bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the dosing-time-dependent antihypertensive effect of valsartan and aspirin through mathematical modeling
Authors: Cortés-Ríos Javiera , Rodriguez-Fernandez Maria
Published: March 2023

Chronopharmacology of arterial hypertension impacts the long-term cardiovascular risk of hypertensive subjects. Therefore, clinical and computational studies have proposed optimizing antihypertensive medications’ dosing time (Ta). However, the causes and mechanisms underlying the Ta-dependency antihypertensive effect have not been elucidated. Here we propose using a Ta- dependent effect model to understand and predict the antihypertensive effect of valsartan and aspirin throughout the day in subjects with grade I or II essential hypertension. The model based on physiological regulation mechanisms includes a periodic function for each parameter that changes significantly after treatment. Circadian variations of parameters depending on the dosing time allowed the determination of regulation mechanisms dependent on the circadian rhythm that were most relevant for the action of each drug. In the case of valsartan, it is the regulation of vasodilation and systemic vascular resistance. In the case of aspirin, the antithrombotic effect generates changes in the sensitivity of systemic vascular resistance and heart rate to changes in physical activity. Dosing time-dependent models predict a more significant effect on systemic vascular resistance and blood pressure when administering valsartan or aspirin at bedtime. However, circadian dependence on the regulation mechanisms showed different sensitivity of their circadian parameters and shapes of functions, presenting different phase shifts and amplitude. Therefore, different mechanisms of action and pharmacokinetic properties of each drug can generate different profiles of Ta-dependence of antihypertensive effect and optimal dosing times.
Causal relationship between thyroid dysfunction and hallux valgus: A two-sample Mendelian randomization study
Authors: Xiong Binglang , Bai Zixing , Cao Xuhan , Nie Duorui , Zhang Cheng , Sun Xudong , Guo Ziyan , Wen Jianmin , Sun Weidong
Published: March 2023

Introduction

Previous observational studies have reported that thyroid dysfunction is associated with hallux valgus (HV). However, the causal effect of thyroid dysfunction on hallux valgus is still unknown. To assess whether there is a causal relationship between thyroid dysfunction and hallux valgus, we performed a two-sample Mendelian randomization (MR) study.

Methods

The data of the two-sample Mendelian randomization study were obtained from public databases. In this study, hypothyroidism, hyperthyroidism, free thyroxine (FT4), and thyrotropin (TSH) were chosen as exposures. The single nucleotide polymorphisms (SNP) of hypothyroidism and hyperthyroidism were from the genome-wide association studies (GWAS) of the IEU database, including 337,159 subjects. Data for FT4 and TSH (72,167 subjects) were extracted from the ThyroidOmics Consortium. HV was used as the outcome. The SNPs associated with HV were selected from a GWAS of 202,617 individuals in the fignngen database. The inverse variance weighted (IVW) method was used as the primary analysis. Four complementary methods were applied, including MR-presso, MR-Egger, and weighted median. In addition, Cochran’s Q test, MR-presso, MR-Egger regression, and the leave-one-out test were used as sensitivity analysis, and the MR-pleiotropy test was performed to examine pleiotropy.

Results

According to the results of IVW, we found that there was a causal relationship between hypothyroidism and HV, and hypothyroidism increased the incidence of HV (OR = 2.838 (95% CI: 1.116–7.213); p = 0.028). There were no significant causal effects of hyperthyroidism, FT4, and TSH on HV (p > 0.05). Sensitivity analyses showed that the results were robust and reliable, and no horizontal pleiotropy was detected.

Conclusions

Our findings provided genetic support that hypothyroidism might increase the risk of HV. It will predict the occurrence of HV in patients with hypothyroidism and provide suggestions for early prevention and intervention.
Less sclerotic microarchitecture pattern with increased bone resorption in glucocorticoid-associated osteonecrosis of femoral head as compared to alcohol-associated osteonecrosis of femoral head
Authors: Chen Yiwei , Miao Yu , Liu Kexin , Zhu Bin , Xue Feng , Yin Junhui , Zou Jian , Li Guangyi , Zhang Changqing , Feng Yong
Published: March 2023

Background

Glucocorticoid usage and alcohol abuse are the most widely accepted risk factors for nontraumatic osteonecrosis of femoral head (ONFH). Despite distinct etiologies between glucocorticoid-associated ONFH (GONFH) and alcohol-associated ONFH (AONFH), little is known about the differences of the microarchitectural and histomorphologic characteristics between these subtypes of ONFH.

Purposes

To investigate bone microarchitecture, bone remodeling activity and histomorphology characteristics of different regions in femoral heads between GONFH and AONFH.

Methods

From September 2015 to October 2020, 85 patients diagnosed with GONFH and AONFH were recruited. Femoral heads were obtained after total hip replacement. Femoral head specimens were obtained from 42 patients (50 hips) with GONFH and 43 patients (50 hips) with AONFH. Micro-CT was utilized to assess the microstructure of 9 regions of interest (ROIs) in the femoral head. Along the supero-inferior orientation, the femoral head was divided into necrotic region, reactive interface, and normal region; along the medio-lateral orientation, the femoral head was divided into medial region, central region and lateral region. Decalcified and undecalcified bone histology was subsequently performed to evaluate histopathological alterations and bone remodeling levels.

Results

In the necrotic region, most of the microarchitectural parameters did not differ significantly between GONFH and AONFH, whereas both the reactive interface and normal region revealed a less sclerotic microarchitecture but a higher bone remodeling level in GONFH than AONFH. Despite similar necrotic pathological manifestations, subchondral trabecular microfracture in the necrotic region was more severe and vasculature of the reactive interface was more abundant in GONFH.

Conclusions

GONFH and AONFH shared similar microarchitecture and histopathological features in the necrotic region, while GONFH exhibited a less sclerotic microarchitecture and a more active bone metabolic status in both the reactive interface and normal region. These differences between GONFH and AONFH in bone microarchitectural and histopathological characteristics might contribute to the development of disease-modifying prevention strategies and treatments for ONFH, taking into etiologies.
Exploration of the skeletal phenotype of the Col1a1+/Mov13 mouse model for haploinsufficient osteogenesis imperfecta type 1
Authors: Claeys Lauria , Zhytnik Lidiia , Wisse Lisanne E. , van Essen Huib W. , Eekhoff E. Marelise W. , Pals Gerard , Bravenboer Nathalie , Micha Dimitra
Published: March 2023

Introduction

Osteogenesis Imperfecta is a rare genetic connective tissue disorder, characterized by skeletal dysplasia and fragile bones. Currently only two mouse models have been reported for haploinsufficient (HI) mild Osteogenesis Imperfecta (OI); the Col1a1+/Mov13 (Mov13) and the Col1a1+/-365 mouse model. The Mov13 mice were created by random insertion of the Mouse Moloney leukemia virus in the first intron of the Col1a1 gene, preventing the initiation of transcription. Since the development of the Mov13 mice almost four decades ago and its basic phenotypic characterization in the 90s, there have not been many further studies. We aimed to extensively characterize the Mov13 mouse model in order to critically evaluate its possible use for preclinical studies of HI OI.

Methods

Bone tissue from ten heterozygous Mov13 and ten wild-type littermates (WT) C57BL/6J mice (50% males per group) was analyzed at eight weeks of age with bone histomorphometry, micro computed tomography (microCT), 3-point bending, gene expression of different collagens, as well as serum markers of bone turnover

Results

The Mov13 mouse presented a lower bone strength and impaired material properties based on our results of 3-point bending and microCT analysis respectively. In contrast, no significant differences were found for all histomorphometric parameters. In addition, no significant differences in Col1a1 bone expression were present, but there was a significant lower P1NP concentration, a bone formation marker, measured in serum. Furthermore, bone tissue of Mov13 mice presented significantly higher expression of collagens (Col1a2, Col5a1 and Col5a2), and bone metabolism markers (Bglap, Fgf23, Smad7, Edn1 and Eln) compared to WT. Finally, we measured a significantly lower Col1a1 expression in heart and skin tissue and also determined a higher expression of other collagens in the heart tissue.

Conclusion

Although we did not detect a significant reduction in Col1a1 expression in the bone tissue, a change in bone structure and reduction in bone strength was noted. Regrettably, the variability of the bone phenotype and the appearance of severe lymphoma in adult Mov13 mice, does not favor their use for the testing of new long-term drug studies. As such, a new HI OI type 1 mouse model is urgently needed.
Thermal field modeling and characteristic analysis based on oil immersed transformer
Authors: Gao Chao , Huang Lijun , Feng Yuhui , Gao Erya , Yang Zhongqing , Wang Kai
Published: March 2023

Oil-immersion transformer plays an important role in the operation of power system, and its reliable operation is the basis of the safe and economic operation of power system. Transformer internal failure will not only cause the transformer to stop, but also damage, affecting the proper operation of the power system. The transformer is often in a high-temperature and high-pressure environment during its operation, so it is difficult to effectively and accurately protect the transformer from failure in the harsh working environment. Because the existing methods can not detect and protect the faults of transformer equipment sensitively and accurately, based on this, this paper carried out the research on the detection and protection of oil immersed transformer. By analyzing the calculation results, the relationship between the temperature rise of the transformer structure and the ambient temperature is discussed. It is found that the higher the ambient temperature of the transformer, the greater the harm to the equipment. High temperature area is mainly concentrated at the pull plate of transformer. This provides a reference for making the starting strategies of transformers in different environments, and helps to avoid mechanical structure damage and insulation aging damage caused by temperature.
Fisheries restoration: Lessons learnt from four benefit-cost models
Authors: Crookes Douglas
Published: March 2023

Globally, fisheries are in decline and in many parts of the world illegal fishing is a major cause of these declines. Ecological restoration of fisheries needs to be promoted, inter alia through improved enforcement, but, which method is the most successful at improving fish stocks, as well as having the highest economic returns? We compare one open-loop (without feedback) and three closed-loop (with feedback) benefit–cost models representing different restoration interventions aimed at promoting compliance. The hybrid systems methodology has been utilized, combining system dynamics, systems archetypes, mathematical differential equations and economic benefit–cost methodologies. The model is tested with reference to a case study of abalone (Haliotis midae) biomass restoration in the Table Mountain National Park marine area (Zone E), Cape Town. Stocks in Zone E have dropped to below the government’s management threshold for sustainable fisheries of 20 percent of the pre-fished levels, and urgent action is required to restore the stocks. According to the model, all proposed restoration interventions produce stock recovery to 100 percent of carrying capacity, well in excess of government targets of 40 percent. Also, all four models had a net present value of greater than zero, indicating substantial positive net benefits to restoration. Each model had specific management recommendations associated with it- greater involvement by the state, capital investment in restoration, changing poacher behavior and entrepreneurship. Although the Post Keynesian and Institutional model produced the highest net returns to restoration over 80 years (Net present value = US$12.66 million at a 6 % discount rate, 2021 prices), all the models are essentially co-evolutionary models, and have merit over different time periods, compliance rates and assumptions around discount rates. While the case study is developed for abalone the findings of the model are likely to be applicable in a wide range of fishery restoration contexts.
High-throughput micro-CT scanning and deep learning segmentation workflow for analyses of shelly invertebrates and their fossils: Examples from marine Bivalvia
Authors: Edie Stewart M. , Collins Katie S. , Jablonski David
Published: March 2023

The largest source of empirical data on the history of life largely derives from the marine invertebrates. Their rich fossil record is an important testing ground for macroecological and macroevolutionary theory, but much of this historical biodiversity remains locked away in consolidated sediments. Manually preparing invertebrate fossils out of their matrix can require weeks to months of careful excavation and cannot guarantee the recovery of important features on specimens. Micro-CT is greatly improving our access to the morphologies of these fossils, but it remains difficult to digitally separate specimens from sediments of similar compositions, e.g., calcareous shells in a carbonate rich matrix. Here we provide a workflow for using deep learning—a subset of machine learning based on artificial neural networks—to augment the segmentation of these difficult fossils. We also provide a guide for bulk scanning fossil and Recent shells, with sizes ranging from 1 mm to 20 cm, enabling the rapid acquisition of large-scale 3D datasets for macroevolutionary and macroecological analyses (300–500 shells in 8 hours of scanning). We then illustrate how these approaches have been used to access new dimensions of morphology, allowing rigorous statistical testing of spatial and temporal patterns in morphological evolution, which open novel research directions in the history of life.
cDNA sequencing increases the molecular diagnostic yield in Chediak-Higashi syndrome
Authors: Kuptanon Chulaluk , Morimoto Marie , Nicoli Elena-Raluca , Stephen Joshi , Yarnell David S. , Dorward Heidi , Owen William , Parikh Suhag , Ozbek Namik Yasar , Malbora Baris , Ciccone Carla , Gunay-Aygun Meral , Gahl William A. , Introne Wendy J. , Malicdan May Christine V.
Published: March 2023

Introduction: Chediak-Higashi syndrome (CHS) is rare autosomal recessive disorder caused by bi-allelic variants in the Lysosomal Trafficking Regulator (LYST) gene. Diagnosis is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects the majority of pathogenic variants, but some remain undetected for several individuals clinically diagnosed with CHS. In this study, cDNA Sanger sequencing was pursued as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing and to increase molecular diagnostic yield.

Methods: Six unrelated individuals with CHS were clinically evaluated and included in this study. gDNA Sanger sequencing and cDNA Sanger sequencing were performed to identify pathogenic LYST variants.

Results: Ten novel LYST alleles were identified, including eight nonsense or frameshift variants and two in-frame deletions. Six of these were identified by conventional gDNA Sanger sequencing; cDNA Sanger sequencing was required to identify the remaining variant alleles.

Conclusion: By utilizing cDNA sequencing as a complementary technique to identify LYST variants, a complete molecular diagnosis was obtained for all six CHS patients. In this small CHS cohort, the molecular diagnostic yield was increased, and canonical splice site variants identified from gDNA Sanger sequencing were validated by cDNA sequencing. The identification of novel LYST alleles will aid in diagnosing patients and these molecular diagnoses will also lead to genetic counseling, access to services and treatments and clinical trials in the future.
Effects of HAR1 on cognitive function in mice and the regulatory network of HAR1 determined by RNA sequencing and applied bioinformatics analysis
Authors: Zhang Luting , Lin Shengmou , Huang Kailing , Chen Allen , Li Nan , Shen Shuhan , Zheng Zhouxia , Shi Xiaoshun , Sun Jimei , Kong Jingyin , Chen Min
Published: March 2023

Background:HAR1 is a 118-bp segment that lies in a pair of novel non-coding RNA genes. It shows a dramatic accelerated change with an estimated 18 substitutions in the human lineage since the human–chimpanzee ancestor, compared with the expected 0.27 substitutions based on the slow rate of change in this region in other amniotes. Mutations of HAR1 lead to a different HAR1 secondary structure in humans compared to that in chimpanzees.

Methods: We cloned HAR1 into the EF-1α promoter vector to generate transgenic mice. Morris water maze tests and step-down passive avoidance tests were conducted to observe the changes in memory and cognitive abilities of mice. RNA-seq analysis was performed to identify differentially expressed genes (DEGs) between the experimental and control groups. Systematic bioinformatics analysis was used to confirm the pathways and functions that the DEGs were involved in.

Results: Memory and cognitive abilities of the transgenic mice were significantly improved. The results of Gene Ontology (GO) analysis showed that Neuron differentiation, Dentate gyrus development, Nervous system development, Cerebral cortex neuron differentiation, Cerebral cortex development, Cerebral cortex development and Neurogenesis are all significant GO terms related to brain development. The DEGs enriched in these terms included Lhx2, Emx2, Foxg1, Nr2e1 and Emx1. All these genes play an important role in regulating the functioning of Cajal–Retzius cells (CRs). The DEGs were also enriched in glutamatergic synapses, synapses, memory, and the positive regulation of long-term synaptic potentiation. In addition, “cellular response to calcium ions” exhibited the second highest rich factor in the GO analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the DEGs showed that the neuroactive ligand–receptor interaction pathway was the most significantly enriched pathway, and DEGs also notably enriched in neuroactive ligand–receptor interaction, axon guidance, and cholinergic synapses.

Conclusion:HAR1 overexpression led to improvements in memory and cognitive abilities of the transgenic mice. The possible mechanism for this was that the long non-coding RNA (lncRNA) HAR1A affected brain development by regulating the function of CRs. Moreover, HAR1A may be involved in ligand–receptor interaction, axon guidance, and synapse formation, all of which are important in brain development and evolution. Furthermore, cellular response to calcium may play an important role in those processes.
Differential regulatory T cell signature after recovery from mild COVID-19
Authors: de Sousa Palmeira Pedro Henrique , Peixoto Rephany Fonseca , Csordas Bárbara Guimarães , de Medeiros Isac Almeida , de Azevedo Fátima de Lourdes Assunção Araújo , Veras Robson Cavalcante , Janebro Daniele Idalino , Amaral Ian P.G. , Keesen Tatjana Souza Lima
Published: March 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a range of symptoms in which host immune response have been associated with disease progression. However, the putative role of regulatory T cells (Tregs) in determining COVID-19 outcomes has not been thoroughly investigated. Here, we compared peripheral Tregs between volunteers not previously infected with SARS-CoV-2 (healthy control [HC]) and volunteers who recovered from mild (Mild Recovered) and severe (Severe Recovered) COVID-19. Peripheral blood mononuclear cells (PBMC) were stimulated with SARS-CoV-2 synthetic peptides (Pool Spike CoV-2 and Pool CoV-2) or staphylococcal enterotoxin B (SEB). Results of a multicolor flow cytometric assay showed higher Treg frequency and expression of IL-10, IL-17, perforin, granzyme B, PD-1, and CD39/CD73 co-expression in Treg among the PBMC from the Mild Recovered group than in the Severe Recovered or HC groups for certain SARS-CoV-2 related stimulus. Moreover, Mild Recovered unstimulated samples presented a higher Tregs frequency and expression of IL-10 and granzyme B than did that of HC. Compared with Pool CoV-2 stimuli, Pool Spike CoV-2 reduced IL-10 expression and improved PD-1 expression in Tregs from volunteers in the Mild Recovered group. Interestingly, Pool Spike CoV-2 elicited a decrease in Treg IL-17+ frequency in the Severe Recovered group. In HC, the expression of latency-associated peptide (LAP) and cytotoxic granule co-expression by Tregs was higher in Pool CoV-2 stimulated samples. While Pool Spike CoV-2 stimulation reduced the frequency of IL-10+ and CTLA-4+ Tregs in PBMC from volunteers in the Mild Recovered group who had not experienced certain symptoms, higher levels of perforin and perforin+granzyme B+ co-expression by Tregs were found in the Mild Recovered group in volunteers who had experienced dyspnea. Finally, we found differential expression of CD39 and CD73 among volunteers in the Mild Recovered group between those who had and had not experienced musculoskeletal pain. Collectively, our study suggests that changes in the immunosuppressive repertoire of Tregs can influence the development of a distinct COVID-19 clinical profile, revealing that a possible modulation of Tregs exists among volunteers of the Mild Recovered group between those who did and did not develop certain symptoms, leading to mild disease.
MC38 colorectal tumor cell lines from two different sources display substantial differences in transcriptome, mutanome and neoantigen expression
Authors: Schrörs Barbara , Hos Brett J. , Yildiz Ikra G. , Löwer Martin , Lang Franziska , Holtsträter Christoph , Becker Julia , Vormehr Mathias , Sahin Ugur , Ossendorp Ferry , Diken Mustafa
Published: March 2023

Introduction

The cell line MC38 is a commonly used murine model for colorectal carcinoma. It has a high mutational burden, is sensitive to immune checkpoint immunotherapy and endogenous CD8+ T cell responses against neoantigens have been reported.

Methods

Here, we re-sequenced exomes and transcriptomes of MC38 cells from two different sources, namely Kerafast (originating from NCI/NIH, MC38-K) and the Leiden University Medical Center cell line collection (MC38-L), comparing the cell lines on the genomic and transcriptomic level and analyzing their recognition by CD8+ T cells with known neo-epitope specificity.

Results

The data reveals a distinct structural composition of MC38-K and MC38-L cell line genomes and different ploidies. Further, the MC38-L cell line harbored about 1.3-fold more single nucleotide variations and small insertions and deletions than the MC38-K cell line. In addition, the observed mutational signatures differed; only 35.3% of the non-synonymous variants and 5.4% of the fusion gene events were shared. Transcript expression values of both cell lines correlated strongly (p = 0.919), but we found different pathways enriched in the genes that were differentially upregulated in the MC38-L or MC38-K cells, respectively. Our data show that previously described neoantigens in the MC38 model such as Rpl18mut and Adpgkmut were absent in the MC38-K cell line resulting that such neoantigen-specific CD8+ T cells recognizing and killing MC38-L cells did not recognize or kill MC38-K cells.

Conclusion

This strongly indicates that at least two sub-cell lines of MC38 exist in the field and underlines the importance of meticulous tracking of investigated cell lines to obtain reproducible results, and for correct interpretation of the immunological data without artifacts. We present our analyses as a reference for researchers to select the appropriate sub-cell line for their own studies.
Humanized MISTRG as a preclinical in vivo model to study human neutrophil-mediated immune processes
Authors: Martinez-Sanz Paula , Laurent Adrien R. G. , Slot Edith , Hoogenboezem Mark , Bąbała Nikolina , van Bruggen Robin , Rongvaux Anthony , Flavell Richard A. , Tytgat Godelieve A. M. , Franke Katka , Matlung Hanke L. , Kuijpers Taco W. , Amsen Derk , Karrich Julien J.
Published: March 2023

Introduction

MISTRG mice have been genetically modified to allow development of a human myeloid compartment from engrafted human CD34+ haemopoietic stem cells, making them particularly suited to study the human innate immune system in vivo. Here, we characterized the human neutrophil population in these mice to establish a model that can be used to study the biology and contribution in immune processes of these cells in vivo.

Methods and results

We could isolate human bone marrow neutrophils from humanized MISTRG mice and confirmed that all neutrophil maturation stages from promyelocytes (CD11b–CD16–) to end-stage segmented cells (CD11b+CD16+) were present. We documented that these cells possessed normal functional properties, including degranulation, reactive oxygen species production, adhesion, and antibody-dependent cellular cytotoxicity towards antibody-opsonized tumor cells ex vivo. The acquisition of functional capacities positively correlated with the maturation state of the cell. We found that human neutrophils were retained in the bone marrow of humanized MISTRG mice during steady state. However, the mature segmented CD11b+CD16+ human neutrophils were released from the bone marrow in response to two well-established neutrophil-mobilizing agents (i.e., G-CSF and/or CXCR4 antagonist Plerixafor). Moreover, the neutrophil population in the humanized MISTRG mice actively reacted to thioglycolate-induced peritonitis and could infiltrate implanted human tumors, as shown by flow cytometry and fluorescent microscopy.

Discussion

These results show that functional human neutrophils are generated and can be studied in vivo using the humanized MISTRG mice, providing a model to study the various functions of neutrophils in inflammation and in tumors.
Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population
Authors: Kawasaki Aya , Sada Ken-ei , Kusumawati Premita Ari , Hirano Fumio , Kobayashi Shigeto , Nagasaka Kenji , Sugihara Takahiko , Ono Nobuyuki , Fujimoto Takashi , Kusaoi Makio , Tamura Naoto , Kusanagi Yasuyoshi , Itoh Kenji , Sumida Takayuki , Yamagata Kunihiro , Hashimoto Hiroshi , Makino Hirofumi , Arimura Yoshihiro , Harigai Masayoshi , Tsuchiya Naoyuki
Published: March 2023

Background

Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV.

Methods

First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method.

Results

The association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40–2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34–2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02).

Conclusion

HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.
Regulation of CD8 T cell by B-cells: A narrative review
Authors: Van Meerhaeghe Tess , Néel Antoine , Brouard Sophie , Degauque Nicolas
Published: March 2023

Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.
Labour promotes systemic mobilisation of monocytes, T cell activation and local secretion of chemotactic factors in the intervillous space of the placenta
Authors: Vikberg Sara , Lindau Robert , Solders Martin , Raffetseder Johanna , Budhwar Snehil , Ernerudh Jan , Tiblad Eleonor , Kaipe Helen
Published: March 2023

During pregnancy, maternal blood circulates through the intervillous space of the placenta and the reciprocal interactions between foetal tissues and maternal immune cells makes the intervillous space a unique immunological niche. Labour is characterised by a proinflammatory response in the myometrium, but the relationship between local and systemic changes during the onset of labour remains elusive. We here aimed to investigate how the systemic and intervillous circulatory systems are affected during labour from an immunological point of view. We report that the proportion of monocytes is dramatically higher in peripheral (PB), intervillous blood (IVB) and decidua in labouring (n = 14) compared to non-labouring women (n = 15), suggesting that labour leads to both a systemic and local mobilisation of monocytes. Labour was associated with a relative increase of effector memory T cells in the intervillous space compared to the periphery, and MAIT cells and T cells showed an elevated expression of activation markers both in PB and IVB. Intervillous monocytes consisted to a higher degree of CD14+CD16+ intermediate monocytes compared to peripheral monocytes, independently of mode of delivery, and displayed an altered phenotypic expression pattern. A proximity extension assay analysis of 168 proteins revealed that several proteins associated to myeloid cell migration and function, including CCL2 and M-CSF, were upregulated in IVB plasma in labouring women. Thus, the intervillous space could be a bridging site for the communication between the placenta and the periphery, which contribute to monocyte mobilisation and generation of inflammatory reactions during spontaneous labour.
Inflammasome and pyroptosis in autoimmune liver diseases
Authors: Wang Jixuan , Sun Zhiwen , Xie Jingri , Ji Wanli , Cui Yang , Ai Zongxiong , Liang Guoying
Published: March 2023

Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.
Integrated analysis of cell-specific gene expression in peripheral blood using ISG15 as a marker of rejection in kidney transplantation
Authors: Zhang Zijian , Qin Yan , Wang Yicun , Li Shuai , Hu Xiaopeng
Published: March 2023

Background

Allograft kidney rejection can lead to graft dysfunction and graft loss. Protocol biopsy poses additional risk for recipients with normal renal function. The transcriptome of peripheral blood mononuclear cells (PBMCs) contains tremendous information and has potential application value for non-invasive diagnosis.

Methods

From the Gene Expression Omnibus database, we collected three datasets containing 109 rejected samples and 215 normal controls. After data filter and normalization, we performed deconvolution of bulk RNA sequencing data to predict cell type and cell-type specific gene expression. Subsequently, we calculated cell communication analysis by Tensor-cell2cell and conducted the least absolute shrinkage and selection operator (LASSO) logistic regression to screen the robust differentially expressed genes (DEGs). These gene expression levels were validated in mice kidney transplantation acute rejection model. The function of the novel gene ISG15 in monocytes was further confirmed by gene knockdown and lymphocyte-stimulated assay.

Results

The bulk RNA-seq hardly predicted kidney transplant rejection accurately. Seven types of immune cells and transcriptomic characteristics were predicted from the gene expression data. The monocytes showed significant differences in amount and gene expression of rejection. The cell-to-cell communication indicated the enrichment of antigen presentation and T cell activation ligand-receptor pairs. Then 10 robust genes were found by Lasso regression and a novel gene ISG15 remained differential expression in monocytes between rejection samples and normal control both in public data and animal model. Furthermore, ISG15 also showed a critical role in promoting the proliferation of T cells.

Conclusion

This study identified and validated a novel gene ISG15 associated with rejection in peripheral blood after kidney transplantation, which is a significant non-invasive diagnosis and a potential therapeutic target.
Interannual modulations in sea level rise over tropical Northwest Pacific in satellite altimeter measurements
Authors: Uppara Umakanth , Moon Jae-Hong , Jang Chan Joo , Jo Young-Heon
Published: March 2023

The sea level rise (SLR) estimates in tropical Pacific are dominantly influenced by interannual and interdecadal variations in limited data sets such as satellite altimeter measurements. The Sea Level Anomaly (SLA) trends during 1993–2012 (extensively reported) and 1993–2020 significantly differ with substantial weakening during 1993–2020 over tropical Northwest Pacific (NWP; 0–15°N; 120°E −170°E). An ensemble empirical mode decomposition (EEMD) approach is employed to derive residual SLA by removing the high-frequency SLA variations including the interannual and interdecadal variations. The linear trends estimated from residual SLA provides a better estimate for the trends in SLA. The residual trends have greatly reduced the observed differences in SLA trends between 1993–2012 and 1993–2020. Our analysis suggests that it is the interdecadal variations in SLA that caused the weakening of overall trend during 1993–2020. In particular, the interdecadal trend in SLA over NWP is ≈ −1.73 mm year−1, whereas the trends in total and the residual SLA are estimated as 4.26 mm year−1 and 6.32 mm year−1, respectively. Furthermore, it is observed that there is an in-phase connection between the interannual and the interdecadal variations of SLA associated with La Niña compared with El Niño. Therefore, the non-occurrence of La Niña after 2012 to 2020 possibly has contributed for the decreasing trend in interdecadal variations due to its in-phase connection. In short, the complexity of variations in SLA at different timescales over NWP and the Pacific significantly influences the SLA trend estimates.
Artificial intelligence-supported web application design and development for reducing polypharmacy side effects and supporting rational drug use in geriatric patients
Authors: Akyon Seyma Handan , Akyon Fatih Cagatay , Yılmaz Tarık Eren
Published: March 2023

Introduction

The main complications of polypharmacy, which is known as the simultaneous use of more than five drugs, are potentially inappropriate medicines(PIMs), drug–drug, and drug-disease interaction. It is aimed to prepare an auxiliary tool to reduce the complications of polypharmacy and to support rational drug use(RDU), by evaluating the patient with age, drugs, and chronic diseases in this study.

Materials and methods

In the first phase of this study, as methodological research, an up-to-date and comprehensive auxiliary tool as a reference method was generated with a database containing interaction information of 430 most commonly used drug agents and chronic diseases in geriatrics in the light of current and valid 6 PIM criteria for geriatric patients, and medication prospectuses, relevant current articles, and guidelines. Then, an artificial intelligence(AI) supported web application was designed and developed to facilitate the practical use of the tool. Afterward, the data of a cross-sectional observational single-center study were used for the rate and time of PIM and drug interaction detection with the web application. The proposed web application is publicly available at https://fastrational.com/.

Results

While the PIM coverage rate with the proposed tool was 75.3%, the PIM coverage rate of EU(7)-PIM, US-FORTA, TIME-to-STOPP, Beers 2019, STOPP, Priscus criteria in the web application database respectively(63.5%–19.5%) from the highest to the lowest. The proposed tool includes all PIMs, drug–drug, and drug-disease interaction information detected with other criteria. A general practitioner detects interactions for a patient without the web application in 2278 s on average, while the time with the web application is decreased to 33.8 s on average, and this situation is statistically significant.

Discussion

In the literature and this study, the PIM criteria alone are insufficient to include actively used medicines and it shows heterogeneity. In addition, many studies showed that the biggest obstacle to drug regulation in practice is “time constraints.” The proposed comprehensive auxiliary tool analyzes age, drugs, and diseases specifically for the patient 60 times faster than the manual method, and it provides quick access to the relevant references, and ultimately supports RDU for the clinician, with the first and only AI-supported web application.
Application of low dose aspirin in pre-eclampsia
Authors: Ren Yu , Zhao Yong , Yang Xiangdong , Shen Chaojun , Luo Hua
Published: March 2023

Aspirin is widely used in the primary and secondary prevention of cardiovascular and cerebrovascular diseases. Low-dose aspirin is also widely used to prevent pre-eclampsia and fetal growth retardation in utero. However, the use of aspirin during pregnancy is controversial. Since 1985, when aspirin was reported to be effective in obstetrics, numerous studies have attempted to determine the effect of low-dose aspirin on the morbidity of pre-eclampsia but have remained inconclusive. Guidelines for aspirin in preventing pre-eclampsia are different in different countries and regions. This article summarizes the research progress, mechanism, and application prospect of aspirin in preventing pre-eclampsia, providing a theoretical basis for the rational use of aspirin in pregnancy.
Trace copper-mediated asexual development via a superoxide dismutase and induction of AobrlA in Aspergillus oryzae
Authors: Katayama Takuya , Maruyama Jun-ichi
Published: March 2023

The filamentous fungus Aspergillus oryzae, in which sexual reproduction remains to be discovered, proliferates mainly via asexual spores (conidia). Therefore, despite its industrial importance in food fermentation and recombinant protein production, breeding beneficial strains by genetic crosses is difficult. In Aspergillus flavus, which is genetically close to A. oryzae, structures known as sclerotia are formed asexually, but they are also related to sexual development. Sclerotia are observed in some A. oryzae strains, although no sclerotia formation has been reported in most strains. A better understanding of the regulatory mechanisms underlying sclerotia formation in A. oryzae may contribute to discover its sexual development. Some factors involved in sclerotia formation have been previously identified, but their regulatory mechanisms have not been well studied in A. oryzae. In this study, we found that copper strongly inhibited sclerotia formation and induced conidiation. Deletion of AobrlA encoding a core regulator of conidiation and ecdR involved in transcriptional induction of AobrlA suppressed the copper-mediated inhibition of sclerotia formation, suggesting that AobrlA induction in response to copper leads not only to conidiation but also to inhibition of sclerotia formation. In addition, deletion of the copper-dependent superoxide dismutase (SOD) gene and its copper chaperone gene partially suppressed such copper-mediated induction of conidiation and inhibition of sclerotia formation, indicating that copper regulates asexual development via the copper-dependent SOD. Taken together, our results demonstrate that copper regulates asexual development, such as sclerotia formation and conidiation, via the copper-dependent SOD and transcriptional induction of AobrlA in A. oryzae.
Cortical activation and functional connectivity during locomotion tasks in Parkinson’s disease with freezing of gait
Authors: Feng HongSheng , Jiang YanNa , Lin JinPeng , Qin WenTing , Jin LingJing , Shen Xia
Published: March 2023

Background

Freezing of gait (FoG) is a severely disabling symptom in Parkinson’s disease (PD). The cortical mechanisms underlying FoG during locomotion tasks have rarely been investigated.

Objectives

We aimed to compare the cerebral haemodynamic response during FoG-prone locomotion tasks in patients with PD and FoG (PD-FoG), patients with PD but without FoG (PD-nFoG), and healthy controls (HCs).

Methods

Twelve PD-FoG patients, 10 PD-nFoG patients, and 12 HCs were included in the study. Locomotion tasks included normal stepping, normal turning and fast turning ranked as three difficulty levels based on kinematic requirements and probability of provoking FoG. During each task, we used functional near-infrared spectroscopy to capture concentration changes of oxygenated haemoglobin (ΔHBO2) and deoxygenated haemoglobin (ΔHHB) that reflected cortical activation, and recorded task performance time. The cortical regions of interest (ROIs) were prefrontal cortex (PFC), supplementary motor area (SMA), premotor cortex (PMC), and sensorimotor cortex (SMC). Intra-cortical functional connectivity during each task was estimated based on correlation of ΔHBO2 between ROIs. Two-way multivariate ANOVA with task performance time as a covariate was conducted to investigate task and group effects on cerebral haemodynamic responses of ROIs. Z statistics of z-scored connectivity between ROIs were used to determine task and group effects on functional connectivity.

Results

PD-FoG patients spent a nearly significant longer time completing locomotion tasks than PD-nFoG patients. Compared with PD-nFoG patients, they showed weaker activation (less ΔHBO2) in the PFC and PMC. Compared with HCs, they had comparable ΔHBO2 in all ROIs but more negative ΔHHB in the SMC, whereas PD-nFoG showed SMA and PMC hyperactivity but more negative ΔHHB in the SMC. With increased task difficulty, ΔHBO2 increased in each ROI except in the PFC. Regarding functional connectivity during normal stepping, PD-FoG patients showed positive and strong PFC-PMC connectivity, in contrast to the negative PFC-PMC connectivity observed in HCs. They also had greater PFC-SMC connectivity than the other groups. However, they exhibited decreased SMA-SMC connectivity when task difficulty increased and had lower SMA-PMC connectivity than HCs during fast turning.

Conclusion

Insufficient compensatory cortical activation and depletion of functional connectivity during complex locomotion in PD-FoG patients could be potential mechanisms underlying FoG.

Clinical trial registration

Chinese clinical trial registry (URL: http://www.chictr.org.cn, registration number: ChiCTR2100042813).
Novel pathophysiological insights into CAR-T cell associated neurotoxicity
Authors: Genoud Vassilis , Migliorini Denis
Published: March 2023

Chimeric antigen receptor (CAR) T cell therapy represents a scientific breakthrough in the treatment of advanced hematological malignancies. It relies on cell engineering to direct the powerful cytotoxic T-cell activity toward tumor cells. Nevertheless, these highly powerful cell therapies can trigger substantial toxicities such as cytokine release syndrome (CRS) and immune cell-associated neurological syndrome (ICANS). These potentially fatal side effects are now better understood and managed in the clinic but still require intensive patient follow-up and management. Some specific mechanisms seem associated with the development of ICANS, such as cytokine surge caused by activated CAR-T cells, off-tumor targeting of CD19, and vascular leak. Therapeutic tools are being developed aiming at obtaining better control of toxicity. In this review, we focus on the current understanding of ICANS, novel findings, and current gaps.