bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the diagnostic genes and immune cell infiltration characteristics of gastric cancer using bioinformatics analysis and machine learning
Authors: Xie Rongjun , Liu Longfei , Lu Xianzhou , He Chengjian , Li Guoxin
Published: January 2023

Background: Finding reliable diagnostic markers for gastric cancer (GC) is important. This work uses machine learning (ML) to identify GC diagnostic genes and investigate their connection with immune cell infiltration.

Methods: We downloaded eight GC-related datasets from GEO, TCGA, and GTEx. GSE13911, GSE15459, GSE19826, GSE54129, and GSE79973 were used as the training set, GSE66229 as the validation set A, and TCGA & GTEx as the validation set B. First, the training set screened differentially expressed genes (DEGs), and gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG), disease Ontology (DO), and gene set enrichment analysis (GSEA) analyses were performed. Then, the candidate diagnostic genes were screened by LASSO and SVM-RFE algorithms, and receiver operating characteristic (ROC) curves evaluated the diagnostic efficacy. Then, the infiltration characteristics of immune cells in GC samples were analyzed by CIBERSORT, and correlation analysis was performed. Finally, mutation and survival analyses were performed for diagnostic genes.

Results: We found 207 up-regulated genes and 349 down-regulated genes among 556 DEGs. gene ontology analysis significantly enriched 413 functional annotations, including 310 biological processes, 23 cellular components, and 80 molecular functions. Six of these biological processes are closely related to immunity. KEGG analysis significantly enriched 11 signaling pathways. 244 diseases were closely related to Ontology analysis. Multiple entries of the gene set enrichment analysis analysis were closely related to immunity. Machine learning screened eight candidate diagnostic genes and further validated them to identify ABCA8, COL4A1, FAP, LY6E, MAMDC2, and TMEM100 as diagnostic genes. Six diagnostic genes were mutated to some extent in GC. ABCA8, COL4A1, LY6E, MAMDC2, TMEM100 had prognostic value.

Conclusion: We screened six diagnostic genes for gastric cancer through bioinformatic analysis and machine learning, which are intimately related to immune cell infiltration and have a definite prognostic value.
Pharmacogenomic variabilities in geo-ancestral subpopulations and their clinical implications: Results of collaborations with Hmong in the United States
Authors: Sun Boguang , Wen Ya-Feng , Culhane-Pera Kathleen A. , Lo Muaj , Straka Robert J.
Published: January 2023

Underrepresentation of subpopulations within geo-ancestral groups engaged in research can exacerbate health disparities and impair progress toward personalized medicine. This is particularly important when implementing pharmacogenomics which uses genomic-based sources of variability to guide medication selection and dosing. This mini-review focuses on pharmacogenomic findings with Hmong in the United States and their potential clinical implications. By actively engaging Hmong community in pharmacogenomic-based research, several clinically relevant differences in allele frequencies were observed within key pharmacogenes such as CYP2C9 and CYP2C19 in Hmong compared to those in either East Asians or Europeans. Additionally, using state-of-the-art genome sequencing approaches, Hmong appear to possess novel genetic variants within CYP2D6, a critical pharmacogene affecting pharmacokinetics of a broad range of medications. The allele frequency differences and novel alleles in Hmong have translational impact and real-world clinical consequences. For example, Hmong patients exhibited a lower warfarin stable dose requirement compared to East Asian patients. This was predicted based on Hmong’s unique genetic and non-genetic factors and confirmed using real-world data from clinical practice settings. By presenting evidence of the genetic uniqueness and its translational impact within subpopulations, such as the Hmong, we hope to inspire greater inclusion of other geo-ancestrally underrepresented subpopulations in pharmacogenomic-based research.
Identification of rare thalassemia variants using third-generation sequencing
Authors: Liu Qin , Chen Qianting , Zhang Zonglei , Peng Shiyi , Liu Jing , Pang Jialun , Jia Zhengjun , Xi Hui , Li Jiaqi , Chen Libao , Liu Yinyin , Peng Ying
Published: January 2023

Routine PCR, Sanger sequencing, and specially designed GAP-PCR are often used in the genetic analysis of thalassemia, but all these methods have limitations. In this study, we evaluated a new third-generation sequencing-based approach termed comprehensive analysis of thalassemia alleles (CATSA) in subjects with no variants identified by routine PCR, Sanger sequencing, and specially designed GAP-PCR. Hemoglobin testing and routine PCR tests for 23 common variants were performed for 3,033 subjects. Then, Sanger sequencing and specially designed GAP-PCR were performed for a subject with no variants identified by routine PCR, no iron deficiency, and positive hemoglobin testing. Finally, the new CATSA method was conducted for the subjects with no variants identified by Sanger sequencing and specially designed GAP-PCR. In the 49 subjects tested by CATSA, eight subjects had variants identified. Sanger sequencing and independent PCR confirmed the CATSA result. In addition, it is the first time that Hb Lepore was identified in Hunan Province. In total, traditional methods identified variants in 759 of the 3,033 subjects, while CATSA identified additional variants in eight subjects. CATSA showed great advantages compared to the other genetic testing methods.
A four-lncRNA risk signature for prognostic prediction of osteosarcoma
Authors: Liu Huanlong , Chen Chao , Liu Long , Wang Zengtao
Published: January 2023

Aim: Osteosarcoma is the most common primary malignant tumor of bone. However, our understanding of the prognostic indicators and the genetic mechanisms of the disease progression are still incomplete. The aim of this study was to identify a long noncoding RNA (lncRNA) risk signature for osteosarcoma survival prediction.

Methods: RNA sequencing data and relevant clinical information of osteosarcoma patients were downloaded from the database of Therapeutically Applicable Research to Generate Effective Treatments (TARGET). We analyzed the differentially expressed lncRNAs between deceased and living patients by univariate and multivariate Cox regression analysis to identify a risk signature. We calculated a prognostic risk score for each sample according to this prognosis signature, and divided patients into high-risk and low-risk groups according to the median value of the risk score (0.975). Kaplan–Meier analysis and receiver operating characteristic (ROC) curve statistics were used to evaluate the performance of the signature. Next, we analyzed the signature’s potential function through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene-set enrichment analysis (GSEA). Lastly, qRT-PCR was used to validate the expression levels of the four lncRNAs in clinical samples.

Results: Twenty-six differentially expressed lncRNAs were identified between deceased and living patients. Four of these lncRNAs (CTB-4E7.1, RP11-553A10.1, RP11-24N18.1, and PVRL3-AS1) were identified as independent prognostic factors, and a risk signature of these four lncRNAs for osteosarcoma survival prediction was constructed. Kaplan–Meier analysis showed that the five-year survival time in high-risk and low-risk groups was 33.1% and 82.5%, and the area under the curve (AUC) of the ROC was 0.784, which demonstrated that the prognostic signature was reliable and had the potential to predict the survival of patients with osteosarcoma. The expression level of the four lncRNAs in osteosarcoma tissues and cells was determined by qRT-PCR. Functional enrichment analysis suggested that the signature might be related to osteosarcoma through regulation of the MAPK signaling pathway, the PI3K-Akt signaling pathway, and the extracellular matrix and also provided new insights into the study of osteosarcoma, including the role of papillomavirus infection, olfactory receptor activity, and olfactory transduction in osteosarcoma.

Conclusion: We constructed a novel lncRNA risk signature that served as an independent biomarker for predicting the prognosis of osteosarcoma patients.
Bioinformatic analysis and machine learning to identify the diagnostic biomarkers and immune infiltration in adenomyosis
Authors: Liu Dan , Yin Xiangjie , Guan Xiaohong , Li Kunming
Published: January 2023

Background: Adenomyosis is a hormone-dependent benign gynecological disease characterized by the invasion of the endometrium into the myometrium. Women with adenomyosis can suffer from abnormal uterine bleeding, severe pelvic pain, and subfertility or infertility, which can interfere with their quality of life. However, effective diagnostic biomarkers for adenomyosis are currently lacking. The aim of this study is to explore the mechanism of adenomyosis by identifying biomarkers and potential therapeutic targets for adenomyosis and analyzing their correlation with immune infiltration in adenomyosis.

Methods: Two datasets, GSE78851 and GSE68870, were downloaded and merged for differential expression analysis and functional enrichment analysis using R software. Weighted gene co-expression network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and support vector machine-recursive feature elimination (SVE-RFE) were combined to explore candidate genes. Quantitative reverse transcriptase PCR (qRT-PCR) was conducted to verify the biomarkers and receiver operating characteristic curve analysis was used to assess the diagnostic value of each biomarker. Single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT were used to explore immune cell infiltration in adenomyosis and the correlation between diagnostic biomarkers and immune cells.

Results: A total of 318 genes were differentially expressed. Through the analysis of differentially expressed genes and WGCNA, we obtained 189 adenomyosis-related genes. After utilizing the LASSO and SVM-RFE algorithms, four hub genes, namely, six-transmembrane epithelial antigen of the prostate-1 (STEAP1), translocase of outer mitochondrial membrane 20 (TOMM20), glycosyltransferase eight domain-containing 2 (GLT8D2), and NME/NM23 family member 5 (NME5) expressed in nucleoside-diphosphate kinase, were identified and verified by qRT-PCR. Immune infiltration analysis indicated that T helper 17 cells, CD56dim natural killer cells, monocytes, and memory B-cell may be associated with the occurrence of adenomyosis. There were significant correlations between the diagnostic biomarkers and immune cells.

Conclusion: STEAP1, TOMM20, GLT8D2, and NME5 were identified as potential biomarkers and therapeutic targets for adenomyosis. Immune infiltration may contribute to the onset and progression of adenomyosis.
Case report: Therapy adherence, MTTP variants, and course of atheroma in two patients with HoFH on low-dose, long-term lomitapide therapy
Authors: Kayikcioglu Meral , Ozkan Hasan Selcuk , Yagmur Burcu , Bayraktaroglu Selen , Vardarli Asli Tetik
Published: January 2023

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare and devastating genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) leading to an increased risk of premature atherosclerosis. Patients with Homozygous familial hypercholesterolemia mostly present with mutations in LDLR; however, herein, we present two cases with concomitant microsomal triglyceride transfer protein mutations, who showed different clinical courses and treatment adherence on long-term therapy with the new MTTP inhibitor lomitapide.

Objectives: We aimed to present the possibility of preventing the progression of atherosclerotic burden with effective and safe LDL-C reduction in patients with Homozygous familial hypercholesterolemia on low-dose lomitapide therapy and emphasize the role of treatment adherence in therapy success.

Methods: We present two patients with phenotypically Homozygous familial hypercholesterolemia, a compound heterozygous woman and a simple homozygous man, both with LDLR and additional MTTP mutations, who were treated with the MTTP-inhibiting agent lomitapide, with different treatment compliances. The role of impulsivity was investigated through Barratt Impulsivity Scale 11, and the extent of the atherosclerotic burden was followed up using coronary artery calcium scoring, echocardiographic and sonographic findings, and, eventually, through a strict follow-up of laboratory parameters. The patients were on lomitapide for 8 and 5 years, respectively, with no adverse effects.

Conclusion: When accompanied by good adherence to therapy, low-dose lomitapide on top of standard lipid-lowering therapy with decreased frequency of lipid apheresis prevented the progression of atherosclerotic burden. Non-compliance might occur due to patient impulsivity and non-adherence to a low-fat diet.
Enrichment of titin-truncating variants in exon 327 in dilated cardiomyopathy and its relevance to reduced nonsense-mediated mRNA decay efficiency
Authors: Kim Young-gon , Ha Changhee , Shin Sunghwan , Park Jong-ho , Jang Ja-Hyun , Kim Jong-Won
Published: January 2023

Titin truncating variants (TTNtvs) are the most common genetic cause of dilated cardiomyopathy (DCM). Among four regions of titin, A-band enrichment of DCM-causing TTNtvs is widely accepted but the underlying mechanism is still unknown. Meanwhile, few reports have identified exon 327 as a highly mutated A-band exon but the degree of exon 327 enrichment has not been quantitatively investigated. To find the real hotspot of DCM-causing TTNtvs, we aimed to reassess the degree of TTNtv enrichment in known titin regions and in exon 327, separately. In addition, we tried to explain exon 327 clustering in terms of nonsense-mediated mRNA decay (NMD) efficiency and a dominant negative mechanism recently proposed. Research papers focusing on TTNtvs found in patients with DCM were collected. A total of 612 patients with TTNtv-realated DCM were obtained from 10 studies. In the four regions of TTN and exon 327, the degree of TTNtvs enrichment was calculated in a way that the effect of distribution of highly expressed exons was normalized. As a result, exon 327 was the only region that showed significant enrichment for DCM-related TTNtv (p < .001). On the other hand, other A-band exons had almost the same number of TTNtv of random distribution. A review of RNAseq data revealed that the median allelic imbalance deviation of exon 327 TTNtvs was .04, indicating almost zero NMD. From these findings, we propose that the widely accepted A-band enrichment of DCM-related TTNtv is mostly attributable to exon 327 enrichment. In addition, based on the recently demonstrated dominant negative mechanism, the extremely low NMD efficiency seems to contribute to exon 327 enrichment.
Identification of a nucleotide metabolism-related signature to predict prognosis and guide patient care in hepatocellular carcinoma
Authors: Li Yu , Wu Chunyan , Ge Yingnan , Chen Xi , Zhu Li , Chu Ling , Wang Jia , Yan Meiling , Deng Hao
Published: January 2023

Background: Hepatocellular carcinoma is a highly malignant tumor with significant heterogeneity. Metabolic reprogramming plays an essential role in the progression of hepatocellular carcinoma. Among them, nucleotide metabolism needs further investigation.

Methods: Based on the bioinformatics approach, eleven prognosis-related nucleotide metabolism genes of hepatocellular carcinoma were screened in this study. Based on the Lasso-Cox regression method, we finally identified a prognostic model containing six genes and calculated the risk score for each patient. In addition, a nomogram was constructed on the basis of pathological stage and risk score.

Results: Patients with high-risk score had worse prognosis than those with low-risk. The predictive efficiency of the model was efficient in both the TCGA dataset and the ICGC dataset. The risk score is an independent prognostic factor that can be used to screen chemotherapy drugs. In addition, the risk score can be useful in guiding patient care at an early stage.

Conclusion: Nucleotide metabolism-related prognostic model can more accurately predict the prognosis of patients with hepatocellular carcinoma. As a novel prediction model, it is expected to help clinical staff to provide targeted treatment and nursing to patients.
Honey bee populations of the USA display restrictions in their mtDNA haplotype diversity
Authors: Alburaki Mohamed , Madella Shayne , Lopez Jillian , Bouga Maria , Chen Yanping , vanEngelsdorp Dennis
Published: January 2023

The genetic diversity of the USA honey bee (Apis mellifera L.) populations was examined through a molecular approach using two mitochondrial DNA (mtDNA) markers. A total of 1,063 samples were analyzed for the mtDNA intergenic region located between the cytochrome c oxidase I and II (COI-COII) and 401 samples were investigated for the NADH dehydrogenase 2 (ND2) coding gene. The samples represented 45 states, the District of Colombia and two territories of the USA. Nationwide, three maternal evolutionary lineages were identified: the North Mediterranean lineage C (93.79%), the West Mediterranean lineage M (3.2%) and the African lineage A (3.01%). A total of 27 haplotypes were identified, 13 of them (95.11%) were already reported and 14 others (4.87%) were found to be novel haplotypes exclusive to the USA. The number of haplotypes per state/territory ranged between two and eight and the haplotype diversity H ranged between 0.236–0.763, with a nationwide haplotype diversity of 0.597. Furthermore, the honey bee populations of the USA were shown to rely heavily (76.64%) on two single haplotypes (C1 = 38.76%, C2j = 37.62%) of the same lineage characterizing A. m. ligustica and A. m. carnica subspecies, respectively. Molecular-variance parsimony in COI-COII and ND2 confirmed this finding and underlined the central and ancestral position of C2d within the C lineage. Moreover, major haplotypes of A. m. mellifera (M3a, M7b, M7c) were recorded in six states (AL, AR, HI, MO, NM and WA). Four classic African haplotypes (A1e, A1v, A4, A4p) were also identified in nine states and Puerto Rico, with higher frequencies in southern states like LA, FL and TX. This data suggests the need to evaluate if a restricted mtDNA haplotype diversity in the US honey bee populations could have negative impacts on the beekeeping sustainability of this country.
Case report: Craniofrontonasal syndrome caused by a novel variant in the EFNB1 gene in a Colombian woman
Authors: Pachajoa Harry , Vasquez-Forero Diana Marcela , Giraldo-Ocampo Sebastian
Published: January 2023

Craniofrontonasal Syndrome is a very rare dominant X-linked genetic disorder characterized by symptoms such as hypertelorism, craniosynostosis, eye alterations, bifid nose tip, and longitudinal ridging and splitting of nails. Heterozygous females are usually the patients severely affected. To date, clinical or genetic data have not been published for these patients in Colombia. Here we report a female proband with coronal craniosynostosis, hypertelorism, strabismus, rotational nystagmus, high-arched palate, dental crowding, scoliosis, severe pectus excavatum, unilateral breast hypoplasia, and brachydactyly; diagnosed with Craniofrontonasal Syndrome with the novel heterozygous variant c.374A>C (p.Glu125Ala) in the EFNB1 gene. So far, she has been treated with physical therapy and surgical correction of the bifid nose and an umbilical hernia. To the best of our knowledge, this is the first report of a patient with this rare genetic disorder in Colombia, expanding its mutational spectrum and highlighting the importance of genetic evaluation of patients with craniosynostosis and facial dysmorphism.
Molecular mechanisms of long noncoding RNAs associated with cervical cancer radiosensitivity
Authors: Wu Shuying , Zhu He , Wu Yishi , Wang Cong , Duan Xuefeng , Xu Tianmin
Published: January 2023

Despite advances in cervical cancer screening and human papilloma virus (HPV) vaccines, cervical cancer remains a global health burden. The standard treatment of cervical cancer includes surgery, radiation therapy, and chemotherapy. Radiotherapy (RT) is the primary treatment for advanced-stage disease. However, due to radioresistance, most patients in the advanced stage have an adverse outcome. Recent studies have shown that long noncoding RNAs (lncRNAs) participate in the regulation of cancer radiosensitivity by regulating DNA damage repair, apoptosis, cancer stem cells (CSCs), and epithelial–mesenchymal transition (EMT). In this review, we summarize the molecular mechanisms of long noncoding RNAs in cervical cancer and radiosensitivity, hoping to provide a theoretical basis and a new molecular target for the cervical cancer RT in the clinic.
An IFN-γ-related signature predicts prognosis and immunotherapy response in bladder cancer: Results from real-world cohorts
Authors: Deng Hao , Deng Dingshan , Qi Tiezheng , Liu Zhi , Wu Longxiang , Yuan Junbin
Published: January 2023

Bladder cancer (BLCA) is featured with high incidence and mortality. Whether the IFN-γ signaling could be used as an immunotherapy determinant for BLCA has not been fully confirmed. In this study, the transcriptome data and clinical information of BLCA samples were collected from The Cancer Genome Atlas (TCGA). Besides, four immunotherapy cohorts including IMvigor210 cohort, Gide cohort, Van Allen cohort, and Lauss cohort were collected. The Xiangya real-world cohort was used for independent validation. An IFN-γ-related signature was developed and validated in BLCA for predicting prognosis, mutation, tumor microenvironment status, and immunotherapy response. This is the first study focusing on the comprehensive evaluation of predictive values on the IFN-γ-related signature in BLCA. The potential clinical application of the IFN-γ-related signature was expected to be further validated with more prospective clinical cohorts.
Data report on three datasets: Mortality patterns between agricultural and non-agricultural ward areas
Authors: Trearty Kelly , Bunting Brendan , Mallett John
Published: January 2023

The health of the farming community in Northern Ireland (NI) requires further research as previous mortality studies have reported contradictory results regarding farmers’ health outcomes compared against other occupations and the general population. This study collated the NINIS area-level farm census with the population census information across 582 non-overlapping wards of NI to compile three mortality datasets (2001, 2011, and pooled dataset) (NISRA 2019). These datasets allow future researchers to investigate the influence of demographic, farming, and economic predictors on all-cause mortality at the ward level. The 2001 and 2011 mortality datasets were compiled for cross-sectional analyses and subsequently pooled for longitudinal analyses. Findings from these datasets will provide evidence of the influence of Farming Intensity scores influence on death risk within the wards for future researchers to utilise. This data report will aid in the understanding of socio-ecological variables’ additive contribution to the risk of death at the ward level within NI. This data report is of interest to the One Health research community as it standardises the environment−human−animal data to pave the way towards a new One Health research paradigm. For example, future researchers can use this nationally representative data to investigate whether agriculturally saturated wards have a higher mortality risk than non-agriculturally based wards of NI.
Novel variants of NEK9 associated with neonatal arthrogryposis: Two case reports and a literature review
Authors: Liu Fang , Dai Liying , Li Zhi , Yin’s Xiaowei
Published: January 2023

Objective: Pathogenic variants in NEK9 (MIM: 609798) have been identified in patients with lethal congenital contracture syndrome 10 (OMIM: 617022) and arthrogryposis, Perthes disease, and upward gaze palsy (APUG and OMIM: 614262). The shared core phenotype is multiple joint contractures or arthrogryposis. In the present study, three novel variants of NEK9 associated with neonatal arthrogryposis were reported.

Methods: The clinical data of two premature infants and their parents were collected. The genomic DNA was extracted from their peripheral blood samples and subjected to trio-whole-exome sequencing (trio-WES) and copy number variation analysis.

Results: Using trio-WES, a total of three novel pathogenic variants of NEK9 were detected in the two families. Patient 1 carried compound heterozygous variations of c.717C > A (p. C239*741) and c.2824delA (p.M942Cfs*21), which were inherited from his father and mother, respectively. Patient 2 also carried compound heterozygous variations of c.61G > T (p. E21*959) and c. 2824delA (p. M942Cfs*21), which were inherited from his father and mother, respectively. These variants have not been previously reported in the ClinVar, HGMD, or gnomAD databases.

Conclusion: This is the first report about NEK9-related arthrogryposis in neonatal patients. The findings from this study suggest that different types of mutations in NEK9 lead to different phenotypes. Our study expanded the clinical phenotype spectrum and gene spectrum of NEK9-associated arthrogryposis.
Policy measures to expand home visiting programs in the postpartum period
Authors: Phung Binh
Published: January 2023

The postpartum period is characterized by a myriad of changes—emotional, physical, and spiritual; whilst the psychosocial health of new parents is also at risk. More alarmingly, the majority of pregnancy-related deaths in the U.S. occur during this critical period. The higher maternal mortality rate is further stratified by dramatic racial and ethnic variations: Black, brown, and American Indian/Alaska Native indigenous people have 3–4x higher rates of pregnancy-related deaths and severe morbidity than their White, non-Hispanic, and Asian/Pacific Islander counterparts. This policy brief explores how expanding evidence based home visiting programs (HVPs) and strengthening reimbursement policies that invest in such programs can be pivoted to optimize the scope of care in the postpartum period.
Characterization of natural killer and T cells in bronchoalveolar lavage and peripheral blood of sarcoidosis patients
Authors: Bergantini Laura , d’Alessandro Miriana , Del Zotto Genny , Marcenaro Emanuela , Bargagli Elena
Published: January 2023

The characterization of frequency and phenotypes of natural killer (NK) cells and T cells in BAL and peripheral blood of patients with sarcoidosis was evaluated, to discriminate the differential status of these cells in these two compartments. The analysis revealed that CD56brightCD16neg resulted higher in BAL than PB of sarcoidosis and healthy subjects, while CD56dimCD16+ showed a different proportion between BAL and PB of both Sarcoidosis patients and HC. Moreover, in comparison with autologous PB, BAL was characterized by a higher expression of activated NK cell markers NKp44, CD69 and CD25. Significantly increased levels of PD-1+ NK cells in the BAL of patients were detected. Regarding the maturation of CD4 and CD8, an increase of Effector Memory T cells (TEM) was reported in BAL compared to PB. A better characterization of NK and T cells may lead to an improvement of the pathogenetic mechanisms in sarcoidosis.
Differential regulation of lineage-determining transcription factor expression in innate lymphoid cell and adaptive T helper cell subsets
Authors: Fang Difeng , Healy Ayanna , Zhu Jinfang
Published: January 2023

CD4 T helper (Th) cell subsets, including Th1, Th2 and Th17 cells, and their innate counterparts innate lymphoid cell (ILC) subsets consisting of ILC1s, ILC2s and ILC3s, display similar effector cytokine-producing capabilities during pro-inflammatory immune responses. These lymphoid cell subsets utilize the same set of lineage-determining transcription factors (LDTFs) for their differentiation, development and functions. The distinct ontogeny and developmental niches between Th cells and ILCs indicate that they may adopt different external signals for the induction of LDTF during lineage commitment. Increasing evidence demonstrates that many conserved cis-regulatory elements at the gene loci of LDTFs are often preferentially utilized for the induction of LDTF expression during Th cell differentiation and ILC development at different stages. In this review, we discuss the functions of lineage-related cis-regulatory elements in inducing T-bet, GATA3 or RORγt expression based on the genetic evidence provided in recent publications. We also review and compare the upstream signals involved in LDTF induction in Th cells and ILCs both in vitro and in vivo. Finally, we discuss the possible mechanisms and physiological importance of regulating LDTF dynamic expression during ILC development and activation.
Increase of ALCAM and VCAM-1 in the plasma predicts the Alzheimer’s disease
Authors: Chen Jian , Dai An-Xiang , Tang Hai-Liang , Lu Chang-Hao , Liu Hao-Xin , Hou Ting , Lu Zhi-Jie , Kong Nan , Peng Xin-Yuan , Lin Kai-Xun , Zheng Zi-Dong , Xu Sheng-Liang , Ying Xiao-Fang , Ji Xiao-Yu , Pan Hui , Wu Jie , Zeng Xin , Wei Nai-Li
Published: January 2023

Cell adhesion molecules (CAM) are crucial in several pathological inflammation processes in Alzheimer’s disease (AD). However, their potential for clinical diagnostics remains unknown. The present investigation evaluated the clinical significance of ALCAM, VCAM-1, NCAM, and ICAM-1 levels in the plasma of participants with cognitive impairment (44 patients with mild cognitive impairment, 71 patients with Alzheimer’s dementia, and 18 patients with other dementia) and 28 controls with normal cognitive ability. We also detected plasma levels of multiple inflammatory factors (IFN-gamma, IL-18, IL-1beta, IL-13, IL-8, IL-7, CCL11, MCP-1, TSLP, IL-10, BDNF, IL-17, IL-5, TREM-1) using Multiplex liquid chip and plasma levels of Abeta1-42 and Abeta1-40 using liquid-phase flow cytometry (FCM). Our findings demonstrated a correlation of ALCAM and VCAM-1 with age, the severity of cognitive decline, and MTA, but no significant difference between groups for NCAM and ICAM-1. ALCAM and VCAM-1 both demonstrated a positive correlation with the degree of atrophy in the medial temporal lobe structure. Further analysis revealed no significant correlation in plasma between VCAM-1, ALCAM and Abeta1-40, Abeta1-42. Nevertheless, there was a significant correlation between VCAM-1, ALCAM and many inflammatory factors. Furthermore, the predictive value of ALCAM and VCAM-1 for AD was assessed using a multi-parameter regression model. ALCAM and VCAM-1 in combination with ApoE4, education, age, and MMSE could predict AD with high precision (AUC=0.891; AIC=146.9) without imaging diagnosis. ALCAM and VCAM-1 combination improved the predictive accuracy significantly. In a nutshell, these findings revealed ALCAM and VCAM-1 as reliable indicators of Alzheimer’s disease.
Desmosterol: A natural product derived from macroalgae modulates inflammatory response and oxidative stress pathways in intestinal epithelial cells
Authors: Qu Huan , Zong Qiufang , Hu Ping , Li Zhaojian , Wang Haifei , Wu Shenglong , Liu Hao-Yu , Bao Wenbin , Cai Demin
Published: January 2023

The serum level of cholesterol and its biosynthetic intermediates are critical indicators to access metabolism-related disorders in humans and animals. However, the molecular actions of these intermediates on gene functions and regulation remained elusive. Here, we show that desmosterol (DES) is the most abundant intermediate involved in cholesterol biosynthesis and is highly enriched in red/brown algae. It exerts a pivotal role in modulating core genes involved in oxidative stress and inflammatory response processes in the ileum epithelial cells (IPI-2I). We observed that the DES extracted from red algae did not affect IPI-2I cell growth or survival. A transcriptomic measurement revealed that the genes enrolled in the oxidative process and cholesterol homeostasis pathway were significantly down-regulated by DES treatment. Consistent with this notion, cellular reactive oxygen species (ROS) levels were markedly decreased in response to DES treatment. In contrast, key inflammatory genes including IL-6, TNF-α, and IFN-γ were remarkably upregulated in the RNA-seq analysis, as further confirmed by qRT-PCR. Given that DES is a specific agonist of nuclear receptor RORγ, we also found that DES caused the elevated expression of RORγ at mRNA and protein levels, suggesting it is a potential mediator under DES administration. Together, these results underscore the vital physiological actions of DES in inflammatory and oxidative processes possibly via RORγ, and may be helpful in anti-oxidation treatment and immunotherapy in the future.
Conventional dendritic cells type 1 are strongly enriched, quiescent and relatively tolerogenic in local inflammatory arthritis
Authors: Boltjes Arjan , Samat Anoushka Ashok Kumar , Plantinga Maud , Mokry Michal , Castelijns Bas , Swart Joost F. , Vastert Sebastiaan J. , Creyghton Menno , Nierkens Stefan , van Loosdregt Jorg , van Wijk Femke
Published: January 2023

Introduction

Dendritic cells (DC) are crucial for initiating and shaping immune responses. So far, little is known about the functional specialization of human DC subsets in (local) inflammatory conditions. We profiled conventional (c)DC1, cDC2 and monocytes based on phenotype, transcriptome and function from a local inflammatory site, namely synovial fluid (SF) from patients suffering from a chronic inflammatory condition, Juvenile Idiopathic Arthritis (JIA) as well as patients with rheumatoid arthritis (RA).

Methods

Paired PB and SF samples from 32 JIA and 4 RA patients were collected for mononuclear cell isolation. Flow cytometry was done for definition of antigen presenting cell (APC) subsets. Cell sorting was done on the FACSAria II or III. RNA sequencing was done on SF APC subsets. Proliferation assays were done on co-cultures after CD3 magnetic activated cell sorting (MACS). APC Toll-like receptor (TLR) stimulation was done using Pam3CSK4, Poly(I:C), LPS, CpG-A and R848. Cytokine production was measured by Luminex.

Results

cDC1, a relatively small DC subset in blood, are strongly enriched in SF, and showed a quiescent immune signature without a clear inflammatory profile, low expression of pathogen recognition receptors (PRRs), chemokine and cytokine receptors, and poor induction of T cell proliferation and cytokine production, but selective production of IFNλ upon polyinosinic:polycytidylic acid exposure. In stark contrast, cDC2 and monocytes from the same environment, showed a pro-inflammatory transcriptional profile, high levels of (spontaneous) pro-inflammatory cytokine production, and strong induction of T cell proliferation and cytokine production, including IL-17. Although the cDC2 and monocytes showed an overlapping transcriptional core profile, there were clear differences in the transcriptional landscape and functional features, indicating that these cell types retain their lineage identity in chronic inflammatory conditions.

Discussion

Our findings suggest that at the site of inflammation, there is specific functional programming of human DCs, especially cDC2. In contrast, the enriched cDC1 remain relatively quiescent and seemingly unchanged under inflammatory conditions, pointing to a potentially more regulatory role.
Current knowledge of targeted-release budesonide in immunoglobulin A nephropathy: A comprehensive review
Authors: Liao Jian , Zhou Yijing , Xu Xiuqin , Huang Ke , Chen Pengtao , Wu Yuhao , Jin Biao , Hu Qianlong , Chen Guanlin , Zhao Shankun
Published: January 2023

Immunoglobulin A (IgA) nephropathy is a common autoimmune kidney disease. Accumulating studies showed that IgA nephropathy may be partially correlated with mucosal immune system dysfunction. Systemic corticosteroid treatment exerts an essential protective effect against renal deterioration in IgA nephropathy. However, long-term use of corticosteroids may cause systemic side effects. The novel targeted-release formulation (TRF) of budesonide has been shown to deliver the drug to the distal ileum with the aim of minimizing adverse events for patients with IgA nephropathy. In this review, we have summarized all the current evidence of the effects of TRF-budesonide protecting against IgA nephropathy. Three randomized controlled trials (RCTs), one cohort, two case reports, and an ongoing Phase 3 trial (Part B, NCT03643965), were under comprehensive review. These included studies demonstrated that TRF-budesonide could remarkably reduce proteinuria, hematuria, and creatinine, as well as preserve renal function. The local immunosuppressive effects exhibited by TRF-budesonide may represent a novel and promising approach to treating IgA nephropathy. However, the current evidence was only derived from limited trials. Therefore, more well-designed RCTs are still warranted to validate the curable profile of TRF-budesonide in treating IgA nephropathy.
Decadal variability of sea surface salinity in the Southeastern Indian Ocean: Roles of local rainfall and the Indonesian throughflow
Authors: Li Jie , Li Yuanlong , Guo Yaru , Li Gang , Wang Fan
Published: January 2023

The southeastern Indian Ocean (SEIO) exhibits prominent decadal variability in sea surface salinity (SSS), showing salinity decreases during 1995-2000 and 2005-2011 and increases during 2000-2005 and after 2011. These salinity changes are linked to the Indo-Pacific climate and have impacts on the regional marine environment. Yet, the underlying mechanism has not been firmly established. In this study, decadal SSS variability of the SEIO is successfully simulated by a high-resolution regional ocean model, and the mechanism is explored through a series of sensitivity experiments. The results suggest that freshwater transport of the Indonesian throughflow (ITF) and local precipitation are two major drivers for the SSS decadal variability. They mutually cause most of the variability, with a generally larger contribution of precipitation. Other processes, such as evaporation and advection driven by local winds, play a minor role. Further analysis shows that the decadal precipitation in the SEIO is mainly associated with the decadal variability of Ningaloo Niño. Ocean dynamic processes significantly modify the relationship between SSS and precipitation, greatly shortening their lag time. The changes in both volume transport and salinity of the ITF water can cause large salinity changes in the SEIO region. Although local wind forcing gives rise to considerable changes in evaporation rate and ocean current advection, its overall contribution to decadal SSS variability is small compared to local precipitation and the ITF.
Study of the properties of high silicon aluminum alloy by laser welding
Authors: Yang Dongsheng , Huang Yilong
Published: January 2023

High silicon aluminum alloy is a kind of high-performance electronic packaging material, due to its excellent thermal conductivity, low thermal expansion coefficient, and low density. The heat affected zone (HAZ) of conventional welding techniques is too wide to weld the high silicon aluminum alloy, as wide HAZ will improve risk of cracking. Laser welding with narrow HAZ, high joint strength, and good morphology, has been considered as a promising method to weld high silicon aluminum alloy. Herein, the surface morphology, microstructure, and microhardness of laser welding joint between Al-50wt.%Si and Al-27wt.%Si alloys were investigated. It has been found that welding speed at 3 mm–5 mm/min can significantly reduce the hydrogen pores and cracks in laser welding joints. Also, the key paraments of laser welding to control the quality of joints are power and pulse width, while the former one is mainly controlling the joint width and the latter one is significantly changing the joint depth. Along the horizontal direction of laser welding joints, the microhardness increases firstly and then decreases, with the highest microhardness of 167 HV in the weld zone. Because the laser welding method could produce uniform microstructure of joints, the microhardness of joints is uniform along the longitudinal direction. The tensile properties of welding samples are almost the same with the properties of the Al-50wt.%Si base materials.
Analyses on face stability of shallow tunnel considering different constitutive models
Authors: Chunyu Luo , Zhengpeng Jia , Zhi Li , Kefeng Xiao , Bohan Wu
Published: January 2023

Based on the finite element limit analysis method, the stability of the face in case of active failure under three constitutive models, the Mohr-Coulomb model (MC), the modified Cambridge model (MCC) and the Drucker-Prager model (DP), were analyzed. The ultimate support pressure of the face and the influence of factors such as different burial depth ratios (C/D), cohesion (c) and friction angle (φ) in the MC model are also discussed. The results show that the safety factor obtained by the MCC model under the same support pressure is always smaller than that of the MC model, and the difference is the largest when there is no support pressure. As the support pressure increases, it will gradually approach the MC model. When the support pressure is small, the safety factor obtained by the DP model is larger than the MC model, but when the support pressure is large, it is smaller than the MC model, and the final difference tends to be stable. It is necessary to select an appropriate constitutive model according to different rock masses in practical engineering. The self-stabilizing performance of the face is not affected by C/D, and the ultimate support pressure will increase with the increase of C/D, decrease linearly with the increase of cohesion, and decrease with the increase of friction angle. When the friction angle is small, the ultimate support pressure is greatly affected by C/D, and when the friction angle is large, it is hardly affected by C/D.
Whole-genome sequencing of SARS-CoV-2 isolates from symptomatic and asymptomatic individuals in Tanzania
Authors: Mziray Shabani Ramadhani , van Zwetselaar Marco , Kayuki Charles C. , Mbelele Peter M. , Makubi Abel N. , Magesa Alex S. , Kisonga Riziki M. , Sonda Tolbert B. , Kibiki Gibson S. , Githinji George , Heysell Scott K. , Chilongola Jaffu O. , Mpagama Stellah G.
Published: January 2023

Background

Coronavirus Disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) accounts for considerable morbidity and mortality globally. Paucity of SARS-CoV-2 genetic data from Tanzania challenges in-country tracking of the pandemic. We sequenced SARS-CoV-2 isolated in the country to determine circulating strains, mutations and phylogenies and finally enrich international genetic databases especially with sequences from Africa.

Methods

This cross-sectional study utilized nasopharyngeal swabs of symptomatic and asymptomatic adults with positive polymerase chain reaction tests for COVID-19 from January to May 2021. Viral genomic libraries were prepared using ARTIC nCoV-2019 sequencing protocol version three. Whole-genome sequencing (WGS) was performed using Oxford Nanopore Technologies MinION device. In silico genomic data analysis was done on ARTIC pipeline version 1.2.1 using ARTIC nCoV-2019 bioinformatics protocol version 1.1.0.

Results

Twenty-nine (42%) out of 69 samples qualified for sequencing based on gel electrophoretic band intensity of multiplex PCR amplicons. Out of 29 isolates, 26 were variants of concern [Beta (n = 22); and Delta (n = 4)]. Other variants included Eta (n = 2) and B.1.530 (n = 1). We found combination of mutations (S: D80A, S: D215G, S: K417N, ORF3a: Q57H, E: P71L) in all Beta variants and absent in other lineages. The B.1.530 lineage carried mutations with very low cumulative global prevalence, these were nsp13:M233I, nsp14:S434G, ORF3a:A99S, S: T22I and S: N164H. The B.1.530 lineage clustered phylogenetically with isolates first reported in south-east Kenya, suggesting regional evolution of SARS-CoV-2.

Conclusion

We provide evidence of existence of Beta, Delta, Eta variants and a locally evolving lineage (B.1.530) from samples collected in early 2021 in Tanzania. This work provides a model for ongoing WGS surveillance that will be required to inform on emerging and circulating SARS-CoV-2 diversity in Tanzania and East Africa.
Comparing absorbed doses and radiation risk of the α-emitting bone-seekers [223Ra]RaCl2 and [224Ra]RaCl2
Authors: Lassmann Michael , Eberlein Uta
Published: January 2023

[223Ra]RaCl2 and [224Ra]RaCl2 are bone seekers, emitting high LET, and short range (< 100 μm) alpha-particles. Both radionuclides show similar decay properties; the total alpha energies are comparable (223Ra: ≈28 MeV, 224Ra: ≈26 MeV). [224Ra]RaCl2 has been used from the mid-1940s until 1990 for treating different bone and joint diseases with activities of up to approximately 50 MBq [224Ra]RaCl2. In 2013 [223Ra]RaCl2 obtained marketing authorization by the FDA and by the European Union for the treatment of metastatic prostate cancer with an activity to administer of 0.055 MBq per kg body weight for six cycles. For intravenous injections in humans a model calculation using the biokinetic model of ICRP67 shows a ratio of organ absorbed dose coefficients (224Ra:223Ra) between 0.37 (liver) and 0.97 except for the kidneys (2.27) and blood (1.57). For the red marrow as primary organ-at-risk, the ratio is 0.57. The differences are mainly caused be the differing half-lives of the decay products of both radium isotopes. Both radionuclides show comparable DNA damage patterns in peripheral blood mononuclear cells after internal ex-vivo irradiation. Data on the long-term radiation-associated side effects are only available for treatment with [224Ra]RaCl2. Two epidemiological studies followed two patient groups treated with [224Ra]RaCl2 for more than 25 years. One of them was the “Spiess study”, a cohort of 899 juvenile patients who received several injections of [224Ra]RaCl2 with a mean specific activity of 0.66 MBq/kg. Another patient group of ankylosing spondylitis patients was treated with 10 repeated intravenous injections of [224Ra]RaCl2, 1 MBq each, 1 week apart. In total 1,471 of these patients were followed-up in the “Wick study”. In both studies, an increased cancer mortality by leukemia and solid cancers was observed. Similar considerations on long-term effects likely apply to [223Ra]RaCl2 as well since the biokinetics are similar and the absorbed doses in the same range. However, this increased risk will most likely not be observed due to the much shorter life expectancy of prostate cancer patients treated with [223Ra]RaCl2.