bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-23 production is regulated via an MSK1/2 – CREB dependent signalling pathway downstream of Toll like receptors
Authors: Houslay Kirsty F. , van Gijsel-Bonnello Manuel , Petrova Tsvetana , Naqvi Shaista , Arthur J. Simon C. 
Published: July 2020

AbstractIL-23 is an IL-12 family cytokine that is important in promoting Th17 responses and has been strongly linked to autoimmunity and psoriasis. It is a heterodimeric cytokine made up of a p19 subunit unique to IL-23 and a p40 subunit that is shared with IL-12. We show here that in response to LPS, the induction of IL-23p19 mRNA is regulated by a MSK1/2 – CREB dependent pathway downstream of ERK1/2 and p38α MAPK. Knockout of MSK1/2 resulted in a decrease in both IL-23p19 mRNA transcription and IL-23 secretion in GM-CSF differentiated bone marrow cells. Similar effects were seen when the MSK1/2 phosphorylation site in CREB was mutated to alanine. Stimulation with PGE2 promotes the nuclear localisation of CRTC3, a co-activator for CREB. In combination with LPS, PGE2 promoted IL-23p19 mRNA transcription and this was blocked by knockdown of CRTC3. Imiquimod induced skin inflammation in mice has been used as a model for psoriasis and is dependent on IL-23. While MSK1/2 knockout reduced the induction of IL-23 in vivo following i.p. injection of LPS, the knockout mice were not protected from Imiquimod induced skin inflammation. MSK1/2 knockout did not reduce the induction of IL-17 producing γδT cells following Imiquimod treatment, although MSK1/2 knockout did reduce the levels of these cells in mice receiving a control cream. The lack of protection in the Imiquimod model may be due to the known anti-inflammatory roles or MSKs, such as its contribution to the induction of IL-10.
ATrypanosoma cruziZinc Finger protein that controls expression of epimastigote specific genes and affects metacyclogenesis
Authors: Tavares Thais Silva , Mügge Fernanda Lins Brandão , Grazielle-Silva Viviane , Valente Bruna Mattioly , Goes Wanessa Moreira , Oliveira Antonio Edson Rocha , Belew Ashton Trey , Guarneri Alessandra Aparecida , Pais Fabiano Sviatopolk-Mirsky , El-Sayed Najib M. , Teixeira Santuza Maria Ribeiro 
Published: July 2020

SummaryTrypanosoma cruzihas three biochemically and morphologically distinct developmental stages that are programed to rapidly respond to environmental changes the parasite faces during its life cycle. Unlike other eukaryotes, Trypanosomatid genomes contain protein coding genes that are transcribed into polycistronic pre-mRNAs and control of gene expression relies on mechanisms acting at the post-transcriptional level. Transcriptome analyses comparing epimastigote, trypomastigote and intracellular amastigote stages revealed changes in gene expression that reflect the parasite adaptation to distinct environments. Several genes encoding RNA binding proteins (RBP), known to act as key post-transcriptional regulatory factors, were also differentially expressed. We characterized oneT. cruziRBP (TcZH3H12) that contains a zinc finger domain, and whose transcripts are upregulated in epimastigotes compared to trypomastigotes and amastigotes. TcZC3H12 knockout epimastigotes showed decreased growth rates and increased capacity to differentiate into metacyclic trypomastigotes. Comparative transcriptome analysis revealed a TcZC3H12-dependent expression of epimastigote specific genes encoding amino acid transporters and proteins associated with differentiation (PAD), among others. RNA immunoprecipitation assays showed that transcripts from the PAD family interact with TcZC3H12. Taken together, these findings suggest that TcZC3H12 positively regulates the expression of genes involved in epimastigote proliferation and also acts as a negative regulator of metacyclogenesis.
Decorin, a novel negative modulator of E-cadherin in inflammatory breast cancer
Authors: Hu Xiaoding , Villodre Emilly S , Larson Richard , Rahal Omar M , Wang Xiaoping , Gong Yun , Song Juhee , Krishnamurthy Savitri , Ueno Naoto T. , Tripathy Debu , Woodward Wendy A , Debeb Bisrat G. 
Published: July 2020

ABSTRACTInflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cellsin vitroand inhibited IBC tumor growth and metastasisin vivo. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.
Integrating Engineered Macro Vessels with Self-assembled Capillaries in 3D Implantable Tissue for Promoting Vascular Integration In-vivo
Authors: Debbi Lior , Zohar Barak , Shandalov Yulia , Levenberg Shulamit 
Published: July 2020

AbstractFabrication of a functional hierarchical vascular network remains an unmet need for cultivation and transplantation of 3D engineered tissues. In this work, an effective approach was developed to fabricate a functional, perfusable and biocompatible, multi-scale vascular network (MSVT) within thick, implantable engineered tissues. Using a templating technique, macro-vessels were patterned in a 3D biodegradable polymeric scaffold seeded with endothelial and support cells within a collagen gel. The lumen of the macro-vessel was lined with endothelial cells, which further sprouted and anastomosed with the surrounding self-assembled capillaries. Anastomoses between the two-scaled vascular systems displayed tightly bonded cell junctions, as indicated by vascular endothelial cadherin expression. Moreover, MSVT functionality and patency were demonstrated by dextran passage through the interconnected hierarchical vasculature. Additionally, physiological flow conditions were applied with home-designed flow bioreactors, to achieve a MSVT with a natural endothelium structure. Finally, implantation of a multi-scale-vascularized graft in a mouse model resulted in a clear beneficial effect, as reflected by extensive host vessel penetration into the graft and an increase in blood perfusion via the engineered vessels as compared to control microscale-vascularized graft. Designing and fabricating such multi-scale vascular architectures within 3D engineered tissues is essential, both for in-vitro models and for therapeutic translation research.
A Small interfering RNA lead targeting RNA-dependent RNA-polymerase effectively inhibit the SARS-CoV-2 infection in Golden Syrian hamster and Rhesus macaque
Authors: Gu Se Hun , Yu Chi Ho , Song Youngjo , Kim Na Young , Sim Euni , Choi Jun Young , Song Dong Hyun , Hur Gyeung Haeng , Shin Young Kee , Jeong Seong Tae 
Published: July 2020

AbstractA small interfering RNA (siRNA) inhibitors have demonstrated the novel modality for suppressing infectious diseases. Sixty-one siRNA molecules, predicted by the bioinformatics programs, were screened for the possibility of treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using anin vitroplaque assay. Among six siRNA leads with the efficacy of reducing plaque number, the siRNA targeting RNA-dependent RNA polymerase (RdRp) showed a reduction in SARS-CoV-2 infection-induced fever and virus titer in the Golden Syrian hamster and rhesus macaque. These results suggest the potential for RdRp targeting siRNA as a new treatment for the coronavirus disease 2019 (COVID-19).
Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during development
Authors: Espinola Sergio Martin , Götz Markus , Fiche Jean-Bernard , Bellec Maelle , Houbron Christophe , Cardozo Gizzi Andrés M. , Lagha Mounia , Nollmann Marcelo 
Published: July 2020

AbstractDuring development, naïve cells gradually acquire distinct cell fates, through sophisticated mechanisms of precise spatio-temporal gene regulation. Acquisition of cell fate is thought to rely on the specific interaction of remotecis-regulatory modules (e.g. enhancers, silencers) (CRM) and target promoters. However, the precise interplay between chromatin structure and gene expression is still unclear, particularly in single cells within multicellular developing organisms. Here we employ Hi-M, a single-cell spatial genomics approach, to systematically detect CRM-promoter looping interactions within topological associating domains (TADs) duringDrosophiladevelopment. By comparingcis-regulatory loops in alternate cell types, we show that physical proximity does not necessarily instruct transcriptional states. Moreover, multi-way analyses revealed the existence of local interactions between multiple remote CRMs to form hubs. We found that loops and CRM hubs are established early during development, prior to the emergence of TADs. Moreover, CRM hubs are formed via the action of the pioneer transcription factor Zelda and precede transcriptional activation. Our approach offers a new perspective on the role of CRM-promoter interactions in defining transcriptional activation and repression states, as well as distinct cell types.
Fgf/Ets signalling inXenopusectoderm initiates neural induction and patterning in an autonomous and paracrine manners
Authors: Hongo Ikuko , Okamoto Harumasa 
Published: July 2020

ABSTRACTFibroblast growth factor (Fgf) and anti-bone morphogenetic protein (Bmp) signals are derived from the organiser of mesoderm origin and cooperate to promoteXenopusneural development from the gastrula ectoderm. Using antisense oligos to Fgf2 and Fgf8 and dominant-negative Ets transcription factors, we showed that the expression of Fgf2, Fgf8, and Ets in ectoderm cells is essential to initiate neural induction bothin vivoandin vitro. Our findings show that neural induction is initiated primarily by autonomous signalling in ectoderm cells, rather than by paracrine signalling from organiser cells. The signalling in ectoderm cells is transduced via the Fgf/Ras/Mapk/Ets pathway, independent of Bmp signal inhibition via the Fgf/Ras/Mapk/Smad1 route, as indicated by earlier studies. Through the same pathway, Fgfs activated position-specific neural genes dose-dependently along the anteroposterior axis in cultured ectoderm cells. The expression of these genes coincides with the establishment of the activated Ets gradient within the gastrula ectoderm. Organiser cells, being located posteriorly to the ectoderm, secrete Fgfs as gastrulation proceeds, which among several candidate molecules initially promote neural patterning of the induced neuroectoderm as morphogens.Summary statementFgf/Ets signalling in ectodermal cells is required to initiate the expression of both anterior and posterior neural genes from the late blastula to gastrula stages, independent of anti-Bmp signalling.
Population-level deep sequencing reveals the interplay of clonal and sexual reproduction in the fungal wheat pathogenZymoseptoria tritici
Authors: Singh Nikhil Kumar , Chanclud Emilie , Croll Daniel 
Published: July 2020

AbstractPathogens can rapidly surmount crop resistance challenging global food security. On annual crops, pathogens must re-infect from environmental sources at the beginning of every growing season. Fungal pathogens evolved mixed reproductive strategies to cope with the distinct life cycle challenges of colonizing plants, spreading within fields and ultimately producing propagules for survival in winter. However, how genotypic diversity evolves over this period remains largely unknown. Here, we performed a deep hierarchical sampling in a single experimental wheat field infected by the major fungal pathogenZymoseptoria tritici. We analyzed whole genome sequences of 177 isolates collected from twelve distinct cultivars replicated in space at three time points of the growing season. The field population was highly diverse with 37 SNPs per kilobase and a linkage disequilibrium decay within 200-700 bp. We found that ~20% of the individual isolates were grouping into 15 clonal groups. Pairs of clones were disproportionally found at short distance (<5m) but a low degree of dispersal occurred also at the scale of the entire field consistent with a predominant leaf-to-leaf dispersal. We found no association of wheat cultivars and clonal genotypes with the exception of one cultivar. Surprisingly, levels of clonality did not increase over time in the field although reproduction is thought to be exclusively asexual during the growing season. Our study shows that the pathogen establishes vast and stable gene pools in single fields over the growing season. Monitoring short-term evolutionary changes in crop pathogens will inform more durable strategies to contain diseases.Data summaryAll Illumina sequencing datasets are available from the NCBI Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra). The Supplementary Tables S1-S3 list the exact strain names, collection location, genotype and genetic diversity indices.
Ingestion of poisonous eggs from the invasive apple snailPomacea canaliculataadversely affects bullfrogLithobathes catesbeianusintestine morphophysiology
Authors: Brola Tabata R. , Dreon Marcos S. , Fernández Patricia E. , Portiansky Enrique L. , Heras Horacio 
Published: July 2020

ABSTRACTThe poisonous eggs ofPomacea canaliculata(Caenogastropoda, Ampullariidae) hardly have any predator. This invasive snail, listed among the 100 worst invasive species, is a serious crop pest and a vector of a human parasitosis. Females lay eggs in pink-reddish masses, presumably as a warning coloration of their chemical defenses. Egg ingestion alters rodents’ gastrointestinal tract and is lethal if injected, but its effect on other taxa is unknown. Here we explored the toxic effects ofPomacea canaliculataeggs on bullfrogLithobathes catesbeianus(Anura, Ranidae).Juvenile bullfrogs were gavaged with egg extracts and their digestive tract analyzed after 24 h and 48 h using histological, immunohistochemical and lectin-histochemical techniques. Toxicity was also evaluated by intraperitoneal injection of eggs extracts.Egg extract ingestion adversely affected small intestine of bullfrogs. Short term (24 h) effects included large, reversible changes of the intestinal wall, villi morphology, and changes in the glycosylation patterns of enterocytes. The mucosal area increased and infiltration of inflammatory cells, mainly eosinophils and macrophages, were observed together with a weak hemorrhage. Most of these changes reversed after 48 h. Besides, intraperitoneal injection of egg extract was nontoxic to bullfrog juveniles and no lethality or behavioral changes were observed, a remarkable difference with egg’ effect on mammals.As a whole, these results indicate that toxins of apple snail eggs reversibly modify gut morphology, which may alter bullfrog physiology limiting their ability to absorb egg nutrients. This study extends the known targets of the apple snail egg defenses against predation to amphibians.
Orientation of Temporal Interference for Non-Invasive Deep Brain Stimulation in Epilepsy
Authors: Missey Florian , Rusina Evgeniia , Acerbo Emma , Botzanowski Boris , Carron Romain , Trébuchon Agnès , Bartolomei Fabrice , Jirsa Viktor , Williamson Adam 
Published: July 2020

AbstractIn patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on nonpenetrating surface electrodes, namely an orientation-tunable form of temporally-interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally-invasive temporally-interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue.
The Connexin 43 Carboxyl Terminal Mimetic Peptide αCT1 Prompts Differentiation of a Collagen Scar Matrix Resembling Unwounded Skin
Authors: Montgomery Jade , Richardson William J. , Rhett J. Matthew , Bustos Francis , Degen Katherine , Ghatnekar Gautam S. , Grek Christina L. , Marsh Spencer , Jourdan L. Jane , Holmes Jeffrey W. , Gourdie Robert G. 
Published: July 2020

AbstractPhase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide αCT1 improves cutaneous scar appearance by 47% 9-months post-surgery – though mode-of-action remains unknown. Scar matrix structure in biopsies 2 to 6 weeks post-wounding treated topically with αCT1 or control treatments from human subjects, Sprague-Dawley rats, and IAF hairless guinea pigs were compared. The sole effect on scar structure in humans was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds, a state that resembles unwounded skin. This more random alignment was recapitulated in both animal models, together with transient increases in collagen density, although the guinea pig was found to more closely replicate the pattern of response to αCT1 in human scars, compared to rat. Fibroblasts treated with αCT1in vitroshowed decreased directionality and an agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix post-wounding that is similar to unwounded skin – changes that correlate with long-term improvement in scar appearance.
Label-free imaging of immune cell dynamics in the living retina using adaptive optics
Authors: Joseph Aby , Chu Colin J , Feng Guanping , Dholakia Kosha , Schallek Jesse 
Published: July 2020

AbstractOur recent work characterized the movement of single blood cells within the retinal vasculature of healthy mice (Joseph et al. 2019) using adaptive optics ophthalmoscopy. Here we apply this technique to the context of acute inflammation and discover both infiltrating and tissue-resident immune cells to be visible without any labelling in the living retina using near - infrared light alone. Intravital imaging of immune cells can be negatively impacted by surgical manipulation, exogenous dyes, transgenic manipulation and phototoxicity. These confounds are now overcome, using phase contrast and time-lapse videography to reveal the dynamic behavior of myeloid cells as they interact, extravasate and survey the retina. Cellular motility and differential vascular responses can be measured noninvasively and in vivo across hours to months at the same retinal location, from initiation to the resolution of inflammation. As comparable systems are already available for clinical research, this approach could be readily translated to human application.Impact statementImmune cell motility and vascular response are imagedin vivoand label-free in the CNS for the first time, using high-resolution phase-contrast adaptive optics retinal imaging.
Enhanced health facility surveys to support malaria control and elimination across different transmission settings in The Philippines
Authors: Reyes Ralph A. , Fornace Kimberly M. , Macalinao Maria Lourdes M. , Boncayao Beaulah L. , De La Fuente Ellaine S. , Sabanal Hennessey M. , Bareng Alison Paolo N. , Medado Inez Andrea P. , Mercado Edelwisa S. , Luchavez Jennifer S. , Hafalla Julius Clemence R. , Drakeley Chris J. , Espino Fe Esperanza J. 
Published: July 2020

AbstractFollowing substantial progress in malaria control in the Philippines, new surveillance approaches are needed to identify and target residual malaria transmission. This study evaluated an enhanced surveillance approach using rolling cross-sectional surveys of all health facility attendees augmented with molecular diagnostics and geolocation. Facility surveys were carried out in 3 sites representing different transmission intensities: Morong, Bataan (pre-elimination), Abra de Ilog, Occidental Mindoro (stable-medium risk) and Rizal, Palawan (high risk, control). Only 1 RDT positive infection and no PCR confirmed infections were found in Bataan and Occidental Mindoro suggesting the absence of transmission. In Rizal, inclusion of all health facility attendees, regardless of symptoms, and use of molecular diagnostics identified an additional 313 infected individuals in addition to 300 cases identified by routine screening of febrile patients with RDT or microscopy. Of these, the majority (313/613) were subpatent infections and only detected using molecular methods. Simultaneous collection of GPS coordinates on tablet-based applications allowed real-time mapping of malaria infections. Risk factor analysis showed higher risks in children and indigenous groups, with bednet use having a protective effect. Subpatent infections were more common in men and older age groups. Overall, malaria risks were not associated with patient status and some of non-patient clinic attendees reported febrile illnesses (1.9%, 26/1369) despite not seeking treatment highlighting the widespread distribution of infection in communities. Together, these data illustrate the utility of health-facility based surveys to augment surveillance data to increase the probability of detecting infections in the wider community.