bluuebunny/crossref_metadata_2025 huggingface dataset:
Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells
Authors: Groza Yaroslava , Lacina Lukáš , Kuchař Milan , Rašková Kafková Leona , Zachová Kateřina , Janoušková Olga , Osička Radim , Černý Jiří , Petroková Hana , Mierzwicka Joanna Maria , Panova Natalya , Kosztyu Petr , Sloupenská Kristýna , Malý Jan , Škarda Jozef , Raška Milan , Smetana Karel , Malý Petr
Published: May 2024

Background

Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target.

Methods

An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking.

Results

We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells.

Conclusion

We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.
Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion
Authors: Hsu Sheng-Kai , Chou Chon-Kit , Lin I-Ling , Chang Wen-Tsan , Kuo I-Ying , Chiu Chien-Chih
Published: May 2024

Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.
Emerging strategies for treating autoimmune disease with genetically modified dendritic cells
Authors: Ma Yunhan , Shi Ruobing , Li Fujun , Chang Haocai
Published: May 2024

Gene editing of living cells has become a crucial tool in medical research, enabling scientists to address fundamental biological questions and develop novel strategies for disease treatment. This technology has particularly revolutionized adoptive transfer cell therapy products, leading to significant advancements in tumor treatment and offering promising outcomes in managing transplant rejection, autoimmune disorders, and inflammatory diseases. While recent clinical trials have demonstrated the safety of tolerogenic dendritic cell (TolDC) immunotherapy, concerns remain regarding its effectiveness. This review aims to discuss the application of gene editing techniques to enhance the tolerance function of dendritic cells (DCs), with a particular focus on preclinical strategies that are currently being investigated to optimize the tolerogenic phenotype and function of DCs. We explore potential approaches for in vitro generation of TolDCs and provide an overview of emerging strategies for modifying DCs. Additionally, we highlight the primary challenges hindering the clinical adoption of TolDC therapeutics and propose future research directions in this field.
Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition
Authors: Beauchamp Erwan , Gamma Jay M. , Cromwell Christopher R. , Moussa Eman W. , Pain Rony , Kostiuk Morris A. , Acevedo-Morantes Claudia , Iyer Aishwarya , Yap Megan , Vincent Krista M. , Postovit Lynne M. , Julien Olivier , Hubbard Basil P. , Mackey John R. , Berthiaume Luc G.
Published: May 2024

Background

In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs.

Methods and results

Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.

Conclusions

Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.
Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders
Authors: Osman Hadley C. , Moreno Rachel , Rose Destanie , Rowland Megan E. , Ciernia Annie Vogel , Ashwood Paul
Published: May 2024

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.
The gut microbiome and HLA-B27-associated anterior uveitis: a case-control study
Authors: Morandi Sophia C. , Herzog Elio L. , Munk Marion , Kreuzer Marco , Largiadèr Carlo R. , Wolf Sebastian , Zinkernagel Martin , Zysset-Burri Denise C.
Published: May 2024

Background

The human gut microbiome (GM) is involved in inflammation and immune response regulation. Dysbiosis, an imbalance in this ecosystem, facilitates pathogenic invasion, disrupts immune equilibrium, and potentially triggers diseases including various human leucocyte antigen (HLA)-B27-associated autoinflammatory and autoimmune diseases such as inflammatory bowel disease (IBD) and spondyloarthropathy (SpA). This study assesses compositional and functional alterations of the GM in patients with HLA-B27-associated non-infectious anterior uveitis (AU) compared to healthy controls.

Methods

The gut metagenomes of 20 patients with HLA-B27-associated non-infectious AU, 21 age- and sex-matched HLA-B27-negative controls, and 6 HLA-B27-positive healthy controls without a history of AU were sequenced using the Illumina NovaSeq 6000 platform for whole metagenome shotgun sequencing. To identify taxonomic and functional features with significantly different relative abundances between groups and to identify associations with clinical metadata, the multivariate association by linear models (MaAsLin) R package was applied.

Results

Significantly higher levels of the Eubacterium ramulus species were found in HLA-B27-negative controls (p = 0.0085, Mann-Whitney U-test). No significant differences in microbial composition were observed at all other taxonomic levels. Functionally, the lipid IVA biosynthesis pathway was upregulated in patients (p < 0.0001, Mann-Whitney U-test). A subgroup analysis comparing patients with an active non-infectious AU to their age- and sex-matched HLA-B27-negative controls, showed an increase of the species Phocaeicola vulgatus in active AU (p = 0.0530, Mann-Whitney U-test). An additional analysis comparing AU patients to age- and sex-matched HLA-B27-positive controls, showed an increase of the species Bacteroides caccae in controls (p = 0.0022, Mann-Whitney U-test).

Conclusion

In our cohort, non-infectious AU development is associated with compositional and functional alterations of the GM. Further research is needed to assess the causality of these associations, offering potentially novel therapeutic strategies.
Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people
Authors: Poisson Johanne , El-Sissy Carine , Serret-Larmande Arnaud , Smith Nikaïa , Lebraud Morgane , Augy Jean-Loup , Conti Catherine , Gonnin Cécile , Planquette Benjamin , Arlet Jean-Benoît , Hermann Bertrand , Charbit Bruno , Pastre Jean , Devaux Floriane , Ladavière Cyrielle , Lim Lydie , Ober Pauline , Cannovas Johanna , Biard Lucie , Gulczynski Marie-Christelle , Blumenthal Noémie , Péré Hélène , Knosp Camille , Gey Alain , Benhamouda Nadine , Murris Juliette , Veyer David , Tartour Eric , Diehl Jean-Luc , Duffy Darragh , Paillaud Elena , Granier Clémence
Published: May 2024

Background

Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity.

Results

One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity.

Conclusions

Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.
Prevailing of HPV-16 and 52 genotype in 2022–2023 in Sanandaj, Iran
Authors: Haddadi Mohammad , Atefmehr Leila , Motlaghzadeh Saeed , Hejami Fatemeh , Elyasi Fatemeh Sadat , Zafarian Negar , Taghiabadi Zahra , Aboofazeli Amir , Yarahmady Hadi , Modaresi Parisa , Dadgar Aniseh , Arbabinia Mersede , Naderisemiromi Mina , Najafpour Sonya , Sharifi Asra , Gholami Anvar , Mamandi Arvin , Letafati Arash
Published: May 2024

Introduction

Human papillomavirus (HPV) presents a potential threat to the onset of carcinogenesis in the cervix, anogenital regions, and oropharynx. HPV encompasses over 200 types, with at least 12 having the potential to cause cancer, impacting the majority of sexually active individuals. In this current research, we explore the occurrence and spread of HPV genotypes.

Material and methods

During this cross-sectional study conducted in Sanandaj, Iran from Feb 2022 to Aug 2023, diverse samples including oral, vaginal, and genital were collected from individuals referred to private laboratories in Sanandaj, Iran. After sample collection and DNA extraction (FAVORGEN, Taiwan), they were subjected to PCR and genotyping (MehrViru, Iran). The subsequent statistical analysis unveiled infection rates across different demographics and age groups. STATA (version 17) were used for statistical analysis. We examined infection rates across demographics using t-tests and Odds Ratio.

Results

Overall, 26% (249) out of 950 cases tested positive for HPV, with 69% of these classified as high-risk. Among the examined population, 98% (933) were female, and 2% (17) were male. Females aged 31–40 exhibited the highest percentage of HPV prevalence (115/460) in the study with the majority of positive cases belonging to HR genotypes. The overall most frequent genotypes identified were 6, 16, 52, 53, 51, 58, and 56. HPV-16 exhibited the highest frequency among HR genotypes, accounting for 42 (17%) occurrences, followed by HPV-52 with a frequency of 32 (13%).

Conclusion

Our findings emphasize the significant prevalence of HPV among females, particularly in the 21–30 age group. The identification of high-risk genotypes, underscores the importance of targeted interventions for specific age cohorts. The age-stratified analysis highlights a consistent predominance of high-risk HPV across age groups, indicating the need for age-specific preventive measures. These results contribute valuable information for designing effective screening and vaccination strategies, to alleviate the impact of diseases associated with HPV.
Global smoking-related deaths averted due to MPOWER policies implemented at the highest level between 2007 and 2020
Authors: Lyle Greg , Hendrie Delia
Published: May 2024

Background

In response to the harm caused by tobacco use worldwide, the World Health Organization (WHO) World Health Assembly actioned the WHO Framework Convention on Tobacco Control (FCTC) in 2005. To help countries meet their FCTC obligations, the WHO introduced in 2008 the MPOWER policy package and by 2020 the FCTC had been ratified by 182 parties. The package consists of six evidence-based demand reduction smoking cessation policies to assist countries to achieve best practice. We used published evaluation results and replicated the published model to estimate current policy achievement and demonstrate the impact and equity of the MPOWER policy package in reducing the global number of smokers and smoking-attributable deaths (SADs) between 2007 and 2020.

Methods

We replicated an evaluation model (the Abridged SimSmoke model) used previously for country impact assessments and validated our replicated reduction in SADs for policies between 2014 and 2016 against the published results. The replicated model was then applied to report on the country level SADs averted from achieving the highest level of implementation, that is best practice in MPOWER policies, between 2016 and 2020. The latest results were then combined with past published results to estimate the reduction in SADs since the commencement of the MPOWER policy package. Country level income status was used to investigate the equity in the uptake of MPOWER policies worldwide.

Results

Identical estimates for SADs in 41 out of 56 MPOWER policies implemented in 43 countries suggested good agreement in the model replication. The replicated model overestimated the reduction in SADs by 159,800 (1.5%) out of a total of 10.5 million SADs with three countries contributing to the majority of this replication discrepancy. Updated analysis estimated a reduction of 8.57 million smokers and 3.37 million SADs between 2016 and 2020. Between 2007 and 2020, 136 countries had adopted and maintained at least one MPOWER policy at the highest level which was associated with a reduction in 81.0 million smokers and 28.3 million SADs. Seventy five percent of this reduction was in middle income countries, 20% in high income and less than 5% in low income countries.

Conclusions

Considerable progress has been made by MPOWER policies to reduce the prevalence of smokers globally. However, there is inequality in the implementation and maintenance, reach and influence, and the number of SADs averted. Future research to modify the model could provide a more comprehensive evaluation of past and future progress in tobacco control policies, worldwide.
Diagnostic value of cytokines in severe childhood Mycoplasma pneumoniae pneumonia combined with Adenovirus infection
Authors: Yi Xiaowen , Jia Wanyu , Li Wanying , Jia Canyang , Song Chunlan
Published: May 2024

Background

To explore the alterations of inflammatory markers and immune-related cytokines in children infected with Mycoplasma pneumoniae (MP) combined with Adenovirus (ADV).

Methods

The study population consisted of 201 children with MPP, and they were grouped according to whether they were coinfected with ADV infection and critically ill. Additionally, comparative analyses were performed. The diagnostic value of different indicators and combined indicators for SMPP combined with ADV was assessed using ROC curves.

Results

There was no difference between group A1 and group A2, group B1 and group B2 in terms of age, gender, duration of hospitalisation and fever. The levels of calcitoninogen(PCT), lactate dehydrogenase concentration(LDH), interleukin(IL)-6, IL-8, IL-10, IL-4, IL-12P70, and IFN-γ in group A were higher than group B. The severe group (A1, B1) was significantly higher than the mild group (A2, B2) in terms of D-dimer, CRP, PCT, LDH, IL-6, IL-8, IL-10, IL-17a and number of patients with pleural effusion, solid lung changes. Among the individual indexes of D-dimer, CRP, N%,LDH, and PCT, the AUC of the combined test was 0.977, which was higher than that of the individual indicators. Among IL-6, IL-8, IL-10, and IL-17a, the AUC of the combined assay was 0.802, which was higher than that of the individual indicators.

Conclusion

MP combined with ADV infection was associated with increased expression levels of IL-6, IL-8, IL-10, IL-4, IL-12P70, IFN-γ, and LDH. IL-6, IL-8, IL-10, IL-17a, LDH, PCT, CRP, and D-dimer could be used as predictors of SMPP and the combined test can improve the diagnostic value.
Critical care outcomes in decompensated cirrhosis: a United States national inpatient sample cross-sectional study
Authors: Goble Spencer R. , Ismail Abdellatif S. , Debes Jose D. , Leventhal Thomas M.
Published: May 2024

Background

Prior assessments of critical care outcomes in patients with cirrhosis have shown conflicting results. We aimed to provide nationwide generalizable results of critical care outcomes in patients with decompensated cirrhosis.

Methods

This is a retrospective study using the National Inpatient Sample from 2016 to 2019. Adults with cirrhosis who required respiratory intubation, central venous catheter placement or both (n = 12,945) with principal diagnoses including: esophageal variceal hemorrhage (EVH, 24%), hepatic encephalopathy (58%), hepatorenal syndrome (HRS, 14%) or spontaneous bacterial peritonitis (4%) were included. A comparison cohort of patients without cirrhosis requiring intubation or central line placement for any principal diagnosis was included.

Results

Those with cirrhosis were younger (mean 58 vs. 63 years, p < 0.001) and more likely to be male (62% vs. 54%, p < 0.001). In-hospital mortality was higher in the cirrhosis cohort (33.1% vs. 26.6%, p < 0.001) and ranged from 26.7% in EVH to 50.6% HRS. Mortality when renal replacement therapy was utilized (n = 1580, 12.2%) was 46.5% in the cirrhosis cohort, compared to 32.3% in other hospitalizations (p < 0.001), and was lowest in EVH (25.7%) and highest in HRS (51.5%). Mortality when cardiopulmonary resuscitation was used was increased in the cirrhosis cohort (88.0% vs. 72.1%, p < 0.001) and highest in HRS (95.7%).

Conclusions

One-third of patients with cirrhosis requiring critical care did not survive to discharge in this U.S. nationwide assessment. While outcomes were worse than in patients without cirrhosis, the results do suggest better outcomes compared to previous studies.
Mapping and functional characterization of structural variation in 1060 pig genomes
Authors: Yang Liu , Yin Hongwei , Bai Lijing , Yao Wenye , Tao Tan , Zhao Qianyi , Gao Yahui , Teng Jinyan , Xu Zhiting , Lin Qing , Diao Shuqi , Pan Zhangyuan , Guan Dailu , Li Bingjie , Zhou Huaijun , Zhou Zhongyin , Zhao Fuping , Wang Qishan , Pan Yuchun , Zhang Zhe , Li Kui , Fang Lingzhao , Liu George E.
Published: May 2024

Background

Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence.

Results

We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV’s impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies.

Conclusions

This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution.
CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration
Authors: Geng Yiting , Zheng Xiao , Zhang Dachuan , Wei Shanshan , Feng Jun , Wang Wei , Zhang Luo , Wu Changping , Hu Wenwei
Published: May 2024

Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.
The effect of oral motor intervention with different initiation times to improve feeding outcomes in preterm infants: protocol for a single-blind, randomized controlled trial
Authors: Li Yingxin , Hu Yanlin , Li Yuan , Li Xia , Huang Xi , Shi Zeyao , Yang Ru , Zhang Xiujuan , Chen Qiong
Published: May 2024

Background

Premature infants commonly encounter difficulties with oral feeding, a complication that extends hospital stays, affects infants’ quality of life, and imposes substantial burdens on families and society. Enhancing preterm infants’ oral feeding skills and facilitating their transition from parenteral or nasal feeding to full oral feeding pose challenges for neonatal intensive care unit (NICU) healthcare professionals. Research indicates that oral motor interventions (OMIs) can enhance preterm infants’ oral feeding capabilities and expedite the transition from feeding initiation to full oral feeding. Nonetheless, the most suitable timing for commencing these interventions remains uncertain.

Methods

This is a single-blind, randomized controlled trial. Preterm with a gestational age between 29+0 to 34+6 weeks will be eligible for the study. These infants will be randomized and allocated to one of two groups, both of which will receive the OMIs. The intervention commences once the infant begins milk intake during the early OMIs. Additionally, in the late OMIs group, the intervention will initiate 48 h after discontinuing nasal continuous positive airway pressure.

Discussion

OMIs encompass non-nutritive sucking and artificial oral stimulation techniques. These techniques target the lips, jaw, muscles, or tongue of premature infants, aiming to facilitate the shift from tube feeding to oral feeding. The primary objective is to determine the ideal intervention timing that fosters the development of oral feeding skills and ensures a seamless transition from parenteral or nasal feeding to full oral feeding among preterm infants. Furthermore, this study might yield insights into the long-term effects of OMIs on the growth and neurodevelopmental outcomes of preterm infants. Such insights could bear substantial significance for the quality of survival among preterm infants and the societal burden imposed by preterm birth.

Trial registration

chictr.org.cn ChiCTR2300076721. Registered on October 17, 2023.
Multi-epitope protein production and its application in the diagnosis of opisthorchiasis
Authors: Sripa Jittiyawadee , Chaiwong Tarinee
Published: May 2024

Background

Opisthorchiasis and cholangiocarcinoma (CCA) continue to be public health concerns in many Southeast Asian countries. Although the prevalence of opisthorchiasis is declining, reported cases tend to have a light-intensity infection. Therefore, early detection by using sensitive methods is necessary. Several sensitive methods have been developed to detect opisthorchiasis. The immunological detection of antigenic proteins has been proposed as a sensitive method for examining opisthorchiasis.

Methods

The Opisthorchis viverrini antigenic proteins, including cathepsin B (OvCB), asparaginyl endopeptidase (OvAEP), and cathepsin F (OvCF), were used to construct multi-antigenic proteins. The protein sequences of OvCB, OvAEP, and OvCF, with a high probability of B cell epitopes, were selected using BepiPred 1.0 and the IEDB Analysis Resource. These protein fragments were combined to form OvCB_OvAEP_OvCF recombinant DNA, which was then used to produce a recombinant protein in Escherichia coli strain BL21(DE3). The potency of the recombinant protein as a diagnostic target for opisthorchiasis was assessed using immunoblotting and compared with that of the gold standard method, the modified formalin-ether concentration technique.

Results

The recombinant OvCB_OvAEP_OvCF protein showed strong reactivity with total immunoglobulin G (IgG) antibodies against light-intensity O. viverrini infections in the endemic areas. Consequently, a high sensitivity (100%) for diagnosing opisthorchiasis was reported. However, cross-reactivity with sera from other helminth and protozoan infections (including taeniasis, strongyloidiasis, giardiasis, E. coli infection, enterobiasis, and mixed infection of Echinostome spp. and Taenia spp.) and no reactivity with sera from patients with non-parasitic infections led to a reduced specificity of 78.4%. In addition, the false negative rate (FNR), false positive rate (FPR), positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were 0%, 21.6%, 81.4%, 100%, and 88.9%, respectively.

Conclusions

The high sensitivity of the recombinant OvCB_OvAEP_OvCF protein in detecting opisthorchiasis demonstrates its potential as an opisthorchiasis screening target. Nonetheless, research on reducing cross-reactivity should be undertaken by detecting other antibodies in other sample types, such as saliva, urine, and feces.

Graphical Abstract
Prenatal nicotine exposure leads to epigenetic alterations in peripheral nervous system signaling genes in the testis of the rat
Authors: Dali Ouzna , Muriel-Muriel Jose Antonio , Vargas-Baco Ana , Tevosian Sergei , Zubcevic Jasenka , Smagulova Fatima , Hayward Linda F.
Published: May 2024

Background

Prenatal nicotine exposure (PNE) has been documented to cause numerous deleterious effects on fetal development. However, the epigenetic changes promoted by nicotine exposure on germ cells are still not well understood.

Objectives

In this study, we focused on elucidating the impact of prenatal nicotine exposure on regulatory epigenetic mechanisms important for germ cell development.

Methods

Sprague-Dawley rats were exposed to nicotine during pregnancy and male progeny was analyzed at 11 weeks of age. Testis morphology was analyzed using frozen testis sections and expression of germ cell markers was examined by RT-qPCR; histone modifications were assessed by Western Blot (WB). DNA methylation analysis was performed by methylation-specific PCR of bisulfite converted DNA. Genome-wide DNA methylation was analyzed using Methylated DNA immunoprecipitation (MeDIP)-seq. We also carried out transcriptomics analysis of pituitary glands by RNA-seq.

Results

We show that gestational exposure to nicotine reduces germ cell numbers, perturbs meiosis, affects the expression of germ line reprogramming responsive genes, and impacts the DNA methylation of nervous system genes in the testis. PNE also causes perturbation of gene expression in the pituitary gland of the brain.

Conclusions

Our data demonstrate that PNE leads to perturbation of male spermatogenesis, and the observed effects are associated with changes of peripheral nervous system signaling pathways. Alterations in the expression of genes associated with diverse biological activities such as cell migration, cell adhesion and GABA signaling in the pituitary gland underscore the complexity of the effects of nicotine exposure during pregnancy.
Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy
Authors: Hjort Line , Bredgaard Sandra Stokholm , Manitta Eleonora , Marques Irene , Sørensen Anja Elaine , Martino David , Grunnet Louise Groth , Kelstrup Louise , Houshmand-Oeregaard Azadeh , Clausen Tine Dalsgaard , Mathiesen Elisabeth Reinhardt , Olsen Sjurdur Frodi , Saffery Richard , Barrès Romain , Damm Peter , Vaag Allan Arthur , Dalgaard Louise Torp
Published: May 2024

Background

Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA.

Methods

To identify DMRs, we employed the bump hunter method in samples from young (9–16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28–33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle.

Results

One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring’s own adiposity.

Conclusions

Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.
The relationship between gamma-band neural oscillations and language skills in youth with Autism Spectrum Disorder and their first-degree relatives
Authors: Arutiunian Vardan , Santhosh Megha , Neuhaus Emily , Borland Heather , Tompkins Chris , Bernier Raphael A. , Bookheimer Susan Y. , Dapretto Mirella , Gupta Abha R. , Jack Allison , Jeste Shafali , McPartland James C. , Naples Adam , Van Horn John D. , Pelphrey Kevin A. , Webb Sara Jane
Published: May 2024

Background

Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance.

Methods

We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals.

Results

First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills.

Limitations

We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis.

Conclusions

Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles.
Solitary primary intraosseous xanthoma of the mandible in a 15-year-old boy: a case report
Authors: Georgiev A. , Genova S. , Uchikov P. , Kraev Krasimir , Kraeva M. , Chakarov D. , Uchikov A.
Published: May 2024

Background

A xanthoma is a rare bone condition consisting of a predominant collection of lipid-rich, foamy histiocytes. The central xanthoma of the jaws is a unique benign tumor.

Case report

A 15-year-old Caucasian male has been presented to our department. He had radiological changes in the area of the left mandibular angle, with an area of diffuse osteolysis of 3.0 cm by 2.0 cm. Computed tomography reveals an area of diffuse osteolysis that starts from the distal root of the lower second molar and reaches the ascending process. A bone biopsy was performed, which revealed a benign proliferative process composed of histiocytic cells involving and infiltrating trabecular bone in a background of loose fibrous connective tissue devoid of any other significant inflammatory infiltrate. The size of the formation was 2.9 cm by 2.0 cm. Immunohistochemical staining for CD68 was strongly positive and negative for S-100 and CD1a. From routine blood tests, cholesterol, triglycerides, and blood sugar are within normal values, which excludes systemic metabolic disease. Subsequent to the surgical intervention, the patient underwent postoperative assessments at intervals of 14, 30, 60 days, and a year later, revealing the absence of any discernible complications during the aforementioned observation periods.

Conclusion

The diagnosis of primary xanthoma of the mandible is rare and can often be confused with other histiocytic lesions. A differential diagnosis should be made with nonossifying fibroma and Langerhans cell histiocytosis, as in our case. In these cases, immunohistochemistry with CD 68, S-100, and CD1a, as well as blood parameters, are crucial for the diagnosis.
Promoting Alzheimer’s disease research and therapy with stem cell technology
Authors: Cao Zimeng , Kong Fanshu , Ding Jiaqi , Chen Chunxia , He Fumei , Deng Wenbin
Published: May 2024

Background

Alzheimer’s disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms.

Main content

Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron–glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics.

Conclusion

Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.
Porcine cis-acting lnc-CAST positively regulates CXCL8 expression through histone H3K27ac
Authors: Gao Junxin , Yu Haidong , Pan Yu , Wang Xinrong , Zhang He , Xu Yunfei , Ma Wenjie , Zhang Wenli , Fu Lizhi , Wang Yue
Published: May 2024

The chemokine CXCL8, also known as the neutrophil chemotactic factor, plays a crucial role in mediating inflammatory responses and managing cellular immune reactions during viral infections. Porcine reproductive and respiratory syndrome virus (PRRSV) primarily infects pulmonary alveolar macrophages (PAMs), leading to acute pulmonary infections. In this study, we explored a novel long non-coding RNA (lncRNA), termed lnc-CAST, situated within the Cxcl8 gene locus. This lncRNA was found to be highly expressed in porcine macrophages. We observed that both lnc-CAST and CXCL8 were significantly upregulated in PAMs following PRRSV infection, and after treatments with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). Furthermore, we noticed a concurrent upregulation of lnc-CAST and CXCL8 expression in lungs of PRRSV-infected pigs. We then determined that lnc-CAST positively influenced CXCL8 expression in PAMs. Overexpression of lnc-CAST led to an increase in CXCL8 production, which in turn enhanced the migration of epithelial cells and the recruitment of neutrophils. Conversely, inhibiting lnc-CAST expression resulted in reduced CXCL8 production in PAMs, leading to decreased migration levels of epithelial cells and neutrophils. From a mechanistic perspective, we found that lnc-CAST, localized in the nucleus, facilitated the enrichment of histone H3K27ac in CXCL8 promoter region, thereby stimulating CXCL8 transcription in a cis-regulatory manner. In conclusion, our study underscores the pivotal critical role of lnc-CAST in regulating CXCL8 production, offering valuable insights into chemokine regulation and lung damage during PRRSV infection.
Characterization and identification of an archaeological “lacquer” pipe
Authors: Huang Yazhen , Fu Yingchun , Shen Dawa , Lindahl Karin , Wei Shuya
Published: May 2024

A pipe with red coating on the surface was excavated from an archaeological site in Sweden, which is supposed to be a lacquer ware imported from China due to the admiration and pursue of lacquer wares from Asia by Europeans during sixteenth to eighteenth centuries. However, materials such as shellac and resins were often used to imitate lacquer during that time in Europe. To determine whether the pipe was Chinese lacquer ware or not, attenuated total reflection of fourier transform infrared spectroscopy (ATR-FTIR), thermally-assisted hydrolysis and methylation pyrolysis gas chromatography-mass spectrometry (THM-Py-GC/MS) were conducted. The detection of significant amount of aleuritic acid, laccijalaric acid, laccishellolic acid, shellolic acid and jalaric acid represents that shellac is the main material used for the pipe coating rather than Chinese lacquer. Long chain fatty alcohols were found in the sample, indicating that the shellac is un-dewaxed. In addition, pine resin and turpentine were also found as additives in the pipe coating. Furthermore, pigments in the coating were determined as cinnabar and carbon black by scanning electron microscopy with element energy dispersive spectroscopy (SEM–EDS) and Raman spectroscopy. The results could definitely support the conservation of the pipe, and also provide the evidence of the cultural exchange between Europe and Asia.
Development of non-destructive isotope measurement of the natural galena (PbS) using negative muon beams
Authors: Terada K. , Ninomiya K. , Sato A. , Tomono D. , Kawashima Y. , Inagaki M. , Nambu A. , Kudo T. , Osawa T. , Kubo M. K.
Published: May 2024

In Earth and planetary science, Pb isotopic composition is well known to play a key role in deciphering the origin and evolution of materials because they provide unique chronological and/or indigenous regional information as a radiogenic daughter nuclide from U and Th. To determine such an isotopic composition, mass spectrometers have been widely used over several decades, which requires a destructive/consuming treatment such as sputtering, laser ablation and thermal ionization. Here, we first report the non-destructive Pb isotopic measurement of natural galena (PbS) using the energy shift of muon-induced characteristic X-rays. The observed Pb isotopic composition of the natural galena is in good agreement with that obtained by conventional mass spectrometry. Such a muon-based Pb isotopic analysis method is expected to be applied to identify the production area of archaeological artefacts (e.g. bronze products), where non-destructive analysis is highly desirable compared to conventional mass spectrometry.