scholarly journals Densified Collagen Tubular Grafts for Human Tissue Replacement and Disease Modelling Applications

2021 ◽  
Author(s):  
Alexander W. Justin ◽  
Sebastian Burgess ◽  
John Ong ◽  
Aishwarya G. Jacob ◽  
Sanjay Sinha ◽  
...  
Keyword(s):  
De Novo ◽  
Disease Modelling ◽  
Luminal Surface ◽  
Luminal Diameter ◽  
Collagen Hydrogel ◽  
Tissue Replacement ◽  
Distinct Cell ◽  
Acid Solubility ◽  
And Function

ABSTRACTFabrication of tubular grafts de novo has been limited by the ability to produce constructs which fulfil the mechanical and biological requirements for implantation and function. In this work, we present a novel method for the formation of densified collagen hydrogel tubular grafts on the scale of human-sized vessels, with the required mechanical strength for future in vivo implantation. The seamless, densified collagen tubes are highly customisable in terms of density, luminal diameter and wall thickness; here we report tubes with luminal diameters 5 mm, 2 mm, and 50 μm, with wall thicknesses of 0.5-3 mm. We show that through genipin crosslinking, acid solubility and swelling of the collagen can be eliminated. Tensile testing shows that axial strength increases with starting collagen and crosslinker concentrations. The cell-compatible densification method enables a high density and uniformly distributed population of cells to be incorporated into the walls of the construct, as well as onto the luminal surface. Additionally, we report a method for generating tubes consisting of distinct cell domains in the walls. The cellular configurations at the boundary between the cell populations may be useful for disease modelling applications. We also demonstrate a method for luminal surface patterning of collagen tubes.

scholarly journals Emergence and function of cortical offset responses in sound termination detection

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Magdalena Solyga ◽  
Tania Rinaldi Barkat
Keyword(s):  
Auditory Cortex ◽  
Auditory System ◽  
Auditory Processing ◽  
De Novo ◽  
Central Auditory System ◽  
In Vivo Electrophysiology ◽  
Termination Detection ◽  
Peripheral Auditory System ◽  
And Function

Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here, we ask what the behavioral relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioral role to offset responses. By combining in vivo electrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generated de novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.

scholarly journals Designed for life: biocompatible de novo designed proteins and components

2018 ◽  
Vol 15 (145) ◽  
pp. 20180472 ◽  
Author(s):  
Katie J. Grayson ◽  
J. L. Ross Anderson
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Building Blocks ◽  
De Novo Design ◽  
Biochemical Processes ◽  
Designed Proteins ◽  
De Novo Protein Design ◽  
Protein Molecules ◽  
And Function

A principal goal of synthetic biology is the de novo design or redesign of biomolecular components. In addition to revealing fundamentally important information regarding natural biomolecular engineering and biochemistry, functional building blocks will ultimately be provided for applications including the manufacture of valuable products and therapeutics. To fully realize this ambitious goal, the designed components must be biocompatible, working in concert with natural biochemical processes and pathways, while not adversely affecting cellular function. For example, de novo protein design has provided us with a wide repertoire of structures and functions, including those that can be assembled and function in vivo . Here we discuss such biocompatible designs, as well as others that have the potential to become biocompatible, including non-protein molecules, and routes to achieving full biological integration.

scholarly journals Secretagogin expression delineates functionally-specialized populations of striatal parvalbumin-containing interneurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Farid N Garas ◽  
Rahul S Shah ◽  
Eszter Kormann ◽  
Natalie M Doig ◽  
Federica Vinciati ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Form And Function ◽  
Cortical Oscillations ◽  
Striatal Projection Neurons ◽  
Distinct Cell ◽  
And Function ◽  
Two Populations

Corticostriatal afferents can engage parvalbumin-expressing (PV+) interneurons to rapidly curtail the activity of striatal projection neurons (SPNs), thus shaping striatal output. Schemes of basal ganglia circuit dynamics generally consider striatal PV+ interneurons to be homogenous, despite considerable heterogeneity in both form and function. We demonstrate that the selective co-expression of another calcium-binding protein, secretagogin (Scgn), separates PV+ interneurons in rat and primate striatum into two topographically-, physiologically- and structurally-distinct cell populations. In rats, these two interneuron populations differed in their firing rates, patterns and relationships with cortical oscillations in vivo. Moreover, the axons of identified PV+/Scgn+ interneurons preferentially targeted the somata of SPNs of the so-called ‘direct pathway’, whereas PV+/Scgn- interneurons preferentially targeted ‘indirect pathway’ SPNs. These two populations of interneurons could therefore provide a substrate through which either of the striatal output pathways can be rapidly and selectively inhibited to subsequently mediate the expression of behavioral routines.

scholarly journals Emergence and function of cortical offset responses in sound termination detection

2021 ◽  
Author(s):  
Magdalena Sołyga ◽  
Tania Rinaldi Barkat
Keyword(s):  
Auditory Cortex ◽  
Auditory System ◽  
Auditory Processing ◽  
De Novo ◽  
Central Auditory System ◽  
Neuronal Circuits ◽  
Termination Detection ◽  
Peripheral Auditory System ◽  
And Function

Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here we ask what the behavioural relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioural role to offset responses. By combining in vivo electrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generated de novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.

scholarly journals ESCRT-III acts in scissioning new peroxisomes from the ER

2017 ◽  
Author(s):  
Fred D. Mast ◽  
Thurston Herricks ◽  
Kathleen M. Strehler ◽  
Leslie R. Miller ◽  
Ramsey A. Saleem ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorders ◽  
Dynamic Control ◽  
Eukaryotic Cell ◽  
Peroxisome Biogenesis ◽  
Endosomal Sorting ◽  
Obesity And Diabetes ◽  
A Cell ◽  
And Function

AbstractDynamic control of peroxisome proliferation is integral to the peroxisome’s many functions. A breakdown in the ability of cells to form peroxisomes is linked to many human health issues, including defense against infectious agents, cancer, aging, heart disease, obesity and diabetes, and forms the basis of a spectrum of peroxisomal genetic disorders that cause severe neuropathologies. The ER serves as a source for preperoxisomal vesicles (PPVs) that mature into peroxisomes during de novo peroxisome biogenesis and to support growth and division of existing peroxisomes. However, the mechanism of PPV formation and release from the ER remains poorly understood. Here we show that the evolutionarily ancient endosomal sorting complexes required for transport (ESCRT)-III are peroxisome biogenesis factors that function to cleave PPVs budding from the ER into the cytosol. Using comprehensive morphological and genetic assays of peroxisome formation and function we find that absence of ESCRT-III proteins impedes de novo peroxisome formation and results in an aberrant peroxisome population in vivo. Using a cell-free PPV budding assay we show that ESCRT-III proteins Vps20 and Snf7 are required to release PPVs from the ER. ESCRT-III is therefore a positive effector of membrane scission for vesicles budding both away from and towards the cytosol, a finding that has important implications for the evolutionary timing of emergence of peroxisomes and the rest of the internal membrane architecture of the eukaryotic cell.

scholarly journals IL-10 Induction from Implants Delivering Pancreatic Islets and Hyaluronan

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Paul L. Bollyky ◽  
Robert B. Vernon ◽  
Ben A. Falk ◽  
Anton Preisinger ◽  
Michel D. Gooden ◽  
...  
Keyword(s):  
T Cells ◽  
Pancreatic Islets ◽  
Implantable Devices ◽  
Model Systems ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Collagen Hydrogel ◽  
And Function

Local induction of pro-tolerogenic cytokines, such as IL-10, is an appealing strategy to help facilitate transplantation of islets and other tissues. Here, we describe a pair of implantable devices that capitalize on our recent finding that hyaluronan (HA) promotes IL-10 production by activated T cells. The first device is an injectable hydrogel made of crosslinked HA and heparan sulfate loaded with anti-CD3/anti-CD28 antibodies and IL-2. T cells embedded within this hydrogel prior to polymerization go on to produce IL-10in vivo. The second device is a bioengineered implant consisting of a polyvinyl alcohol sponge scaffold, supportive collagen hydrogel, and alginate spheres mediating sustained release of HA in fluid form. Pancreatic islets that expressed ovalbumin (OVA) antigen were implanted within this device for 14 days into immunodeficient mice that received OVA-specific DO.11.10 T cells and a subsequent immunization with OVA peptide. Splenocytes harvested from these mice produced IL-10 upon re-challenge with OVA or anti-CD3 antibodies. Both of these devices represent model systems that will be used, in future studies, to further evaluate IL-10 induction by HA, with the objective of improving the survival and function of transplanted islets in the setting of autoimmune (type 1) diabetes.

An in vitro model of tissue boundary formation for dissecting the contribution of different boundary forming mechanisms

2015 ◽  
Vol 7 (3) ◽  
pp. 298-312 ◽  
Author(s):  
Sahar Javaherian ◽  
Elisa D'Arcangelo ◽  
Benjamin Slater ◽  
Teresa Zulueta-Coarasa ◽  
Rodrigo Fernandez-Gonzalez ◽  
...  
Keyword(s):  
In Vitro Model ◽  
Model System ◽  
Cell Populations ◽  
Boundary Formation ◽  
Distinct Cell ◽  
Vitro Model ◽  
And Function ◽  
Cell Segregation

Separation of phenotypically distinct cell populations is necessary to ensure proper organization and function of tissues and organs therefore understanding fundamental mechanisms that drive this cell segregation is important. In this work, authors present an in vivo model system that accurately recapitulates important aspects of cell segregation in vivo and allows dissection of cell behaviours driving cell segregation.

scholarly journals A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

2019 ◽  
Vol 216 (12) ◽  
pp. 2778-2799 ◽  
Author(s):  
Michael T. Lam ◽  
Simona Coppola ◽  
Oliver H.F. Krumbach ◽  
Giusi Prencipe ◽  
Antonella Insalaco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
Early Recognition ◽  
Immune Dysregulation ◽  
Marrow Transplant ◽  
Neonatal Onset ◽  
And Function ◽  
Autoinflammatory Condition

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.

scholarly journals Adenosine receptors in regulation of dendritic cell differentiation and function

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1822-1831 ◽  
Author(s):  
Sergey V. Novitskiy ◽  
Sergey Ryzhov ◽  
Rinat Zaynagetdinov ◽  
Anna E. Goldstein ◽  
Yuhui Huang ◽  
...  
Keyword(s):  
Adenosine Receptors ◽  
Peritoneal Macrophages ◽  
Extracellular Adenosine ◽  
Dendritic Cell Differentiation ◽  
Distinct Cell ◽  
A2b Receptor ◽  
And Function ◽  
Knockout Animals ◽  
Mouse Peritoneal Macrophages

Abstract Differentiation of functional dendritic cells (DCs) critically depends on the microenvironment. DCs differentiate in hypoxic tumor sites and inflamed or damaged tissue. Because local concentrations of adenosine reach high physiologically relevant levels in these conditions, we assessed the expression of adenosine receptors and the effect of their activation on differentiation of human monocytes and mouse peritoneal macrophages and hematopoietic progenitor cells (HPCs) into myeloid DCs. Stimulation of adenosine receptors skews DC differentiation toward a distinct cell population characterized by expression of both DC and monocyte/macrophage cell surface markers. Pharmacologic analysis and experiments with cells from A2B adenosine receptor knockout mice identified A2B receptor as the mediator of adenosine effects on DCs. Unlike normal myeloid DCs, adenosine-differentiated DCs have impaired allostimulatory activity and express high levels of angiogenic, pro-inflammatory, immune suppressor, and tolerogenic factors, including VEGF, IL-8, IL-6, IL-10, COX-2, TGF-β, and IDO. They promoted tumor growth if injected into tumors implanted in mice. Using adenosine desaminase knockout animals, we showed that DCs with proangiogenic phenotype are highly abundant under conditions associated with elevated levels of extracellular adenosine in vivo. Adenosine signaling through A2B receptor is an important factor of aberrant DC differentiation and generation of tolerogenic, angiogenic, and proinflammatory cells.

scholarly journals Reversal of Tumor-induced Dendritic Cell Paralysis by CpG Immunostimulatory Oligonucleotide and Anti–Interleukin 10 Receptor Antibody

2002 ◽  
Vol 196 (4) ◽  
pp. 541-549 ◽  
Author(s):  
Alain P. Vicari ◽  
Claudia Chiodoni ◽  
Céline Vaure ◽  
Smina Aït-Yahia ◽  
Christophe Dercamp ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Immune Memory ◽  
Mouse Tumor ◽  
Tumor Associated Antigen ◽  
Functional Defect ◽  
And Function

Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon γ, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti–IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti–IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti–IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.

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