bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemonucleolysis combined with dynamic loading for inducing degeneration in bovine caudal intervertebral discs
Authors: Vernengo Andrea , Bumann Helen , Kluser Nadine , Soubrier Astrid , Šećerović Amra , Gewiess Jan , Jansen Jan Ulrich , Neidlinger-Wilke Cornelia , Wilke Hans-Joachim , Grad Sibylle
Published: August 2023

Chemonucleolysis has become an established method of producing whole organ culture models of intervertebral disc (IVD) degeneration. However, the field needs more side-by-side comparisons of the degenerative effects of the major enzymes used in chemonucleolysis towards gaining a greater understanding of how these organ culture models mimic the wide spectrum of characteristics observed in human degeneration. In the current work we induced chemonucleolysis in bovine coccygeal IVDs with 100 µL of papain (65 U/mL), chondroitinase ABC (chABC, 5 U/mL), or collagenase II (col’ase, 0.5 U/mL). Each enzyme was applied in a concentration projected to produce moderate levels of degeneration. After 7 days of culture with daily dynamic physiological loading (0.02–0.2 MPa, 0.2 Hz, 2 h), the cellular, biochemical and histological properties of the IVDs were evaluated in comparison to a PBS-injected control. Papain and collagenase, but not chABC, produced macroscopic voids in the tissues. Compared to day 0 intact IVDs, papain induced the greatest magnitude glycosaminoglycan (GAG) loss compared to chABC and col’ase. Papain also induced the greatest height loss (3%), compared to 0.7%, 1.2% and 0.4% for chABC, col’ase, and PBS, respectively. Cell viability in the region adjacent to papain and PBS-injection remained at nearly 100% over the 7-day culture period, whereas it was reduced to 60%–70% by chABC and col’ase. Generally, enzyme treatment tended to downregulate gene expression for major ECM markers, type I collagen (COL1), type II collagen (COL2), and aggrecan (ACAN) in the tissue adjacent to injection. However, chABC treatment induced an increase in COL2 gene expression, which was significant compared to the papain treated group. In general, papain and col’ase treatment tended to recapitulate aspects of advanced IVD degeneration, whereas chABC treatment captured aspects of early-stage degeneration. Chemonucleolysis of whole bovine IVDs is a useful tool providing researchers with a robust spectrum of degenerative changes and can be utilized for examination of therapeutic interventions.
Cell encapsulation in gelatin methacryloyl bioinks impairs microscale diffusion properties
Authors: Dogan Elvan , Holshue Christina , Bhusal Anant , Shukla Roshni , Miri Amir K.
Published: August 2023

Light-assisted bioprinted gelatin methacryloyl (GelMA) constructs have been used for cell-laden microtissues and organoids. GelMA can be loaded by desired cells, which can regulate the biophysical properties of bioprinted constructs. We study how the degree of methacrylation (MA degree), GelMA mass concentration, and cell density change mass transport properties. We introduce a fluorescent-microscopy-based method of biotransport testing with improved sensitivity compared to the traditional particle tracking methods. The diffusion capacity of GelMA with a higher MA significantly decreased compared to a lower MA. Opposed to a steady range of linear elastic moduli, the diffusion coefficient in GelMA varied when cell densities ranged from 0 to 10 × 106 cells/ml. A comparative study of different cell sizes showed a higher diffusivity coefficient for the case of larger cells. The results of this study can help bioengineers and scientists to better control the biotransport characteristics in light-assisted bioprinted microtissues and organoids.
Aggregatibacter actinomycetemcomitans cytolethal distending toxin modulates host phagocytic function
Authors: Kim Taewan J. , Shenker Bruce J. , MacElroy Andrew S. , Spradlin Samuel , Walker Lisa P. , Boesze-Battaglia Kathleen
Published: August 2023

Cytolethal distending toxins (Cdt) are a family of toxins produced by several human pathogens which infect mucocutaneous tissue and induce inflammatory disease. Human macrophages exposed to Aggregatibacter actinomycetemcomitans (Aa) Cdt respond through canonical and non-canonical inflammasome activation to stimulate cytokine release. The inflammatory response is dependent on PI3K signaling blockade via the toxin’s phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase activity; converting PIP3 to phosphatidylinsoitol-3,4-diphosphate (PI3,4P2) thereby depleting PIP3 pools. Phosphoinositides, also play a critical role in phagosome trafficking, serving as binding domains for effector proteins during phagosome maturation and subsequent fusion with lysosomes. We now demonstrate that AaCdt manipulates the phosphoinositide (PI) pools of phagosome membranes and alters Rab5 association. Exposure of macrophages to AaCdt slowed phagosome maturation and decreased phago-lysosome formation, thereby compromising macrophage phagocytic function. Moreover, macrophages exposed to Cdt showed decreased bactericidal capacity leading to increase in Aggregatibacter actinomycetemcomitans survival. Thus, Cdt may contribute to increased susceptibility to bacterial infection. These studies uncover an underexplored aspect of Cdt function and provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such as Aa.
Bacterial biofilms in the human body: prevalence and impacts on health and disease
Authors: Perry Elena K. , Tan Man-Wah
Published: August 2023

Bacterial biofilms can be found in most environments on our planet, and the human body is no exception. Consisting of microbial cells encased in a matrix of extracellular polymers, biofilms enable bacteria to sequester themselves in favorable niches, while also increasing their ability to resist numerous stresses and survive under hostile circumstances. In recent decades, biofilms have increasingly been recognized as a major contributor to the pathogenesis of chronic infections. However, biofilms also occur in or on certain tissues in healthy individuals, and their constituent species are not restricted to canonical pathogens. In this review, we discuss the evidence for where, when, and what types of biofilms occur in the human body, as well as the diverse ways in which they can impact host health under homeostatic and dysbiotic states.
Financing the green transition. The role of macro-economic policies in ensuring a just transition
Authors: Braga João Paulo , Ernst Ekkehard
Published: August 2023

The transition to a green economy requires significant resources, both from private investors and public policy makers with important implications for employment and living standards. This paper argues that green macro-economic policies are essential in accelerating the transition through three channels: they can strengthen the price signals from externality pricing; they can mobilize additional public and hybrid funding for green transition projects; and they can soften the social and labor market impact of the transition for those workers currently still employed in polluting industries. The paper provides an overview of the main fiscal, monetary and financial market policies that can help provide the necessary fund for a successful transition. It highlights different trade-offs regarding instrument choice and policy outcomes, notably regarding the need to achieve a transition that is both ecological and socially sustainable. We provide an overview of current policy choices and document their economic, social and ecological outcomes. In particular, we demonstrate that the proper use of price regulation and financial instruments—carbon taxes, cap-and-trade schemes, green bonds, nature-based capital—can mobilize additional resources that can be usefully invested to ensure a socially just transition.
Preparing students for a changing world: how geography curricula in Europe are tackling climate change
Authors: Enke Klaas Alexander , Budke Alexandra
Published: August 2023

Climate change education has gained attention in recent years, with curriculum analyses conducted primarily at the national level. However, a comparative analysis of implementation in different European countries is still lacking. This study aims to address this research gap by comparatively examining the geography curricula of France, Spain, Germany, and Italy. The analysis reveals differences in the inclusion of physical-geographical content related to climate change. Likewise, the emphasis on either the natural or the socio-economic effects of climate change varies across the countries. All curricula include concrete competencies and learning objectives for climate education, but a gap is visible in social learning objectives. The analysis highlights the importance of exchanging best practices an experiences among European countries.
Impact of growth hormone on IVF/ICSI outcomes and endometrial receptivity of patients undergoing GnRH antagonist protocol with fresh embryo transfer: a pilot study
Authors: Chu Yifan , Wang Luyao , Xie Jiaxin , Yang Shulin , Liu Si , Hu Dan , Yue Jing
Published: August 2023

Introduction

Gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is widely used in the world for controlled ovarian hyperstimulation (COH). However, previous studies have shown that pregnancy outcomes of fresh embryo transfer with GnRH-ant protocol are not ideal. Current studies have demonstrated the value of growth hormone (GH) in improving the pregnancy outcome of elderly women and patients with diminished ovarian reserve, but no prospective studies have confirmed the efficacy of GH in fresh embryo transfer with GnRH-ant protocol, and its potential mechanism is still unclear. This study intends to evaluate the impact of GH on IVF/ICSI outcomes and endometrial receptivity of patients undergoing GnRH-ant protocol with fresh embryo transfer, and preliminarily explore the possible mechanism.

Methods

We designed a randomized controlled trial of 120 infertile patients with normal ovarian response (NOR) who will undergo IVF/ICSI from April 2023 to April 2025, at Department of Reproductive Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients will be divided into the depot gonadotropin-releasing hormone agonist (GnRH-a) protocol group, GnRH-ant protocol control group, and GnRH-ant protocol plus GH intervention group at a ratio of 1:1:1 by block randomization design. Patients will be followed on enrollment day, trigger day, embryo transfer day, 7 days after oocytes pick-up, 15 days after embryo transfer, 28 days after embryo transfer, and 12 weeks of gestation. The primary outcome is the ongoing pregnancy rate. Secondary outcomes include the gonadotropin dosage, duration of COH, endometrial thickness and pattern, luteinizing hormone, estradiol, progesterone level on trigger day, numbers of retrieved oocytes, high-quality embryo rate, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, early miscarriage rate, multiple pregnancy rate and incidence of moderate and severe ovarian hyperstimulation syndrome. The endometrium of certain patients will be collected and tested for endometrial receptivity.

Ethics and dissemination

The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology [approval number: TJ-IRB20230236; approval date: February 10, 2023]. The research results will be presented at scientific/medical conferences and published in academic journals.

Clinical trial registration

Chinese Clinical Trial Registry; identifier: ChiCTR2300069397.
Study on inflammation and fibrogenesis in MAFLD from 2000 to 2022: a bibliometric analysis
Authors: Luo Kuanhong , Chen Yang , Fang Shuzheng , Wang Siqi , Wu Zhixin , Li Huiqing
Published: August 2023

Chronic inflammation and fibrosis are significant factors in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). In this study, we conducted a bibliometric analysis of publications on inflammation and fibrogenesis in MAFLD, with a focus on reporting publication trends. Our findings indicate that the USA and China are the most productive countries in the field, with the University of California San Diego being the most productive institution. Over the past 23 years, Prof. Diehl AM has published 25 articles that significantly contributed to the research community. Notably, the research focus of the field has shifted from morbid obesity and adiponectin to metabolic syndrome, genetics, and microbiome. Our study provides a comprehensive and objective summary of the historical characteristics of research on inflammation and fibrogenesis in MAFLD, which will be of interest to scientific researchers in this field.
18F-labeled PEGylated exendin-4 imaging noninvasively differentiates insulinoma from an accessory spleen: the first case report of [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography for insulinoma
Authors: Sakaki Kentaro , Murakami Takaaki , Fujimoto Hiroyuki , Shimizu Yoichi , Miyake Kanae Kawai , Otani Daisuke , Kiyobayashi Sakura , Okada Takuya , Fujimoto Masakazu , Hakata Takuro , Yamauchi Ichiro , Shimada Kotaro , Shimizu Hironori , Nagai Kazuyuki , Nakamoto Yuji , Inagaki Nobuya
Published: August 2023

Background

Insulinomas are the most common functioning pancreatic neuroendocrine neoplasms, and these tumors induce hypoglycemia due to hyperinsulinemia. Hypoglycemia caused by insulinomas can cause seizures, coma or death due to the delayed diagnosis. The only curative treatment is surgical resection. To perform curative surgical resection of insulinomas, preoperative localization is crucial. However, localization of insulinomas is often challenging using conventional imaging methods such as computed tomography (CT) and magnetic resonance imaging. Although endoscopic ultrasound (EUS) fine-needle aspiration and selective arterial calcium stimulation test, which can reflect the endocrine character of the tumor, are performed in such cases, these modalities are invasive and require operator-dependent techniques. Additionally, somatostatin receptor (SSTR)-targeted imaging has a relatively low sensitivity for detecting insulinomas due to its low SSTR type 2 expression. Thus, there is an urgent need for developing a noninvasive diagnostic technique which is specific for detecting insulinomas. Consequently, glucagon-like peptide-1 receptor-targeted imaging has recently emerged and gained a wide interest. Recently, we have developed a novel 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), for positron emission tomography (PET) imaging. Here we report a case of insulinoma in which 18F-exendin-4 PET/CT noninvasively provided critical information for localization.

Case description

This is a case of a 58-year-old male with symptomatic hypoglycemia for 10 years; however, a preoperative diagnosis of insulinoma was not established due to the difficulty in differentiating it from an accessory spleen using conventional imaging. Moreover, the patient requested to avoid invasive diagnostic procedures including EUS. 18F-exendin-4 PET/CT revealed significant uptakes in the pancreatic tail whereas no apparent uptakes were observed in the spleen; thus, curative laparoscopic enucleation of the pancreatic tail was performed. The diagnosis of insulinoma was confirmed via histopathological examination. This is the first case report of insulinoma diagnosed using 18F-exendin-4 PET/CT.

Conclusion

In this case, PET information led to curative resection through enucleation of the pancreas. 18F-exendin-4 PET/CT may serve as a useful noninvasive clinical tool for insulinoma localization.
Mercury transport and methylmercury production in the lower Cedar River (Iowa) floodplain
Authors: Graham Andrew M. , Van Helten Seth , Wadle Austin , Mamrak Emily , Morsch Jacob , Lopez Samuel , Smith Katherine
Published: August 2023

Scant attention has been paid to cycling of total mercury (THg) and methylmercury (MeHg) in agriculturally intensive watersheds. Monitoring of Hg and MeHg in river basins provides valuable information on the efficacy of environmental policy and the impacts of land use and climate change on Hg fluxes and biogeochemistry. We report on Hg and MeHg yields in the Cedar River (Iowa), a major tributary of the Upper Mississippi River, and on Hg biogeochemistry in a floodplain of the lower Cedar River, with emphasis on Hg cycling in groundwater and wetland ponds. For the period 2016 to 2018, total Hg yields for the 21,000 km2 Cedar River watershed ranged from 2.6 to 6.9 μg m−2 yr−1, or 25% to 70% of estimated wet deposition, and MeHg yields ranged from 0.09 to 0.18 μg m−2 yr−1. High watershed transfer efficiencies for THg are driven by soil erosion and suspended sediment delivery. Policies and land management practices targeting soil conservation are thus likely to have significant impacts on downstream transport of Hg. Within alluvial groundwaters, Hg and MeHg concentrations were highly spatiotemporally variable, ranging from 0.5 to 2.0 ng/L for THg and 0.03–1.50 ng/L for MeHg. Microtopography exerted strong control on groundwater geochemistry and Hg biogeochemical cycling, with groundwater sampled from lower lying swales exhibiting less dissolved oxygen (DO), higher conductivity, higher dissolved organic carbon (DOC), and higher THg and MeHg. The alluvial aquifer exhibits high hydrologic connectivity with the river and groundwater THg and MeHg concentrations responded rapidly to hydrologic events, with MeHg concentrations increasing with a rising water table. Concentrations of THg and MeHg in wetland ponds were elevated compared to groundwater and most strongly correlated with DOC and UV-absorbance. Methylation potentials in pond sediments were among the highest reported for freshwater sediments, up to 0.15 d−1, which we hypothesize to be linked to high primary productivity associated with nutrient enrichment. Floodplain groundwaters and wetlands constitute important ecosystem control points for downstream MeHg delivery, the magnitude of which is sensitive to changing hydroclimate, especially flood frequency.
Does managerial myopia hinder green technological innovations? an examination based on Chinese-listed heavy polluters
Authors: Li Ziwei , Wu Yuan
Published: August 2023

Under the guidance of a high-quality development strategy, upholding the long-term concept of green development is the foundation allowing polluting companies to resist external environmental threats and retain their legitimate business statuses. However, the top managers of companies do not always hold long-term perspectives. To this end, we investigate the impact of management myopia on green technological innovation and its mechanism of action for heavy polluters using zero-inflated Poisson regression analysis for 2007–2020 for A-share listed heavy polluters. The empirical results show that the logarithmic value of green technological innovation decreases 1.251 units for each 1-unit increase in the management myopia level demonstrated by heavily polluting enterprises. Moreover, these results are more significant in heavily polluting enterprises with high management shareholding and those that receive more government subsidies. However, managerial myopia is suppressed in heavily polluting firms with many independent directors and institutional investors. A further study found that managerial myopia had the most significant negative impact on green technological innovation for heavy polluters in the central region, and each 1-unit increase in the managerial myopia level decreased the firm’s green technology innovation level by 3.577 units. The findings of this paper have important implications for heavily polluting firms seeking to improve their senior management appointments and governance structures, promote green technology and technological innovation, and achieve high-quality corporate development.
Development of a novel, clinically relevant anoikis-related gene signature to forecast prognosis in patients with prostate cancer
Authors: Liu Xiaolin , Wang Kunming
Published: August 2023

Introduction: Anoikis is a specific form of programmed cell death and is related to prostate cancer (PC) metastasis. This study aimed to develop a reliable anoikis-related gene signature to accurately forecast PC prognosis.

Methods: Based on anoikis-related genes and The Cancer Genome Atlas (TCGA) data, anoikis-related molecular subtypes were identified, and their differences in disease-free survival (DFS), stemness, clinical features, and immune infiltration patterns were compared. Differential expression analysis of the two subtypes and weighted gene co-expression network analysis (WGCNA) were employed to identify clinically relevant anoikis-related differentially expressed genes (DEGs) between subtypes, which were then selected to construct a prognostic signature. The clinical utility of the signature was verified using the validation datasets GSE116918 and GSE46602. A nomogram was established to predict patient survival. Finally, differentially enriched hallmark gene sets were revealed between the different risk groups.

Results: Two anoikis-related molecular subtypes were identified, and cluster 1 had poor prognosis, higher stemness, advanced clinical features, and differential immune cell infiltration. Next, 13 clinically relevant anoikis-related DEGs were identified, and five of them (CKS2, CDC20, FMOD, CD38, and MSMB) were selected to build a prognostic signature. This gene signature had a high prognostic value. A nomogram that combined Gleason score, T stage, and risk score could accurately predict patient survival. Furthermore, gene sets closely related with DNA repair were differentially expressed in the different risk groups.

Conclusion: A novel, clinically relevant five-anoikis-related gene signature was a powerful prognostic biomarker for PC.
Sedimentary diterpane origins—inferences from oils of varying source depositional environment and age
Authors: Killops S. D. , Bishop A. N. , Tegelaar E. W. , Urdal K. , Ghammari M. R. K. , Weijers J. W. H.
Published: August 2023

The potential of C20 tricyclic and tetracyclic diterpane distributions in oils (and by extension, rock extracts) to aid the interpretation of sources of organic matter and depositional environments—spanning carbonate, marl, freshwater and saline lacustrine, normal marine and transitional—from Neoproterozoic to Neogene, is investigated using GC-MS and GC-MS-MS analysis of a range of oils of known origin. Contributions from gymnosperms are readily distinguished by abundant characteristic tricyclics and/or tetracyclics [e.g., 5β(H)-rimuane, 5β(H)-rosane, isopimarane and phyllocladanes]. Even at low levels, phyllocladane appears a reliable indicator of Carboniferous or younger source. A fairly uniform, limited range of diterpanes at relatively low abundance is observed in oils from other sources, with the 13β(H),14α(H)-cheilanthane often being the most abundant C20 diterpane associated with carbonates and marls. Other tricyclics include the previously proposed 8β-methyl-13α-ethylpodocarpane and a series of unidentified compounds, mostly sharing mass spectra with abundant fragment ions at m/z 123, 163 and 191, together with methyl (m/z 261), but not ethyl, loss from the molecular ion. This limited range of tricyclics suggests a common group of source organisms (probably bacterial) and or diagenetic transformation resulting in a few thermodynamically stable products. It may explain why pimarane is at most a trace component, despite pimaroids being widely occurring natural products. Where gymnosperms have made little contribution, C20 tetracyclic diterpanes are typically sparse and comprise beyerane, atisanes and possibly also 16α(H)-kaurane (which co-elutes with the first of the pair of atisane isomers), with beyerane usually the most abundant in terms of m/z 276→123 response. These compounds are not detected in oils from Neoproterozoic and Cambrian carbonates, but analysis of more samples is required to confirm this trend. Despite some caveats, diterpane distributions can provide useful information related to age and depositional environment as well as providing a tool for oil-oil correlation.
Mapping the splicing landscape of the human immune system
Authors: Ner-Gaon Hadas , Peleg Ronnie , Gazit Roi , Reiner-Benaim Anat , Shay Tal
Published: August 2023

Most human genes code for more than one transcript. Different ratios of transcripts of the same gene can be found in different cell types or states, indicating differential use of transcription start sites or differential splicing. Such differential transcript use (DTUs) events provide an additional layer of regulation and protein diversity. With the exceptions of PTPRC and CIITA, there are very few reported cases of DTU events in the immune system. To rigorously map DTUs between different human immune cell types, we leveraged four publicly available RNA sequencing datasets. We identified 282 DTU events between five human healthy immune cell types that appear in at least two datasets. The patterns of the DTU events were mostly cell-type-specific or lineage-specific, in the context of the five cell types tested. DTUs correlated with the expression pattern of potential regulators, namely, splicing factors and transcription factors. Of the several immune related conditions studied, only sepsis affected the splicing of more than a few genes and only in innate immune cells. Taken together, we map the DTUs landscape in human peripheral blood immune cell types, and present hundreds of genes whose transcript use changes between cell types or upon activation.
Characterization of infectious and non-infectious gastrointestinal disease in common variable immunodeficiency: analysis of 114 patient cohort
Authors: Sanchez David A. , Rotella Karina , Toribio Crhistian , Hernandez Matthew , Cunningham-Rundles Charlotte
Published: August 2023

Common Variable Immunodeficiency (CVID), a complex primary immunodeficiency syndrome defined by defective B cell responses to infection and vaccination, has heterogeneous clinical manifestations. Gastrointestinal (GI) complications in CVID, both infectious and non-infectious, can cause significant impairment leading to malabsorption and frank malnutrition. In order to better characterize the spectrum of GI disease associated with CVID, we describe 114 patients with GI disease (15.6%) from our 728 patient single center CVID cohort. Norovirus, Giardia and Cytomegalovirus were the most frequently isolated infectious pathogens. CVID enteropathy was the most encountered GI diagnosis based on endoscopy, with only a minority of patients having Crohn’s disease (6.1%) or ulcerative colitis/proctitis (4.5%). Concurrent autoimmunity (30.7%), lung disease (18.4%) and malignancy (8.7%) were also present in significant proportion of subjects. Lastly, 16 of 47 (34%) who underwent whole exome sequencing demonstrated a culprit gene defect associated with CVID.
Pannexin1: insight into inflammatory conditions and its potential involvement in multiple organ dysfunction syndrome
Authors: Chen Xiangyu , Yuan Siyi , Mi Liangyu , Long Yun , He Huaiwu
Published: August 2023

Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated with elevated mortality rates and a poorer prognosis. The development of sepsis involves hyperactive inflammation, immune disorder, and disrupted microcirculation. It is crucial to identify targets within these processes to develop therapeutic interventions. One such potential target is Panx1 (pannexin-1), a widely expressed transmembrane protein that facilitates the passage of molecules smaller than 1 KDa, such as ATP. Accumulating evidence has implicated the involvement of Panx1 in sepsis-associated MODS. It attracts immune cells via the purinergic signaling pathway, mediates immune responses via the Panx1-IL-33 axis, promotes immune cell apoptosis, regulates blood flow by modulating VSMCs’ and vascular endothelial cells’ tension, and disrupts microcirculation by elevating endothelial permeability and promoting microthrombosis. At the level of organs, Panx1 contributes to inflammatory injury in multiple organs. Panx1 primarily exacerbates injury and hinders recovery, making it a potential target for sepsis-induced MODS. While no drugs have been developed explicitly against Panx1, some compounds that inhibit Panx1 hemichannels have been used extensively in experiments. However, given that Panx1’s role may vary during different phases of sepsis, more investigations are required before interventions against Panx1 can be applied in clinical. Overall, Panx1 may be a promising target for sepsis-induced MODS. Nevertheless, further research is needed to understand its complex role in different stages of sepsis fully and to develop suitable pharmaceutical interventions for clinical use.
Cost-effectiveness of serplulimab as first-line therapy for extensive-stage small cell lung cancer in China
Authors: Xiang Guiyuan , Jiang Tingting , Gan Lanlan , Wu Yuanlin , Zhang Ni , Xing Haiyan , Su Hui , Li Yanping , Peng Dan , Ni Rui , Liu Yao
Published: August 2023

Objective

The ASTRUM-005 trial demonstrated that adding serplulimab to chemotherapy significantly prolonged the survival of patients with extensive-stage small cell lung cancer (SCLC), but also increased the risk of adverse events. Given the high cost of serplulimab compared to chemotherapy, this study aimed to evaluate the cost-effectiveness of serplulimab plus chemotherapy as a first-line treatment for extensive-stage SCLC from the perspective of China’s healthcare system.

Methods

A Markov model was developed to simulate the disease process of extensive-stage SCLC and estimate the health outcomes and direct medical costs of patients. Scenario analyses, univariate sensitivity analyses, and probabilistic sensitivity analyses were conducted to explore the impact of different parameters on model uncertainty. The primary model outcomes included costs, life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).

Results

Compared to placebo plus chemotherapy, serplulimab plus chemotherapy resulted in an additional 0.25 life-years and 0.15 QALYs, but also increased costs by $26,402, resulting in an ICER of 179,161 USD/QALY. Sensitivity analysis showed that the ICER was most sensitive to the cost of serplulimab, and the probability that serplulimab was cost-effective when added to chemotherapy was only 0 at the willingness-to-pay threshold of 37,423 USD/QALY. Scenario analysis revealed that price discounts on serplulimab could increase its probability of being cost-effective.

Conclusion

Serplulimab plus chemotherapy is not a cost-effective strategy for first-line treatment of extensive-stage SCLC in China. Price discounts on serplulimab can enhance its cost-effectiveness.
Activity of granulomatosis with polyangiitis and its correlation with mTOR phosphoproteomics in neutrophils
Authors: Surmiak Marcin , Wawrzycka-Adamczyk Katarzyna , Kosałka-Węgiel Joanna , Włudarczyk Anna , Sanak Marek , Musiał Jacek
Published: August 2023

Introduction

Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis with a complex pathomechanism. Organ damage in GPA is also mediated by extracellular trap formation (NETosis). We analyzed the functional status of phosphoproteins modulating NETosis in neutrophils by the mammalian target of rapamycin (mTOR) pathway in GPA along with NETosis biomarkers.

Methods

Phosphoproteins levels measured in isolated neutrophils from 42 patients with GPA (exacerbation n=21; remission n=21) and 21 healthy controls were compared to serum biomarkers of the disease.

Results

Neutrophils in active disease manifested lowered levels of phosphorylated mTOR(Ser2448), PTEN(Ser380) and ULK1(Ser555), whereas phosphorylated GSK-3α/β(Ser21/Ser9) was elevated. Exacerbation of GPA was characterized by elevated neutrophil dsDNA in serum, circulating mitochondrial DNA, and DNA-MPO complexes. A significant negative correlation between mTOR or PTEN phosphoproteins and biomarkers of GPA activity was also present, reflecting the clinical activity score of GPA. Positive correlations between phosphorylated GSK-3 α/β and circulating mtDNA, DNA-MPO complexes, neutrophil-released dsDNA, or circulating proteins were also significant. Increased serum levels of IGFBP-2, TFF-3, CD147, and CHI3L1 accompanied GPA exacerbation, whereas DPP-IV levels were the lowest in active GPA. Using a principal component analysis basigin, PTEN and mTOR had the highest loadings on the discrimination function, allowing classification between active, remission, and control subjects with 98% performance.

Conclusions

We present evidence that inhibited mTOR signaling accompanies NETosis in patients with GPA. The functional status of phosphoproteins suggests simultaneous activation of NETosis and autophagy. These results give rise to the study of autophagy as a mechanism underlying granuloma formation in GPA.
Causal effects of systemic inflammatory regulators on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study
Authors: Li Hongdian , Li Mingxuan , Liu Cong , He Pengfei , Dong Ao , Dong Shaoning , Zhang Mianzhi
Published: August 2023

Background

While targeted systemic inflammatory modulators show promise in preventing chronic kidney disease (CKD) progression, the causal link between specific inflammatory factors and CKD remains uncertain.

Methods

Using a genome-wide association study of 41 serum cytokines from 8,293 Finnish individuals, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. In addition, we genetically predicted causal associations between inflammatory factors and 5 phenotypes, including CKD, estimated glomerular filtration rate (eGFR), dialysis, rapid progression of CKD, and rapid decline in eGFR. Inverse variance weighting (IVW) served as the primary MR method, while MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were utilized for sensitivity analysis. Cochrane’s Q test for heterogeneity. Leave-one-out method ensured stability of MR results, and Bonferroni correction assessed causal relationship strength.

Results

Seventeen cytokines were associated with diverse renal outcomes. Among them, after Bonferroni correction test, higher tumor necrosis factor alpha levels were associated with a rapid decrease in eGFR (OR = 1.064, 95% CI 1.028 – 1.103, P = 0.001), higher interleukin-4 levels were associated with an increase in eGFR (β = 0.003, 95% CI 0.001 – 0.005, P = 0.002), and higher growth regulated oncogene alpha (GROα) levels were associated with an increased risk of CKD (OR=1.035, 95% CI 1.012 - 1.058, P = 0.003). In contrast, genetic susceptibility to CKD was associated with an increase in GROa, and a decrease in eGFR may lead to an increase in stem cell factor. We did not find the presence of horizontal pleiotropy during the analysis.

Conclusion

We discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.
Exploring the potential relationship between frozen shoulder and Dupuytren’s disease through bioinformatics analysis and machine learning
Authors: Ouyang Yulong , Chen Shuilin , Tu Yuanqing , Wan Ting , Fan Hao , Sun Guicai
Published: August 2023

Background

Frozen shoulder (FS) and Dupuytren’s disease (DD) are two closely related diseases, but the mechanism of their interaction is unknown. Our study sought to elucidate the molecular mechanism of these two diseases through shared gene and protein interactions.

Methods

GSE75152 and GSE140731 data were downloaded from the Gene Expression Omnibus (GEO) database, and shared genes between FS and DD were selected by using R packages. Then, we used Cytoscape software and the STRING database to produce a protein−protein interaction (PPI) network. Important interaction networks and hub genes were selected through MCODE and cytoHubba algorithms. To explore the potential mechanisms of the development of the two diseases, the hub genes were further enriched by GO and KEGG analyses. We predicted the transcription factors (TFs) of hub genes with Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST). Moreover, we identified candidate genes for FS with DD with cytoHubba and machine learning algorithms. Finally, we analyzed the role of immunocyte infiltration in FS and constructed the relationship between candidate genes and immunocytes in FS.

Results

We identified a total of 321 shared genes. The results of GO and KEGG enrichment of shared genes showed that extracellular matrix and collagen fibril tissue play a certain role in the occurrence and development of disease. According to the importance of genes, we constructed the key PPI network of shared genes and the top 15 hub genes for FS with DD. Then, we predicted that five TFs are related to the hub genes and are highly expressed in the FS group. Machine learning results show that the candidate genes POSTN and COL11A1 may be key for FS with DD. Finally, immune cell infiltration revealed the disorder of immunocytes in FS patients, and expression of candidate genes can affect immunocyte infiltration.

Conclusion

We identified a PPI network, 15 hub genes, and two immune-related candidate genes (POSTN and COL11A1) using bioinformatics analysis and machine learning algorithms. These genes have the potential to serve as diagnostic genes for FS in DD patients. Furthermore, our study reveals disorder of immunocytes in FS.
Different behavioral strategies of two sympatric seahorses: habitat availability and increased density of Hippocampus guttulatus alter the behavior of Hippocampus hippocampus
Authors: Spatafora Davide , Gristina Michele , Quattrocchi Federico , Pierri Cataldo , Lazic Tamara , Palma Jorge
Published: August 2023

In the light of future ocean warming scenarios and habitat fragmentation, coastal fishes must adjust their physiological and behavioral traits to face the combined effect of global warming and ecological interactions. Seahorses (Hippocampus spp.) are charismatic fishes with peculiar life cycle traits, which make them vulnerable to several anthropic pressures and natural disturbances. In this study, we investigated the behavior of two sympatric seahorse species, the long-snouted Hippocampus guttulatus (Cuvier, 1829) and the short-snouted Hippocampus hippocampus (Linnaeus, 1758). Specifically, we carried out two manipulative experiments to assess (i) the effect of temperature and habitat availability on both H. hippocampus and H. guttulatus behavior and (ii) the effect of temperature and an increased density of H. guttulatus (by 3×) on the activity level of congeneric species H. hippocampus. Our results showed that +3°C warming did not affect seahorse behavior in both experiments, suggesting greater behavioral tolerance to thermal variation. However, a significant reduction of the active behavior of H. hippocampus was observed when the artificial habitat was introduced in the tank, while H. guttulatus maintained its activity. Furthermore, a significant decrease of the H. hippocampus activity was observed with an increased relative dominance of H. guttulatus. Our results suggest that both increased density of H. guttulatus and habitat availability, but not ocean warming, will affect the behavior of H. hippocampus. Therefore, different interspecific behavioral strategies may occur, thus affecting the distribution of the two species among shallow habitats when they occur in sympatry.
Inferring potential causative microbial factors of intestinal atrophic disease in the sea cucumber Apostichopus japonicus
Authors: Yu Juanwen , Sawabe Tomoo , Yamano Ryota , Koike Shotaro , Sakai Yuichi , Mino Sayaka
Published: August 2023

The overexploitation of the wild populations of Apostichopus japonicus has caused a significant decline in their numbers, prompting the establishment of a sea cucumber aquaculture industry that has become a major player in East Asia. Recent research has focused on identifying the various factors that may affect sea cucumber aquaculture, including water quality, diet, and the microbiome associated with their hosts. Notably, studies on host-associated microbiomes have emerged as a prominent area of research, particularly in the context of investigating the relationship of the microbiome with diseases that have caused significant economic losses. Intestinal atrophy of A. japonicus larvae has been reported at a number of sea cucumber farms in Japan, but there have been no factor screenings, and there is currently no efficient mitigation. In this study, we applied metagenomic analyses for the first time to an intestinal atrophic case of the sea cucumber A. japonicus larvae, which occurred in an aquaculture facility in Hokkaido, Japan, elucidating potential causative microbial factors and comparing the diseased microbiome against the healthy pan-microbiome. Through our metagenome comparisons, we have found significant increases in Oceanicoccus, Ruegeria, Nioella, Labrenzia, Tenacibaculum, and Muricauda in the diseased larvae. Among those, Tenacibaculum was estimated to potentially be the most pathogenic bacterium in the development of intestinal atrophic disease due to previous outbreaks of sea urchin diseases in the same facility. Our metagenomic approach demonstrates the further need of microbial screening of such causative agents and identification of the pathogenesis of such diseases, which could contribute to establishing more sustainable aquaculture in the sea cucumber industry.
Experimental ocean acidification and food limitation reveals altered energy budgets and synergistic effects on mortality of larvae of a coastal fish
Authors: Siegfried Emma , Johnson Darren W.
Published: August 2023

Ocean acidification (OA) presents a unique challenge to early life stages of marine species. Developing organisms must balance the need to grow rapidly with the energetic demands of maintaining homeostasis. The small sizes of early life stages can make them highly sensitive to changes in environmental CO2 levels, but studies have found wide variation in responses to OA. Thus far most OA studies have manipulated CO2 only, and modifying factors need to be considered in greater detail. We investigated the effects of high pCO2 and food ration on rates of growth and mortality of a coastal fish, the California Grunion (Leuresthes tenuis). We also examined how CO2 and food levels affected feeding success, metabolic rate, and swimming activity – processes reflective of energy acquisition and expenditure. In general, exposure to high CO2 decreased energy intake by reducing feeding success, and increased energy expenditure by increasing metabolic rate and routine swimming speed, though the magnitudes of these effects varied somewhat with age. Despite these changes in energetics, growth of biomass was not affected significantly by pCO2 level but was reduced by low ration level, and we did not detect an interactive effect of food ration and pCO2 on growth. However, under OA conditions, larvae were in poorer condition (as evaluated by the mass to length ratio) by the end of the experiment and our analysis of mortality revealed a significant interaction in which the effects of OA were more lethal when food energy was limited. These results are consistent with the idea that although energy can be reallocated to preserve biomass growth, increased energetic demand under ocean acidification may draw energy away from maintenance, including those processes that foster homeostasis during development. Overall, these results highlight both the need to consider the availability of food energy as a force governing species’ responses to ocean acidification and the need to explicitly consider the energy allocated to both growth and maintenance as climate changes.
Enhancement of heat transfer in heat sink under the effect of a magnetic field and an impingement jet
Authors: Azadi Shervin , Abjadi Ali , Vahdat Azad Abazar , Ahmadi Danesh Ashtiani Hossein , Afshar Hossein
Published: August 2023

Improving the performance of heat sinks is very important in the development of cooling systems. In this study, the use of a novel combination method [magnetic field impingement jet (MF-IJ)] to improve the convective heat transfer coefficient in a designed heat sink is numerically investigated. To model heat transfer, a steady three-dimensional computational fluid dynamics (CFD) approach is employed. Numerical results including velocity and temperature contours, as well as the distribution of wall temperature of the heat sink and also the convective heat transfer coefficient are analyzed. The results show that the use of ferrofluid (Fe3O4/water) flow with an external magnetic field alone increases the heat transfer coefficient by 10%, while the use of an air impingement jet with pure water and without a magnetic field increases it by 22.4%. By using the MF-IJ method, a 32% enhancement of heat transfer coefficient is achieved compared to the case of pure water flow and without MF-IJ. Based on results, at a Reynolds number of 600, by applying the magnetic field intensities of 400, 800, and 1600 G, the average heat transfer coefficient increases by 5.35, 11.77, and 16.11%, respectively. It is also found that the cooling of the heat sink and temperature distribution is improved by increasing the Reynolds number and the inlet mass flow rate of the impingement jet. For instance, at z = 0.02 m, the application of an impingement jet with mass flow rates of 0.001, 0.004, and 0.005 kg/s results in a respective decrease of 0.36, 1.62, and 1.82% in wall temperature. The results of the current study suggest that the combination method of MF-IJ can be utilized for heat sinks with high heat flux generation as a flow control device.
Validation of a new portable system containing both FeNO analysis and spirometry measurement
Authors: Li Yong , Huang Ke , Li Wei , Peng Yaodie , Tang Xingyao , Yang Ting
Published: August 2023

Introduction

Pulmonary function tests and FeNO measurements are widely used for the diagnosis and management of respiratory diseases. They are used to evaluate airway limitation and respiratory inflammation. Standard spirometers and nitric oxide (NO) analyzers are widely used in hospitals. However, their high price has made some hospitals in underdeveloped areas unable to afford or purchase these devices. The development of a new portable system (SUNVOU TM2125) combining FeNO measurement and spirometry provides additional possibilities for optimizing the diagnosis and management of respiratory diseases. However, its accuracy needs further validation.

Methods

The FeNO analysis component of SUNVOU TM2125 was compared with that of a widely used NO analyzer (NIOX VERO). The spirometry component of the TM2125 was compared with a standard spirometer (Jaeger MasterScreen) for pulmonary parameters such as FEV1, FVC, FEV1/FVC, and PEF. Pearson correlation and Bland–Altman plots were used to evaluate the agreement between the devices.

Results

FeNO values measured using TM2125 were higher than those measured using VERO, with a mean difference of 1.8 ppb. There was a strong correlation between FeNO values measured using the two devices (r = 0.988, p < 0.001). Bland–Altman plots showed a high degree of agreement between the two devices, with 93.3% of values within the 95% confidence interval range. The spirometric parameters (FEV1, FVC, FEV1/FVC, and PEF) measured using the TM2125 were lower than those measured using the MasterScreen. Good correlations were observed between the values measured using the TM2125 and MasterScreen (r > 0.9). Based on the Bland–Altman plots, there was a high degree of agreement between the devices.

Conclusion

The accuracy of FeNO and spirometry measurements using SUNVOU TM2125 was validated. This can help improve the diagnosis and monitoring of chronic respiratory diseases in underdeveloped countries.