bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrahepatic macrophage reprogramming associated with lipid metabolism in hepatitis B virus-related acute-on-chronic liver failure
Authors: Peng Bo , Li Hao , Liu Kai , Zhang Pengpeng , Zhuang Quan , Li Junhui , Yang Min , Cheng Ke , Ming Yingzi 
Published: June 2023

Abstract
Background
Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation and metabolic disorders contribute to the progression of ACLF, but the crosstalk between immunity and metabolism during ACLF is less understood. This study aims to depict the immune microenvironment in the liver during ACLF, and explore the role of lipid metabolic disorder on immunity.

Methods
Single-cell RNA-sequencing (scRNA-seq) was performed using the liver non-parenchymal cells (NPCs) and peripheral blood mononuclear cells (PBMCs) from healthy controls, cirrhosis patients and ACLF patients. A series of inflammation-related cytokines and chemokines were detected using liver and plasma samples. The lipid metabolomics targeted free fatty acids (FFAs) in the liver was also detected.

Results
The scRNA-seq analysis of liver NPCs showed a significant increase of monocytes/macrophages (Mono/Mac) infiltration in ACLF livers, whereas the resident Kupffer cells (KCs) were exhausted. A characterized TREM2+ Mono/Mac subpopulation was identified in ACLF, and showed immunosuppressive function. Combined with the scRNA-seq data from PBMCs, the pseudotime analysis revealed that the TREM2+ Mono/Mac were differentiated from the peripheral monocytes and correlated with lipid metabolism-related genes including APOE, APOC1, FABP5 and TREM2. The targeted lipid metabolomics proved the accumulation of unsaturated FFAs associated with α-linolenic acid (α-LA) and α-LA metabolism and beta oxidation of very long chain fatty acids in the ACLF livers, indicating that unsaturated FFAs might promote the differentiation of TREM2+ Mono/Mac during ACLF.

Conclusions
The reprogramming of macrophages was found in the liver during ACLF. The immunosuppressive TREM2+ macrophages were enriched in the ACLF liver and contributed to the immunosuppressive hepatic microenvironment. The accumulation of unsaturated FFAs in the ACLF liver promoted the reprogramming of the macrophages. It might be a potential target to improve the immune deficiency of ACLF patients through regulating lipid metabolism.
Long term sequelae after SARS-CoV-2 infection in children: a household study
Authors: Sluiter-Post Judith G. C. , Fourie Elandri , Wildenbeest Joanne G. , van Lelyveld Steven F. L. , Bruijning-Verhagen Patricia C. J. L. , van Houten Marianne A. 
Published: June 2023

Abstract
Background
In children persistent symptoms after SARS-CoV-2 infection have been reported, however, duration and characteristics of symptoms in previously healthy children remain unclear. Therefore this study aimed to evaluate persisting symptoms in children at 6 and 12 months after a SARS-CoV-2 infection.

Methods
In this prospective cohort study households with a confirmed SARS-CoV-2 positive outbreak were matched 1:1 to household controls from SARS-CoV-2 negative outbreaks. These households completed questionnaires at 6 and 12 months on the presence and severity of SARS-CoV-2 related symptoms, general well-being/functioning, cognition, persisting symptoms and quality of life.

Findings
None of the children who had a SARS-CoV-2 infection during the study reported persistent symptoms at 6 and 12 months after infection, whereas almost 8% of the children with a negative RT-PCR test during the study reported symptoms such as coughing and mild fever, however, no significant differences were found. In addition, for all other outcomes, no differences were observed between the two groups.

Take home message
Post-acute sequelae of mild SARS-CoV-2 infections appears to be uncommon in previously healthy children.
Ethical challenges and dilemmas in the rationing of health commodities and provision of high-risk clinical services during COVID-19 pandemic in Ethiopia: the experiences of frontline health workers
Authors: Melaku Tsegaye , Zeynudin Ahmed , Suleman Sultan 
Published: June 2023

Abstract
Background
Ethical reasoning and sensitivity are always important in public health, but it is especially important in the sensitive and complex area of public health emergency preparedness. Here, we explored the ethical challenges, and dilemmas encountered by frontline health workers amid the coronavirus disease-19 (COVID-19) pandemic in Ethiopia.

Methods
A nationwide survey was conducted amongst the frontline health workers from nineteen public hospitals. Health workers were invited to respond to a self-administered questionnaire. Data were weighted and analyzed using descriptive statistics.

Results
Of the 285 frontline health workers to whom questionnaires were distributed, 217 of them gave their responses (response rate 76.1%). Respondents frequently reported encountering rationing dilemmas on health commodities directly used for the prevention and treatment of COVID-19. Most (83.9%) of the health workers agreed that they encountered ethical challenges very frequently or frequently. Almost all [215(99.1%)] claimed that the limitation of resources was directly used for the treatment and prevention of COVID-19. The frequency of difficulty in the provision of essential clinical services varied between 77% and 98.7% for different services. More than half of the study participants reported that they had encountered difficulty in the provision of clinical care on a daily or weekly basis. Regarding rationing strategies, isolating COVID-19 treatment units and limiting admission were the most frequent rationing strategies used by two-thirds of health workers on a daily or weekly basis.

Conclusion
Front-line health workers encountered numerous ethically challenging situations during COVID-19. More than half of health workers reported that they encountered ethical challenges in rationing the resources and delivery of different clinical services such as family planning services, maternal and childcare, immunization, and chronic care. With limited resources such as ventilators and hospital beds, healthcare providers have been faced with the difficult task of deciding who gets access to these resources and who doesn't. Overall, the COVID-19 pandemic has presented numerous ethical challenges for healthcare providers, highlighting the importance of ethical considerations in healthcare delivery. By being aware of these dilemmas and having policies in place to address them, healthcare providers can ensure that they are providing the best possible care to their patients while upholding ethical standards.
Epigenetic reprogramming-induced guanidinoacetic acid synthesis promotes pancreatic cancer metastasis and transcription-activating histone modifications
Authors: Yang Jinshou , Ren Bo , Ren Jie , Yang Gang , Fang Yuan , Wang Xing , Zhou Feihan , You Lei , Zhao Yupei 
Published: June 2023

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) tends to undergo distant metastasis, especially liver metastasis, leading to a poor prognosis. Metabolic remodelling and epigenetic reprogramming are two important hallmarks of malignant tumours and participate in regulating PDAC tumorigenesis and metastasis. However, the interaction between these two processes during PDAC metastasis has not been fully elucidated.

Methods
We performed metabolomics analysis to identify the critical metabolites associated with PDAC liver metastasis and focused on guanidinoacetic acid (GAA). Intracellular GAA content was significantly increased in liver metastatic PDAC cells compared to primary cancer cells in mouse xenograft tumour models. The effects of GAA supplementation and glycine amidinotransferase (GATM) knockdown on PDAC metastasis were assessed by analysing cell migration, filopodia formation, epithelial-mesenchymal transition (EMT), and in vivo metastasis in different cell and animal models. Next, ChIP‒qPCR, 3C‒qPCR, and CRISPRi/dCas9-KRAB experiments were used to validate the “epigenome-metabolome" mechanism. Finally, the results of in vitro approaches, including RNA-seq, CUT&RUN, RT‒qPCR, and western blot analyses, as well as luciferase reporter gene assay and transwell assay, revealed the GAA-c-Myc-HMGA axis and transcription-activating histone modifications reprogramming.

Results
A high level of intracellular GAA was associated with PDAC liver metastasis. GAA could promote the migration, EMT, and liver metastasis of pancreatic cancer cells in vitro and in vivo. Next, we explored the role of GATM-mediated de novo GAA synthesis in pancreatic cancer metastasis. High expression of GATM was positively correlated with advanced N stage in PDAC. Knockdown of GATM significantly reduced the intracellular level of GAA, suppressed EMT, and inhibited PDAC liver metastasis, and these effects were attenuated by GAA supplementation. Mechanistically, we identified the active enhancers looped to the Gatm gene locus that promoted GATM expression and PDAC liver metastasis. Furthermore, we found that GAA promoted cell migration and EMT by regulating c-Myc-mediated high mobility group AT-hook protein expression. Moreover, GAA increased the H3K4me3 modification level by upregulating histone methyltransferases, which induced the transcription of metastasis-related genes, including Myc.

Conclusions
These findings revealed the critical role of the epigenome-metabolome interaction in regulating PDAC liver metastasis and suggested potential therapeutic strategies targeting GAA metabolism and epigenetic regulatory mechanisms.
The effects of metformin on anti-Müllerian hormone levels in patients with polycystic ovary syndrome: a systematic review and meta-analysis
Authors: Zhou Zhijiao , Chen Hongzhi , Chu Ling , Zou Qiong , Chen Qian , Yang Jun , Liu Yang , Ou Xiang 
Published: June 2023

Abstract
Objective
To analyze whether metformin treatment in patients with polycystic ovary syndrome (PCOS) results in a decrease of anti-Müllerian hormone (AMH) levels, we reviewed and analyzed PCOS studies which evaluated serum AMH levels before and after metformin treatment.

Methods
This is a systematic review and meta-analysis of self-controlled clinical trials. Databases including PubMed, Embase, and Web of Science library were searched to identify eligible studies published before February 2023. Random-effects models were applied to assess standardized mean differences (SMDs) with 95% confidence intervals (95% CI).

Results
The electronic-based search retrieved 167 articles of which 14 studies (12 publications) involving 257 women with PCOS were included. In general, AMH levels decreased significantly after metformin treatment [SMD (95% CI) of -0.70 (-1.13 to -0.28); P = 0.001]. Metformin exhibited a strong inhibitory effect on AMH levels for PCOS patients with age less than 28 [SMD − 1.24, 95% CI − 2.15 to − 0.32, P = 0.008]. Additionally, AMH levels significantly slid down in PCOS patients with no more than 6 months metformin treatment [SMD − 1.38, 95% CI − 2.18 to − 0.58, P = 0.0007], or with no more than a dose of 2000 mg/day [SMD -0.70, 95% CI -1.11 to -0.28; P = 0.001]. Notably, suppressive effects of metformin treatment were merely observed in patients with AMH levels at baseline higher than 4.7 ng/ml [SMD − 0.66, 95% CI − 1.02 to − 0.31, P = 0.0003].

Conclusion
This meta-analysis provided quantitative evidence demonstrating that metformin significantly decreased AMH levels, especially for young patients and those with AMH levels at baseline higher than 4.7 ng/ml.

Trial registration
PROSPERO CRD42020149182.
RAD21 is the core subunit of the cohesin complex involved in directing genome organization
Authors: Sun Yuao , Xu Xin , Zhao Wenxue , Zhang Yu , Chen Keyang , Li Yongzheng , Wang Xiaotian , Zhang Mengling , Xue Boxin , Yu Wanting , Hou Yingping , Wang Chaobin , Xie Wei , Li Cheng , Kong Daochun , Wang Shu , Sun Yujie 
Published: June 2023

Abstract
Background
The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation.

Results
We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes.

Conclusions
Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.
Exploratory analysis of L1 retrotransposons expression in autism﻿
Authors: Spirito Giovanni , Filosi Michele , Domenici Enrico , Mangoni Damiano , Gustincich Stefano , Sanges Remo 
Published: June 2023

Abstract
Background
Autism spectrum disorder (ASD) is a set of highly heterogeneous neurodevelopmental diseases whose genetic etiology is not completely understood. Several investigations have relied on transcriptome analysis from peripheral tissues to dissect ASD into homogenous molecular phenotypes. Recently, analysis of changes in gene expression from postmortem brain tissues has identified sets of genes that are involved in pathways previously associated with ASD etiology. In addition to protein-coding transcripts, the human transcriptome is composed by a large set of non-coding RNAs and transposable elements (TEs). Advancements in sequencing technologies have proven that TEs can be transcribed in a regulated fashion, and their dysregulation might have a role in brain diseases.

Methods
We exploited published datasets comprising RNA-seq data from (1) postmortem brain of ASD subjects, (2) in vitro cell cultures where ten different ASD-relevant genes were knocked out and (3) blood of discordant siblings. We measured the expression levels of evolutionarily young full-length transposable L1 elements and characterized the genomic location of deregulated L1s assessing their potential impact on the transcription of ASD-relevant genes. We analyzed every sample independently, avoiding to pool together the disease subjects to unmask the heterogeneity of the molecular phenotypes.

Results
We detected a strong upregulation of intronic full-length L1s in a subset of postmortem brain samples and in in vitro differentiated neurons from iPSC knocked out for ATRX. L1 upregulation correlated with an high number of deregulated genes and retained introns. In the anterior cingulate cortex of one subject, a small number of significantly upregulated L1s overlapped with ASD-relevant genes that were significantly downregulated, suggesting the possible existence of a negative effect of L1 transcription on host transcripts.

Limitations
Our analyses must be considered exploratory and will need to be validated in bigger cohorts. The main limitation is given by the small sample size and by the lack of replicates for postmortem brain samples. Measuring the transcription of locus-specific TEs is complicated by the repetitive nature of their sequence, which reduces the accuracy in mapping sequencing reads to the correct genomic locus.

Conclusions
L1 upregulation in ASD appears to be limited to a subset of subjects that are also characterized by a general deregulation of the expression of canonical genes and an increase in intron retention. In some samples from the anterior cingulate cortex, L1s upregulation seems to directly impair the expression of some ASD-relevant genes by a still unknown mechanism. L1s upregulation may therefore identify a group of ASD subjects with common molecular features and helps stratifying individuals for novel strategies of therapeutic intervention.
Spatiotemporal control of genome engineering in cone photoreceptors
Authors: Wang Nan-Kai , Liu Pei-Kang , Kong Yang , Tseng Yun-Ju , Jenny Laura A. , Nolan Nicholas D. , Chen Nelson , Wang Hung-Hsi , Hsu Chun Wei , Huang Wan-Chun , Sparrow Janet R. , Lin Chyuan-Sheng , Tsang Stephen H. 
Published: June 2023

Abstract
Background
Cones are essential for color recognition, high resolution, and central vision; therefore cone death causes blindness. Understanding the pathophysiology of each cell type in the retina is key to developing therapies for retinal diseases. However, studying the biology of cone cells in the rod-dominant mammalian retina is particularly challenging. In this study, we used a bacterial artificial chromosome (BAC) recombineering method to knock in the “CreERT2” sequence into the Gnat2 and Arr3 genes, respectively and generated three novel inducible CreERT2 mice with different cone cell specificities.

Results
These models (Gnat2CreERT2, Arr3T2ACreERT2, and Arr3P2ACreERT2) express temporally controllable Cre recombinase that achieves conditional alleles in cone photoreceptors. Cre-LoxP recombination can be induced as early as postnatal day (PD) two upon tamoxifen injection at varying efficiencies, ranging from 10 to 15% in Gnat2CreERT2, 40% in Arr3T2ACreERT2, and 100% in Arr3P2ACreERT2. Notably, knocking in the P2A-CreERT2 cassette does not affect cone cell morphology and functionality. Most cone-phototransduction enzymes, including Opsins, CNGA3, etc. are not altered except for a reduction in the Arr3 transcript.

Conclusions
The Arr3P2ACreERT2 mouse, an inducible cone-specific Cre driver, is a valuable line in studying cone cell biology, function, as well as its relationship with rod and other retinal cells. Moreover, the Cre activity can be induced by delivering tamoxifen intragastrically as early as PD2, which will be useful for studying retinal development or in rapid degenerative mouse models.
In vivo dynamics and regulation of DNA G-quadruplex structures in mammals
Authors: Zhang Ze-Hao , Qian Sheng Hu , Wei Dengguo , Chen Zhen-Xia 
Published: June 2023

AbstractG-quadruplex (G4) is a four-stranded helical DNA secondary structure formed by guanine-rich sequence folding, and G4 has been computationally predicted to exist in a wide range of species. Substantial evidence has supported the formation of endogenous G4 (eG4) in living cells and revealed its regulatory dynamics and critical roles in several important biological processes, making eG4 a regulator of gene expression perturbation and a promising therapeutic target in disease biology. Here, we reviewed the methods for prediction of potential G4 sequences (PQS) and detection of eG4s. We also highlighted the factors affecting the dynamics of eG4s and the effects of eG4 dynamics. Finally, we discussed the future applications of eG4 dynamics in disease therapy.
Segmentation algorithm can be used for detecting hepatic fibrosis in SD rat
Authors: Hwang Ji-Hee , Lim Minyoung , Han Gyeongjin , Park Heejin , Kim Yong-Bum , Park Jinseok , Jun Sang-Yeop , Lee Jaeku , Cho Jae-Woo 
Published: June 2023

Abstract
Background
Liver fibrosis is an early stage of liver cirrhosis. As a reversible lesion before cirrhosis, liver failure, and liver cancer, it has been a target for drug discovery. Many antifibrotic candidates have shown promising results in experimental animal models; however, due to adverse clinical reactions, most antifibrotic agents are still preclinical. Therefore, rodent models have been used to examine the histopathological differences between the control and treatment groups to evaluate the efficacy of anti-fibrotic agents in non-clinical research. In addition, with improvements in digital image analysis incorporating artificial intelligence (AI), a few researchers have developed an automated quantification of fibrosis. However, the performance of multiple deep learning algorithms for the optimal quantification of hepatic fibrosis has not been evaluated. Here, we investigated three different localization algorithms, mask R-CNN, DeepLabV3+, and SSD, to detect hepatic fibrosis.

Results
5750 images with 7503 annotations were trained using the three algorithms, and the model performance was evaluated in large-scale images and compared to the training images. The results showed that the precision values were comparable among the algorithms. However, there was a gap in the recall, leading to a difference in model accuracy. The mask R-CNN outperformed the recall value (0.93) and showed the closest prediction results to the annotation for detecting hepatic fibrosis among the algorithms. DeepLabV3+ also showed good performance; however, it had limitations in the misprediction of hepatic fibrosis as inflammatory cells and connective tissue. The trained SSD showed the lowest performance and was limited in predicting hepatic fibrosis compared to the other algorithms because of its low recall value (0.75).

Conclusions
We suggest it would be a more useful tool to apply segmentation algorithms in implementing AI algorithms to predict hepatic fibrosis in non-clinical studies.
Injection and nucleation of topological defects in the quench dynamics of the Frenkel-Kontorova model
Authors: Chelpanova Oksana , Kelly Shane P. , Morigi Giovanna , Schmidt-Kaler Ferdinand , Marino Jamir 
Published: June 2023

Abstract
Topological defects have strong impact on both elastic and inelastic properties of materials. In this article, we investigate the possibility to controllably inject topological defects in quantum simulators of solid state lattice structures. We investigate the quench dynamics of a Frenkel-Kontorova chain, which is used to model discommensurations of particles in cold atoms and trapped ionic crystals. The interplay between an external periodic potential and the inter-particle interaction makes lattice discommensurations, the topological defects of the model, energetically favorable and can tune a commensurate-incommensurate structural transition. Our key finding is that a quench from the commensurate to incommensurate phase causes a controllable injection of topological defects at periodic time intervals. We employ this mechanism to generate quantum states which are a superposition of lattice structures with and without topological defects. We conclude by presenting concrete perspectives for the observation and control of topological defects in trapped ion experiments.