Miracle-dz/UniFAR-FTUs huggingface dataset:
Persistent Pulmonary Hypertension of the Newborn: Pathophysiological Mechanisms and Novel Therapeutic Approaches

Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.
CLDN3 expression and function in pregnancy-induced hypertension

This aim of the present study was to investigate the expression and function of claudin 3 (CLDN3) in pregnancy-induced hypertension. The mRNA expression levels of CLDN3 in the placental tissue and peripheral blood of patients with pregnancy-induced hypertension were measured using reverse transcription-quantitative PCR. Human trophoblast HTR8/SVneo cells overexpressing CLDN3 were generated using a lentiviral vector. Cell Counting kit-8 (CCK-8) assay, flow cytometry, Transwell chamber assays, confocal laser scanning microscopy and western blot analysis were performed to detect cell proliferation, invasion, migration and apoptosis, in addition to matrix metalloproteinase (MMP) expression and ERK1/2 phosphorylation. The mRNA expression levels of CLDN3 were significantly reduced in the placental tissues and peripheral blood samples of patients with pregnancy-induced hypertension compared with healthy pregnant controls. CLDN3 overexpression significantly increased HTR8/SVneo cell proliferation, invasion and migration whilst reducing apoptosis. HTR8/SVneo cells overexpressing CLDN3 also exhibited increased myofiber levels, increased MMP-2 and MMP-9 expression and increased ERK1/2 signaling activity. CLDN3 downregulation may be associated with the pathogenesis of pregnancy-induced hypertension. In conclusion, CLDN3 promotes the proliferative and invasive capabilities of human trophoblast cells, with the underlying mechanisms possibly involving upregulation of MMP expression via the ERK1/2 signaling pathway.
Predator–prey interactions in a restored eelgrass ecosystem: strategies for maximizing success of reintroduced bay scallops (Argopecten irradians)

Predation is a key determinant of community structure and function, and thus should play a central role in successful ecological restoration strategies. The bay scallop, Argopecten irradians, was once abundant in the coastal bays of Virginia, U.S.A. , until the complete loss of their eelgrass habitat, Zostera marina, in the 1930s. With the successful restoration of Z. marina in these coastal bays, attention has turned to reintroducing A. irradians with the intent of producing a self‐sustaining population. The success of this effort requires an understanding of the sources and degree of natural mortality that A. irradians experiences throughout their ontogeny. The objectives of this study were to: (1) quantify predatory mortality during two successive life history stages of A. irradians, in both spring and fall spawns and (2) identify possible predators of A. irradians in the Virginia coastal bays. We conducted tethering experiments to quantify the proportional losses due to predation, and used otter trawls and suction samples to characterize the predator community over two consecutive years. Losses due to predation ranged from 4 to 80% per day, with smaller juveniles (<15 mm shell height) experiencing greater mortality in 2013, and larger juveniles (>20 mm shell height) in 2014, which we infer is driven by the absence and presence of adult blue crabs in 2013 and 2014, respectively. We propose that managers should look toward relatively inexpensive predator surveys to best judge both when and at what size restored species should be introduced into the wild.
Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NFkB, were found exclusively in the responders. Mutations in NKBIE-related genes were also enriched in the responder group compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the TNFalpha signaling via NFkB pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro NFkB activity assays indicated that the G34E variant caused loss-of-function of NFKBIE, and resulted in activation of NFkB signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB-related genes should be considered.
Identification and Characterization of MAPK Signaling Pathway Genes and Associated lncRNAs in the Ileum of Piglets Infected by Clostridium perfringens Type C

Clostridium perfringens type C (C. perfringens type C) is one of the main microbial pathogens responsible for piglet diarrhea worldwide, causing substantial economic losses for pig-rearing industries. The mitogen-activated protein kinase (MAPK) signaling pathway is a key regulator of inflammatory bowel disease, especially necrotic enteritis. However, whether and how the MAPK signaling pathway is involved in regulating the process of piglet diarrhea when challenged by C. perfringens type C are still unknown. Here, we screened 38 differentially expressed genes (DEGs) in piglets' ileum tissues experimentally infected with C. perfringens type C that were enriched in the Sus scrofa MAPK signaling pathway, based on our previous transcriptome data. Of these DEGs, 12 genes (TRAF2, MAPK8, and GADD45G, among others) were upregulated whereas 26 genes (MAPK1, TP53, and CHUK, among others) were downregulated in the infected group. Our results showed that MAPK1, TP53, MAPK8, MYC, and CHUK were in the core nodes of the PPI network. Additionally, we obtained 35 lncRNAs from the sequencing data, which could be trans-targeted to MAPK signaling pathway genes and were differentially expressed in the ileum tissues infected with C. perfringens. We used qRT-PCR to verify the expression levels of genes and lncRNAs related to the MAPK signaling pathway; their expression patterns were consistent with RNA sequencing data. Our results provide strong support for deeply exploring the role of the MAPK signaling pathway in diarrhea caused by C. perfringens type C.
Lectins in Cervical Screening

Cervical screening in low-resource settings remains an unmet need. Lectins are naturally occurring sugar-binding glycoproteins whose binding patterns change as cancer develops. Lectins discriminate between dysplasia and normal tissue in several precancerous conditions. We explored whether lectins could be developed for cervical screening via visual inspection. Discovery work comprised lectin histochemistry using a panel of candidate lectins on fixed-human cervix tissue (high-grade cervical intraepithelial neoplasia (CIN3, n = 20) or normal (n = 20)), followed by validation in a separate cohort (30 normal, 25 CIN1, 25 CIN3). Lectin binding was assessed visually according to staining intensity. To validate findings macroscopically, near-infra red fluorescence imaging was conducted on freshly-resected cervix (1 normal, 7 CIN3), incubated with topically applied fluorescently-labelled lectin. Fluorescence signal was compared for biopsies and whole specimens according to regions of interest, identified by the overlay of histopathology grids. Lectin histochemistry identified two lectins—wheat germ agglutinin (WGA) and Helix pomatia agglutinin (HPA)—with significantly decreased binding to CIN3 versus normal in both discovery and validation cohorts. Findings at the macroscopic level confirmed weaker WGA binding (lower signal intensity) in CIN3 vs. normal for biopsies (p = 0.0308) and within whole specimens (p = 0.0312). Our findings confirm proof-of-principle and indicate that WGA could potentially be developed further as a probe for high-grade cervical disease.
Detection of microRNA expression levels based on microarray analysis for classification of idiopathic pulmonary fibrosis

The etiology and pathophysiological mechanisms of idiopathic pulmonary fibrosis (IPF) are yet to be fully elucidated; however, mining of disease-related microRNAs (miRNAs/miRs) has improved the understanding of the progression of IPF. The aim of the current study was to screen miRNAs associated with IPF using three mathematical algorithms: One-way ANOVA, least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). Using ANOVA, three miRNAs and two miRNAs were selected with opposite expression patterns in moderate and severe IPF, respectively. In total, two algorithms, LASSO and SVM-RFE, were used to perform feature selection of miRNAs. miRNAs from patients were also extracted from formalin-fixed paraffin-embedded tissues and detected using reverse transcription-quantitative PCR (RT-qPCR). The intersection of the three algorithms (ANOVA, LASSO and SVM-RFE) was taken as the final result of the miRNA candidates. Three miRNA candidates, including miR-124, hsa-miR-524-5p and hsa-miR-194 were therefore used as biomarkers. The receiver operating characteristic model demonstrated favorable discrimination between IPF and control groups, with an area under the curve of 78.5%. Moreover, RT-qPCR results indicated that miR-124, hsa-miR-524-5p, hsa-miR-194 and hsa-miR-133a were differentially expressed between patients with IPF and age-matched men without fibrotic lung disease. The target genes of these miRNAs were further predicted and Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed. Collectively, the present results suggested that the identified miRNAs associated with IPF may be useful biomarkers for the diagnosis of this disease.
Salivary IL-17A, IL-17F, and TNF-α Are Associated with Disease Advancement in Patients with Oral and Oropharyngeal Cancer

Delayed diagnosis of oral cavity and oropharyngeal cancer is associated with a poor prognosis. Despite progress in systemic therapy and radiotherapy, there has only been a slight improvement in the five-year survival rate. A non-invasive diagnostic method that consists of an assessment of specific proteins in saliva samples may significantly facilitate assessment of treatment results in patients diagnosed with oral and oropharyngeal cancer. The aim of this study was to assess the levels of IL-17 and TNF-α in the saliva of patients with oral and oropharyngeal cancer. The study was conducted prior to treatment in patients hospitalized in the Frederic Chopin Provincial Specialist Hospital No. 1 in Rzeszów, Poland. Saliva samples were collected from subjects on an empty stomach. Cytokine concentrations in the saliva were measured with ELISA and Luminex Multiplex Assays. The higher salivary concentrations of IL-17A, IL-17F, and TNF-α were significantly associated with disease advancement. Lower levels of IL-17A were associated with colonization of the oral cavity with aerobic bacteria. On the other hand, higher concentration of TNF-α was observed in patients with positive aerobic culture of oral swabs. Our results suggest that IL-17A, IL-17F, and TNF-α measured in the saliva may be a potential biomarker for cancer of the oral cavity and oropharynx.
In vitro Edwardsiella piscicida CK108 Transcriptome Profiles with Subinhibitory Concentrations of Phenol and Formalin Reveal New Insights into Bacterial Pathogenesis Mechanisms

Phenol and formalin are major water pollutants that are frequently discharged into the aquatic milieu. These chemicals can affect broad domains of life, including microorganisms. Aquatic pollutants, unlike terrestrial pollutants, are easily diluted in water environments and exist at a sub-inhibitory concentration (sub-IC), thus not directly inhibiting bacterial growth. However, they can modulate gene expression profiles. The sub-IC values of phenol and formalin were measured by minimal inhibitory concentration (MIC) assay to be 0.146% (1.3 mM) and 0.0039% (0.38 mM), respectively, in Edwardsiella piscicida CK108, a Gram-negative fish pathogen. We investigated the differentially expressed genes (DEG) by RNA-seq when the cells were exposed to the sub-ICs of phenol and formalin. DEG analyses revealed that genes involved in major virulence factors (type I fimbriae, flagella, type III and type VI secretion system) and various cellular pathways (energy production, amino acid synthesis, carbohydrate metabolism and two-component regulatory systems) were up- or downregulated by both chemicals. The genome-wide gene expression data corresponded to the results of a quantitative reverse complementary-PCR and motility assay. This study not only provides insight into how a representative fish pathogen, E. piscicida CK108, responds to the sub-ICs of phenol and formalin but also shows the importance of controlling chemical pollutants in aquatic environments.
Détection de processus sexuellement antagonistes dans le génome humain

Chez les especes sexuees, une selection sexuellement antagoniste (SA) peut agir si les deux sexes ont des optimums en fitness differents pour un meme trait. De plus, si l'architecture genetique de ce trait est partagee entre les sexes, un conflit sexuel intralocus (IASC) peut se produire, menant a l'evolution d'un dimorphisme sexuel. Un modele de genetique des populations classique predit que le chromosome X offre un environnement plus favorable a l'accumulation de locus sous selection SA en comparaison aux autosomes. Nous nous sommes dans un premier temps interessee a la detection d'une signature d'IASC dans le genome humain, c'est-a-dire des differences de frequences alleliques entre les sexes. En effectuant un balayage du genome, nous avons mis en evidence un enrichissement en locus montrant une signature d'IASC sur le chromosome X en comparaison aux autosomes. Un mecanisme possible a l'origine des differences de frequences alleliques entre les sexes dans une population est une distorsion de transmission sexe-specifique. Dans un second temps, nous avons donc mis au point une methode de detection de locus pour lesquels les parents transmettent preferentiellement un allele a leurs fils, et un autre allele a leurs filles, en utilisant une base de donnees de sequencage de trios parents-enfant. Nos resultats indiquent que des processus de distorsion de transmission sexe-specifique seraient a l'origine d'une grande partie des differences de frequences alleliques entre les sexes observees chez les enfants. Cela suggere que des processus sexuellement antagonistes agissant sur la survie pourraient avoir lieu entre la production des gametes et la naissance chez l'Homme.
Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides

Eucommia ulmoides Oliv. , a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.
Engineered Extracellular Vesicles Loaded With miR-124 Attenuate Cocaine-Mediated Activation of Microglia

MicroRNA-124 (miR-124), a brain-enriched microRNA, is known to regulate microglial quiescence. Psychostimulants such as cocaine have been shown to activate microglia by downregulating miR-124, leading, in turn, to neuroinflammation. We thus rationalized that restoring the levels of miR-124 could function as a potential therapeutic approach for cocaine-mediated neuroinflammation. Delivering miRNA based drugs in the brain that are effective and less invasive, however, remains a major challenge in the field. Herein we engineered extracellular vesicles (EVs) and loaded them with miR-124 for delivery in the brain. Approach involved co-transfection of mouse dendritic cells with Dicer siRNA and RVG-Lamp2b plasmid to deplete endogenous miRNAs and for targeting the CNS, respectively. Mouse primary microglia (mPm) were treated with purified engineered EVs loaded with either Cy5-miR-124 or Cy5-scrambled miRNA oligos in the presence or absence of cocaine followed by assessing EV uptake and microglial activation. In vivo studies involved pretreating mice intranasally with engineered EVs followed by cocaine injection (20 mg/kg, i.p.). mPm exposed to EV-miR-124 exhibited reduced expression of miR-124 targets – TLR4 and STAT3 as well as ERK-1/2 and Iba1. In cocaine administered mice, EV-Cy5-miR-124 delivered intranasally were detected in the CNS and significantly reduced the expression of inflammatory markers TLR4, MYD88, STAT3 and NF-kB p65 while also downregulating the microglial activation marker, Iba1. Collectively, these findings suggest that engineered EVs can deliver miR-124 into the CNS, thereby alleviating cocaine-mediated microglial activation. Manipulating EV miRNAs can thus be envisioned as an efficient means for delivery of RNA-based therapeutics to target organs.
Senescence and Host–Pathogen Interactions

Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.