bluuebunny/crossref_metadata_2025_split huggingface dataset:
A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity
Authors: Ortiz Geovanny Genaro Reivan , Mohammadi Yasaman , Nazari Ahmad , Ataeinaeini Mehrnaz , Kazemi Parisa , Yasamineh Saman , Al-Naqeeb Bashar Zuhair Talib , Zaidan Haider Kamil , Gholizadeh Omid 
Published: April 2023

AbstractAging is a biological process determined through time-related cellular and functional impairments, leading to a decreased standard of living for the organism. Recently, there has been an unprecedented advance in the aging investigation, especially the detection that the rate of senescence is at least somewhat regulated via evolutionarily preserved genetic pathways and biological processes. Hematopoietic stem cells (HSCs) maintain blood generation over the whole lifetime of an organism. The senescence process influences many of the natural features of HSC, leading to a decline in their capabilities, independently of their microenvironment. New studies show that HSCs are sensitive to age-dependent stress and gradually lose their self-renewal and regeneration potential with senescence. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally inhibit translation or stimulate target mRNA cleavage of target transcripts via the sequence-particular connection. MiRNAs control various biological pathways and processes, such as senescence. Several miRNAs are differentially expressed in senescence, producing concern about their use as moderators of the senescence process. MiRNAs play an important role in the control of HSCs and can also modulate processes associated with tissue senescence in specific cell types. In this review, we display the contribution of age-dependent alterations, including DNA damage, epigenetic landscape, metabolism, and extrinsic factors, which affect HSCs function during aging. In addition, we investigate the particular miRNAs regulating HSCs senescence and age-associated diseases.
Graphical Abstract
ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability
Authors: Skopkova Martina , Stufkova Hana , Rambani Vibhuti , Stranecky Viktor , Brennerova Katarina , Kolnikova Miriam , Pietrzykova Michaela , Karhanek Miloslav , Noskova Lenka , Tesarova Marketa , Hansikova Hana , Gasperikova Daniela 
Published: April 2023

Abstract
Background
Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses.

Results
Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3–4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients.

Conclusion
The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function.
Development of anti-aflatoxin B1 nanobodies from a novel mutagenesis-derived synthetic library for traditional Chinese medicine and foods safety testing
Authors: Lee Yu-Ching , Lai Gar-Hwa , Lin Tsai-Yu , Tseng Tien-Sheng , Tsai Tsung-Hsun , Chen Wang-Chuan , Lee Cheng-Chung , Tsai Keng-Chang 
Published: April 2023

AbstractBackgroundThe main commercially available methods for detecting small molecules of mycotoxins in traditional Chinese medicine (TCM) and functional foods are enzyme-linked immunosorbent assay and mass spectrometry. Regarding the development of diagnostic antibody reagents, effective methods for the rapid preparation of specific monoclonal antibodies are inadequate.MethodsIn this study, a novel synthetic phage-displayed nanobody Golden Glove (SynaGG) library with a glove-like cavity configuration was established using phage display technology in synthetic biology. We applied this unique SynaGG library on the small molecule aflatoxin B1 (AFB1), which has strong hepatotoxicity, to isolate specific nanobodies with high affinity for AFB1.ResultThese nanobodies exhibit no cross-reactivity with the hapten methotrexate, which is recognized by the original antibody template. By binding to AFB1, two nanobodies can neutralize AFB1-induced hepatocyte growth inhibition. Using molecular docking, we found that the unique non-hypervariable complementarity-determining region 4 (CDR4) loop region of the nanobody was involved in the interaction with AFB1. Specifically, the CDR4’s positively charged amino acid arginine directed the binding interaction between the nanobody and AFB1. We then rationally optimized the interaction between AFB1 and the nanobody by mutating serine at position 2 into valine. The binding affinity of the nanobody to AFB1 was effectively improved, and this result supported the use of molecular structure simulation for antibody optimization.ConclusionIn summary, this study revealed that the novel SynaGG library, which was constructed through computer-aided design, can be used to isolate nanobodies that specifically bind to small molecules. The results of this study could facilitate the development of nanobody materials to detect small molecules for the rapid screening of TCM materials and foods in the future.
Toosendanin targeting eEF2 impedes Topoisomerase I & II protein translation to suppress esophageal squamous cell carcinoma growth
Authors: Jia Xuechao , Wang Penglei , Huang Chuntian , Zhao Dengyun , wu Qiong , Lu Bingbing , Nie Wenna , Huang Limeng , Tian Xueli , li Pan , Laster Kyle Vaughn , Jiang Yanan , Li Xiang , Li Honglin , Dong Zigang , Liu Kangdong 
Published: April 2023

Abstract
Background
Although molecular targets such as HER2, TP53 and PIK3CA have been widely studied in esophageal cancer, few of them were successfully applied for clinical treatment. Therefore, it is urgent to discover novel actionable targets and inhibitors. Eukaryotic translational elongation factor 2 (eEF2) is reported to be highly expressed in various cancers. However, its contribution to the maintenance and progression of cancer has not been fully clarified.

Methods
In the present study, we utilized tissue array to evaluate eEF2 protein expression and clinical significance in esophageal squamous cell carcinoma (ESCC). Next, we performed knockdown, overexpression, RNA-binding protein immunoprecipitation (RIP) sequence, and nascent protein synthesis assays to explore the molecular function of eEF2. Furthermore, we utilized compound screening, Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC) assay, cell proliferation and Patient derived xenograft (PDX) mouse model assays to discover an eEF2 inhibitor and assess its effects on ESCC growth.

Results
We found that eEF2 were highly expressed in ESCC and negatively associated with the prognosis of ESCC patients. Knocking down of eEF2 suppressed the cell proliferation and colony formation of ESCC. eEF2 bond with the mRNA of Topoisomerase II (TOP1) and Topoisomerase II (TOP2) and enhanced the protein biosynthesis of TOP1 and TOP2. We also identified Toosendanin was a novel inhibitor of eEF2 and Toosendanin inhibited the growth of ESCC in vitro and in vivo.

Conclusions
Our findings show that Toosendanin treatment suppresses ESCC growth through targeting eEF2 and regulating downstream TOP1 and TOP2 biosynthesis. eEF2 could be supplied as a potential therapeutic target in the further clinical studies.
Transformation of alignment files improves performance of variant callers for long-read RNA sequencing data
Authors: de Souza Vladimir B. C. , Jordan Ben T. , Tseng Elizabeth , Nelson Elizabeth A. , Hirschi Karen K. , Sheynkman Gloria , Robinson Mark D. 
Published: April 2023

AbstractLong-read RNA sequencing (lrRNA-seq) produces detailed information about full-length transcripts, including novel and sample-specific isoforms. Furthermore, there is an opportunity to call variants directly from lrRNA-seq data. However, most state-of-the-art variant callers have been developed for genomic DNA. Here, there are two objectives: first, we perform a mini-benchmark on GATK, DeepVariant, Clair3, and NanoCaller primarily on PacBio Iso-Seq, data, but also on Nanopore and Illumina RNA-seq data; second, we propose a pipeline to process spliced-alignment files, making them suitable for variant calling with DNA-based callers. With such manipulations, high calling performance can be achieved using DeepVariant on Iso-seq data.
Combining different CRISPR nucleases for simultaneous knock-in and base editing prevents translocations in multiplex-edited CAR T cells
Authors: Glaser Viktor , Flugel Christian , Kath Jonas , Du Weijie , Drosdek Vanessa , Franke Clemens , Stein Maik , Pruß Axel , Schmueck-Henneresse Michael , Volk Hans-Dieter , Reinke Petra , Wagner Dimitrios L. 
Published: April 2023

Abstract
Background
Multiple genetic modifications may be required to develop potent off-the-shelf chimeric antigen receptor (CAR) T cell therapies. Conventional CRISPR-Cas nucleases install sequence-specific DNA double-strand breaks (DSBs), enabling gene knock-out or targeted transgene knock-in. However, simultaneous DSBs provoke a high rate of genomic rearrangements which may impede the safety of the edited cells.

Results
Here, we combine a non-viral CRISPR-Cas9 nuclease-assisted knock-in and Cas9-derived base editing technology for DSB free knock-outs within a single intervention. We demonstrate efficient insertion of a CAR into the T cell receptor alpha constant (TRAC) gene, along with two knock-outs that silence major histocompatibility complexes (MHC) class I and II expression. This approach reduces translocations to 1.4% of edited cells. Small insertions and deletions at the base editing target sites indicate guide RNA exchange between the editors. This is overcome by using CRISPR enzymes of distinct evolutionary origins. Combining Cas12a Ultra for CAR knock-in and a Cas9-derived base editor enables the efficient generation of triple-edited CAR T cells with a translocation frequency comparable to unedited T cells. Resulting TCR- and MHC-negative CAR T cells resist allogeneic T cell targeting in vitro.

Conclusions
We outline a solution for non-viral CAR gene transfer and efficient gene silencing using different CRISPR enzymes for knock-in and base editing to prevent translocations. This single-step procedure may enable safer multiplex-edited cell products and demonstrates a path towards off-the-shelf CAR therapeutics.
A myeloid leukemia factor homolog is involved in tolerance to stresses and stress-induced protein metabolism in Giardia lamblia
Authors: Wu Jui-Hsuan , Lee Jen-Chi , Ho Chun-Che , Chiu Pei-Wei , Sun Chin-Hung 
Published: April 2023

Abstract
Background
The eukaryotic membrane vesicles contain specific sets of proteins that determine vesicle function and shuttle with specific destination. Giardia lamblia contains unknown cytosolic vesicles that are related to the identification of a homolog of human myeloid leukemia factor (MLF) named MLF vesicles (MLFVs). Previous studies suggest that MLF also colocalized with two autophagy machineries, FYVE and ATG8-like protein, and that MLFVs are stress-induced compartments for substrates of the proteasome or autophagy in response to rapamycin, MG132, and chloroquine treatment. A mutant protein of cyclin-dependent kinase 2, CDK2m3, was used to understand whether the aberrant proteins are targeted to degradative compratments. Interestingly, MLF was upregulated by CDK2m3 and they both colocalized within the same vesicles. Autophagy is a self-digestion process that is activated to remove damaged proteins for preventing cell death in response to various stresses. Because of the absence of some autophagy machineries, the mechanism of autophagy is unclear in G. lamblia.

Results
In this study, we tested the six autophagosome and stress inducers in mammalian cells, including MG132, rapamycin, chloroquine, nocodazole, DTT, and G418, and found that their treatment increased reactive oxygen species production and vesicle number and level of MLF, FYVE, and ATG8-like protein in G. lamblia. Five stress inducers also increased the CDK2m3 protein levels and vesicles. Using stress inducers and knockdown system for MLF, we identified that stress induction of CDK2m3 was positively regulated by MLF. An autophagosome-reducing agent, 3-methyl adenine, can reduce MLF and CDK2m3 vesicles and proteins. In addition, knockdown of MLF with CRISPR/Cas9 system reduced cell survival upon treatment with stress inducers. Our newly developed complementation system for CRISPR/Cas9 indicated that complementation of MLF restored cell survival in response to stress inducers. Furthermore, human MLF2, like Giardia MLF, can increase cyst wall protein expression and cyst formation in G. lamblia, and it can colocalize with MLFVs and interact with MLF.

Conclusions
Our results suggest that MLF family proteins are functionally conserved in evolution. Our results also suggest an important role of MLF in survival in stress conditions and that MLFVs share similar stress-induced characteristics with autophagy compartments.
Cumulative exposure to metabolic syndrome in a national population-based cohort of young adults and sex-specific risk for type 2 diabetes
Authors: Lee Min-Kyung , Lee Jae-Hyuk , Sohn Seo Young , Ahn Jiyeon , Hong Oak-Kee , Kim Mee-Kyoung , Baek Ki-Hyun , Song Ki-Ho , Han Kyungdo , Kwon Hyuk-Sang 
Published: April 2023

Abstract
Background
Metabolic syndrome is associated with type 2 diabetes and its prevalence is increasing worldwide in young adults. We aimed to determine whether cumulative exposure to metabolic syndrome is associated with type 2 diabetes risk in young adults.

Methods
Data of 1,376,540 participants aged 20–39 years without a history of type 2 diabetes and who underwent four annual health check-ups were collected. In this large-scale prospective cohort study, we evaluated the incidence rates and hazard ratios (HRs) of diabetes according to cumulative frequencies of metabolic syndrome over 4 years of consecutive annual health check-ups (burden score 0–4). Subgroup analyses were performed by sex and age.

Results
During 5.18 years of follow-up, 18,155 young adults developed type 2 diabetes. The incidence of type 2 diabetes increased with burden score (P < 0.0001). The multivariable-adjusted HRs for type 2 diabetes were 4.757, 10.511, 18.288, and 31.749 in participants with a burden score of 1 to 4, respectively, compared to those with 0. In subgroup analyses, the risk of incident diabetes was greater in women than men and in the 20–29 years age group than the 30–39 years age group. The HRs were 47.473 in women and 27.852 in men with four burden scores.

Conclusion
The risk of type 2 diabetes significantly increased with an increase in the cumulative burden of metabolic syndrome in young adults. Additionally, the association between cumulative burden and diabetes risk was stronger in women and the 20s age group.
CT analysis of thoracolumbar body composition for estimating whole-body composition
Authors: Hong Jung Hee , Hong Hyunsook , Choi Ye Ra , Kim Dong Hyun , Kim Jin Young , Yoon Jeong-Hwa , Yoon Soon Ho 
Published: April 2023

Abstract
Background
To evaluate the correlation between single- and multi-slice cross-sectional thoracolumbar and whole-body compositions.

Methods
We retrospectively included patients who underwent whole-body PET–CT scans from January 2016 to December 2019 at multiple institutions. A priori-developed, deep learning-based commercially available 3D U-Net segmentation provided whole-body 3D reference volumes and 2D areas of muscle, visceral fat, and subcutaneous fat at the upper, middle, and lower endplate of the individual T1–L5 vertebrae. In the derivation set, we analyzed the Pearson correlation coefficients of single-slice and multi-slice averaged 2D areas (waist and T12–L1) with the reference values. We then built prediction models using the top three correlated levels and tested the models in the validation set.

Results
The derivation and validation datasets included 203 (mean age 58.2 years; 101 men) and 239 patients (mean age 57.8 years; 80 men). The coefficients were distributed bimodally, with the first peak at T4 (coefficient, 0.78) and the second peak at L2-3 (coefficient 0.90). The top three correlations in the abdominal scan range were found for multi-slice waist averaging (0.92) and single-slice L3 and L2 (0.90, each), while those in the chest scan range were multi-slice T12–L1 averaging (0.89), single-slice L1 (0.89), and T12 (0.86). The model performance at the top three levels for estimating whole-body composition was similar in the derivation and validation datasets.

Conclusions
Single-slice L2–3 (abdominal CT range) and L1 (chest CT range) analysis best correlated with whole-body composition around 0.90 (coefficient). Multi-slice waist averaging provided a slightly higher correlation of 0.92.
Giant Morgagni hernia with transthoracic herniation of the left liver lobe and transverse colon: a case report
Authors: Albasheer Osama , Hakami Nasser , Ahmed Anas A. 
Published: April 2023

Abstract
Background
A Morgagni hernia is a rare diaphragmatic hernia that is usually asymptomatic but can present with gastrointestinal and chest symptoms and is reported in many cases with strangulation. Here we report a rare case of a Morgagni hernia with transthoracic herniation of the left lobe of the liver and transverse colon that presented with abdominal pain.

Case presentation
A 54-year-old Saudi female presented with abdominal pain, vomiting, and shortness of breath. Chest radiography revealed an air-containing viscus and a wide mediastinum. Computed tomography confirmed the presence of a right-sided Morgagni hernia. Reduction of the defect contents and repair of the hernia together with cholecystectomy were successfully performed using the laparoscopic approach. The patient recovered smoothly with complete resolution of preoperative symptoms.

Conclusion
A Morgagni hernia is a rare diaphragmatic defect with an increased risk of incarceration. In addition to the omentum, transverse colon, and small bowel, the defect may involve the left lobe of the liver. Surgical repair is recommended in all cases of Morgagni hernia, to avoid the risk of incarceration.
Characteristics of the nasal mucosa of commercial pigs during normal development
Authors: Li Yuchen , Yang Chengjie , Jiang Yuqi , Wang Xiuyu , Yuan Chen , Qi Jiaxin , Yang Qian 
Published: April 2023

AbstractThe nasal mucosa is constantly exposed to inhaled pathogens and is the first defence against respiratory infections. Here, we investigated the structural and compositional characteristics of the nasal mucosa of commercial pigs at various growth stages. The epithelial thickness, number of capillaries, and secretion function of the nasal mucosa dramatically increased with age; however, underlying lymphoid follicles in the respiratory region were rarely observed across the growth stages. The nasal mucosa was explored at the epithelial, immunological, and biological (commensal microbiota) barriers. In the epithelial barrier, the proliferative capacity of the nasal epithelia and the expression of tight junction proteins were high after birth; however, they decreased significantly during the suckling stage and increased again during the weaning stage. In the immunological barrier, most pattern recognition receptors were expressed at very low levels in neonatal piglets, and the innate immune cell distribution was lower. During the suckling stage, increased expression of Toll-like receptor (TLR) 2 and TLR4 was observed; however, TLR3 expression decreased. TLR expression and innate immune cell quantity significantly increased from the weaning to the finishing stage. In the biological barrier, Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes comprised the dominant phyla in neonatal piglets. A dramatic decrease in nasal microbial diversity was observed during the suckling stage, accompanied by an increase in potentially pathogenic bacteria. Proteobacteria, Bacteroidetes, and Firmicutes were identified as the core phyla of the nasal microbiota; among these, the three dominant genera, Actinobacter, Moraxella, and Bergerella, may be opportunistic pathogens in the respiratory tract. These characteristics comprise an essential reference for respiratory infection prevention at large-scale pig farms.
Model integrating CT-based radiomics and genomics for survival prediction in esophageal cancer patients receiving definitive chemoradiotherapy
Authors: Cui Jinfeng , Li Li , Liu Ning , Hou Wenhong , Dong Yinjun , Yang Fengchang , Zhu Shouhui , Li Jun , Yuan Shuanghu 
Published: April 2023

AbstractBackgroundDefinitive chemoradiotherapy (dCRT) is a standard treatment option for locally advanced stage inoperable esophageal squamous cell carcinoma (ESCC). Evaluating clinical outcome prior to dCRT remains challenging. This study aimed to investigate the predictive power of computed tomography (CT)-based radiomics combined with genomics for the treatment efficacy of dCRT in ESCC patients.MethodsThis retrospective study included 118 ESCC patients who received dCRT. These patients were randomly divided into training (n = 82) and validation (n = 36) groups. Radiomic features were derived from the region of the primary tumor on CT images. Least absolute shrinkage and selection operator (LASSO) regression was conducted to select optimal radiomic features, and Rad-score was calculated to predict progression-free survival (PFS) in training group. Genomic DNA was extracted from formalin-fixed and paraffin-embedded pre-treatment biopsy tissue. Univariate and multivariate Cox analyses were undertaken to identify predictors of survival for model development. The area under the receiver operating characteristic curve (AUC) and C-index were used to evaluate the predictive performance and discriminatory ability of the prediction models, respectively.ResultsThe Rad-score was constructed from six radiomic features to predict PFS. Multivariate analysis demonstrated that the Rad-score and homologous recombination repair (HRR) pathway alterations were independent prognostic factors correlating with PFS. The C-index for the integrated model combining radiomics and genomics was better than that of the radiomics or genomics models in the training group (0.616 vs. 0.587 or 0.557) and the validation group (0.649 vs. 0.625 or 0.586).ConclusionThe Rad-score and HRR pathway alterations could predict PFS after dCRT for patients with ESCC, with the combined radiomics and genomics model demonstrating the best predictive efficacy.