bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of endothelial EMCN drives tumor lung metastasis through the premetastatic niche
Authors: Zhang Guoxin , Li Mengyuan , Zhou Dandan , Yang Xingjiu , Zhang Wenlong , Gao Ran 
Published: October 2022

Abstract
Background
Metastasis is the primary cause of cancer-related mortality. Metastasis involves a complex multistep process during which individual tumor cells spread primarily through destruction of the endothelial barrier, entering the circulatory system to colonize distant organs. However, the role of the endothelial barrier as the rate-limiting process in tumor metastasis and how these processes affect the regulation of the host microenvironment at the molecular level are poorly understood.

Methods
Here, we analyzed differentially expressed genes in breast cancer and lung adenocarcinoma, including metastatic and recurrent specimens, using TCGA dataset. The effects of EMCN on endothelial cells in vitro and in vivo were analyzed by assessing angiogenesis and vascular permeability, respectively. We established a syngeneic mouse model of endothelial cell-specific knockout of EMCN (EMCNecko) to study the role of EMCN in tumor growth and metastasis. Transcriptome sequencing, Western blotting, qPCR and immunofluorescence confirmed important factors in the premetastatic niche. A mouse model of allograft tumor resection with lung metastasis was established to confirm the therapeutic effect of a notch inhibitor combined with an anti-TGF-β antibody.

Results
We found a strong correlation of EMCN deficiency with tumor recurrence and metastasis. Comparative experiments in WT and EMCNecko mice revealed that endothelial EMCN deficiency did not affect primary tumor growth significantly but strongly promoted spontaneous metastasis. EMCN deficiency was associated with gene profiles that regulate cell junctions in vitro and enhance vascular permeability in vivo. Mechanistically, EMCN deficiency mainly affected the host microenvironment and led to the formation of a lung premetastatic niche by recruiting Ly6G+ neutrophils and upregulating MMP9, S100A8/A9 and TGF-β expression. Anti-TGF-β antibody effectively eliminated TGF-β-induced neutrophil polarization, thereby reducing lung metastasis. Notably, the combination of a Notch inhibitor and an anti-TGF-β antibody effectively inhibited tumor growth and lung metastasis and prolonged the survival time of mice.

Conclusions
We present a new translational strategy of EMCN as a new key player in tumor lung metastasis by affecting the host microenvironment. These findings could provide a sound theoretical basis for clinical treatment.
SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity
Authors: O’Connell Patrick , Blake Maja K. , Godbehere Sarah , Amalfitano Andrea , Aldhamen Yasser A. 
Published: October 2022

Abstract
Background
Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7.

Methods
We subjected WT and SLAMF7−/− mice to multiple EAE models, compared disease severity, and comprehensively profiled the CNS immune landscape of these mice. We identified all SLAMF7-expressing CNS immune cells and compared the entire CNS immune niche between genotypes. We performed deep phenotyping and in vitro functional studies of B and T cells via spectral cytometry and BioPlex assays. Adoptive transfer studies involving the transfer of WT and SLAMF7−/− B cells into B cell-deficient mice (μMT) were also performed. Finally, B–T cell co-culture studies were performed, and a comparative cell–cell interaction network derived from scRNA-seq data of SLAMF7+ vs. SLAMF7− human CSF immune cells was constructed.

Results
We found SLAMF7−/− mice to be more susceptible to EAE compared to WT mice and found SLAMF7 to be expressed on numerous CNS immune cell subsets. Absence of SLAMF7 did not grossly alter the CNS immune landscape, but allowed for altered immune cell subset infiltration during EAE in a model-dependent manner. Global lack of SLAMF7 expression increased myeloid cell activation states along with augmented T cell anti-MOG immunity. B cell profiling studies revealed increased activation states of specific plasma and B cell subsets in SLAMF7−/− mice during EAE, and functional co-culture studies determined that SLAMF7−/− B cells induce exaggerated T cell activation. Adoptive transfer studies revealed that the increased susceptibility of SLAMF7−/− mice to EAE is partly B cell dependent and reconstruction of the human CSF SLAMF7-interactome found B cells to be critical to cell–cell communication between SLAMF7-expressing cells.

Conclusions
Our studies have identified novel roles for SLAMF7 in CNS immune regulation and B cell function, and illuminate underpinnings of the genetic association between SLAMF7 and MS.
Microglial–oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury
Authors: Song Shanshan , Hasan Md Nabiul , Yu Lauren , Paruchuri Satya S. , Bielanin John P. , Metwally Shamseldin , Oft Helena C. M. , Fischer Sydney G. , Fiesler Victoria M. , Sen Tanusree , Gupta Rajaneesh K. , Foley Lesley M. , Hitchens T. Kevin , Dixon C. Edward , Cambi Franca , Sen Nilkantha , Sun Dandan 
Published: October 2022

AbstractDifferential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia–OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1–7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.
Parental genomes segregate into distinct blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts
Authors: De Coster Tine , Masset Heleen , Tšuiko Olga , Catteeuw Maaike , Zhao Yan , Dierckxsens Nicolas , Aparicio Ainhoa Larreategui , Dimitriadou Eftychia , Debrock Sophie , Peeraer Karen , de Ruijter-Villani Marta , Smits Katrien , Van Soom Ann , Vermeesch Joris Robert 
Published: October 2022

Abstract
Background
During normal zygotic division, two haploid parental genomes replicate, unite and segregate into two biparental diploid blastomeres.

Results
Contrary to this fundamental biological tenet, we demonstrate here that parental genomes can segregate to distinct blastomeres during the zygotic division resulting in haploid or uniparental diploid and polyploid cells, a phenomenon coined heterogoneic division. By mapping the genomic landscape of 82 blastomeres from 25 bovine zygotes, we show that multipolar zygotic division is a tell-tale of whole-genome segregation errors. Based on the haplotypes and live-imaging of zygotic divisions, we demonstrate that various combinations of androgenetic, gynogenetic, diploid, and polyploid blastomeres arise via distinct parental genome segregation errors including the formation of additional paternal, private parental, or tripolar spindles, or by extrusion of paternal genomes. Hence, we provide evidence that private parental spindles, if failing to congress before anaphase, can lead to whole-genome segregation errors. In addition, anuclear blastomeres are common, indicating that cytokinesis can be uncoupled from karyokinesis. Dissociation of blastocyst-stage embryos further demonstrates that whole-genome segregation errors might lead to mixoploid or chimeric development in both human and cow. Yet, following multipolar zygotic division, fewer embryos reach the blastocyst stage and diploidization occurs frequently indicating that alternatively, blastomeres with genome-wide errors resulting from whole-genome segregation errors can be selected against or contribute to embryonic arrest.

Conclusions
Heterogoneic zygotic division provides an overarching paradigm for the development of mixoploid and chimeric individuals and moles and can be an important cause of embryonic and fetal arrest following natural conception or IVF.
Excretory-secretory products from the brown stomach worm, Teladorsagia circumcincta, exert antimicrobial activity in in vitro growth assays
Authors: Rooney James , Williams Timothy L. , Northcote Holly M. , Frankl Fiona E. Karet , Price Daniel R. G. , Nisbet Alasdair J. , Morphew Russell M. , Cantacessi Cinzia 
Published: October 2022

Abstract
Background
Over the past decade, evidence has emerged of the ability of gastrointestinal (GI) helminth parasites to alter the composition of the host gut microbiome; however, the mechanism(s) underpinning such interactions remain unclear. In the current study, we (i) undertake proteomic analyses of the excretory-secretory products (ESPs), including secreted extracellular vesicles (EVs), of the ‘brown stomach worm’ Teladorsagia circumcincta, one of the major agents causing parasite gastroenteritis in temperate areas worldwide; (ii) conduct bioinformatic analyses to identify and characterise antimicrobial peptides (AMPs) with putative antimicrobial activity; and (iii) assess the bactericidal and/or bacteriostatic properties of T. circumcincta EVs, and whole and EV-depleted ESPs, using bacterial growth inhibition assays.

Methods
Size-exclusion chromatography was applied to the isolation of EVs from whole T. circumcincta ESPs, followed by EV characterisation via nanoparticle tracking analysis and transmission electron microscopy. Proteomic analysis of EVs and EV-depleted ESPs was conducted using liquid chromatography-tandem mass spectrometry, and prediction of putative AMPs was performed using available online tools. The antimicrobial activities of T. circumcincta EVs and of whole and EV-depleted ESPs against Escherichia coli were evaluated using bacterial growth inhibition assays.

Results
Several molecules with putative antimicrobial activity were identified in both EVs and EV-depleted ESPs from adult T. circumcincta. Whilst exposure of E. coli to whole ESPs resulted in a significant reduction of colony-forming units over 3 h, bacterial growth was not reduced following exposure to worm EVs or EV-depleted ESPs.

Conclusions
Our data points towards a bactericidal and/or bacteriostatic function of T. circumcincta ESPs, likely mediated by molecules with antimicrobial activity.

Graphical Abstract
Africa-wide meta-analysis on the prevalence and distribution of human cystic echinococcosis and canine Echinococcus granulosus infections
Authors: Karshima Solomon Ngutor , Ahmed Musa Isiyaku , Adamu Nuhu Bala , Magaji Abdullahi Alhaji , Zakariah Musa , Mohammed Konto 
Published: October 2022

Abstract
Background
Echinococcosis is a neglected zoonosis of increasing public health concern worldwide. According to the World Health Organization, 19,300 lives and 871,000 disability-adjusted life-years are lost globally each year because of cystic echinococcosis. Annual costs associated with cystic echinococcosis were estimated at US$ 3 billion because of treatment of cases and losses in the livestock industry.

Methods
We performed the random-effects model of meta-analysis using 51-year (1970–2021) data available from AJOL, Google Scholar, PubMed, Science Direct, Scopus and Web of Science. We also applied the Joanna Briggs Institute critical appraisal instrument for studies reporting prevalence data, the Cochran’s Q-test, Egger’s regression test and the single study deletion technique to respectively examine within-study bias, heterogeneity, across-study bias and sensitivity.

Results
Thirty-nine eligible studies on human cystic echinococcosis (HCE) from 13 countries across the five African sub-regions showed an overall prevalence of 1.7% (95% CI 1.1, 2.6) with a statistically significant (P < 0.001) sub-group range of 0.0% (95% CI 0.0, 14.1) to 11.0% (95% CI 7.6, 15.7). Highest prevalences were observed in Eastern Africa (2.7%; 95% CI 1.4, 5.4) by sub-region and Sudan (49.6%; 95% 41.2, 58.1) by country. Another set of 42 studies on Echinococcus granulosus infections (EGI) in dogs from 14 countries across the five African sub-regions revealed an overall prevalence of 16.9% (95% CI 12.7, 22.3) with a significant (P < 0.001) variation of 0.4 (95% CI 0.0, 5.9) to 35.8% (95% CI 25.4, 47.8) across sub-groups. Highest prevalences of E. granulosus were observed in North Africa (25.6%; 95% CI 20.4, 31.6) by sub-region and Libya (9.2%; 95% CI 5.7, 13.9) by country.

Conclusion
Human cystic echinococcosis and EGI are respectively prevalent among Africans and African dogs. We recommend a holistic control approach that targets humans, livestock, dogs and the environment, which all play roles in disease transmission. This approach should involve strategic use of anthelminthics in animals, standardized veterinary meat inspection in abattoirs, control of stray dogs to reduce environmental contamination and proper environmental sanitation. Mass screening of humans in hyper-endemic regions will also encourage early detection and treatment.

Graphical abstract
Modelling the optimal dosing schedule for artemether-lumefantrine chemoprophylaxis against malaria
Authors: Tarning Joel , von Seidlein Lorenz , Dondorp Arjen M. , White Nicholas J. , Maude Richard J. 
Published: October 2022

Abstract
Objective
Antimalarial chemoprophylaxis for high risk groups in endemic areas of Southeast Asia has the potential to reduce malaria transmission and accelerate elimination. However, the optimal choice of medication and dosing for many potential candidates is not clear. For a planned randomised controlled trial of prophylaxis for forest goers in Cambodia, artemether-lumefantrine (AL) was selected because of its ongoing efficacy and excellent tolerability and safety. As AL had not been used before for this purpose, a previously published pooled pharmacometric meta-model was used to determine the optimal dosing schedule.

Results
A full 3 day AL treatment course given twice a month, and twice daily treatment given once a week, resulted in trough concentrations consistently above the therapeutic threshold of 200 ng/mL. However, the most favourable exposure profile, and arguably most practical dosing scenario, was an initial 3 day full AL treatment course followed by twice daily dosing given once a week for the duration of chemoprevention. The latter was adopted as the dosing schedule for the trial.
Anti-asthmatic miR-224-5p inhibits the FHL1/MAPK pathway to repress airway smooth muscle cell proliferation in a murine model of asthma-like airway inflammation
Authors: Zhuang Zhifang , Zhou Yanjuan , Xu Jiao , Pan Leying 
Published: October 2022

Abstract
Background
The proliferation of airway smooth muscle cells (ASMCs) contributes to the contractility and inflammation in the pathophysiology of asthma. This intrigued us to clarify the effect of microRNA (miR)-224-5p on biological characteristics of ASMCs in mice with asthma-like airway inflammation and responses through the FHL1-dependent MAPK pathway.

Methods
An ovalbumin (OVA)-induced asthma mouse model was established, where ASMCs were isolated. The expression of FHL1 was determined in asthmatic mice. Artificial modulation of FHL1 expression was performed to explore its effect on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Afterwards, we analyzed the interaction among miR-224-5p, FHL1 and the MAPK pathway, and explored their combined impacts on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis.

Results
FHL1 was highly expressed and miR-224-5p was poorly expressed in asthmatic mice. FHL1 was verified to be a target of miR-224-5p. Loss of FHL1 function reduced airway inflammation in asthmatic mice and proliferation of ASMCs while inducing their apoptosis. Besides, miR-224-5p inhibited the MAPK pathway by binding to FHL1. Overexpression of miR-224-5p relieved airway inflammation, inhibited ASMC proliferation, and increased apoptosis, which could be reversed by overexpression of FHL1.

Conclusion
Altogether, miR-224-5p inhibited airway inflammation in asthmatic mice and ASMC proliferation through blocking the MAPK pathway by down-regulating FHL1.
Two cases of dupilumab-associated conjunctivitis with high expression of IL-8 mRNA on the ocular surface: a case report
Authors: Adachi Rumi , Shoji Jun , Hirota Akira , Tomioka Akiko , Tonozuka Yukiko , Inada Noriko , Yamagami Satoru 
Published: October 2022

AbstractBackgroundDupilumab-induced ocular surface disease (DIOSD) has been reported in patients with atopic dermatitis treated with dupilumab, and has been recognized as an adverse event of dupilumab. Our objective was to describe two cases of DIOSD with alterations in eotaxin-2 and interleukin (IL)-8 messenger ribonucleic acid (mRNA) expression on the ocular surface.Case presentationIn the ocular surface test, specimens were collected from the patient's ocular surface, and eotaxin-2 and IL-8 mRNA levels in the specimens were measured using real-time polymerase chain reaction. The clinical score of ocular surface findings was quantified using a 5-5-5 exacerbation grading scale for allergic conjunctivitis. The first case was of a 27-year-old man who developed DIOSD 3 months after starting treatment with dupilumab injection for atopic dermatitis. After 5 weeks of topical instillation of tacrolimus ophthalmic suspension, the clinical score of ocular surface findings improved and IL-8 and eotaxin-2 mRNA expression levels gradually decreased. The second patient was a 55-year-old man who developed DIOSD 11 weeks after the start of treatment with dupilumab injection for atopic dermatitis. Four weeks after starting ophthalmological treatment with tacrolimus ophthalmic suspension, his clinical scores on ocular surface findings improved and IL-8 mRNA expression levels decreased. The ocular surface test in this case revealed increased expression levels of IL-8 mRNA on the ocular surface at the onset of DIOSD, which decreased with the improvement of objective findings.ConclusionsDIOSD, which has been successfully treated with tacrolimus ophthalmic suspension, may involve IL-8-related inflammation in addition to type 2 inflammation.
Descemet’s membrane folds in ochronosis: a case report
Authors: de Azevedo Magalhaes Otavio , Abdel Rahman Abu Hwas Dunia 
Published: October 2022

Abstract
Background
We present this report of a new ophthalmic finding in a patient with ochronosis.

Case presentation
An 85-year-old Caucasian male patient with bilateral dark temporal and nasal pigmentation of conjunctiva and sclera was referred to our hospital owing to low visual acuity. On biomicroscopic examination, bilateral horizontal Descemet’s membrane folds were observed. Corneal tomography revealed irregular and asymmetric “against-the-rule” astigmatism in both eyes. Anterior segment optical coherence tomography demonstrated numerous central Descemet’s without edema or other corneal structure alterations.

Conclusion
This is the first report of Descemet’s membrane folds in ochronosis. These corneal findings suggest that the accumulation of homogentisic acid in the sclera leads to thickening and stiffness of this region. These alterations could remarkably decrease visual acuity owing to topographic corneal curvature alterations, especially in elderly patients.
A mouse model of vitiligo based on endogenous auto-reactive CD8 + T cell targeting skin melanocyte
Authors: Chen Daoming , Xu Zijian , Cui Jun , Chen Ting 
Published: October 2022

AbstractVitiligo is the most common human skin depigmenting disorder. It is mediated by endogenous autoreactive CD8 + T cells that destruct skin melanocytes. This disease has an estimated prevalence of 1% of the global population and currently has no cure. Animal models are indispensable tools for understanding vitiligo pathogenesis and for developing new therapies. Here, we describe a vitiligo mouse model which recapitulates key clinical features of vitiligo, including epidermis depigmentation, CD8 + T cell infiltration in skin, and melanocyte loss. To activate endogenous autoreactive cytotoxic CD8 + T cells targeting melanocytes, this model relies on transient inoculation of B16F10 melanoma cells and depletion of CD4 + regulatory T cells. At cellular level, epidermal CD8 + T cell infiltration and melanocyte loss start as early as Day 19 after treatment. Visually apparent epidermis depigmentation occurs 2 months later. This protocol can efficiently induce vitiligo in any C57BL/6 background mouse strain, using only commercially available reagents. This enables researchers to carry out in-depth in vivo vitiligo studies utilizing mouse genetics tools, and provides a powerful platform for drug discovery.