Osteoarthritis affects the whole joint and is usually treated using pain relief for many years followed by arthroplasty. Mesenchymal stem/stromal cells have the potential to form cartilage and bone ...and have been investigated for their capacity to repair these tissues, but until recently there has been no strong rationale for their use in the treatment of age-related, idiopathic osteoarthritis.
The aim of this review is to explore the origins of cell therapy for joint diseases and how the early work in cartilage repair has built toward the possibility of an injectable mesenchymal cell approach for osteoarthritis.
A broad selection of publications has been identified relating to cartilage repair, mesenchymal cell biology, meniscal cartilage repair, and osteoarthritis therapeutics. Primary studies as well as several systematic reviews and meta-analyses have been included.
Cell therapies for cartilage lesions have been shown to be successful for traumatic injury but will be difficult to adapt for the treatment of idiopathic osteoarthritis. However the biological understanding of mesenchymal cells as a reservoir for trophic factors has led to their use as an injectable therapy. These studies have provided good evidence that sustained pain reduction can be achieved by injecting mesenchymal cells into the osteoarthritic joint, with some evidence also for functional improvement. Exosomes derived from mesenchymal may provide a scalable alternative to the cell therapy approach in future.
Mesenchymal cells have potential as a possible injectable cell therapy for idiopathic osteoarthritis and should be further explored through larger-scale, carefully designed clinical trials.
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► Pseudomonas chlororaphis was investigated for production of mcl-PHA latex under controlled conditions on bioreactor scale ► A surplus material, namely saturated biodiesel fraction ...from animal waste lipids, was used as the sole carbon source ► A detailed kinetic analysis of the bioprocess is provided ► Productivity of the mcl-PHA latex is competitive to other mcl-PHA producing organisms on expensive carbon sources.
A novel description of mcl-PHA biosynthesis by Ps. chlororaphis from tallow-based biodiesel as an inexpensive carbon feed stock is presented. Fermentation protocols, kinetic analysis, an efficient product recovery strategy, and product characterization are included. Maximum specific growth rates (μmax.) of 0.08 h−1, 0.10 h−1 and 0.13 h−1, respectively, were achieved in three different fermentation set-ups. Volumetric productivity for mcl-PHA amounted to 0.071g/L h, 0.094g/L h and 0.138g/L h, final intracellular PHA contents calculated from the sum of active biomass and PHA from 22.1 to 29.4wt.-%, respectively. GC-FID analysis showed that the obtained biopolyester predominantly consists of 3-hydroxyoctanoate and 3-hydroxydecanoate, and, to a minor extent, 3-hydroxydodecanoate, 3-hydroxynonanoate, 3-hydroxyhexanoate, and 3-hydroxyheptanoate monomers. The overall distribution of the monomers remained similar, regardless to working volumes, biodiesel concentrations and pre-treatment of the inoculum.
The review highlights the correlation between removal of various eco-toxins by micro algae and the production of high-value products thereof. It appraises established and novel strategies for micro ...algal cultivation, downstream processing methods for product recovery, and recent progress in algal generation of the green energy carriers biogas and biohydrogen micro algae. The suitability of selected micro algal species for various final products, and the potential of different strains for abating environmental problems are discussed.
Due to the fact that low cell densities and moderate growth rates are known as the major obstacles towards a broad market penetration of micro algal products, the article shows how high cell densities and reasonable volumetric productivities can be obtained. Here, the article deals with the improvements of process design and nutrient supply regimes that are needed to achieve these goals.
As demonstrated by an integrated case study, mixotrophic cultivation results in increased biomass concentration in a first cultivation step for some micro algal strains like Nannochloropsis oculata. In a second step, the fresh active algal biomass accumulates desired products via CO2 fixation, e.g. from industrial effluent gases, as the sole carbon source. This can be realized by a novel, two-stage, continuously operated closed photo-bioreactor system. After cell harvest and optimized product recovery, the value-added conversion of residual algal biomass for generation of green energy carriers, e.g. in biogas plants, constitutes another focal point of the ongoing research.
In mammalian cells, spurious transcription results in a vast repertoire of unproductive non-coding RNAs, whose deleterious accumulation is prevented by rapid decay. The nuclear exosome targeting ...(NEXT) complex plays a central role in directing non-functional transcripts to exosome-mediated degradation, but the structural and molecular mechanisms remain enigmatic. Here, we elucidated the architecture of the human NEXT complex, showing that it exists as a dimer of MTR4-ZCCHC8-RBM7 heterotrimers. Dimerization preconfigures the major MTR4-binding region of ZCCHC8 and arranges the two MTR4 helicases opposite to each other, with each protomer able to function on many types of RNAs. In the inactive state of the complex, the 3' end of an RNA substrate is enclosed in the MTR4 helicase channel by a ZCCHC8 C-terminal gatekeeping domain. The architecture of a NEXT-exosome assembly points to the molecular and regulatory mechanisms with which the NEXT complex guides RNA substrates to the exosome.
The industrial implementation of cost- and eco-efficient production of bio-based polymeric materials such as polyhydroxyalkanoates (PHAs) or polylactic acid (PLA) requires the comprehension of all ...process steps. The article at hand provides an insight into recent advances in allocation, pretreatment and utilization of raw materials available for biopolymer production in different areas of the world. Further, the high potential and risks of applying continuous process conduction in comparison with batch and fed-batch fermentation mode are elucidated. It is shown that the process design for continuous PHA production strongly depends on the kinetic characteristics for growth and product formation of the applied production strain. In addition, the triggering of the biopolymer properties by fine-tuning of the polyester composition during biosynthesis is demonstrated. Here, the impact of certain process parameters like the partial oxygen tension on the intracellular metabolic fluxes and the supplementation of cosubstrates on the polyester composition are discussed. In addition, such specialists among microbes are presented that possess the metabolic prerequisites to accumulate high-quality copolyesters merely from cheap unrelated carbon sources without the necessity for supplying expensive cosubstrates. In the field of downstream processing, sustainable methods for product isolation during biopolymer production that do not have a negative influence on the environment are presented. Key words: biopolymers, downstream processing, fermentation strategy, polyhydroxyalkanoates, process design, raw materials, white biotechnology
► Valuable mathematical models for PHA production by Cupriavidus necator on combined substrates. ► PHA production on waste substrates from biodiesel (FAME and glycerol). ► New low structured model ...for fed-batch fermentation on glucose with glycerol. ► New low structured model for fed-batch fermentation on FAME with valeric acid. ► In silico optimized feeding of C-sources and PHB/PHBV content by mathematical models.
Two low structured mathematical models for fed-batch production of polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate by Cupriavidus necator DSM 545 on renewable substrates (glycerol and fatty acid methyl esters-FAME) combined with glucose and valeric acid, were established. The models were used for development/optimization of feeding strategies of carbon and nitrogen sources concerning PHA content and polymer/copolymer composition. Glycerol/glucose fermentation featured a max. specific growth rate of 0.171h−1, a max. specific production rate of 0.038h−1 and a PHB content of 64.5%, whereas the FAME/valeric acid fermentation resulted in a max. specific growth rate of 0.046h−1, a max. specific production rate of 0.07h−1 and 63.6% PHBV content with 4.3% of 3-hydroxyvalerate (3HV) in PHBV. A strong inhibition of glycerol consumption by glucose was confirmed (inhibition constant ki,G=4.28×10−4gL−1). Applied concentration of FAME (10–12gL−1) positively influenced on PHBV synthesis. HV/PHBV ratio depends on applied VA concentration.
The RNA exosome is a versatile ribonuclease. In the nucleoplasm of mammalian cells, it is assisted by its adaptors the nuclear exosome targeting (NEXT) complex and the poly(A) exosome targeting ...(PAXT) connection. Via its association with the ARS2 and ZC3H18 proteins, NEXT/exosome is recruited to capped and short unadenylated transcripts. Conversely, PAXT/exosome is considered to target longer and adenylated substrates via their poly(A) tails. Here, mutational analysis of the core PAXT component ZFC3H1 uncovers a separate branch of the PAXT pathway, which targets short adenylated RNAs and relies on a direct ARS2-ZFC3H1 interaction. We further demonstrate that similar acidic-rich short linear motifs of ZFC3H1 and ZC3H18 compete for a common ARS2 epitope. Consequently, while promoting NEXT function, ZC3H18 antagonizes PAXT activity. We suggest that this organization of RNA decay complexes provides co-activation of NEXT and PAXT at loci with abundant production of short exosome substrates.
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•ZFC3H1 directly interacts with ARS2 to mediate the degradation of short pA+ RNAs•The ZC3H18 protein can antagonize the ARS2-dependent PAXT pathway•ZFC3H1 and ZC3H18 compete to bind ARS2 via their similar ARMs
Polák et al. show that the PAXT factor ZFC3H1 interacts with ARS2 via an identified ARS2 recruitment motif (ARM), promoting turnover of short, polyadenylated transcripts. A similar ARM is found in the NEXT-interacting factor ZC3H18, which competes with ZFC3H1 to bind ARS2. This facilitates co-activation of the NEXT and PAXT pathways.
Cerebellar ataxias are severe neurodegenerative disorders with an early onset and progressive and inexorable course of the disease. Here, we report a single point mutation in the gene encoding ...Elongator complex subunit 6 causing Purkinje neuron degeneration and an ataxia-like phenotype in the mutant wobbly mouse. This mutation destabilizes the complex and compromises its function in translation regulation, leading to protein misfolding, proteotoxic stress, and eventual neuronal death. In addition, we show that substantial microgliosis is triggered by the NLRP3 inflammasome pathway in the cerebellum and that blocking NLRP3 function in vivo significantly delays neuronal degeneration and the onset of ataxia in mutant animals. Our data provide a mechanistic insight into the pathophysiology of a cerebellar ataxia caused by an Elongator mutation, substantiating the increasing body of evidence that alterations of this complex are broadly implicated in the onset of a number of diverse neurological disorders.
Abstract It has been shown that the metabotropic glutamate receptor subtype 5 (mGluR5) is functionally associated with the NMDA subtype of the glutamate receptor family (NMDA receptors). These two ...receptors colocalize in brain regions associated with schizophrenia. Although the role of the NMDA receptor in cognitive and negative symptoms of schizophrenia is well studied, information about the role of mGluR5 receptors in schizophrenia is sparse. In our work, we show that subchronic administration of ketamine, a well-studied, non-competitive antagonist of NMDA receptors, caused cognitive deficits in rats as shown by testing novel object recognition (NOR). Moreover, we reveal that subchronic administration of ketamine increased the mRNA and protein expression levels of mGluR5 receptors in regions CA1 and CA3 of the dorsal part of the hippocampus, both of which are strongly associated with the formation of visual memory, which is tested via NOR. We postulate that increased expression of mGluR5 receptors in the dorsal part of the hippocampus may reflect compensatory changes to imbalanced glutamate neurotransmission associated with the hypoactivation of NMDA receptors.
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