bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fragmentation in mitochondrial genomes in relation to elevated sequence divergence and extreme rearrangements
Authors: Feng Shiqian , Pozzi Andrea , Stejskal Vaclav , Opit George , Yang Qianqian , Shao Renfu , Dowling Damian K. , Li Zhihong 
Published: January 2022

AbstractBackgroundA single circular mitochondrial (mt) genome is a common feature across most metazoans. The mt-genome includes protein-coding genes involved in oxidative phosphorylation, as well as RNAs necessary for translation of mt-RNAs, whose order and number are highly conserved across animal clades, with few known exceptions of alternative mt-gene order or mt-genome architectures. One such exception consists of the fragmented mitochondrial genome, a type of genome architecture where mt-genes are split across two or more mt-chromosomes. However, the origins of mt-genome fragmentation and its effects on mt-genome evolution are unknown. Here, we investigate these origin and potential mechanisms underlying mt-genome fragmentation, focusing on a genus of booklice,Liposcelis, which exhibits elevated sequence divergence, frequent rearrangement of mt-gene order, and fragmentation of the mt genome, and compare them to other Metazoan clades.ResultsWe found this genusLiposcelisexhibits very low conservation of mt-gene order across species, relative to other metazoans. Levels of gene order rearrangement were, however, unrelated to whether or not mt-genomes were fragmented or intact, suggesting mitochondrial genome fragmentation is not affecting mt-gene order directly. We further investigated possible mechanisms underpinning these patterns and revealed very high conservation of non-coding sequences at the edges of multiple recombination regions across populations of one particularLiposcelisspecies, supportive of a hypothesis that mt-fragmentation arises from recombination errors between mt-genome copies. We propose these errors may arise as a consequence of a heightened mutation rate in clades exhibiting mt-fragmentation. Consistent with this, we observed a striking pattern across three Metazoan phyla (Arthropoda, Nematoda, Cnidaria) characterised by members exhibiting high levels of mt-gene order rearrangement and cases of mt-fragmentation, whereby the mt-genomes of species more closely related to species with fragmented mt-genomes diverge more rapidly despite experiencing strong purifying selection.ConclusionsWe showed that contrary to expectations, mt-genome fragmentation is not correlated with the increase in mt-genome rearrangements. Furthermore, we present evidence that fragmentation of the mt-genome may be part of a general relaxation of a natural selection on the mt-genome, thus providing new insights into the origins of mt-genome fragmentation and evolution.
DSP missense variant in a Scottish Highland calf with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects
Authors: Häfliger Irene M. , Koch Caroline T. , Michel Astrid , Rüfenacht Silvia , Meylan Mireille , Welle Monika M. , Drögemüller Cord 
Published: January 2022

Abstract
Background
Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis.

Results
A 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds.

Conclusions
This study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).
The prognosis biomarkers based on m6A-related lncRNAs for myeloid leukemia patients
Authors: Yang Li-Rong , Lin Zhu-Ying , Hao Qing-Gang , Li Tian-Tian , Zhu Yun , Teng Zhao-Wei , Zhang Jun 
Published: January 2022

Abstract
Background
Chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are two common malignant disorders in leukemia. Although potent drugs are emerging, CML and AML may still relapse after the drug treatment is stopped. N6-methyladenosine (m6A) and lncRNAs play certain roles in the occurrence and development of tumors, but m6A-modified LncRNAs in ML remain to be further investigated.

Methods
In this study, we extracted and analyzed the TCGA gene expression profile of 151 ML patients and the clinical data. On this basis, we then evaluated the immune infiltration capacity of ML and LASSO-penalized Cox analysis was applied to construct the prognostic model based on m6A related lncRNAs to verify the prognostic risk in clinical features of ML. Quantitative reverse transcription PCR was used to detect the expression level of LncRNA in in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1.

Results
We found 70 m6A-related lncRNAs that were related to prognosis, and speculated that the content of stromal cells and immune cells would correlate with the survival of patients with ML. Next, Prognostic risk model of m6A-related lncRNAs was validated to have excellent consistency in clinical features of ML. Finally, we verified the expression levels of CRNDE, CHROMR and NARF-IT1 in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1, which were significant.

Conclusions
The research provides clues for the prognosis prediction of ML patients by using the m6A-related lncRNAs model we have created, and clarifies the accuracy and authenticity of it.
METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification
Authors: Xu Yiming , Lv Dandan , Yan Chao , Su Hua , Zhang Xue , Shi Yangfeng , Ying Kejing 
Published: January 2022

Abstract
Background
N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.

Methods
The expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.

Results
The results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc−, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.

Conclusions
These findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.
NAFLD fibrosis score is correlated with PCSK9 and improves outcome prediction of PCSK9 in patients with chest pain: a cohort study
Authors: Peng Jia , Liu Ming-Ming , Jin Jing-Lu , Cao Ye-Xuan , Guo Yuan-Lin , Wu Na-Qiong , Zhu Cheng-Gang , Dong Qian , Sun Jing , Xu Rui-Xia , Li Jian-Jun 
Published: January 2022

Abstract
Background
The risk of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) can be easily evaluated by noninvasive scoring systems, of which the NAFLD fibrosis score (NFS) is the most commonly used. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a new predictor of cardiovascular events, has been reported to be associated with cardiovascular outcomes and NAFLD. However, the relationship of NFS with PCSK9 and their prognostic abilities in cardiovascular risks are unknown.

Methods
A total of 2008 hospitalized subjects who had chest pain without lipid-lowering therapy were consecutively included. Baseline clinical data were collected, and the NFS was calculated. The circulating PCSK9 concentration was determined by enzyme immunoassay. The major adverse cardiovascular event (MACE) occurrences were recorded in the follow-up period. Associations of PCSK9 concentration with NFS were examined. All of the participants were categorized into three groups according to NFS levels and were further stratified by PCSK9 tertiles to evaluate the MACEs.

Results
158 (7.87%) MACEs were observed during a mean of 3.2 years of follow-up. NFS levels were independently related to higher PCSK9 levels according to multivariable linear regression analysis. Furthermore, elevated PCSK9 and NFS concentrations were respectively associated with increased MACE incidence in multivariable Cox regression models. When combining NFS status with PCSK9 tertiles as a stratifying factor, patients with intermediate-high NFS and high PCSK9 levels had higher risks of events than those with low NFS and low PCSK9 levels.

Conclusions
This study revealed for the first time that NFS is positively related to PCSK9 and that the combination of NFS and PCSK9 greatly increased the risk of MACEs in patients with chest pain, providing a potential link between NFS and PCSK9 for predicting cardiovascular events.
Characteristics and clinical significance of lipid metabolism in patients with gastrointestinal stromal tumor
Authors: Liu Xiaoling , Hu Jun , Liu Bende 
Published: January 2022

Abstract
Background
To investigate the characteristics and clinical significance of serum lipids in patients with gastrointestinal stromal tumors (GISTs).

Methods
The clinical and pathological data of 694 GIST patients in Liyuan hospital and Union hospital from 2012 to 2016 were retrospectively analyzed. Blood lipid levels in patients with varying degrees of risk were compared.

Results
The findings showed that LDL-C, HDL-C, and CHOL increased significantly in women, and CD34 positive. In patients with tumors size less than 5 cm in diameter, TG, HDL-C, and CHOL were significantly higher. TG levels were significantly higher in DOG-1 (a marker and has a high specificity and sensitivity in the diagnosis of GIST) positive patients than in DOG-1 negative patients (P < 0.05). S-100 positive patients had lower HDL-C levels than S-100 negative patients (P < 0.05). Lipids indexes were found to be correlated with GIST risk stratification and tumor site (P < 0.05). TG/HDL-C was were significantly different among patients with GIST in different locations (P < 0.05).

Conclusion
The clinical and pathological characteristics of the patients with GIST are closely related to the level of blood lipids. To a certain extent, information about level of blood lipids can be helpful for distinguishing benign and malignant GIST.
Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice
Authors: Li Fu , Xiang Haitao , Gu Yue , Ye Ting , Lu Xu , Huang Chao 
Published: January 2022

Abstract
Background
Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities.

Methods
The experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers.

Results
A single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain.

Conclusions
Pre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.
Exposure to environmentally relevant concentrations of ambient fine particulate matter (PM2.5) depletes the ovarian follicle reserve and causes sex-dependent cardiovascular changes in apolipoprotein E null mice
Authors: Luderer Ulrike , Lim Jinhwan , Ortiz Laura , Nguyen Johnny D. , Shin Joyce H. , Allen Barrett D. , Liao Lisa S. , Malott Kelli , Perraud Veronique , Wingen Lisa M. , Arechavala Rebecca J. , Bliss Bishop , Herman David A. , Kleinman Michael T. 
Published: January 2022

Abstract
Background
Fine particulate matter (PM2.5) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM2.5 in females.

Results
Hyperlipidemic apolipoprotein E (Apoe) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM2.5-exposed ovary-intact mice compared to controls (P < 0.05). The percentage of primary follicles with granulosa cells positive for the mitosis marker Ki67 was increased in the ovaries from PM2.5-exposed females versus controls (P < 0.05), consistent with increased recruitment of primordial follicles into the growing pool. Exposure to PM2.5 increased the percentages of primary and secondary follicles with DNA damage, assessed by γH2AX immunostaining (P < 0.05). Exposure to PM2.5 increased the percentages of apoptotic antral follicles, determined by TUNEL and activated caspase 3 immunostaining (P < 0.05). Removal of the ovaries and PM2.5-exposure exacerbated the atherosclerotic effects of hyperlipidemia in females (P < 0.05). While there were statistically significant changes in blood pressure and heart rate variability in PM2.5-compared to Air-exposed gonad-intact males and females and ovariectomized females, the changes were not consistent between exposure years and assessment methods.

Conclusions
These results demonstrate that subchronic PM2.5 exposure depletes the ovarian reserve by increasing recruitment of primordial follicles into the growing pool and increasing apoptosis of growing follicles. Further, PM2.5 exposure and removal of the ovaries each increase atherosclerosis progression in Apoe-/- females. Premature loss of ovarian function is associated with increased risk of osteoporosis, cardiovascular disease and Alzheimer’s disease in women. Our results thus support possible links between PM2.5 exposure and other adverse health outcomes in women.
SOX11 is a sensitive and specific marker for pulmonary high-grade neuroendocrine tumors
Authors: Yu Lu , Dong Yuting , Xue Jin , Xu Sanpeng , Wang Guoping , Kuang Dong , Duan Yaqi 
Published: January 2022

Abstract
Background
Synaptophysin (SYN), chromogranin A (CGA), CD56 and insulinoma-associated protein 1 (INSM1) are proposed neuroendocrine (NE) markers used for diagnosis of pulmonary NE tumors. These NE markers have been identified in subsets of non-NE tumors requiring differential diagnosis, thus we sought to explore new NE markers.

Methods
We evaluated the immunohistochemical expression of SOX11, a transcription factor involved in neurogenesis, in pulmonary NE tumors and large cell carcinomas (LCCs).

Results
We found that SOX11 showed a sensitivity similar to INSM1 and CGA, and less than SYN and CD56 in small cell lung carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). While SOX11 is more specific than the other four markers for diagnosis of high-grade neuroendocrine carcinomas (HG-NECs) because 1) None of LCCs (0/63), the most challenging non-NE tumor type for differential diagnosis due to overlapped morphology with LCNECs displayed SOX11 positivity. While expression of at least one of SYN, CGA, CD56 or INSM1 was identified in approximately 60% (18/30) of LCCs. 2) SOX11 was only expressed in 1 of 37 carcinoid tumors in contrast to diffuse expression of SYN, CGA, CD56 and INSM1. In HG-NECs, we noticed that SOX11 was a good complementary marker for SCLC diagnosis as it was positive in 7 of 18 SYN−/CGA−/CD56− SCLCs and 3 of 8 SYN−/CGA−/CD56−/INSM1− SCLCs, and SOX11 positivity in 4 of 6 SYN−/CGA−/CD56− cases previously diagnosed as LCCs with NE morphology provides additional evidence of NE differentiation for reclassification into LCNECs, which was further confirmed by electromicroscopical identification of neurosecretory granules. We also found SOX11 expression cannot predict the prognosis in patients with HG-NECs.

Conclusions
Therefore, SOX11 is a useful complementary transcriptional NE marker for diagnosis and differential diagnosis of SCLC and LCNEC.
INPP5F translocates into cytoplasm and interacts with ASPH to promote tumor growth in hepatocellular carcinoma
Authors: Zhou Qianlei , Lin Jianhong , Yan Yongcong , Meng Shiyu , Liao Hao , Chen Ruibin , He Gui , Zhu Yue , He Chuanchao , Mao Kai , Wang Jie , Zhang Jianlong , Zhou Zhenyu , Xiao Zhiyu 
Published: January 2022

Abstract
Background
Increasing evidence has suggested inositol polyphosphate 5-phosphatase family contributes to tumorigenesis and tumor progression. However, the role of INPP5F in hepatocellular carcinoma (HCC) and its underlying mechanisms is unclear.

Methods
The expression of INPP5F in HCC was analyzed in public databases and our clinical specimens. The biological functions of INPP5F were investigated in vitro and vivo. The molecular mechanism of INPP5F in regulating tumor growth were studied by transcriptome-sequencing analysis, mass spectrometry analysis, immunoprecipitation assay and immunofluorescence assay.

Results
High expression of INPP5F was found in HCC tissues and was associated with poor prognosis in HCC patients. Overexpression of INPP5F promoted HCC cell proliferation, and vice versa. Knockdown of INPP5F suppressed tumor growth in vivo. Results from transcriptome-sequencing analysis showed INPP5F not only regulated a series of cell cycle related genes expression (c-MYC and cyclin E1), but also promoted many aerobic glycolysis related genes expression. Further studies confirmed that INPP5F could enhance lactate production and glucose consumption in HCC cell. Mechanistically, INPP5F activated Notch signaling pathway and upregulated c-MYC and cyclin E1 in HCC via interacting with ASPH. Interestingly, INPP5F was commonly nuclear-located in cells of adjacent non-tumor tissues, while in HCC, cytoplasm-located was more common. LMB (nuclear export inhibitor) treatment restricted INPP5F in nucleus and was associated with inhibition of Notch signaling and cell proliferation. Sequence of nuclear localization signals (NLSs) and nuclear export signals (NESs) in INPP5F aminoacidic sequence were then identified. Alteration of the NLSs or NESs influenced the localization of INPP5F and the expression of its downstream molecules. Furthermore, we found INPP5F interacted with both exportin and importin through NESs and NLSs, respectively, but the interaction with exportin was stronger, leading to cytoplasmic localization of INPP5F in HCC.

Conclusion
These findings indicate that INPP5F functions as an oncogene in HCC via a translocation mechanism and activating ASPH-mediated Notch signaling pathway. INPP5F may serve as a potential therapeutic target for HCC patients.