Search Results (6)

Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (P_d31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (P_d31 = 0.03, P_dob-d31 < 0.001) were seen 31 days after BDL with increased creatine (P_d35, P_d42, and P_d56 < 0.05) and transaminases (P_d31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (P_d56 < 0.001) accompanied by macrophage infiltration (CD68: P_group < 0.001) and systemic inflammation (TNFα: P_group < 0.001, white blood cell count: P_group < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (P_d31 < 0.001) and decreased after 42 (P_d42 < 0.001) and 56 days (P_d56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (P_d31 = 0.005; P_d56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve. Full article

Mandibulofacial dysostosis (MFD) is a human congenital disorder characterized by hypoplastic neural-crest-derived craniofacial bones often associated with outer and middle ear defects. There is growing evidence that mutations in components of the spliceosome are a major cause for MFD. Genetic variants affecting the function of several core splicing factors, namely SF3B4, SF3B2, EFTUD2, SNRPB and TXNL4A, are responsible for MFD in five related but distinct syndromes known as Nager and Rodriguez syndromes (NRS), craniofacial microsomia (CFM), mandibulofacial dysostosis with microcephaly (MFDM), cerebro-costo-mandibular syndrome (CCMS) and Burn–McKeown syndrome (BMKS), respectively. Animal models of NRS and MFDM indicate that MFD results from an early depletion of neural crest progenitors through a mechanism that involves apoptosis. Here we characterize the knockdown phenotype of Eftud2, Snrpb and Txnl4a in Xenopus embryos at different stages of neural crest and craniofacial development. Our results point to defects in cranial neural crest cell formation as the likely culprit for MFD associated with EFTUD2, SNRPB and TXNL4A haploinsufficiency, and suggest a commonality in the etiology of these craniofacial spliceosomopathies. Full article

Cerebral cavernous malformation (CCM) is a cerebromicrovascular disease that affects up to 0.5% of the population. Vessel dilation, decreased endothelial cell–cell contact, and loss of junctional complexes lead to loss of brain endothelial barrier integrity and hemorrhagic lesion formation. Leakage of hemorrhagic lesions results in patient symptoms and complications, including seizures, epilepsy, focal headaches, and hemorrhagic stroke. CCMs are classified as sporadic (sCCM) or familial (fCCM), associated with loss-of-function mutations in KRIT1/CCM1, CCM2, and PDCD10/CCM3. Identifying the CCM proteins has thrust the field forward by (1) revealing cellular processes and signaling pathways underlying fCCM pathogenesis, and (2) facilitating the development of animal models to study CCM protein function. CCM animal models range from various murine models to zebrafish models, with each model providing unique insights into CCM lesion development and progression. Additionally, these animal models serve as preclinical models to study therapeutic options for CCM treatment. This review briefly summarizes CCM disease pathology and the molecular functions of the CCM proteins, followed by an in-depth discussion of animal models used to study CCM pathogenesis and developing therapeutics. Full article

Corneal confocal microscopy (CCM) is emerging as a tool for identifying small fiber neuropathy in both peripheral neuropathies and neurodegenerative disease of the central nervous system (CNS). The value of corneal nerves as biomarkers for efficacy of clinical interventions against small fiber neuropathy and neurodegenerative disease is less clear but may be supported by preclinical studies of investigational agents. We, therefore, used diverse investigational agents to assess concordance of efficacy against corneal nerve loss and peripheral neuropathy in a mouse model of diabetes. Ocular delivery of the peptides ciliary neurotrophic factor (CNTF) or the glucagon-like peptide (GLP) analog exendin-4, both of which prevent diabetic neuropathy when given systemically, restored corneal nerve density within 2 weeks. Similarly, ocular delivery of the muscarinic receptor antagonist cyclopentolate protected corneal nerve density while concurrently reversing indices of systemic peripheral neuropathy. Conversely, systemic delivery of the muscarinic antagonist glycopyrrolate, but not gallamine, prevented multiple indices of systemic peripheral neuropathy and concurrently protected against corneal nerve loss. These data highlight the potential for use of corneal nerve quantification by confocal microscopy as a bridging assay between in vitro and whole animal assays in drug development programs for neuroprotectants and support its use as a biomarker of efficacy against peripheral neuropathy. Full article

Labeling of samples is a recurrent and time-consuming task in data analysis and machine learning and yet generally overlooked in terms of visual analytics approaches to improve the process. As the number of tailored applications of learning models increases, it is crucial that more effective approaches to labeling are developed. In this paper, we report the development of a methodology and a framework to support labeling, with an application case as background. The methodology performs visual active learning and label propagation with 2D embeddings as layouts to achieve faster and interactive labeling of samples. The framework is realized through SoundscapeX, a tool to support labeling in soundscape ecology data. We have applied the framework to a set of audio recordings collected for a Long Term Ecological Research Project in the Cantareira-Mantiqueira Corridor (LTER CCM), localized in the transition between northeastern São Paulo state and southern Minas Gerais state in Brazil. We employed a pre-label data set of groups of animals to test the efficacy of the approach. The results showed the best accuracy at $94.58\%$ in the prediction of labeling for birds and insects; and $91.09\%$ for the prediction of the sound event as frogs and insects. Full article

Background: Brain arteriovenous malformations (BAVMs) and cerebral cavernous malformations (CCMs) are rare developmental anomalies of the intracranial vasculature, with an irregular tendency to rupture, and as of yet incompletely deciphered pathophysiology. Because of their variety in location, morphology, and size, as well as unpredictable natural history, they represent a management challenge. MicroRNAs (miRNAs) are strands of non-coding RNA of around 20 nucleotides that are able to modulate the expression of target genes by binding completely or partially to their respective complementary sequences. Recent breakthroughs have been made on elucidating their contribution to BAVM and CCM occurrence, growth, and evolution; however, there are still countless gaps in our understanding of the mechanisms involved. Methods: We have searched the Medline (PubMed; PubMed Central) database for pertinent articles on miRNAs and their putative implications in BAVMs and CCMs. To this purpose, we employed various permutations of the terms and idioms: ‘arteriovenous malformation’, ‘AVM’, and ‘BAVM’, or ‘cavernous malformation’, ‘cavernoma’, and ‘cavernous angioma’ on the one hand; and ‘microRNA’, ‘miRNA’, and ‘miR’ on the other. Using cross-reference search; we then investigated additional articles concerning the individual miRNAs identified in other cerebral diseases. Results: Seven miRNAs were discovered to play a role in BAVMs, three of which were downregulated (miR-18a, miR-137, and miR-195*) and four upregulated (miR-7-5p, miR-199a-5p, miR-200b-3p, and let-7b-3p). Similarly, eight miRNAs were identified in CCM in humans and experimental animal models, two being upregulated (miR-27a and mmu-miR-3472a), and six downregulated (miR-125a, miR-361-5p, miR-370-3p, miR-181a-2-3p, miR-95-3p, and let-7b-3p). Conclusions: The following literature review endeavored to address the recent discoveries related to the various implications of miRNAs in the formation and growth of BAVMs and CCMs. Additionally, by presenting other cerebral pathologies correlated with these miRNAs, it aimed to emphasize the potential directions of upcoming research and biological therapies. Full article