subtypes are warranted for identifying subtype- and menopausal-status-specific DNAm biomarkers for BC prognosis.
Comparison of NK alloreactivity prediction models based on KIR-MHC interactions in haematopoietic stem cell transplantation
Authors: Dhuyser Adèle , Remen Thomas , Pérès Michaël , Chamberlain-Evans Vitalina , Nemat-Gorgani Neda , Campidelli Arnaud , Clément Sandra , Rubio Marie Thérèse , Trowsdale John , Aarnink Alice , Traherne James
Published: March 2023

The biological processes underlying NK cell alloreactivity in haematopoietic stem cell transplantation (HSCT) remain unclear. Many different models to predict NK alloreactivity through KIR and MHC genotyping exist, raising ambiguities in its utility and application for clinicians. We assessed 27 predictive models, broadly divided into six categories of alloreactivity prediction: ligand-ligand, receptor-ligand, educational, KIR haplotype-based, KIR matching and KIR allelic polymorphism. The models were applied to 78 NGS-typed donor/recipient pairs undergoing allogeneic HSCT in genoidentical (n=43) or haploidentical (n=35) matchings. Correlations between different predictive models differed widely, suggesting that the choice of the model in predicting NK alloreactivity matters. For example, two broadly used models, educational and receptor-ligand, led to opposing predictions especially in the genoidentical cohort. Correlations also depended on the matching fashion, suggesting that this parameter should also be taken into account in the choice of the scoring strategy. The number of centromeric B-motifs was the only model strongly correlated with the incidence of acute graft-versus-host disease in our set of patients in both the genoidentical and the haploidentical cohorts, suggesting that KIR-based alloreactivity, not MHC mismatches, are responsible for it. To our best knowledge, this paper is the first to experimentally compare NK alloreactivity prediction models within a cohort of genoidentical and haploidentical donor-recipient pairs. This study helps to resolve current discrepancies in KIR-based alloreactivity predictions and highlights the need for deeper consideration of the models used in clinical studies as well as in medical practice.
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

Introduction

Gastric 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.

Methods

This 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.

Results

After 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.

Discussion

In 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

Introduction

Macrophages 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.

Methods

C2C12 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.

Results

EVs 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.

Discussion

Skeletal 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

Introduction

Most 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.

Methods

As 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.

Results

We show that anti-TCRVβ CAR-T cells selectively kill their cognate tumour targets while leaving >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.

Discussion

Thus 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.
Oral inactivated whole cell vaccine for mucosal immunization: ETVAX case study
Authors: Walker Richard I. , Bourgeois A. Louis
Published: March 2023

Oral immunization is an effective strategy for inducing protective immunity against mucosal enteric pathogens. Although live-attenuated as well as subunit approaches have been explored for vaccination against enteric pathogens, inactivated whole bacterial cells may also be effective in introducing protective immunity. Successfully accomplishing this goal with inactivated whole bacterial cells will require that a complex antigenic repertoire be presented in controlled immunogenic amounts, in a safe and relatively simple and self-contained delivery format. The benefit from immunization with whole cell vaccines can be further enhanced through genetic engineering to over-express selected antigens and also by the use of mucosal adjuvants to direct a more robust immunologic response. These steps are being taken for the development of ETVAX, the most clinically advanced vaccine candidate against the major enteric pathogen, enterotoxigenic Escherichia coli (ETEC) with significant positive impact.
A theoretical framework of immune cell phenotypic classification and discovery
Authors: Hu Yuzhe , Liu Chen , Han Wenling , Wang Pingzhang
Published: March 2023

Immune cells are highly heterogeneous and show diverse phenotypes, but the underlying mechanism remains to be elucidated. In this study, we proposed a theoretical framework for immune cell phenotypic classification based on gene plasticity, which herein refers to expressional change or variability in response to conditions. The system contains two core points. One is that the functional subsets of immune cells can be further divided into subdivisions based on their highly plastic genes, and the other is that loss of phenotype accompanies gain of phenotype during phenotypic conversion. The first point suggests phenotypic stratification or layerability according to gene plasticity, while the second point reveals expressional compatibility and mutual exclusion during the change in gene plasticity states. Abundant transcriptome data analysis in this study from both microarray and RNA sequencing in human CD4 and CD8 single-positive T cells, B cells, natural killer cells and monocytes supports the logical rationality and generality, as well as expansibility, across immune cells. A collection of thousands of known immunophenotypes reported in the literature further supports that highly plastic genes play an important role in maintaining immune cell phenotypes and reveals that the current classification model is compatible with the traditionally defined functional subsets. The system provides a new perspective to understand the characteristics of dynamic, diversified immune cell phenotypes and intrinsic regulation in the immune system. Moreover, the current substantial results based on plasticitomics analysis of bulk and single-cell sequencing data provide a useful resource for big-data–driven experimental studies and knowledge discoveries.
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

Background

Immune 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.

Methods

In 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.

Results

The 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.

Conclusion

In 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

Rationale

Predicting 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.

Objective

To determine the incremental value of complete blood count parameters over clinical characteristics for predicting 90-day outcomes in sepsis survivors.

Methods

Electronic 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 results

We 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<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.

Conclusions

The 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

Introduction

Proteasome 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.

Methods

In 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).

Results

Our 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.

Conclusion

Altogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.
Filariasis research – from basic research to drug development and novel diagnostics, over a decade of research at the Institute for Medical Microbiology, Immunology and Parasitology, Bonn, Germany
Authors: Karunakaran Indulekha , Ritter Manuel , Pfarr Kenneth , Klarmann-Schulz Ute , Debrah Alexander Yaw , Debrah Linda Batsa , Katawa Gnatoulma , Wanji Samuel , Specht Sabine , Adjobimey Tomabu , Hübner Marc Peter , Hoerauf Achim
Published: March 2023

Filariae are vector borne parasitic nematodes, endemic in tropical and subtropical regions causing avoidable infections ranging from asymptomatic to stigmatizing and disfiguring disease. The filarial species that are the major focus of our institution’s research are Onchocerca volvulus causing onchocerciasis (river blindness), Wuchereria bancrofti and Brugia spp. causing lymphatic filariasis (elephantiasis), Loa loa causing loiasis (African eye worm), and Mansonella spp. causing mansonellosis. This paper aims to showcase the contribution of our institution and our collaborating partners to filarial research and covers more than two decades of research spanning basic research using the Litomosoides sigmodontis animal model to development of drugs and novel diagnostics. Research with the L. sigmodontis model has been extensively useful in elucidating protective immune responses against filariae as well as in identifying the mechanisms of filarial immunomodulation during metabolic, autoimmune and infectious diseases. The Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn (UKB), Bonn, Germany has also been actively involved in translational research in contributing to the identification of new drug targets and pre-clinical drug research with successful and ongoing partnership with sub-Saharan Africa, mainly Ghana (the Kumasi Centre for Collaborative Research (KCCR)), Cameroon (University of Buea (UB)) and Togo (Laboratoire de Microbiologie et de Contrôle de Qualité des Denrées Alimentaires (LAMICODA)), Asia and industry partners. Further, in the direction of developing novel diagnostics that are sensitive, time, and labour saving, we have developed sensitive qPCRs as well as LAMP assays and are currently working on artificial intelligence based histology analysis for onchocerciasis. The article also highlights our ongoing research and the need for novel animal models and new drug targets.
Reflections on the Nicaragua v. Colombia case (2022): From the perspective of traditional fishing rights
Authors: Wang Jingyao , Xu Qi
Published: March 2023

With respect to theNicaragua v. Colombiacase in 2022, whether Colombian fishermen in the San Andrés Archipelago, particularly the Raizales, have traditional fishing rights in the Nicaraguan Exclusive Economic Zone (EEZ) is one of controversial issues. Since Colombia is not a party to the United Nations Convention on the Law of the Sea (UNCLOS), the International Court of Justice (the Court or the ICJ) embodied customary international law as applicable law. It adopted a two-step method to examine Colombian claims and found that their fishermen did not enjoy traditional fishing rights. The Court found that affidavits of Colombian fishermen as major evidence were too sparse to prove the existence of a long-standing fishing practice. In light of a series of statements from the Nicaraguan President, there was a neither express nor implied recognition of traditional fishing rights of Colombian fishermen. This study reviews the ICJ’s judgment from three aspects. First, the paper will evaluate the Court’s (in)flexibility about the time requirement when examining the spanning period of a long-standing practice relating to traditional fishing activities. Second, concerning whether or in which circumstances the traditional fishing rights of a particular community can survive the establishment of the EEZ of another State, the Court found it unnecessary to examine this issue, the paper will also appraise potential legal impacts at this regard. Third, the Court did not identify Colombian claims of traditional fishing rights as indigenous rights, particularly for the Raizales. An increasing number of scholars of the law of the sea call for applying human rights norms to UNCLOS provisions, but the Court takes a cautious attitude in this regard. The paper will make more comments on the interaction between human rights law and the law of the sea.
Assessment of soluble skin surface protein levels for monitoring psoriasis vulgaris in adult psoriasis patients using non-invasive transdermal analysis patch: A pilot study
Authors: Orro Kadri , Salk Kristiina , Abram Kristi , Arshavskaja Jelena , Meikas Anne , Karelson Maire , Neuman Toomas , Kingo Külli , Spee Pieter
Published: March 2023

To improve the care of patients with chronic inflammatory skin conditions, such as psoriasis, there is a need for diagnostic methods that can facilitate personalized medicine. This exploratory pilot study aimed to determine whether non-invasive measurements of inflammation-related proteins from psoriatic skin can be sampled using the FibroTx Transdermal Analysis Patch (TAP) to assess disease severity and monitor pharmacodynamic changes. Ten healthy volunteers and 44 psoriasis vulgaris patients were enrolled in the exploratory pilot study. Skin surface protein measurements for healthy and lesional skin were performed using TAP. Patients’ scores of psoriasis activity and severity (PASI) were documented, and differences in the thickness of skin layers were determined using sonography. The study assessed the skin surface protein levels of psoriasis patients undergoing whole-body treatment with narrow-band UVB to evaluate whether the levels of the skin surface proteins IL-1α, IL-1RA CXCL-1/2, and hBD-1 were associated with the disease activity and severity measurements. Using TAP technology, it was observed that there were clear differences in levels of IL-1α, IL-1RA, CXCL-1/2, and hBD-1 between psoriasis lesional and non-lesional skin. In addition, a positive correlation between CXCL-1/2 and desquamation, and between CXCL-1/2 and SLEB thickness was observed. During UVB treatment, the TAP measurements revealed a clear reduction of IL-1RA, CXCL 1/2, and hBD-1 on lesional skin. Further, skin surface measurements of IL-1RA and CXCL-1/2 displayed a different profile than those achieved by visual scoring of local inflammation, thus indicating that measuring the ‘molecular root’ of inflammation appears to have value as an objective, non-invasive biomarker measurement for scoring disease severity.