bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional hair follicle regeneration: an updated review
Authors: Ji Shuaifei , Zhu Ziying , Sun Xiaoyan , Fu Xiaobing
Published: February 2021

The hair follicle (HF) is a highly conserved sensory organ associated with the immune response against pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing. Although recent advances in lineage-tracing techniques and the ability to profile gene expression in small populations of cells have increased the understanding of how stem cells operate during hair growth and regeneration, the construction of functional follicles with cycling activity is still a great challenge for the hair research field and for translational and clinical applications. Given that hair formation and cycling rely on tightly coordinated epithelial–mesenchymal interactions, we thus review potential cell sources with HF-inducive capacities and summarize current bioengineering strategies for HF regeneration with functional restoration.
Risk SNP-induced lncRNA-SLCC1 drives colorectal cancer through activating glycolysis signaling
Authors: Yan Tingting , Shen Chaoqin , Jiang Penglei , Yu Chenyang , Guo Fangfang , Tian Xianglong , Zhu Xiaoqiang , Lu Shiyuan , Han Bingshe , Zhong Ming , Chen Jinxian , Liu Qiang , Chen Yingxuan , Zhang Junfang , Hong Jie , Chen Haoyan , Fang Jing-Yuan
Published: February 2021

Long non-coding RNAs (lncRNAs) play key roles in colorectal carcinogenesis. Here, we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis. First, we identified rs6695584 as the causative SNP in 1q41 locus. The A>G mutation of rs6695584 created a protein-binding motif of BATF, altered the enhancer activity, and subsequently activated lncSLCC1 expression. Further validation in two independent CRC cohorts confirmed the upregulation of lncSLCC1 in CRC tissues, and revealed that increased lncSLCC1 expression was associated with poor survival in CRC patients. Mechanistically, lncRNA-SLCC1 interacted with AHR and transcriptionally activated HK2 expression, the crucial enzyme in glucose metabolism, thereby driving the glycolysis pathway and accelerating CRC tumor growth. The functional assays revealed that lncSLCC1 induced glycolysis activation and tumor growth in CRC mediated by HK2. In addition, HK2 was upregulated in colorectal cancer tissues and positively correlated with lncSLCC1 expression and patient survival. Taken together, our findings reveal a risk SNP-mediated oncogene lncRNA-SLCC1 promotes CRC through activating the glycolysis pathway.
The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens
Authors: Khushman Moh’d , Patel Girijesh Kumar , Maharjan Anu Singh , McMillin Gwendolyn A. , Nelson Cindy , Hosein Peter , Singh Ajay P.
Published: February 2021

Introduction

The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20–30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.

Methods

Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher’s exact test was used for statistical analysis.

Results

The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3–4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3–4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3–4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3–4 FrAEs (p = 0.1108).

Conclusion

The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
A systematic review of childhood maltreatment and DNA methylation: candidate gene and epigenome-wide approaches
Authors: Parade Stephanie H. , Huffhines Lindsay , Daniels Teresa E. , Stroud Laura R. , Nugent Nicole R. , Tyrka Audrey R.
Published: February 2021

Childhood maltreatment is a major risk factor for chronic and severe mental and physical health problems across the lifespan. Increasing evidence supports the hypothesis that maltreatment is associated with epigenetic changes that may subsequently serve as mechanisms of disease. The current review uses a systematic approach to identify and summarize the literature related to childhood maltreatment and alterations in DNA methylation in humans. A total of 100 empirical articles were identified in our systematic review of research published prior to or during March 2020, including studies that focused on candidate genes and studies that leveraged epigenome-wide data in both children and adults. Themes arising from the literature, including consistent and inconsistent patterns of results, are presented. Several directions for future research, including important methodological considerations for future study design, are discussed. Taken together, the literature on childhood maltreatment and DNA methylation underscores the complexity of transactions between the environment and biology across development.
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness
Authors: Bonneau Marion , Sullivan Shane T. O’ , Gonzalez-Lozano Miguel A. , Baxter Paul , Gautier Phillippe , Marchisella Elena , Hardingham Neil R. , Chesters Robert A. , Torrance Helen , Howard David M. , Jansen Maurits A. , McMillan Melanie , Singh Yasmin , Didier Michel , Koopmans Frank , Semple Colin A. , McIntosh Andrew M. , Volkmer Hansjürgen , Loos Maarten , Fox Kevin , Hardingham Giles E. , Vernon Anthony C. , Porteous David J. , Smit August B. , Price David J. , Kirsty Millar J.
Published: February 2021

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.
A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models
Authors: Morimoto Yoshiro , Ono Shinji , Yoshida Shintaro , Mishima Hiroyuki , Kinoshita Akira , Tanaka Takeshi , Komohara Yoshihiro , Kurotaki Naohiro , Kishino Tatsuya , Okazaki Yuji , Ozawa Hiroki , Yoshiura Koh-ichiro , Imamura Akira
Published: February 2021

Genetic and epidemiological evidence has suggested that genetic factors are important in schizophrenia, although its pathophysiology is poorly understood. This study used whole-exome sequencing to investigate potential novel schizophrenia-causing genes in a Japanese family containing several members affected by severe or treatment-resistant schizophrenia. A missense variant, chr12:132064747C>T (rs200626129, P2805L), in the E1A-binding protein P400 (EP400) gene completely segregated with schizophrenia in this family. Furthermore, numerous other EP400 mutations were identified in the targeted sequencing of a schizophrenia patient cohort. We also created two lines of Ep400 gene-edited mice, which had anxiety-like behaviours and reduced axon diameters. Our findings suggest that rs200626129 in EP400 is likely to cause schizophrenia in this Japanese family, and may lead to a better understanding and treatment of schizophrenia.
Author Correction: Clonal hematopoiesis in patients with rheumatoid arthritis
Authors: Savola Paula , Lundgren Sofie , Keränen Mikko A. I. , Almusa Henrikki , Ellonen Pekka , Leirisalo-Repo Marjatta , Kelkka Tiina , Mustjoki Satu
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41408-021-00427-1
Key chemokines direct migration of immune cells in solid tumors
Authors: Kohli Karan , Pillarisetty Venu G. , Kim Teresa S.
Published: February 2021

Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.
Correction to: Cutting the molecular brakes to achieve cardiac regeneration
Authors: Nelson Victoria L. , Brunt Keith R.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41418-021-00748-5
Zinc transporter ZIP7 is a novel determinant of ferroptosis
Authors: Chen Po-Han , Wu Jianli , Xu Yitong , Ding Chien-Kuang Cornelia , Mestre Alexander A. , Lin Chao-Chieh , Yang Wen-Hsuan , Chi Jen-Tsan
Published: February 2021

Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.
GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway
Authors: Yu Xiaoting , Jin Jing , Zheng Yanwen , Zhu Hua , Xu Hui , Ma Jun , Lan Qing , Zhuang Zhixiang , Chen Clark C. , Li Ming
Published: February 2021

Guanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.
Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma
Authors: Chen Xiaopeng , Cheng Bin , Dai Dafei , Wu Yuhai , Feng Zhiwen , Tong Chaogang , Wang Xiangming , Zhao Jun
Published: February 2021

Heparanase (HPSE) is a kind of multifunctional extracellular hydrolase, and related to metastasis of hepatocellular carcinoma (HCC). Endothelial necroptosis promotes the metastasis of cancer cells. It is not clear whether HPSE could mediate necroptosis of microvascular endothelial cells (MVECs) to promote HCC metastasis. Here we found HPSE expression was up-regulated in HCC tissues and its over-expression was correlated with multiple tumor foci, microvascular invasion, and poor outcome of HCC patients. Non-contact co-culture experiments showed high-expressed HPSE in HCC cells mediated the necroptosis of human umbilical vein endothelial cells (HUVECs) and elevated the expression levels of syndecan-1 (SDC-1) and tumor necrosis factor-α (TNF-α) in vitro. As a result of necroptosis, trans-endothelial migration (TEM) of HCC cells was increased. Conversely, both HPSE and SDC-1 knockdowns reversed necroptosis and decreased TNF-α expression level, while HPSE over-expression increased SDC-1 and TNF-α expression and aggravated necroptosis. Animal experiments found that the nude mice, intraperitoneally injected with HPSE high expressing HCC cells, had obvious necroptosis of MVECs and high intrahepatic metastasis rate, which could be relieved by inhibitor of necroptosis. Morever, HPSE elevated the expression levels of p38 mitogen-activated protein kinase (p38 MAPK) rather than nuclear factor kappa B in vitro. Our data suggest that HPSE induces necroptosis of MVECs to promote the metastasis of HCC by activating HPSE/SDC-1/TNF-α axis and p38 MAPK pathway.
Smac-mimetics reduce numbers and viability of human osteoclasts
Authors: Moen Ingrid Nyhus , Westhrin Marita , Håland Erling , Haug Markus , Nonstad Unni , Klaharn Merisa , Standal Therese , Starheim Kristian K.
Published: February 2021

Elevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-κB and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of drugs that block RIPK1 ubiquitination and shifts RIPK1 to activation of apoptosis or necroptosis. In this manuscript, we show that the two SM birinapant and LCL-161 reduced the number and viability of primary human OC, and induced TNF-dependent cell death in OC precursors (pre-OC). Birinapant was more cytotoxic than LCL-161 and induced predominantly apoptosis and to some degree necroptosis. Both inhibitors restrained osteoclastogenesis induced by myeloma patient bone-marrow aspirates. SM has gained attention as novel treatment strategies both for cancer and chronic inflammatory pathologies, but limited information has been available on interactions with primary human immune cells. As LCL-161 is in phase 2 clinical studies for multiple myeloma, we propose that SM might possess additional benefits in reducing bone degradation in myeloma patients. Taken together, we show that SM reduces human osteoclastogenesis, and that these compounds may represent promising drug candidates for pathological bone degradation.
Diatom fucan polysaccharide precipitates carbon during algal blooms
Authors: Vidal-Melgosa Silvia , Sichert Andreas , Francis T. Ben , Bartosik Daniel , Niggemann Jutta , Wichels Antje , Willats William G. T. , Fuchs Bernhard M. , Teeling Hanno , Becher Dörte , Schweder Thomas , Amann Rudolf , Hehemann Jan-Hendrik
Published: February 2021

The formation of sinking particles in the ocean, which promote carbon sequestration into deeper water and sediments, involves algal polysaccharides acting as an adhesive, binding together molecules, cells and minerals. These as yet unidentified adhesive polysaccharides must resist degradation by bacterial enzymes or else they dissolve and particles disassemble before exporting carbon. Here, using monoclonal antibodies as analytical tools, we trace the abundance of 27 polysaccharide epitopes in dissolved and particulate organic matter during a series of diatom blooms in the North Sea, and discover a fucose-containing sulphated polysaccharide (FCSP) that resists enzymatic degradation, accumulates and aggregates. Previously only known as a macroalgal polysaccharide, we find FCSP to be secreted by several globally abundant diatom species including the genera Chaetoceros and Thalassiosira. These findings provide evidence for a novel polysaccharide candidate to contribute to carbon sequestration in the ocean.
Robust inference of kinase activity using functional networks
Authors: Yılmaz Serhan , Ayati Marzieh , Schlatzer Daniela , Çiçek A. Ercüment , Chance Mark R. , Koyutürk Mehmet
Published: February 2021

Mass spectrometry enables high-throughput screening of phosphoproteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer’s disease and Parkinson’s disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently enhances the accuracy of kinase activity inference methods while making them more robust to missing annotations and quantifications. This enables the identification of understudied kinases and will likely lead to the development of novel kinase inhibitors for targeted therapy of many diseases. RoKAI is available as web-based tool at http://rokai.io.
GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression
Authors: Wu Yeda , Murray Graham K. , Byrne Enda M. , Sidorenko Julia , Visscher Peter M. , Wray Naomi R.
Published: February 2021

Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genesMUC1,MUC6, FUT2,PSCA,ABO,CDX2, GASTandCCKBR. There are previously established roles in susceptibility toHelicobacter pyloriinfection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
A high throughput optical method for studying compositional effects in electrocatalysts for CO2 reduction
Authors: Hitt Jeremy L. , Li Yuguang C. , Tao Songsheng , Yan Zhifei , Gao Yue , Billinge Simon J. L. , Mallouk Thomas E.
Published: February 2021

In the problem of electrochemical CO2 reduction, the discovery of earth-abundant, efficient, and selective catalysts is essential to enabling technology that can contribute to a carbon-neutral energy cycle. In this study, we adapt an optical high throughput screening method to study multi-metallic catalysts for CO2 electroreduction. We demonstrate the utility of the method by constructing catalytic activity maps of different alloyed elements and use X-ray scattering analysis by the atomic pair distribution function (PDF) method to gain insight into the structures of the most active compositions. Among combinations of four elements (Au, Ag, Cu, Zn), Au6Ag2Cu2 and Au4Zn3Cu3 were identified as the most active compositions in their respective ternaries. These ternary electrocatalysts were more active than any binary combination, and a ca. 5-fold increase in current density at potentials of −0.4 to −0.8 V vs. RHE was obtained for the best ternary catalysts relative to Au prepared by the same method. Tafel plots of electrochemical data for CO2 reduction and hydrogen evolution indicate that the ternary catalysts, despite their higher surface area, are poorer catalysts for the hydrogen evolution reaction than pure Au. This results in high Faradaic efficiency for CO2 reduction to CO.
Moiré pattern of interference dislocations in condensate of indirect excitons
Authors: Leonard J. R. , Hu Lunhui , High A. A. , Hammack A. T. , Wu Congjun , Butov L. V. , Campman K. L. , Gossard A. C.
Published: February 2021

Interference patterns provide direct measurement of coherent propagation of matter waves in quantum systems. Superfluidity in Bose–Einstein condensates of excitons can enable long-range ballistic exciton propagation and can lead to emerging long-scale interference patterns. Indirect excitons (IXs) are formed by electrons and holes in separated layers. The theory predicts that the reduced IX recombination enables IX superfluid propagation over macroscopic distances. Here, we present dislocation-like phase singularities in interference patterns produced by condensate of IXs. We analyze how exciton vortices and skyrmions should appear in the interference experiments and show that the observed interference dislocations are not associated with these phase defects. We show that the observed interference dislocations originate from the moiré effect in combined interference patterns of propagating condensate matter waves. The interference dislocations are formed by the IX matter waves ballistically propagating over macroscopic distances. The long-range ballistic IX propagation is the evidence for IX condensate superfluidity.
Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages
Authors: Ochocka Natalia , Segit Pawel , Walentynowicz Kacper Adam , Wojnicki Kamil , Cyranowski Salwador , Swatler Julian , Mieczkowski Jakub , Kaminska Bozena
Published: February 2021

Microglia are resident myeloid cells in the central nervous system (CNS) that control homeostasis and protect CNS from damage and infections. Microglia and peripheral myeloid cells accumulate and adapt tumor supporting roles in human glioblastomas that show prevalence in men. Cell heterogeneity and functional phenotypes of myeloid subpopulations in gliomas remain elusive. Here we show single-cell RNA sequencing (scRNA-seq) of CD11b+ myeloid cells in naïve and GL261 glioma-bearing mice that reveal distinct profiles of microglia, infiltrating monocytes/macrophages and CNS border-associated macrophages. We demonstrate an unforeseen molecular heterogeneity among myeloid cells in naïve and glioma-bearing brains, validate selected marker proteins and show distinct spatial distribution of identified subsets in experimental gliomas. We find higher expression of MHCII encoding genes in glioma-activated male microglia, which was corroborated in bulk and scRNA-seq data from human diffuse gliomas. Our data suggest that sex-specific gene expression in glioma-activated microglia may be relevant to the incidence and outcomes of glioma patients.
Cre-Controlled CRISPR mutagenesis provides fast and easy conditional gene inactivation in zebrafish
Authors: Hans Stefan , Zöller Daniela , Hammer Juliane , Stucke Johanna , Spieß Sandra , Kesavan Gokul , Kroehne Volker , Eguiguren Juan Sebastian , Ezhkova Diana , Petzold Andreas , Dahl Andreas , Brand Michael
Published: February 2021

Conditional gene inactivation is a powerful tool to determine gene function when constitutive mutations result in detrimental effects. The most commonly used technique to achieve conditional gene inactivation employs the Cre/loxP system and its ability to delete DNA sequences flanked by two loxP sites. However, targeting a gene with two loxP sites is time and labor consuming. Here, we show Cre-Controlled CRISPR (3C) mutagenesis to circumvent these issues. 3C relies on gRNA and Cre-dependent Cas9-GFP expression from the same transgene. Exogenous or transgenic supply of Cre results in Cas9-GFP expression and subsequent mutagenesis of the gene of interest. The recombined cells become fluorescently visible enabling their isolation and subjection to various omics techniques. Hence, 3C mutagenesis provides a valuable alternative to the production of loxP-flanked alleles. It might even enable the conditional inactivation of multiple genes simultaneously and should be applicable to other model organisms amenable to single integration transgenesis.
Inequality is rising where social network segregation interacts with urban topology
Authors: Tóth Gergő , Wachs Johannes , Di Clemente Riccardo , Jakobi Ákos , Ságvári Bence , Kertész János , Lengyel Balázs
Published: February 2021

Social networks amplify inequalities by fundamental mechanisms of social tie formation such as homophily and triadic closure. These forces sharpen social segregation, which is reflected in fragmented social network structure. Geographical impediments such as distance and physical or administrative boundaries also reinforce social segregation. Yet, less is known about the joint relationships between social network structure, urban geography, and inequality. In this paper we analyze an online social network and find that the fragmentation of social networks is significantly higher in towns in which residential neighborhoods are divided by physical barriers such as rivers and railroads. Towns in which neighborhoods are relatively distant from the center of town and amenities are spatially concentrated are also more socially segregated. Using a two-stage model, we show that these urban geography features have significant relationships with income inequality via social network fragmentation. In other words, the geographic features of a place can compound economic inequalities via social networks.
An annotation-free whole-slide training approach to pathological classification of lung cancer types using deep learning
Authors: Chen Chi-Long , Chen Chi-Chung , Yu Wei-Hsiang , Chen Szu-Hua , Chang Yu-Chan , Hsu Tai-I , Hsiao Michael , Yeh Chao-Yuan , Chen Cheng-Yu
Published: February 2021

Deep learning for digital pathology is hindered by the extremely high spatial resolution of whole-slide images (WSIs). Most studies have employed patch-based methods, which often require detailed annotation of image patches. This typically involves laborious free-hand contouring on WSIs. To alleviate the burden of such contouring and obtain benefits from scaling up training with numerous WSIs, we develop a method for training neural networks on entire WSIs using only slide-level diagnoses. Our method leverages the unified memory mechanism to overcome the memory constraint of compute accelerators. Experiments conducted on a data set of 9662 lung cancer WSIs reveal that the proposed method achieves areas under the receiver operating characteristic curve of 0.9594 and 0.9414 for adenocarcinoma and squamous cell carcinoma classification on the testing set, respectively. Furthermore, the method demonstrates higher classification performance than multiple-instance learning as well as strong localization results for small lesions through class activation mapping.
Long-term exposure to a hypomagnetic field attenuates adult hippocampal neurogenesis and cognition
Authors: Zhang Bingfang , Wang Lei , Zhan Aisheng , Wang Min , Tian Lanxiang , Guo Weixiang , Pan Yongxin
Published: February 2021

Adult hippocampal neurogenesis contributes to learning and memory, and is sensitive to a variety of environmental stimuli. Exposure to a hypomagnetic field (HMF) influences the cognitive processes of various animals, from insects to human beings. However, whether HMF exposure affect adult hippocampal neurogenesis and hippocampus-dependent cognitions is still an enigma. Here, we showed that male C57BL/6 J mice exposed to HMF by means of near elimination of the geomagnetic field (GMF) exhibit significant impairments of adult hippocampal neurogenesis and hippocampus-dependent learning, which is strongly correlated with a reduction in the content of reactive oxygen species (ROS). However, these deficits seen in HMF-exposed mice could be rescued either by elevating ROS levels through pharmacological inhibition of ROS removal or by returning them back to GMF. Therefore, our results suggest that GMF plays an important role in adult hippocampal neurogenesis through maintaining appropriate endogenous ROS levels.
Fecal microbiota transplantation in HIV: A pilot placebo-controlled study
Authors: Serrano-Villar Sergio , Talavera-Rodríguez Alba , Gosalbes María José , Madrid Nadia , Pérez-Molina José A. , Elliott Ryan J. , Navia Beatriz , Lanza Val F. , Vallejo Alejandro , Osman Majdi , Dronda Fernando , Budree Shrish , Zamora Javier , Gutiérrez Carolina , Manzano Mónica , Vivancos María Jesús , Ron Raquel , Martínez-Sanz Javier , Herrera Sabina , Ansa Uxua , Moya Andrés , Moreno Santiago
Published: February 2021

Changes in the microbiota have been linked to persistent inflammation during treated HIV infection. In this pilot double-blind study, we study 30 HIV-infected subjects on antiretroviral therapy (ART) with a CD4/CD8 ratio < 1 randomized to either weekly fecal microbiota capsules or placebo for 8 weeks. Stool donors were rationally selected based on their microbiota signatures. We report that fecal microbiota transplantation (FMT) is safe, not related to severe adverse events, and attenuates HIV-associated dysbiosis. FMT elicits changes in gut microbiota structure, including significant increases in alpha diversity, and a mild and transient engraftment of donor’s microbiota during the treatment period. The greater engraftment seems to be achieved by recent antibiotic use before FMT. The Lachnospiraceae and Ruminococcaceae families, which are typically depleted in people with HIV, are the taxa more robustly engrafted across time-points. In exploratory analyses, we describe a significant amelioration in the FMT group in intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal damage that independently predicts mortality. Gut microbiota manipulation using a non-invasive and safe strategy of FMT delivery is feasible and deserves further investigation. Trial number: NCT03008941.
Calculating metalation in cells reveals CobW acquires CoII for vitamin B12 biosynthesis while related proteins prefer ZnII
Authors: Young Tessa R. , Martini Maria Alessandra , Foster Andrew W. , Glasfeld Arthur , Osman Deenah , Morton Richard J. , Deery Evelyne , Warren Martin J. , Robinson Nigel J.
Published: February 2021

Protein metal-occupancy (metalation) in vivo has been elusive. To address this challenge, the available free energies of metals have recently been determined from the responses of metal sensors. Here, we use these free energy values to develop a metalation-calculator which accounts for inter-metal competition and changing metal-availabilities inside cells. We use the calculator to understand the function and mechanism of GTPase CobW, a predicted CoII-chaperone for vitamin B12. Upon binding nucleotide (GTP) and MgII, CobW assembles a high-affinity site that can obtain CoII or ZnII from the intracellular milieu. In idealised cells with sensors at the mid-points of their responses, competition within the cytosol enables CoII to outcompete ZnII for binding CobW. Thus, CoII is the cognate metal. However, after growth in different [CoII], CoII-occupancy ranges from 10 to 97% which matches CobW-dependent B12 synthesis. The calculator also reveals that related GTPases with comparable ZnII affinities to CobW, preferentially acquire ZnII due to their relatively weaker CoII affinities. The calculator is made available here for use with other proteins.
Author Correction: Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells
Authors: Tremblay Cedric S. , Chiu Sung Kai , Saw Jesslyn , McCalmont Hannah , Litalien Veronique , Boyle Jacqueline , Sonderegger Stefan E. , Chau Ngoc , Evans Kathryn , Cerruti Loretta , Salmon Jessica M. , McCluskey Adam , Lock Richard B. , Robinson Phillip J. , Jane Stephen M. , Curtis David J.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21688-1
Characterization of oral virome and microbiome revealed distinctive microbiome disruptions in paediatric patients with hand, foot and mouth disease
Authors: Ho Si Xian , Min Nyo , Wong Emmerie Phaik Yen , Chong Chia Yin , Chu Justin Jang Hann
Published: February 2021

While the underlying determinants are unclear, hand, foot and mouth disease (HFMD) presents a wide spectrum of clinical manifestations with varying severity in different individuals. Recently, many studies identified the human microbiome as a critical factor in the pathogenesis of various diseases. Therefore, we here investigated the ecological dynamics of the oral microbiome changes during the HFMD infection. After targeted enrichment of all known vertebrate viruses, the virome profiles of symptomatic and asymptomatic HFMD patients were examined and revealed to be significantly altered from those of healthy individuals, with nine discriminative viruses detected. Further characterization of the prokaryotic microbiome revealed an elevated level of Streptococcus sp. as the most important signature of the symptomatic HFMD cohort, positively correlating to the level of enterovirus A RNA. In addition, we found that while coxsackievirus A5 is detected in saliva RNA of all asymptomatic cases, coxsackievirus A6 dominates the majority of the symptomatic cohort.
Faecal pollution source tracking in the holy Bagmati River by portable 16S rRNA gene sequencing
Authors: Pantha Kalyan , Acharya Kishor , Mohapatra Sanjeeb , Khanal Santosh , Amatya Niroj , Ospina-Betancourth Carolina , Butte Giacomo , Shrestha Suman Dhun , Rajbhandari Prajwal , Werner David
Published: February 2021

A suitcase laboratory was used for 16S rRNA amplicon sequencing to assess microbial water quality in the holy Bagmati River, Kathmandu, Nepal. SourceTracker analysis and Volcano plots revealed that microbial communities in the downstream part of the river were mainly contributed by untreated sewage. Seasonal variability in the sewage microbiome was reflected in the downstream river water quality. The bacterial genera Acidovorax, Geobacillus and Caulobacter predominated in the upstream sites, while genera containing putative human pathogens and gut bacteria, such as Clostridium, Prevotella, Arcobacter, Lactobacillus, Enterococcus and Streptococcus become prominent in the downstream sites. Marker gene qPCR assays for total bacteria, total coliforms, Human E. coli, Arcobacter butzleri and Vibrio cholerae confirmed the sequencing data trends. Even though basic sanitation provision is nowadays near universal in Nepal, our findings show how inadequate wastewater management may turn an urban river into an open sewer, which poses a public health risk.
Author Correction: Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts
Authors:   PDXNET Consortium, Woo Xing Yi ,   EurOPDX Consortium, Giordano Jessica , Srivastava Anuj , Zhao Zi-Ming , Lloyd Michael W. , de Bruijn Roebi , Suh Yun-Suhk , Patidar Rajesh , Chen Li , Scherer Sandra , Bailey Matthew H. , Yang Chieh-Hsiang , Cortes-Sanchez Emilio , Xi Yuanxin , Wang Jing , Wickramasinghe Jayamanna , Kossenkov Andrew V. , Rebecca Vito W. , Sun Hua , Mashl R. Jay , Davies Sherri R. , Jeon Ryan , Frech Christian , Randjelovic Jelena , Rosains Jacqueline , Galimi Francesco , Bertotti Andrea , Lafferty Adam , O’Farrell Alice C. , Modave Elodie , Lambrechts Diether , ter Brugge Petra , Serra Violeta , Marangoni Elisabetta , El Botty Rania , Kim Hyunsoo , Kim Jong-Il , Yang Han-Kwang , Lee Charles , Dean Dennis A. , Davis-Dusenbery Brandi , Evrard Yvonne A. , Doroshow James H. , Welm Alana L. , Welm Bryan E. , Lewis Michael T. , Fang Bingliang , Roth Jack A. , Meric-Bernstam Funda , Herlyn Meenhard , Davies Michael A. , Ding Li , Li Shunqiang , Govindan Ramaswamy , Isella Claudio , Moscow Jeffrey A. , Trusolino Livio , Byrne Annette T. , Jonkers Jos , Bult Carol J. , Medico Enzo , Chuang Jeffrey H.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00811-4.
Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis
Authors: Mosleth Ellen F. , Vedeler Christian Alexander , Liland Kristian Hovde , McLeod Anette , Bringeland Gerd Haga , Kroondijk Liesbeth , Berven Frode Steingrimsen , Lysenko Artem , Rawlings Christopher J. , Eid Karim El-Hajj , Opsahl Jill Anette , Gjertsen Bjørn Tore , Myhr Kjell-Morten , Gavasso Sonia
Published: February 2021

Despite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.
Key factors leading to fatal outcomes in COVID-19 patients with cardiac injury
Authors: He Yiyu , Zheng Xiaoxin , Li Xiaoyan , Jiang Xuejun
Published: February 2021

Cardiac injury among patients with COVID-19 has been reported and is associated with a high risk of mortality, but cardiac injury may not be the leading factor related to death. The factors related to poor prognosis among COVID-19 patients with myocardial injury are still unclear. This study aimed to explore the potential key factors leading to in-hospital death among COVID-19 patients with cardiac injury. This retrospective single-center study was conducted at Renmin Hospital of Wuhan University, from January 20, 2020 to April 10, 2020, in Wuhan, China. All inpatients with confirmed COVID-19 (≥ 18 years old) and cardiac injury who had died or were discharged by April 10, 2020 were included. Demographic data and clinical and laboratory findings were collected and compared between survivors and nonsurvivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with mortality in COVID-19 patients with cardiac injury. A total of 173 COVID-19 patients with cardiac injury were included in this study, 86 were discharged and 87 died in the hospital. Multivariable regression showed increased odds of in-hospital death were associated with advanced age (odds ratio 1.12, 95% CI 1.05–1.18, per year increase; p < 0.001), coagulopathy (2.54, 1.26–5.12; p = 0·009), acute respiratory distress syndrome (16.56, 6.66–41.2; p < 0.001), and elevated hypersensitive troponin I (4.54, 1.79–11.48; p = 0.001). A high risk of in-hospital death was observed among COVID-19 patients with cardiac injury in this study. The factors related to death include advanced age, coagulopathy, acute respiratory distress syndrome and elevated levels of hypersensitive troponin I.
New combination approaches to combat methicillin-resistant Staphylococcus aureus (MRSA)
Authors: Sharaf Mohamed H. , El-Sherbiny Gamal M. , Moghannem Saad A. , Abdelmonem Mohamed , Elsehemy Islam A. , Metwaly Ahmed M. , Kalaba Mohamed H.
Published: February 2021

The herbal products proved to be more promising antimicrobials even though their antimicrobial activity is milder than commercially available antibiotics. Moreover, herbal drugs may act synergistically with antibiotics to kill microbes. In this study, we aimed to enhance the activity of penicillin against MRSA through combination with the active saponin fraction isolated from theZygophyllum albumplant. Three different types of metabolites (saponins, sterols, and phenolics) have been extracted fromZygophyllum albumwith ethanol and purified using different chromatographic techniques. The antibacterial activity of crude extract and the separated metabolites were checked against MRSA isolates, Saponin fraction (ZA-S) was only the active one followed by the crude extract. Therefore, the compounds in this fraction were identified using ultra-high-performance liquid chromatography connected to quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS) operated in positive and negative ionization modes. UHPLC/QTOF-MS revealed the presence of major six ursane-type tritepenoidal saponins (Quinovic acid, Quinovic acid 3β-O-β-D-quinovopyranoside, Zygophylloside C, Zygophylloside G, Zygophylloside K and Ursolic acid), in addition to Oleanolic acid. Interaction studies between saponin fraction and penicillin against MRSA were performed through the checkerboard method and time-kill assay. According to checkerboard results, only three combinations showed a fractional inhibitory concentration index less than 0.5 at concentrations of (62.5 + 312.5, 62.5 + 156.25, and 62.5 + 78.125 of penicillin and ZA-S, respectively). Time kill assay results showed that the highest reduction in log10 colony-forming unit (CFU)/ml of initial inoculum of MRSA after 24 h occurred by 3.7 at concentrations of 62.5 + 312.5 (µg/µg)/ml of penicillin and ZA-S, respectively. Thus, the combination between saponin fraction ofZygophyllum albumand penicillin with these concentrations could be a potential agent against MRSA that can serve as possible model for new antibacterial drug.
Author Correction: The trans-kingdom battle between donor and recipient gut microbiome influences fecal microbiota transplantation outcome
Authors: Kazemian Negin , Ramezankhani Milad , Sehgal Aarushi , Khalid Faizan Muhammad , Kalkhoran Amir Hossein Zeinali , Narayan Apurva , Wong Gane Ka‑Shu , Kao Dina , Pakpour Sepideh
Published: February 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Effects of maoto (ma-huang-tang) on host lipid mediator and transcriptome signature in influenza virus infection
Authors: Nishi Akinori , Kaifuchi Noriko , Shimobori Chika , Ohbuchi Katsuya , Iizuka Seiichi , Sugiyama Aiko , Ogura Keisuke , Yamamoto Masahiro , Kuroki Haruo , Nabeshima Shigeki , Yachie Ayako , Matsuoka Yukiko , Kitano Hiroaki
Published: February 2021

Maoto, a traditional kampo medicine, has been clinically prescribed for influenza infection and is reported to relieve symptoms and tissue damage. In this study, we evaluated the effects of maoto as an herbal multi-compound medicine on host responses in a mouse model of influenza infection. On the fifth day of oral administration to mice intranasally infected with influenza virus [A/PR/8/34 (H1N1)], maoto significantly improved survival rate, decreased viral titer, and ameliorated the infection-induced phenotype as compared with control mice. Analysis of the lung and plasma transcriptome and lipid mediator metabolite profile showed that maoto altered the profile of lipid mediators derived from ω-6 and ω-3 fatty acids to restore a normal state, and significantly up-regulated the expression of macrophage- and T-cell-related genes. Collectively, these results suggest that maoto regulates the host’s inflammatory response by altering the lipid mediator profile and thereby ameliorating the symptoms of influenza.