bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic NOD2 promotes hepatocarcinogenesis via a RIP2-mediated proinflammatory response and a novel nuclear autophagy-mediated DNA damage mechanism
Authors: Zhou Yi , Hu Liang , Tang Wenqing , Li Dongping , Ma Lijie , Liu Hongchun , Zhang Shuncai , Zhang Xiaojie , Dong Ling , Shen Xizhong , Chen She , Xue Ruyi , Zhang Si 
Published: January 2021

Abstract
Background
Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (−) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis.

Methods
NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2△hep), Rip2-knockout (Rip2△hep), Lamin A/C-knockout (Lamn△hep) and Rip2/Lamin A/C double-knockout (Rip2/Lamn△hep) mice models of diethylnitrosamine (DEN)/CCl4-induced HCC.

Results
NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl4-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability.

Conclusions
We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
Exosomal ANGPTL1 attenuates colorectal cancer liver metastasis by regulating Kupffer cell secretion pattern and impeding MMP9 induced vascular leakiness
Authors: Jiang Kai , Chen Haiyan , Fang Yimin , Chen Liubo , Zhong Chenhan , Bu Tongtong , Dai Siqi , Pan Xiang , Fu Dongliang , Qian Yucheng , Wei Jingsun , Ding Kefeng 
Published: January 2021

Abstract
Background
Angiopoietin-like protein 1 (ANGPTL1) has been proved to suppress tumor metastasis in several cancers. However, its extracellular effects on the pre-metastatic niches (PMNs) are still unclear. ANGPTL1 has been identified in exosomes, while its function remains unknown. This study was designed to explore the role of exosomal ANGPTL1 on liver metastasis in colorectal cancer (CRC).

Methods
Exosomes were isolated by ultracentrifugation. The ANGPTL1 level was detected in exosomes derived from human CRC tissues. The effects of exosomal ANGPTL1 on CRC liver metastasis were explored by the intrasplenic injection mouse model. The liver PMN was examined by vascular permeability assays. Exosomal ANGPTL1 localization was validated by exosome labeling. The regulatory mechanisms of exosomal ANGPTL1 on Kupffer cells were determined by RNA sequencing. qRT-PCR, Western Blot, and ELISA analysis were conducted to examine gene expressions at mRNA and protein levels.

Results
ANGPTL1 protein level was significantly downregulated in the exosomes derived from CRC tumors compared with paired normal tissues. Besides, exosomal ANGPTL1 attenuated liver metastasis and impeded vascular leakiness in the liver PMN. Moreover, exosomal ANGPTL1 was mainly taken up by KCs and regulated the KCs secretion pattern, enormously decreasing the MMP9 expression, which finally prevented the liver vascular leakiness. In mechanism, exosomal ANGPTL1 downregulated MMP9 level in KCs by inhibiting the JAK2-STAT3 signaling pathway.

Conclusions
Taken together, exosomal ANGPTL1 attenuated CRC liver metastasis and impeded vascular leakiness in the liver PMN by reprogramming the Kupffer cell and decreasing the MMP9 expression. This study suggests a suppression role of exosomal ANGPTL1 on CRC liver metastasis and expands the approach of ANGPTL1 functioning.
PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells
Authors: Liotti Federica , Kumar Narender , Prevete Nella , Marotta Maria , Sorriento Daniela , Ieranò Caterina , Ronchi Andrea , Marino Federica Zito , Moretti Sonia , Colella Renato , Puxeddu Efiso , Paladino Simona , Kano Yoshihito , Ohh Michael , Scala Stefania , Melillo Rosa Marina 
Published: January 2021

Abstract
Background
The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC).

Methods
PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice.

Results
Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation.

Conclusions
PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.
The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat
Authors: Hwang Jung Wook , Lee Min Ji , Chung Tae Nyoung , Lee Han A. Reum , Lee Jung Ho , Choi Seo Yoon , Park Ye Jin , Kim Chul Hee , Jin Isom , Kim Seong Hoon , Kwak Hyo-Bum , Heo Jun-Won , Na Kwangmin , Choi Sangchun , Choi Yong-Soo , Kim Kyuseok 
Published: January 2021

Abstract
Background
Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis.

Methods
We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens.

Results
Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study.

Conclusions
In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.
High B3GALT5 expression confers poor clinical outcome and contributes to tumor progression and metastasis in breast cancer
Authors: Liao Yu-Mei , Wang Ya-Hui , Hung Jung-Tung , Lin Yu-Ju , Huang Yen-Lin , Liao Guo-Shiou , Hsu Ya-Ling , Wu Jen-Chien , Yu Alice L. 
Published: January 2021

Abstract
Background
Existence of breast cancer stem cells (BCSCs) is implicated in disease relapse, metastasis, and resistance of treatment. β1,3-Galactosyltransferase 5 (B3GALT5) has been shown to be a pro-survival marker for BCSCs. However, little is known about the prognostic significance of B3GALT5 in breast cancer.

Methods
Paired tissues (tumor part and adjacent non-tumor part) from a cohort of 202 women with breast cancer were used to determine the expression levels of B3GALT5 mRNA by qRT-PCR. Kaplan–Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of relapse-free survival (RFS) and overall survival (OS). Both breast cancer cells and cancer stem cells (BCSCs) were used to see the in vitro effects of knockdown or overexpression of B3GALT5 on cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). A patient-derived xenograft (PDX) model was used to see the in vivo effects of knockdown of B3GALT5 in BCSCs on tumor growth and metastasis.

Results
Higher expression of B3GALT5 in 202 breast cancer tissues, especially in adjacent non-tumor tissue, correlated with poor clinical outcomes including shorter OS and RFS in all patients, especially those with early stage breast cancer. In vitro studies showed B3GALT5 could enhance cell migration, invasion, mammosphere formation, and EMT. Of note, B3GALT5 upregulated the expression of β-catenin and EMT activator zinc finger E-box binding homeobox 1 (ZEB1) pathway in BCSCs. In vivo studies showed B3GALT5 expression in BCSCs is critical for not only tumor growth but also lymph node and lung metastasis in PDX mice.

Conclusion
Our results demonstrated the value of B3GALT5 as a prognostic marker of breast cancer, especially among the early stage patients, and its crucial roles in regulating EMT, cell migration, and stemness thereby promoting breast cancer progression.
HiDeF: identifying persistent structures in multiscale ‘omics data
Authors: Zheng Fan , Zhang She , Churas Christopher , Pratt Dexter , Bahar Ivet , Ideker Trey 
Published: January 2021

AbstractIn any ‘omics study, the scale of analysis can dramatically affect the outcome. For instance, when clustering single-cell transcriptomes, is the analysis tuned to discover broad or specific cell types? Likewise, protein communities revealed from protein networks can vary widely in sizes depending on the method. Here, we use the concept of persistent homology, drawn from mathematical topology, to identify robust structures in data at all scales simultaneously. Application to mouse single-cell transcriptomes significantly expands the catalog of identified cell types, while analysis of SARS-COV-2 protein interactions suggests hijacking of WNT. The method, HiDeF, is available via Python and Cytoscape.
Quantitative profiling of N6-methyladenosine at single-base resolution in stem-differentiating xylem of Populus trichocarpa using Nanopore direct RNA sequencing
Authors: Gao Yubang , Liu Xuqing , Wu Bizhi , Wang Huihui , Xi Feihu , Kohnen Markus V. , Reddy Anireddy S. N. , Gu Lianfeng 
Published: January 2021

AbstractThere are no comprehensive methods to identifyN6-methyladenosine (m6A) at single-base resolution for every single transcript, which is necessary for the estimation of m6A abundance. We develop a new pipeline called Nanom6A for the identification and quantification of m6A modification at single-base resolution using Nanopore direct RNA sequencing based on an XGBoost model. We validate our method using methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and m6A-sensitive RNA-endoribonuclease–facilitated sequencing (m6A-REF-seq), confirming high accuracy. Using this method, we provide a transcriptome-wide quantification of m6A modification in stem-differentiating xylem and reveal that different alternative polyadenylation (APA) usage shows a different ratio of m6A.
Efficacy of acupuncture for sciatica: study protocol for a randomized controlled pilot trial
Authors: Yu Fang-Ting , Ni Guang-Xia , Cai Guo-Wei , Wan Wen-Jun , Zhou Xiao-Qing , Meng Xiu-Li , Li Jin-Ling , Tu Jian-Feng , Wang Li-Qiong , Yang Jing-Wen , Fu Hai-Yang , Zhang Xin-Chang , Li Jing , Wang Yan-Fu , Zhang Beng , Zhang Xiao-Hui , Zhang Hao-Lin , Shi Guang-Xia , Liu Cun-Zhi 
Published: January 2021

AbstractBackgroundAcupuncture is widely used for pain diseases while evidence of its efficacy for sciatica is insufficient. We aim to explore the feasibility and efficacy of acupuncture with different acupoint selecting strategies for sciatica induced by lumbar disc herniation.MethodsThis is a multicenter, three-arm, patient-assessor-blinded randomized controlled pilot trial. Ninety patients will be assigned randomly into 3 groups including disease-affected meridians (DAM) group, non-affected meridians (NAM) group, and sham acupuncture (SA) group in a 1:1:1 ratio. The trial involves a 4-week treatment along with follow-up for 22 weeks. The primary outcome is the change of leg pain intensity measured by the visual analogue scale (VAS) from baseline to week 4 after randomization. Secondary outcomes include functional status, back pain intensity, and quality of life. Adverse events will also be recorded.DiscussionThe results will inspire the optimal acupuncture strategy for sciatica and help establish a better design as well as power calculation for a full-scale study.Trial registrationChiCTR2000030680(Chinese Clinical Trial Registry,http://www.chictr.org.cn, registered on 9 March 2020).
Novel ethanol production using biomass preprocessing to increase ethanol yield and reduce overall costs
Authors: Pascoli Danielle Uchimura , Suko Azra , Gustafson Rick , Gough Heidi L. , Bura Renata 
Published: January 2021

AbstractBackgroundEthanol biorefineries need to lower their overall production costs to become economically feasible. Two strategies to achieve this are to reduce costs using cheaper feedstocks or to increase the ethanol production yield. Low-cost feedstocks usually have high non-structural components (NSC) content; therefore, a new process is necessary to accommodate these feedstocks and overcome the negative effects of NSC. This study developed a novel ethanol biorefinery process including a biomass preprocessing step that enabled the use of lower-cost feedstocks while improving ethanol production without detoxification (overliming). Two types of poplar feedstocks were used, low-quality whole-tree chips (WTC) and high-quality clean pulp chips (CPC), to determine if the proposed process is effective while using feedstocks with different NSC contents.ResultsTechnical assessment showed that acidic preprocessing increased the monomeric sugar recovery of WTC from 73.2% (untreated) to 87.5% due to reduced buffering capacity of poplar, improved sugar solubilization during pretreatment, and better enzymatic hydrolysis conversion. Preprocessing alone significantly improved the fermentability of the liquid fraction from 1–2% to 49–56% for both feedstocks while overliming improved it to 45%. Consequently, it was proposed that preprocessing can substitute for the detoxification step. The economic assessment revealed that using poplar WTC via the new process increased annual ethanol production of 10.5 million liters when compared to using CPC via overliming (base case scenario). Also, savings in total operating costs were about $10 million per year when using cheaper poplar WTC instead of CPC, and using recycled water for preprocessing lowered its total operating costs by 45-fold.ConclusionsThe novel process developed in this study was successful in increasing ethanol production while decreasing overall costs, thus facilitating the feasibility of lignocellulosic ethanol biorefineries. Key factors to achieving this outcome included substituting overliming by preprocessing, enabling the use of lower-quality feedstock, increasing monomeric sugar recovery and ethanol fermentation yield, and using recycled water for preprocessing. In addition, preprocessing enabled the implementation of an evaporator-combustor downstream design, resulting in a low-loading waste stream that can be treated in a wastewater treatment plant with a simple configuration.
Solid-state NMR of unlabeled plant cell walls: high-resolution structural analysis without isotopic enrichment
Authors: Zhao Wancheng , Kirui Alex , Deligey Fabien , Mentink-Vigier Frederic , Zhou Yihua , Zhang Baocai , Wang Tuo 
Published: January 2021

Abstract
Background
Multidimensional solid-state nuclear magnetic resonance (ssNMR) spectroscopy has emerged as an indispensable technique for resolving polymer structure and intermolecular packing in primary and secondary plant cell walls. Isotope (13C) enrichment provides feasible sensitivity for measuring 2D/3D correlation spectra, but this time-consuming procedure and its associated expenses have restricted the application of ssNMR in lignocellulose analysis.

Results
Here, we present a method that relies on the sensitivity-enhancing technique Dynamic Nuclear Polarization (DNP) to eliminate the need for 13C-labeling. With a 26-fold sensitivity enhancement, a series of 2D 13C–13C correlation spectra were successfully collected using the unlabeled stems of wild-type Oryza sativa (rice). The atomic resolution allows us to observe a large number of intramolecular cross peaks for fully revealing the polymorphic structure of cellulose and xylan. NMR relaxation and dipolar order parameters further suggest a sophisticated change of molecular motions in a ctl1 ctl2 double mutant: both cellulose and xylan have become more dynamic on the nanosecond and microsecond timescale, but the motional amplitudes are uniformly small for both polysaccharides.

Conclusions
By skipping isotopic labeling, the DNP strategy demonstrated here is universally extendable to all lignocellulose materials. This time-efficient method has landed the technical foundation for understanding polysaccharide structure and cell wall assembly in a large variety of plant tissues and species.
Production of 10-methyl branched fatty acids in yeast
Authors: Blitzblau Hannah G. , Consiglio Andrew L. , Teixeira Paulo , Crabtree Donald V. , Chen Shuyan , Konzock Oliver , Chifamba Gamuchirai , Su Austin , Kamineni Annapurna , MacEwen Kyle , Hamilton Maureen , Tsakraklides Vasiliki , Nielsen Jens , Siewers Verena , Shaw A. Joe 
Published: January 2021

Abstract
Background
Despite the environmental value of biobased lubricants, they account for less than 2% of global lubricant use due to poor thermo-oxidative stability arising from the presence of unsaturated double bonds. Methyl branched fatty acids (BFAs), particularly those with branching near the acyl-chain mid-point, are a high-performance alternative to existing vegetable oils because of their low melting temperature and full saturation.

Results
We cloned and characterized two pathways to produce 10-methyl BFAs isolated from actinomycetes and γ-proteobacteria. In the two-step bfa pathway of actinomycetes, BfaB methylates Δ9 unsaturated fatty acids to form 10-methylene BFAs, and subsequently, BfaA reduces the double bond to produce a fully saturated 10-methyl branched fatty acid. A BfaA-B fusion enzyme increased the conversion efficiency of 10-methyl BFAs. The ten-methyl palmitate production (tmp) pathway of γ-proteobacteria produces a 10-methylene intermediate, but the TmpA putative reductase was not active in E. coli or yeast. Comparison of BfaB and TmpB activities revealed a range of substrate specificities from C14-C20 fatty acids unsaturated at the Δ9, Δ10 or Δ11 position. We demonstrated efficient production of 10-methylene and 10-methyl BFAs in S. cerevisiae by secretion of free fatty acids and in Y. lipolytica as triacylglycerides, which accumulated to levels more than 35% of total cellular fatty acids.

Conclusions
We report here the characterization of a set of enzymes that can produce position-specific methylene and methyl branched fatty acids. Yeast expression of bfa enzymes can provide a platform for the large-scale production of branched fatty acids suitable for industrial and consumer applications.
Artificial light and biting flies: the parallel development of attractive light traps and unattractive domestic lights
Authors: Wilson Roksana , Wakefield Andrew , Roberts Nicholas , Jones Gareth 
Published: January 2021

AbstractLight trapping is an important tool for monitoring insect populations. This is especially true for biting Diptera, where light traps play a crucial role in disease surveillance by tracking the presence and abundance of vector species. Physiological and behavioural data have been instrumental in identifying factors that influence dipteran phototaxis and have spurred the development of more effective light traps. However, the development of less attractive domestic lights has received comparatively little interest but could be important for reducing interactions between humans and vector insects, with consequences for reducing disease transmission. Here, we discuss how dipteran eyes respond to light and the factors influencing positive phototaxis, and conclude by identifying key areas for further research. In addition, we include a synthesis of attractive and unattractive wavelengths for a number of vector species. A more comprehensive understanding of how Diptera perceive and respond to light would allow for more efficient vector sampling as well as potentially limiting the risk posed by domestic lighting.
Graphical Abstract