Publications by authors named "Jose Otero"

118 Publications

Biochemical and Structural Characterization of a novel thermophilic esterase EstD11 provide catalytic insights for the HSL family.

Comput Struct Biotechnol J 2021 10;19:1214-1232. Epub 2021 Feb 10.

Department of Crystallography and Structural Biology, Institute of Physical-Chemistry "Rocasolano", Spanish National Research Council (CSIC), Madrid, Spain.

A novel esterase, EstD11, has been discovered in a hot spring metagenomic library. It is a thermophilic and thermostable esterase with an optimum temperature of 60°C. A detailed substrate preference analysis of EstD11 was done using a library of chromogenic ester substrate that revealed the broad substrate specificity of EstD11 with significant measurable activity against 16 substrates with varied chain length, steric hindrance, aromaticity and flexibility of the linker between the carboxyl and the alcohol moiety of the ester. The tridimensional structures of EstD11 and the inactive mutant have been determined at atomic resolutions. Structural and bioinformatic analysis, confirm that EstD11 belongs to the family IV, the hormone-sensitive lipase (HSL) family, from the α/β-hydrolase superfamily. The canonical α/β-hydrolase domain is completed by a cap domain, composed by two subdomains that can unmask of the active site to allow the substrate to enter. Eight crystallographic complexes were solved with different substrates and reaction products that allowed identification of the hot-spots in the active site underlying the specificity of the protein. Crystallization and/or incubation of EstD11 at high temperature provided unique information on cap dynamics and a first glimpse of enzymatic activity . Very interestingly, we have discovered a unique Met zipper lining the active site and the cap domains that could be essential in pivotal aspects as thermo-stability and substrate promiscuity in EstD11.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.csbj.2021.01.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905190PMC
February 2021

Machine learning approaches reveal subtle differences in breathing and sleep fragmentation in -derived astrocytes ablated mice.

J Neurophysiol 2021 Apr 27;125(4):1164-1179. Epub 2021 Jan 27.

Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine.

Modern neurophysiology research requires the interrogation of high-dimensionality data sets. Machine learning and artificial intelligence (ML/AI) workflows have permeated into nearly all aspects of daily life in the developed world but have not been implemented routinely in neurophysiological analyses. The power of these workflows includes the speed at which they can be deployed, their availability of open-source programming languages, and the objectivity permitted in their data analysis. We used classification-based algorithms, including random forest, gradient boosted machines, support vector machines, and neural networks, to test the hypothesis that the animal genotypes could be separated into their genotype based on interpretation of neurophysiological recordings. We then interrogate the models to identify what were the major features utilized by the algorithms to designate genotype classification. By using raw EEG and respiratory plethysmography data, we were able to predict which recordings came from genotype class with accuracies that were significantly improved relative to the no information rate, although EEG analyses showed more overlap between groups than respiratory plethysmography. In comparison, conventional methods where single features between animal classes were analyzed, differences between the genotypes tested using baseline neurophysiology measurements showed no statistical difference. However, ML/AI workflows successfully were capable of providing successful classification, indicating that interactions between features were different in these genotypes. ML/AI workflows provide new methodologies to interrogate neurophysiology data. However, their implementation must be done with care so as to provide high rigor and reproducibility between laboratories. We provide a series of recommendations on how to report the utilization of ML/AI workflows for the neurophysiology community. ML/AI classification workflows are capable of providing insight into differences between genotypes for neurophysiology research. Analytical techniques utilized in the neurophysiology community can be augmented by implementing ML/AI workflows. Random forest is a robust classification algorithm for respiratory plethysmography data. Utilization of ML/AI workflows in neurophysiology research requires heightened transparency and improved community research standards.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/jn.00155.2020DOI Listing
April 2021

Effects of Total Thermal Balance on the Thermal Energy Absorbed or Released by a High-Temperature Phase Change Material.

Molecules 2021 Jan 12;26(2). Epub 2021 Jan 12.

Tecnológico de Monterrey, Escuela de Ingeniería y Ciencias, Carr. al Lago de Guadalupe Km. 3.5, State of Mexico 52926, Mexico.

Front tracking and enthalpy methods used to study phase change processes are based on a local thermal energy balance at the liquid-solid interface where mass accommodation methods are also used to account for the density change during the phase transition. Recently, it has been shown that a local thermal balance at the interface does not reproduce the thermodynamic equilibrium in adiabatic systems. Total thermal balance through the entire liquid-solid system can predict the correct thermodynamic equilibrium values of melted (solidified) mass, system size, and interface position. In this work, total thermal balance is applied to systems with isothermal-adiabatic boundary conditions to estimate the sensible and latent heat stored (released) by KNO3 and KNO3/NaNO3 salts which are used as high-temperature phase change materials. Relative percent differences between the solutions obtained with a local thermal balance at the interface and a total thermal balance for the thermal energy absorbed or released by high-temperature phase change materials are obtained. According to the total thermal balance proposed, a correction to the liquid-solid interface dynamics is introduced, which accounts for an extra amount of energy absorbed or released during the phase transition. It is shown that melting or solidification rates are modified by using a total thermal balance through the entire system. Finally, the numerical and semi-analytical methods illustrate that volume changes and the fraction of melted (solidified) solid (liquid) estimated through a local thermal balance at the interface are not invariant in adiabatic systems. The invariance of numerical and semi-analytical solutions in adiabatic systems is significantly improved through the proposed model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26020365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828123PMC
January 2021

Astrocyte regional heterogeneity revealed through machine learning-based glial neuroanatomical assays.

J Comp Neurol 2021 Jan 7. Epub 2021 Jan 7.

Department of Pathology, Division of Neuropathology, The Ohio State University College of Medicine, Columbus, OH, USA.

Evaluation of reactive astrogliosis by neuroanatomical assays represents a common experimental outcome for neuroanatomists. The literature demonstrates several conflicting results as to the accuracy of such measures. We posited that the diverging results within the neuroanatomy literature were due to suboptimal analytical workflows in addition to astrocyte regional heterogeneity. We therefore generated an automated segmentation workflow to extract features of glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase family 1, member L1 (ALDH1L1) labeled astrocytes with and without neuroinflammation. We achieved this by capturing multiplexed immunofluorescent confocal images of mouse brains treated with either vehicle or lipopolysaccharide (LPS) followed by implementation of our workflows. Using classical image analysis techniques focused on pixel intensity only, we were unable to identify differences between vehicle-treated and LPS-treated animals. However, when utilizing machine learning-based algorithms, we were able to (1) accurately predict which objects were derived from GFAP or ALDH1L1-stained images indicating that GFAP and ALDH1L1 highlight distinct morphological aspects of astrocytes, (2) we could predict which neuroanatomical region the segmented GFAP or ALDH1L1 object had been derived from, indicating that morphological features of astrocytes change as a function of neuroanatomical location. (3) We discovered a statistically significant, albeit not highly accurate, prediction of which objects had come from LPS versus vehicle-treated animals, indicating that although features exist capable of distinguishing LPS-treated versus vehicle-treated GFAP and ALDH1L1-segmented objects, that significant overlap between morphologies exists. We further determined that for most classification scenarios, nonlinear models were required for improved treatment class designations. We propose that unbiased automated image analysis techniques coupled with well-validated machine learning tools represent highly useful models capable of providing insights into neuroanatomical assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cne.25105DOI Listing
January 2021

Revisiting the Neuropathology of Sudden Infant Death Syndrome (SIDS).

Front Neurol 2020 17;11:594550. Epub 2020 Dec 17.

Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.

Sudden infant death syndrome (SIDS) is one of the leading causes of infant mortality in the United States (US). The extent to which SIDS manifests with an underlying neuropathological mechanism is highly controversial. SIDS correlates with markers of poor prenatal and postnatal care, generally rooted in the lack of access and quality of healthcare endemic to select racial and ethnic groups, and thus can be viewed in the context of health disparities. However, some evidence suggests that at least a subset of SIDS cases may result from a neuropathological mechanism. To explain these issues, a triple-risk hypothesis has been proposed, whereby an underlying biological abnormality in an infant facing an extrinsic risk during a critical developmental period SIDS is hypothesized to occur. Each SIDS decedent is thus thought to have a unique combination of these risk factors leading to their death. This article reviews the neuropathological literature of SIDS and uses machine learning tools to identify distinct subtypes of SIDS decedents based on epidemiological data. We analyzed US Period Linked Birth/Infant Mortality Files from 1990 to 2017 (excluding 1992-1994). Using t-SNE, an unsupervised machine learning dimensionality reduction algorithm, we identified clusters of SIDS decedents. Following identification of these groups, we identified changes in the rates of SIDS at the state level and across three countries. Through t-SNE and distance based statistical analysis, we identified three groups of SIDS decedents, each with a unique peak age of death. Within the US, SIDS is geographically heterogeneous. Following this, we found low birth weight and normal birth weight SIDS rates have not been equally impacted by implementation of clinical guidelines. We show that across countries with different levels of cultural heterogeneity, reduction in SIDS rates has also been distinct between decedents with low vs. normal birth weight. Different epidemiological and extrinsic risk factors exist based on the three unique SIDS groups we identified with t-SNE and distance based statistical measurements. Clinical guidelines have not equally impacted the groups, and normal birth weight infants comprise more of the cases of SIDS even though low birth weight infants have a higher SIDS rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.594550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773837PMC
December 2020

Machine learning-based data analytic approaches for evaluating post-natal mouse respiratory physiological evolution.

Respir Physiol Neurobiol 2021 Jan 30;283:103558. Epub 2020 Sep 30.

Department of Pathology, Division of Neuropathology, The Ohio State University College of Medicine, Columbus, OH, United States. Electronic address:

Respiratory parameters change during post-natal development, but the nature of their changes have not been well-described. The advent of commercially available plethysmographic instruments provided improved repeatability of measurements and standardization of measured breathing in mice across laboratories. These technologies thus allowed for exploration of more precise respiratory pattern changes during the post-natal developmental epoch. Current methods to analyze respiratory behavior utilize plethysmography to acquire standing values of frequency, volume and flow at specific time points in murine maturation. These metrics have historically been independently analyzed as a function of time with no further analysis examining the interplay these variables have with each other and in the context of postnatal maturation or during blood gas homeostasis. We posit that machine learning workflows can provide deeper physiological understanding into the postnatal development of respiration. In this manuscript, we delineate a machine learning workflow based on the R-statistical programming language to examine how variation and relationships of frequency (f) and tidal volume (TV) change with respect to inspiratory and expiratory parameters. Our analytical workflows could successfully predict age and found that the variation and relationships between respiratory metrics are dynamically shifting with age and during hypercapnic breathing. Thus, our work demonstrates the utility of high dimensional analyses to provide reliable class label predictions using non-invasive respiratory metrics. These approaches may be useful in large-scale phenotyping across development and in disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.resp.2020.103558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881416PMC
January 2021

Sellar Cholesterol Granuloma Mimicking Cystic Sellar Lesions: A Report of Three Cases and Literature Review.

World Neurosurg 2020 Dec 8;144:250-255. Epub 2020 Aug 8.

Department of Neurological Surgery, Wexner Medical Center at The Ohio State University, Columbus, Ohio, USA; Department of Otolaryngology-Head and Neck Surgery, Wexner Medical Center at The Ohio State University, Columbus, Ohio, USA. Electronic address:

Background: Cystic lesions in the sellar region include a variety of entities, such as craniopharyngioma, Rathke cleft cyst (RCC), intrasellar arachnoid cyst, cystic pituitary adenomas, cholesterol granulomas (CGs), and xanthogranulomas (XGs). The distinction among them remains a preoperative challenge due to similarities in their clinical and radiologic findings.

Case Description: We describe 3 cases with cystic sellar lesions. The first patient is a woman who presented with headache and hormonal disturbances, including high levels of prolactin, with a sellar and suprasellar cystic lesion discovered on magnetic resonance imaging. She was initially treated with dopamine agonists with normalization of prolactin levels but no changes on the size of the lesion. She underwent an endoscopic endonasal resection and the histology resulted in a CG/XG. The second patient is a woman who consulted for an incidentally discovered sellar cyst. During the follow-up, the lesion demonstrated enlargement with compression of the optic chiasm. With a preoperative diagnosis of RCC, the lesion was removed through an endoscopic endonasal transsellar approach. Final pathologic diagnosis was consistent with CG/XG. The third case was that of a man who presented with refractory headaches and vision loss, with a sellar/suprasellar cystic lesion on magnetic resonance imaging. He underwent endoscopic endonasal transsellar surgery for resection of what preoperatively was thought to be a giant RCC; final pathology again was consistent with CG/XG.

Conclusions: CG/XG is an uncommon pathology with unspecific clinical and radiologic features. However, this pathology should be considered in the differential diagnosis of mixed cystic/solid lesions in the sellar region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.07.234DOI Listing
December 2020

Hyaluronic acid induces ROCK-dependent amoeboid migration in glioblastoma cells.

Biomater Sci 2020 Sep 4;8(17):4821-4831. Epub 2020 Aug 4.

Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA.

Glioblastoma (GBM) is the most aggressive and deadly adult brain tumor, primarily because of its high infiltrative capacity and development of resistance to therapy. Although GBM cells are typically believed to migrate via mesenchymal (e.g., fibroblast-like) migration modes, amoeboid (e.g., leucocyte-like) migration modes have been identified and may constitute a salvage pathway. However, the mesenchymal to amoeboid transition (MAT) process in GB is not well characterized, most likely because most culture models induce MAT via pharmacological or genetic inhibition conditions that are far from physiological. In this study, we examined the ability of hyaluronic acid (HA) content in three-dimensional collagen (Col) hydrogels to induce MAT in U87 GBM cells. HA and Col are naturally-occurring components of the brain extracellular matrix (ECM). In pure Col gels, U87 cells displayed primarily mesenchymal behaviors, including elongated cell morphology, clustered actin and integrin expression, and crawling migration behaviors. Whereas an increasing population of cells displaying amoeboid behaviors, including rounded morphology, cortical actin expression, low/no integrin expression, and squeezing or gliding motility, were observed with increasing HA content (0.1-0.2 wt% in Col). Consistent with amoeboid migration, these behaviors were abrogated by ROCK inhibition with the non-specific small molecule inhibitor Y27632. Toward identification of histological MAT classification criteria, we also examined the correlation between cell and nuclear aspect ratio (AR) in Col and Col-HA gels, finding that nuclear AR has a small variance and is not correlated to cell AR in HA-rich gels. These results suggest that HA may regulate GBM cell motility in a ROCK-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0bm00505cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473492PMC
September 2020

Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non-cell autonomous developmental mechanisms.

Brain Pathol 2021 Jan 4;31(1):84-102. Epub 2020 Aug 4.

Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO and/or O respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881415PMC
January 2021

Stimulation of retrotrapezoid nucleus Phox2b-expressing neurons rescues breathing dysfunction in an experimental Parkinson's disease rat model.

Brain Pathol 2020 09 2;30(5):926-944. Epub 2020 Jul 2.

Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo (USP), São Paulo, Brazil.

Emerging evidence from multiple studies indicates that Parkinson's disease (PD) patients suffer from a spectrum of autonomic and respiratory motor deficiencies in addition to the classical motor symptoms attributed to substantia nigra degeneration of dopaminergic neurons. Animal models of PD show a decrease in the resting respiratory rate as well as a decrease in the number of Phox2b-expressing retrotrapezoid nucleus (RTN) neurons. The aim of this study was to determine the extent to which substantia nigra pars compact (SNc) degeneration induced RTN biomolecular changes and to identify the extent to which RTN pharmacological or optogenetic stimulations rescue respiratory function following PD-induction. SNc degeneration was achieved in adult male Wistar rats by bilateral striatal 6-hydroxydopamine injection. For proteomic analysis, laser capture microdissection and pressure catapulting were used to isolate the RTN for subsequent comparative proteomic analysis and Ingenuity Pathway Analysis (IPA). The respiratory parameters were evaluated by whole-body plethysmography and electromyographic analysis of respiratory muscles. The results confirmed reduction in the number of dopaminergic neurons of SNc and respiratory rate in the PD-animals. Our proteomic data suggested extensive RTN remodeling, and that pharmacological or optogenetic stimulations of the diseased RTN neurons promoted rescued the respiratory deficiency. Our data indicate that despite neuroanatomical and biomolecular RTN pathologies, that RTN-directed interventions can rescue respiratory control dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12868DOI Listing
September 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Cancer Res 2021 Feb 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Near field non-invasive electrophysiology of retrotrapezoid nucleus using amperometric cation sensor.

Biosens Bioelectron 2020 Mar 18;151:111975. Epub 2019 Dec 18.

Division of Department of Pathology, The Ohio State University, 333 W 10(th) Ave, Columbus, 43210, Ohio, United States. Electronic address:

Central chemoreception is the process whereby the brainstem senses blood gas levels and adjusts homeostatic functions such as breathing and cardiovascular tone accordingly. Rodent evidence suggests that the retrotrapezoid nucleus (RTN) is a master regulator of central chemoreception, in particular, through direct sensation of acidosis induced by CO levels. The oscillatory dynamics caused by pH changes as sensed by the RTN surface and its relationship to the fluctuations in cation flux is not clearly understood due to the current limitations of electrophysiology tools and this article presents our investigations to address this need. A cation selective sensor fabricated from polypyrrole doped with dodecyl benzenesulfonate (PPy (DBS)) is placed over RTN in an ex-vivo en bloc brain and changes in cation concentration in the diffusion limited region above the RTN is measured due to changes in externally imposed basal pH. The novelty of this technique lies in its feasibility to detect cation fluxes from the cells in the RTN region without having to access either sides of the cell membrane. Owing to the placement of the sensor in close proximity to the tissue, we refer to this technique as near-field electrophysiology. It is observed that lowering the pH in the physiological range (7.4-7.2) results in a significant increase in cation concentration in the vicinity of RTN with a median value of ~5 μM. The utilization of such quantifiable measurement techniques to detect sub-threshold brain activity may help provide a platform for future neural network architectures. Findings from this paper present a quantifiable, sensitive, and robust electrophysiology technique with minimal damage to the underlying tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2019.111975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153495PMC
March 2020

MicroRNA-mRNA Interactions at Low Levels of Compressive Solid Stress Implicate mir-548 in Increased Glioblastoma Cell Motility.

Sci Rep 2020 01 15;10(1):311. Epub 2020 Jan 15.

Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.

Glioblastoma (GBM) is an astrocytic brain tumor with median survival times of <15 months, primarily as a result of high infiltrative potential and development of resistance to therapy (i.e., surgical resection, chemoradiotherapy). A prominent feature of the GBM microenvironment is compressive solid stress (CSS) caused by uninhibited tumor growth within the confined skull. Here, we utilized a mechanical compression model to apply CSS (<115 Pa) to well-characterized LN229 and U251 GBM cell lines and measured their motility, morphology, and transcriptomic response. Whereas both cell lines displayed a peak in migration at 23 Pa, cells displayed differential response to CSS with either minimal (i.e., U251) or large changes in motility (i.e., LN229). Increased migration of LN229 cells was also correlated to increased cell elongation. These changes were tied to epigenetic signaling associated with increased migration and decreases in proliferation predicted via Ingenuity® Pathway Analysis (IPA), characteristics associated with tumor aggressiveness. miRNA-mRNA interaction analysis revealed strong influence of the miR548 family (i.e., mir-548aj, mir-548az, mir-548t) on differential signaling induced by CSS, suggesting potential targets for pharmaceutical intervention that may improve patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-56983-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962377PMC
January 2020

Identification of Novel Cyclin A2 Binding Site and Nanomolar Inhibitors of Cyclin A2-CDK2 Complex.

Curr Comput Aided Drug Des 2021 ;17(1):57-68

Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, 43210, United States.

Background: Given the diverse roles of cyclin A2 both in cell cycle regulation and in DNA damage response, identifying small molecule regulators of cyclin A2 activity carries significant potential to regulate diverse cellular processes in both ageing/neurodegeneration and in cancer.

Objective: Based on cyclin A2's recently discovered role in DNA repair, we hypothesized that small molecule inhibitors that were predicted to bind to both cyclin A2 and CDK2 will be useful as a radiosensitizer of cancer cells. In this study, we used structure-based drug discovery to find inhibitors that target both cyclin A2 and CDK2.

Methods: Molecular dynamics simulations were used to generate diverse binding pocket conformations for application of the relaxed complex scheme. We then used structure-based virtual screening to find potential dual cyclin A2 and CDK2 inhibitors. Based on a consensus score of docked poses from Glide and AutoDock Vina, we identified about 40 promising hit compounds, where all PAINS scaffolds were removed from consideration. A biochemical luminescence assay of cyclin A2-CDK2 function was used for experimental verification.

Results: Four lead inhibitors of cyclin A2-CDK2 complex have been identified using a relaxed complex scheme virtual screen have been verified in a biochemical luminescence assay of cyclin A2- CDK2 function. Two of the four lead inhibitors had inhibitory concentrations in the nanomolar range.

Conclusion: The four cyclin A2-CDK2 complex inhibitors are the first reported inhibitors that were specifically designed not to target the cyclin A2-CDK2 protein-protein interface. Overall, our results highlight the potential of combined advanced computational tools and biochemical verification to discover novel binding scaffolds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573409916666191231113055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326642PMC
January 2021

Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation.

Nat Biomed Eng 2020 01 16;4(1):69-83. Epub 2019 Dec 16.

Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.

Exosomes are attractive as nucleic-acid carriers because of their favourable pharmacokinetic and immunological properties and their ability to penetrate physiological barriers that are impermeable to synthetic drug-delivery vehicles. However, inserting exogenous nucleic acids, especially large messenger RNAs, into cell-secreted exosomes leads to low yields. Here we report a cellular-nanoporation method for the production of large quantities of exosomes containing therapeutic mRNAs and targeting peptides. We transfected various source cells with plasmid DNAs and stimulated the cells with a focal and transient electrical stimulus that promotes the release of exosomes carrying transcribed mRNAs and targeting peptides. Compared with bulk electroporation and other exosome-production strategies, cellular nanoporation produced up to 50-fold more exosomes and a more than 10-fold increase in exosomal mRNA transcripts, even from cells with low basal levels of exosome secretion. In orthotopic phosphatase and tensin homologue (PTEN)-deficient glioma mouse models, mRNA-containing exosomes restored tumour-suppressor function, enhanced inhibition of tumour growth and increased survival. Cellular nanoporation may enable the use of exosomes as a universal nucleic-acid carrier for applications requiring transcriptional manipulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-019-0485-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080209PMC
January 2020

Modeling the release of curcumin from microparticles of poly(hydroxybutyrate) [PHB].

Int J Biol Macromol 2020 Feb 5;144:47-52. Epub 2019 Dec 5.

Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Campus Estado de México, Av Lago de Guadalupe KM 3.5, Margarita Maza de Juárez, Cd. López Mateos, Atizapán de Zaragoza, Estado de México 52926, Mexico; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

Polyhydroxybutyrate (PHB) is biodegradable and biocompatible polyester that has been recently used for developing different drug delivery systems (DDS). Microspheres as DDS, consist of a polymeric matrix with a diameter of 1-125 μm which contains a substance entrapped, and then released mainly through diffusion. In order to make DDS viable for commercial applications, it is essential to develop models that describe and predict the substance release kinetic. In this study, microspheres of PHB with curcumin entrapped were synthesized; the release of curcumin was studied and modeled. As a first approach, a physical model was introduced, in which mass transference was considered analogous to heat transference. The proposed model was based on local mass balance through the classical diffusion equation and total mass balance imposed through an integro-differential equation. The total mass balance introduced nonlinearities in the dynamics of the drug within the fluid; therefore, a semi-analytical approach based on the heat balance integral method was applied to solve the proposed model. Finally, by using the experimental rate of release of curcumin, the semi-analytical solutions to the proposed model were compared with the experimental release data, showing the importance of adding mass balance in the nonlinear mathematical model in order to describe more accurately the release kinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2019.11.242DOI Listing
February 2020

Neomicrambe subgen. nov. of Micrambe Thomson, 1863 (Coleoptera: Cryptophagidae) from East Africa.

Zootaxa 2019 Sep 23;4674(1):zootaxa.4674.1.2. Epub 2019 Sep 23.

Departamento de Zoología, Genética y Antropología Física, Facultad de Biología, 15782 Santiago de Compostela, Spain..

The isolation of a small group of species of the genus Micrambe Thomson, 1863 (Coleoptera: Cryptophagidae) in the eastern mountains of Africa, together with the exclusivity of habitat and the characteristics of their aedeagus have led to proposing a new subgenus, which we have called Neomicrambe subgen. nov. The differential diagnosis is established in relation to a group of other species of the genus. Two species are new records for Kenya.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11646/zootaxa.4674.1.2DOI Listing
September 2019

Unusual Forearm Deformity Solved by 3D Custom Made Guides.

J Hand Surg Asian Pac Vol 2019 Dec;24(4):483-487

Marques de Valdecilla University Hospital, Santander, Spain.

We report a case of a symptomatic forearm deformity due to a premature distal ulnar fracture solved by 3D custom made cutting guides. Our patient is a sixteen years old girl referred to us due to a forearm deformity and a dysplasic ulnar head associated to pain at the dorsum of the distal ulna and at the radial head at the elbow. Using custom-made cutting guides on a 3D model, a both bone forearm osteotomy was performed. At 18 months of follow up, the range of motion did not improve significantly but our patient referred no pain and she was satisfied with the procedure. The accuracy of single cut osteotomies, utilizing three-dimensional planning and custom patient guides has been previously established. This technique helped with the pain in our case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1142/S2424835519720184DOI Listing
December 2019

Beyond Linear Elastic Modulus: Viscoelastic Models for Brain and Brain Mimetic Hydrogels.

ACS Biomater Sci Eng 2019 Aug 1;5(8):3964-3973. Epub 2019 May 1.

Department of Mechanical Engineering, Iowa State University, Ames, Iowa 50011, United States.

With their high degree of specificity and investigator control, in vitro disease models provide a natural complement to in vivo models. Especially in organs such as the brain, where anatomical limitations make in vivo experiments challenging, in vitro models have been increasingly used to mimic disease pathology. However, brain mimetic models may not fully replicate the mechanical environment in vivo, which has been shown to influence a variety of cell behaviors. Specifically, many disease models consider only the linear elastic modulus of brain, which describes the stiffness of a material with the assumption that mechanical behavior is independent of loading rate. Here, we characterized porcine brain tissue using a modified stress relaxation test, and across a panel of viscoelastic models, showed that stiffness depends on loading rate. As such, the linear elastic modulus does not accurately reflect the viscoelastic properties of native brain. Among viscoelastic models, the Maxwell model was selected for further analysis because of its simplicity and excellent curve fit ( = 0.99 ± 0.0006). Thus, mechanical response of native brain and hydrogel mimetic models was analyzed using the Maxwell model and the linear elastic model to evaluate the effects of strain rate, time post mortem, region, tissue type (i.e., bulk brain vs white matter), and in brain mimetic models, hydrogel composition, on observed mechanical properties. In comparing the Maxwell and linear elastic models, linear elastic modulus is consistently lower than the Maxwell elastic modulus across all brain regions. Additionally, the Maxwell model is sensitive to changes in viscosity and small changes in elasticity, demonstrating improved fidelity. These findings demonstrate the insufficiency of linear elastic modulus as a primary mechanical characterization for brain mimetic materials and provide quantitative information toward the future design of materials that more closely mimic mechanical features of brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsbiomaterials.8b01390DOI Listing
August 2019

Spinal Cord Toxicity from Intrathecal Chemotherapy: A Case with Clinicopathologic Correlation.

World Neurosurg 2019 Aug 23;128:381-384. Epub 2019 May 23.

Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Division of Neuro-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

Background: Myelopathy of the dorsal columns is a rare complication of intrathecal (IT) chemotherapy that occurs most frequently with IT methotrexate and cytarabine. This diagnosis is made with a combination of magnetic resonance imaging, somatosensory evoked potentials, and elevated cerebrospinal fluid (CSF) protein levels, particularly myelin basic protein.

Case Description: A 73-year-old man with blastic plasmacytoid dendritic cell neoplasm and known central nervous system involvement underwent standard treatment, including 5 doses of IT cytosine arabinoside. Following this, he had documented CSF clearance of disease. One year later, he developed progressive lower extremity weakness, numbness, and bowel/bladder dysfunction. Magnetic resonance imaging and repeat CSF analysis demonstrated recurrence, and he underwent further IT administration of methotrexate and cytarabine. CSF clearance of malignant cells was again established. However, weakness progressed to quadriplegia; loss of bowel/bladder control; and severe sensory loss, particularly vibration and proprioception. Repeat magnetic resonance imaging demonstrated high signal intensity in bilateral posterior columns. A lower thoracic spine dorsal column biopsy revealed cord destruction and diffuse macrophage infiltration with profound destruction of the neuropil.

Conclusions: Although dorsal column myelopathy has previously been described in association with IT chemotherapy, this has solely been diagnosed on the basis of clinical examination, electrodiagnostic criteria, radiographic findings, and CSF analysis. This case provides a pathologic evaluation of an antemortem obtained specimen revealing diffuse macrophage infiltration and profound destruction of the neuropil. Whereas the mechanism underlying spinal cord toxicity following IT chemotherapy remains largely unknown, this case demonstrates a potentially macrophage-mediated process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2019.05.123DOI Listing
August 2019

Effects of Pressure-Induced Density Changes in the Thermal Energy Absorbed by a Micro-Encapsulated Phase-Change Material.

Molecules 2019 Mar 30;24(7). Epub 2019 Mar 30.

Departamento de Ciencias, Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey Campus Estado de México, Atizapán de Zaragoza, Estado de México 52900, México.

Density changes produced by pressure increments during melting of a spherically confined phase-change material have an impact on the thermal energy absorbed by the heat storage unit. Several authors have assumed incompressible phases to estimate the volume change of the phase-change material and the thermal balance at the liquid⁻solid interface. This assumption simplifies the problem but neglects the contribution of density changes to the thermal energy absorbed. In this work, a thermal balance at the interface that depends on the rate of change of the densities and on the shape of the container is found by imposing total mass conservation. The rigidity of the container is tuned through the coupling constant of an array of springs surrounding the phase-change material. This way, the behavior of the system can be probed from the isobaric to the isochoric regimes. The sensible and latent heat absorbed during the melting process are obtained by solving the proposed model through numerical and semi-analytical methods. Comparing the predictions obtained through our model, it is found that even for moderate pressures, the absorbed thermal energy predicted by other authors can be significantly overestimated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24071254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480058PMC
March 2019

Histologic findings associated with laser interstitial thermotherapy for glioblastoma multiforme.

Diagn Pathol 2019 Feb 15;14(1):19. Epub 2019 Feb 15.

Department of Neurological Surgery, The Ohio State University Wexner Medical Center, 410 West 10th Avenue, Doan 1047, Columbus, OH, 43210, USA.

Background: Laser-interstitial thermal therapy (LITT) has been supported by some authors as an ablative treatment of glioblastoma multiforme (GBM). Although the effects of LITT have been modeled in vivo, the histologic effects in a clinical circumstance have not been described. We analyzed tissue from a patient who underwent LITT as primary treatment for GBM.

Case Presentation: A 62-year-old male was diagnosed with a left temporal GBM and underwent LITT at an outside institution. Despite corticosteroid therapy, the patient was referred with increasing headache and acalculia associated with progressive peritumoral edema two weeks after LITT procedure. En bloc resection of the enhancing lesion and adjacent temporal lobe was performed with steroid-independent symptom resolution (follow-up, > 2 years). Histologic analysis revealed three distinct histologic zones concentrically radiating from the center of the treatment site. An acellular central region of necrosis (Zone 1) was surrounded by a rim of granulation tissue with macrophages (CD68) (Zone 2; mean thickness, 1.3 ± 0.3 mm [±S.D.]). Viable tumor cells (identified by Ki-67, p53 and Olig2 immunohistochemistry) were found (Zone 3) immediately adjacent to granulation tissue. The histologic volume of thermal tissue ablation/granulation was consistent with preoperative (pre-resection) magnetic resonance (MR)-imaging.

Conclusion: These findings are the first in vivo in humans to reveal that LITT causes a defined pattern of tissue necrosis, concentric destruction of tumor and tissue with viable tumor cells just beyond the zones of central necrosis and granulation. Furthermore, MR-imaging appears to be an accurate surrogate of tissue/tumor ablation in the early period (2 weeks) post-LITT treatment. Surgery is an effective strategy for patients with post-LITT swelling which does not respond to steroids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-019-0794-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376796PMC
February 2019

The role of PHOX2B-derived astrocytes in chemosensory control of breathing and sleep homeostasis.

J Physiol 2019 04 19;597(8):2225-2251. Epub 2019 Mar 19.

Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.

Key Points: The embryonic PHOX2B-progenitor domain generates neuronal and glial cells which together are involved in chemosensory control of breathing and sleep homeostasis. Ablating PHOX2B-derived astrocytes significantly contributes to secondary hypoxic respiratory depression as well as abnormalities in sleep homeostasis. PHOX2B-derived astrocyte ablation results in axonal pathologies in the retrotrapezoid nucleus.

Abstract: We identify in mice a population of ∼800 retrotrapezoid nucleus (RTN) astrocytes derived from PHOX2B-positive, OLIG3-negative progenitor cells, that interact with PHOX2B-expressing RTN chemosensory neurons. PHOX2B-derived astrocyte ablation during early life results in adult-onset O chemoreflex deficiency. These animals also display changes in sleep homeostasis, including fragmented sleep and disturbances in delta power after sleep deprivation, all without observable changes in anxiety or social behaviours. Ultrastructural evaluation of the RTN demonstrates that PHOX2B-derived astrocyte ablation results in features characteristic of degenerative neuro-axonal dystrophy, including abnormally dilated axon terminals and increased amounts of synapses containing autophagic vacuoles/phagosomes. We conclude that PHOX2B-derived astrocytes are necessary for maintaining a functional O chemosensory reflex in the adult, modulate sleep homeostasis, and are key regulators of synaptic integrity in the RTN region, which is necessary for the chemosensory control of breathing. These data also highlight how defects in embryonic development may manifest as neurodegenerative pathology in an adult.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP277082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462490PMC
April 2019

CCNA2 Ablation in Aged Mice Results in Abnormal rRNA Granule Accumulation in Hippocampus.

Am J Pathol 2019 02 21;189(2):426-439. Epub 2018 Dec 21.

Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio. Electronic address:

Mounting evidence in the literature suggests that RNA-RNA binding protein aggregations can disturb neuronal homeostasis and lead to symptoms associated with normal aging as well as dementia. The specific ablation of cyclin A2 in adult neurons results in neuronal polyribosome aggregations and learning and memory deficits. Detailed histologic and ultrastructural assays of aged mice revealed that post-mitotic hippocampal pyramidal neurons maintain cyclin A2 expression and that proliferative cells in the dentate subgranular zone express cyclin A2. Cyclin A2 loss early during neural development inhibited hippocampal development through canonical/cell-cycle mechanisms, including prolonged cell cycle timing in embryonic hippocampal progenitor cells. However, in mature neurons, cyclin A2 colocalized with dendritic rRNA. Cyclin A2 ablation in adult hippocampus resulted in decreased synaptic density in the hippocampus as well as in accumulation of rRNA granules in dendrite shafts. We conclude that cyclin A2 functions in a noncanonical/non-cell cycle regulatory role to maintain adult pyramidal neuron ribostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2018.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412465PMC
February 2019

A new species and a key to the species of from Guatemala (Coleoptera, Latridiidae).

Zookeys 2018 25(786):69-73. Epub 2018 Sep 25.

University of Santiago de Compostela, Department of Zoology, Genetics and Physical Anthropology, Santiago de Compostela 15782, Spain University of Santiago de Compostela Santiago de Compostela Spain.

A new species of Reitter, 1881 (Coleoptera: Latridiidae), from Guatemala is described and illustrated. The differential diagnosis is established in relation to a group of other species of the genus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3897/zookeys.786.26553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168616PMC
September 2018

Development of a Novel FIJI-Based Method to Investigate Neuronal Circuitry in Neonatal Mice.

Dev Neurobiol 2018 11 20;78(11):1146-1167. Epub 2018 Sep 20.

Department of Pathology, Division of Neuropathology, The Ohio State University College of Medicine, Columbus, Ohio.

The emergence of systems neuroscience tools requires parallel generation of objective analytical workflows for experimental neuropathology. We developed an objective analytical workflow that we used to determine how specific autonomic neural lineages change during postnatal development. While a wealth of knowledge exists regarding postnatal alterations in respiratory neural function, how these neural circuits change and develop in the weeks following birth remains less clear. In this study, we developed our workflow by combining genetic mouse modeling and quantitative immunofluorescent confocal microscopy and used this to examine the postnatal development of neural circuits derived from the transcription factors NKX2.2 and OLIG3 into three medullary respiratory nuclei. Our automated FIJI-based image analysis workflow rapidly and objectively quantified synaptic puncta in user-defined anatomic regions. Using our objective workflow, we found that the density and estimated total number of Nkx2.2-derived afferents into the pre-Bötzinger Complex significantly decreased with postnatal age during the first three weeks of postnatal life. These data indicate that Nkx2.2-derived structures differentially influence pre-Bötzinger Complex respiratory oscillations at different stages of postnatal development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dneu.22636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391728PMC
November 2018

Laryngeal anatomical variants and their impact on the diagnosis of mechanical asphyxias by neck pressure.

Forensic Sci Int 2018 Sep 25;290:1-10. Epub 2018 Jun 25.

Institute of Forensic Sciences, University of Santiago de Compostela, Spain. Electronic address:

The aims of this investigation were to determine the characteristics and prevalence of anatomical variants of the larynx apparatus and to evaluate the impact of these variants on the accurate diagnosis of laryngeal fractures. A population-based study was carried out, analyzing a series of 207 consecutive autopsied cases in the Institute of Legal Medicine of Galicia (Northwestern Spain). The prevalence of triticeal cartilage was 52.7% and that of agenesis of thyroid horns 10%. Calcification of the stylo-hyoid ligament accounted for 1.4%. We identified three new anatomical variants: the terminal segmentation of the thyroid horns (11.6%), ectopic superior thyroid horns (8%) and lateral thyrohyoid ossification (5.3%). These three names, based on anatomical criteria, are the author's proposal to solve the lack of uniformity in the designation of these variants. Agenesis of thyroid horns were related to the presence of ectopic superior thyroid horns in 93% of cases, either uni or bilateral. The combination of variants was present in 6.8% of the cases, being the terminal segmentation of the thyroid horns in association with triticeal cartilage the most frequent (3.8%). The probability of misdiagnosis due to the presence of anatomical variations in deaths by pressure on the neck was high in this population (71.5%). The prevalence of triticeal cartilage in more than half of the sample, determined an important rate of potential errors (46.4%), followed by the mistaken diagnoses induced by terminal segmentation of thyroid horns (7.3%) and by ectopic superior thyroid horns (6.3%). The likelihood of a misdiagnosed laryngeal fracture was greater if the thyroid cartilage was affected, with a higher proportion of false positives comparing to the hyoid bone (p<0.001). The higher frequency of thyroid fractures in neck pressure together with the prevalence and location of triticeal cartilage on the lower third of the lateral thyrohyoid ligament are the main reasons for these results. Further studies should be done with larger samples to expand epidemiological data and consolidate these results and their influence on the diagnosis of mechanical asphyxias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.forsciint.2018.06.019DOI Listing
September 2018

MiR-155 deletion reduces ischemia-induced paralysis in an aortic aneurysm repair mouse model: Utility of immunohistochemistry and histopathology in understanding etiology of spinal cord paralysis.

Ann Diagn Pathol 2018 Oct 18;36:12-20. Epub 2018 Jun 18.

Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH 43210, USA.

Spinal cord paralysis is relatively common after surgical repair of thoraco-abdominal aortic aneurysm (TAAA) and its etiology is unknown. The present study was designed to examine the histopathology of the disease and investigate whether miR-155 ablation would reduce spinal cord ischemic damage and delayed hindlimb paralysis induced by aortic cross-clamping (ACC) in our mouse model. The loss of locomotor function in ACC-paralyzed mice correlated with the presence of extensive gray matter damage and central cord edema, with minimal white matter histopathology. qRTPCR and Western blotting showed that the spinal cords of wild-type ACC mice that escaped paralysis showed lower miR-155 expression and higher levels of transcripts encoding Mfsd2a, which is implicated in the maintenance of blood-brain barrier integrity. In situ based testing demonstrated that increased miR-155 detection in neurons was highly correlated with the gray matter damage and the loss of one of its targets, Mfsd2a, could serve as a good biomarker of the endothelial cell damage. In vitro, we demonstrated that miR-155 targeted Mfsd2a in endothelial cells and motoneurons and increased endothelial cell permeability. Finally, miR-155 ablation slowed the progression of central cord edema, and reduced the incidence of paralysis by 40%. In sum, the surgical pathology findings clearly indicated that the epicenter of the ischemic-induced paralysis was the gray matter and that endothelial cell damage correlated to Mfsd2a loss is a good biomarker of the disease. MiR-155 targeting therefore offers new therapeutic opportunity for edema caused by traumatic spinal cord injury and diagnostic pathologists, by using immunohistochemistry, can clarify if this mechanism also is important in other ischemic diseases of the CNS, including stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2018.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208131PMC
October 2018

Adsorption of Pharmaceutical Pollutants from Water Using Covalent Organic Frameworks.

Chemistry 2018 Jul 9;24(42):10601-10605. Epub 2018 Jul 9.

International Iberian Nanotechnology Laboratory (INL), Av. Mestre José Veiga, Braga, 4715-330, Portugal.

Capture of pharmaceutical pollutants from water was studied using a novel fluorine-bearing covalent organic framework TpBD-(CF ) , which showed ibuprofen adsorption capacity of 119 mg g at neutral pH. This value is further enhanced at pH 2, highlighting the potential of this class of materials to serve as adsorbents even under harsh conditions. The adsorbed pharmaceutical can be recovered from TpBD-(CF ) in high yield, offering the option of recycling both the adsorbent and the pharmaceutical. The high efficiency of ibuprofen capture as compared to other less lipophilic pharmaceuticals suggests that COFs can be pre-designed for selective capture of contaminants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.201801649DOI Listing
July 2018

On a new species of from Africa (Coleoptera, Cryptophagidae).

Zookeys 2018 4(748):47-56. Epub 2018 Mar 4.

Departamento de Zoología, Genética y Antropología Física, Facultad de Biología, 15782 Santiago de Compostela, Spain.

A new species of Thomson, 1863 (Coleoptera, Cryptophagidae), from Cameroon is described and illustrated. No other record of any Cryptophagidae of Cameroon is known. The differential diagnosis is established in relation to a group of other species of the genus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3897/zookeys.748.23856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904456PMC
March 2018