bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory immune checkpoints PDCD-1 and LAG-3 hypermethylation may reduce the risk of colorectal cancer
Authors: Zhang Yuanyuan , zhang Lei , Sun Hongru , Liu Ying , Xu Jing , Huang Hao , Fu Jinming , Zhang Ding , Tian Tian , Zhao Yashuang , Wang Guiyu 
Published: September 2021

Abstract
Background
Changes in DNA methylation of immunosuppressive checkpoints may impact express and consequently affect antigen processing and presentation by tumor cells and facilitates evasion of immunosurveillance and lead to colorectal cancer (CRC). This study is to investigate the effect of PDCD-1, LAG-3 methylation statuses in peripheral blood leukocytes on CRC risk.

Methods
GSE51032 dataset from Gene Expression Omnibus comprised of 166 CRC patients and 424 normal samples was used to identify significantly differentially methylated CpG sites of the two genes. A case–control study with 390 CRC patients and 397 cancer-free controls was carried out to validate the relationship between the methylation levels of the two genes and CRC susceptibility and then estimated their interactions with environmental factors on CRC risk.

Results
In the GSE51032 dataset, cg06291111 (PDCD-1) and cg10191002 (LAG-3) were screened as the candidate CpG sites for the following study. There were significant associations between hypermethylation of PDCD-1 and LAG-3 and lower risk of CRC (ORadj = 0.322, 95% CI 0.197–0.528; ORadj = 0.666, 95% CI 0.446–0.5996, respectively). Moreover, the results in case–control study showed similar trend, that hypermethylation of PDCD-1 and LAG-3 were associated with lower CRC risk (ORadj = 0.448, 95% CI 0.322–0.622; ORadj = 0.417, 95% CI 0.301–0.578, respectively). A synergistic interaction between LAG-3 hypermethylation and intake of eggs on CRC risk was observed. There were combination effects between hypermethylation of PDCD-1 and LAG-3 and environmental factors on CRC risk.

Conclusions
PDCD-1 and LAG-3 may potentially serve as blood-based predictive biomarkers for CRC risk.
ncDLRES: a novel method for non-coding RNAs family prediction based on dynamic LSTM and ResNet
Authors: Wang Linyu , Zhong Xiaodan , Wang Shuo , Liu Yuanning 
Published: September 2021

Abstract
Background
Studies have proven that the same family of non-coding RNAs (ncRNAs) have similar functions, so predicting the ncRNAs family is helpful to the research of ncRNAs functions. The existing calculation methods mainly fall into two categories: the first type is to predict ncRNAs family by learning the features of sequence or secondary structure, and the other type is to predict ncRNAs family by the alignment among homologs sequences. In the first type, some methods predict ncRNAs family by learning predicted secondary structure features. The inaccuracy of predicted secondary structure may cause the low accuracy of those methods. Different from that, ncRFP directly learning the features of ncRNA sequences to predict ncRNAs family. Although ncRFP simplifies the prediction process and improves the performance, there is room for improvement in ncRFP performance due to the incomplete features of its input data. In the secondary type, the homologous sequence alignment method can achieve the highest performance at present. However, due to the need for consensus secondary structure annotation of ncRNA sequences, and the helplessness for modeling pseudoknots, the use of the method is limited.

Results
In this paper, a novel method “ncDLRES”, which according to learning the sequence features, is proposed to predict the family of ncRNAs based on Dynamic LSTM (Long Short-term Memory) and ResNet (Residual Neural Network).

Conclusions
ncDLRES extracts the features of ncRNA sequences based on Dynamic LSTM and then classifies them by ResNet. Compared with the homologous sequence alignment method, ncDLRES reduces the data requirement and expands the application scope. By comparing with the first type of methods, the performance of ncDLRES is greatly improved.
Elevated transcription of transposable elements is accompanied by het-siRNA-driven de novo DNA methylation in grapevine embryogenic callus
Authors: Lizamore Darrell , Bicknell Ross , Winefield Chris 
Published: September 2021

Abstract
Background
Somatic variation is a valuable source of trait diversity in clonally propagated crops. In grapevine, which has been clonally propagated worldwide for centuries, important phenotypes such as white berry colour are the result of genetic changes caused by transposable elements. Additionally, epiallele formation may play a role in determining geo-specific (‘terroir’) differences in grapes and thus ultimately in wine. This genomic plasticity might be co-opted for crop improvement via somatic embryogenesis, but that depends on a species-specific understanding of the epigenetic regulation of transposable element (TE) expression and silencing in these cultures. For this reason, we used whole-genome bisulphite sequencing, mRNA sequencing and small RNA sequencing to study the epigenetic status and expression of TEs in embryogenic callus, in comparison with leaf tissue.

Results
We found that compared with leaf tissue, grapevine embryogenic callus cultures accumulate relatively high genome-wide CHH methylation, particularly across heterochromatic regions. This de novo methylation is associated with an abundance of transcripts from highly replicated TE families, as well as corresponding 24 nt heterochromatic siRNAs. Methylation in the TE-specific CHG context was relatively low over TEs located within genes, and the expression of TE loci within genes was highly correlated with the expression of those genes.

Conclusions
This multi-‘omics analysis of grapevine embryogenic callus in comparison with leaf tissues reveals a high level of genome-wide transcription of TEs accompanied by RNA-dependent DNA methylation of these sequences in trans. This provides insight into the genomic conditions underlying somaclonal variation and epiallele formation in plants regenerated from embryogenic cultures, which is an important consideration when using these tissues for plant propagation and genetic improvement.
Effects of mulberry leaf silage on antioxidant and immunomodulatory activity and rumen bacterial community of lambs
Authors: Wang Bing , Luo Hailing 
Published: September 2021

Abstract
Background
Rumen is a natural fermentation system and the microorganisms inside can effectively utilize plant bioresource and interact with host metabolism. Here, analysis of rumen microbiome, together with animal performance and serum metabolism in a lamb model were performed to identify the potential use of mulberry leaf silage (MS) to replace alfalfa silage (AS) as a new functional feed resource and to mining the novel specific mulberry leaf associated rumen bacteria interact with host metabolism.

Results
The lambs fed with MS diet showed improved antioxidant capacity and immune function compared to those fed AS diet. The MS diet significantly altered rumen microbiota α- and β-diversity and taxonomic composition. Microbial analysis revealed that Bifidobacterium, Lactobacillus and Schwartzia were enhanced, and Ruminococcaceae UCG-010 and Lachnospiraceae_XPB1014_group were down-regulated in the rumen of MS group. A strong association was also found between these rumen microbial taxa and host antioxidant and immunomodulatory capacity.

Conclusion
These findings indicated that mulberry leaf silage can be a high-quality feed source or bioactive pharmaceutical that is responsible for ruminant’s health benefits. The modified rumen microbial community by mulberry leaf silage were associated with the enhanced antioxidant capacity and immunomodulatory of lambs.
Esophageal metastasis of renal cell carcinoma resected by endoscopic submucosal dissection: a case report
Authors: Ohnita Ken , Higashi Shuntaro , Hirai Satoshi , Kuwahara Ai , Kakigao Kana , Nakashiki Suguru , Inoue Kenichiro , Kurohama Hirokazu , Nakashima Masahiro , Nakao Kazuhiko 
Published: September 2021

Abstract
Background
Esophageal metastasis of renal cell carcinoma (RCC) is extremely rare. We have described herein a case of a 59-year-old man with esophageal metastasis of RCC that was endoscopically resected.

Case presentation
The case was a 59-year-old man who had undergone left nephrectomy for renal clear cell carcinoma 17 years ago and splenectomy for splenic metastasis 3 years ago. Esophagogastroduodenoscopy (EGD) performed 9 years ago revealed a small reddish elevated lesion with a smooth surface in the middle esophagus; this lesion increased in size 4 years ago. However, no biopsy was performed. The lesion continued to grow in size and was found to have become nodular during the present observation. Biopsy revealed clear cell carcinoma. Endoscopic ultrasound (EUS) revealed that the lesion had not invaded the submucosa, and contrast-enhanced computed tomography did not reveal any other metastasis. The lesion was successfully removed en bloc via endoscopic submucosal dissection (ESD). Pathologically, the tumor was detected in the subepithelium with focal infiltration of the muscularis mucosa. It consisted of monotonous cells with small nuclei and a clear cytoplasm. Immunohistological findings indicated that the tumor was a metastasis of RCC. The lateral and vertical margins were noted to be free.

Conclusions
We have presented herein a case of esophageal metastasis of RCC that had progressed over 9 years and was then resected en bloc through endoscopic submucosal dissection.
Cecal epidermoid cyst: a neonatal case with clinicopathological consideration
Authors: Na Joo-Young , Kim Soo-Hong , Lee Narae 
Published: September 2021

Abstract
Background
Only 10 cases of cecal epidermoid cyst (CEC) have been reported in the literature. Furthermore, its pathogenesis remains unclear. We report a rare case of congenital CEC in neonate, and discuss its clinicopathological findings.

Case presentation
A cystic lesion was incidentally identified in the retroperitoneal area of the abdominal right lower quadrant during a routine prenatal ultrasonography (US), prompting an ileocolectomy 3 days after birth. This congenital cyst was composed of mucosal lining cells and submucosal connective tissues, and the inner lining mucosa was composed of stratified squamous epithelium and focally mucin-producing ciliated epithelium. Based on the macroscopic and microscopic findings, the cystic lesion was diagnosed as a congenital cecal epidermoid cyst.

Conclusions
The management of a fetal abdominal mass should be tailored individually, considering that epidermoid cysts can occur in the cecum during the perinatal period. We report the clinicopathological findings in this case, including its possible pathogenesis.
Expansion of targetable sites for the ribonucleoprotein-based CRISPR/Cas9 system in the silkworm Bombyx mori
Authors: Zou Yun-long , Ye Ai-jun , Liu Shuo , Wu Wen-tao , Xu Li-feng , Dai Fang-yin , Tong Xiao-ling 
Published: September 2021

Abstract
Background
With the emergence of CRISPR/Cas9 technology, multiple gene editing procedures became available for the silkworm. Although binary transgene-based methods have been widely used to generate mutants, delivery of the CRISPR/Cas9 system via DNA-free ribonucleoproteins offers several advantages. However, the T7 promoter that is widely used in the ribonucleoprotein-based method for production of sgRNAs in vitro requires a 5′ GG motif for efficient initiation. The resulting transcripts bear a 5′ GG motif, which significantly constrains the number of targetable sites in the silkworm genome.

Results
In this study, we used the T7 promoter to add two supernumerary G residues to the 5′ end of conventional (perfectly matched) 20-nucleotide sgRNA targeting sequences. We then asked if sgRNAs with this structure can generate mutations even if the genomic target does not contain corresponding GG residues. As expected, 5′ GG mismatches depress the mutagenic activity of sgRNAs, and a single 5′ G mismatch has a relatively minor effect. However, tests involving six sgRNAs targeting two genes show that the mismatches do not eliminate mutagenesis in vivo, and the efficiencies remain at useable levels. One sgRNA with a 5′ GG mismatch at its target performed mutagenesis more efficiently than a conventional sgRNA with 5′ matched GG residues at a second target within the same gene. Mutations generated by sgRNAs with 5′ GG mismatches are also heritable. We successfully obtained null mutants with detectable phenotypes from sib-mated mosaics after one generation.

Conclusions
In summary, our method improves the utility and flexibility of the ribonucleoprotein-based CRISPR/Cas9 system in silkworm.
The determinants of burnout and professional turnover intentions among Canadian physicians: application of the job demands-resources model
Authors: Chênevert Denis , Kilroy Steven , Johnson Kevin , Fournier Pierre-Luc 
Published: September 2021

Abstract
Background
Burnout among physicians is growing at an exponential rate and many are leaving the profession. Nevertheless, the specific antecedents and intermediary stages involved in predicting their professional turnover intentions are not fully clear.

Purpose
We apply the Job Demands-Resources model and investigate an innovative model which predicts physician burnout and its ultimate consequences on professional turnover intentions.

Methodology/approach
Structural equation modeling was used on cross-sectional survey data from a sample of 407 Canadian physicians.

Results/conclusions
Job demands (work stress, work overload, and work-family conflict) and job resources (patient recognition and meaning at work) influence intention to leave the profession through a two stage health-impairment and motivational process related to health problems and professional commitment, respectively.

Practical implications
This study identifies key job resources and job demands which predict physician burnout and professional turnover intentions thereby pinpointing which levers managers can use improve their health and retain them in the profession.
USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1
Authors: Pan Xiu-wu , Xu Da , Chen Wen-jin , Chen Jia-xin , Chen Wei-jie , Ye Jian-qing , Gan Si-shun , Zhou Wang , Song Xu , Shi Lei , Cui Xin-gang 
Published: September 2021

Abstract
Background
The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC.

Methods
We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays.

Results
The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P < 0.001), and negatively correlated with the survival rate of RCC patients (P < 0.01). Silencing of USP39 in 786-O and ACHN cells inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P < 0.05) and branches (P < 0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P < 0.05). The USP39 (101–565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P < 0.05).

Conclusion
USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through inhibiting VEGF-A165b alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC.

Graphic abstract
Therapy of spinal cord injury by zinc modified gold nanoclusters via immune-suppressing strategies
Authors: Lin Sen , Li Dan , Zhou Zipeng , Xu Chang , Mei Xifan , Tian He 
Published: September 2021

Abstract
Background
Spinal cord injury (SCI) is damage to the central nervous system (CNS) that causes devastating complications from chronic pain to breathing problems. Unfortunately, few effective and safe treatments are known to relieve the damages of SCI. Nanomedicines are used for the treatment of SCI with relatively few side effects, but only depending on the delivery of additional drugs, which increase complexity to the treatment. Considering the urgent need for saving SCI patients, it is important to develop promising nanobiotechnology for relieving their pains.

Methods
The clinical survey was used to investigate SCI patients, thereafter the therapy plan was designed. The receiver-operating characteristics (ROC) curves of the prediction model were built to find symptoms after SCI. The treatment plan (i.e. immunosuppressive strategy) was designed by manufacturing therapies based on gold nanoclusters (AuNCs). The response of the immune cells (macrophages) was studied accordingly. The western blot, reactive oxygen species (ROS) activity assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (RT-qPCR), and immunochemical staining were used for evaluation of the in vivo and in vitro therapeutic effects.

Results
We found increased monocytes/macrophages (M/Ms) levels in 114 SCI subjects (44.7% with severe SCI complications) by the clinical survey. Additionally, the enhanced macrophage level was found to be closely related to the walking disorder after SCI. Since macrophages were central effector cells of the immune system, we assumed that the immune-suppressing strategies could be used for SCI therapy. Thereafter, AuNCs were stabilized by dihydrolipoic acid (DHLA) enantiomers (including DL-DHLA, R-DHLA; A racemic mixture (R and S) was denoted as DL; R and S refer to Rectus and Sinister), obtaining DL-DHLA-AuNCs and R-DHLA-AuNCs, respectively. In addition, zinc-modified DL-DHLA and R-DHLA stabilized AuNCs (i.e., DL-DHLA-AuNCs-Zn and R-DHLA-AuNCs-Zn) were investigated. Among these AuNCs, R-DHLA-AuNCs-Zn showed the most remarkable therapeutic effect for promoting the polarization of pro-inflammatory macrophages and reducing neuronal ROS-induced apoptosis and inflammation in vitro and in vivo; the lesion size was decreased and the survival rate of ventral neurons is higher.

Conclusions
R-DHLA-AuNCs-Zn have comprehensive therapeutic capabilities, especially the immune-suppressing effects for the therapy of SCI, which is promising to relieve the pain or even recover SCI for the patients.

Graphical abstract
Molecularly engineered carrier-free co-delivery nanoassembly for self-sensitized photothermal cancer therapy
Authors: Shan Xinzhu , Zhang Xuanbo , Wang Chen , Zhao Zhiqiang , Zhang Shenwu , Wang Yuequan , Sun Bingjun , Luo Cong , He Zhonggui 
Published: September 2021

Abstract
Background
Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors.

Methods
A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo.

Results
The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model.

Conclusion
Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.

Graphic abstract
Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events
Authors: Jang Tim , Poplawska Maria , Cimpeanu Emanuela , Mo George , Dutta Dibyendu , Lim Seah H. 
Published: September 2021

AbstractPainful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.