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Fibrotic diseases account for 45% of all deaths in the developed world, and progressive scarring conditions, such as dystrophic epidermolysis bullosa (EB), result in a significant reduction in quality of life. There is thus a need for novel approaches in fibrosis prevention. Herein, it is shown that iota carrageenan, a low‐cost, regulatory approved polysaccharide, is effective at preventing scarring by inhibiting collagen fibrillogenesis, abrogating the transforming growth factor beta 1 (TGFβ1) pathway, and lubricating the epithelium. It is demonstrated that iota carrageenan, and other anionic polysaccharides, can prevent collagen fibril formation, a key step in scar formation. It also binds TGFβ1 to prevent myofibroblast transdifferentiation, evidenced by a significant reduction in both transcription and translation of collagen 1 and alpha smooth muscle actin. Iota carrageenan may be formulated as a microparticle suspension, to allow spraying for even coverage on hard‐to‐reach anatomical sites, like the oral mucosa. This formulation provides good lubrication, to reduce the shear forces that initiate the progressive oral scarring in EB. This study not only provides a novel therapy for fibrosis prevention, but also demonstrates the potential of self‐delivering immunomodulatory polysaccharides as a safe, cost‐effective, and stable platform, which can be more easily translated for clinical benefit.

Mesenchymal stem cells (MSCs) are a promising cell population for regenerative medicine applications, where paracrine signalling through the extracellular vesicles (EVs) regulates bone tissue homeostasis and development. MSCs are known to reside in low oxygen tension, which promotes osteogenic differentiation via hypoxia-inducible factor-1α activation. Epigenetic reprogramming has emerged as a promising bioengineering strategy to enhance MSC differentiation. Particularly, the process of hypomethylation may enhance osteogenesis through gene activation. Therefore, this study aimed to investigate the synergistic effects of inducing hypomethylation and hypoxia on improving the therapeutic efficacy of EVs derived from human bone marrow MSCs (hBMSCs). The effects of the hypoxia mimetic agent deferoxamine (DFO) and the DNA methyltransferase inhibitor 5-azacytidine (AZT) on hBMSC viability was assessed by quantifying the DNA content. The epigenetic functionality was evaluated by assessing histone acetylation and histone methylation. hBMSC mineralisation was determined by quantifying alkaline phosphate activity, collagen production and calcium deposition. EVs were procured from AZT, DFO or AZT/DFO-treated hBMSCs over a two-week period, with EV size and concentration defined using transmission electron microscopy, nanoflow cytometry and dynamic light scattering. The effects of AZT-EVs, DFO-EVs or AZT/DFO-EVs on the epigenetic functionality and mineralisation of hBMSCs were evaluated. Moreover, the effects of hBMSC-EVs on human umbilical cord vein endothelial cells (HUVECs) angiogenesis was assessed by quantifying pro-angiogenic cytokine release. DFO and AZT caused a time–dose dependent reduction in hBMSC viability. Pre-treatment with AZT, DFO or AZT/DFO augmented the epigenetic functionality of the MSCs through increases in histone acetylation and hypomethylation. AZT, DFO and AZT/DFO pre-treatment significantly enhanced extracellular matrix collagen production and mineralisation in hBMSCs. EVs derived from AZT/DFO-preconditioned hBMSCs (AZT/DFO-EVs) enhanced the hBMSC proliferation, histone acetylation and hypomethylation when compared to EVs derived from AZT-treated, DFO-treated and untreated hBMSCs. Importantly, AZT/DFO-EVs significantly increased osteogenic differentiation and mineralisation of a secondary hBMSC population. Furthermore, AZT/DFO-EVs enhanced the pro-angiogenic cytokine release of HUVECs. Taken together, our findings demonstrate the considerable utility of synergistically inducing hypomethylation and hypoxia to improve the therapeutic efficacy of the MSC-EVs as a cell-free approach for bone regeneration.

The use of extracellular vesicles (EVs) is emerging as a promising acellular approach for bone regeneration, overcoming translational hurdles associated with cell-based therapies. Despite their potential, EVs short half-life following systemic administration hinders their therapeutic efficacy. EVs have been reported to bind to extracellular matrix (ECM) proteins and play an essential role in matrix mineralisation. Chitosan and collagen type I are naturally-derived pro-osteogenic biomaterials, which have been demonstrated to control EV release kinetics. Therefore, this study aimed to develop an injectable ECM-mimetic hydrogel capable of controlling the release of osteoblast-derived EVs to promote bone repair. Pure chitosan hydrogels significantly enhanced compressive modulus (2.48-fold) and osteogenic differentiation (3.07-fold), whilst reducing gelation times (2.09-fold) and proliferation (2.7-fold) compared to pure collagen gels (p ≤ 0.001). EV release was strongly associated with collagen concentration (R2 > 0.94), where a significantly increased EV release profile was observed from chitosan containing gels using the CD63 ELISA (p ≤ 0.001). Hydrogel-released EVs enhanced human bone marrow stromal cells (hBMSCs) proliferation (1.12-fold), migration (2.55-fold), and mineralisation (3.25-fold) compared to untreated cells (p ≤ 0.001). Importantly, EV-functionalised chitosan-collagen composites significantly promoted hBMSCs extracellular matrix mineralisation when compared to the EV-free gels in a dose-dependent manner (p ≤ 0.001). Taken together, these findings demonstrate the development of a pro-osteogenic thermosensitive chitosan-collagen hydrogel capable of enhancing the therapeutic efficacy of osteoblast-derived EVs as a novel acellular tool for bone augmentation strategy.

Extracellular Vesicles (EVs) are considered promising nanoscale therapeutics for bone regeneration. To date, EVs are typically procured from cells on 2D tissue culture plastic, an artificial environment that limits cell growth and does not replicate in situ biochemical or biophysical conditions. This study investigated the potential of 3D printed titanium scaffolds coated with hydroxyapatite to promote the therapeutic efficacy of osteoblast-derived EVs. Ti6Al4V titanium scaffolds with different pore sizes (500 and 1000 µm) and shapes (square and triangle) were fabricated by selective laser melting. A bone-mimetic nano-needle hydroxyapatite (nnHA) coating was then applied. EVs were procured from scaffold-cultured osteoblasts over 2 weeks and vesicle concentration was determined using the CD63 ELISA. Osteogenic differentiation of human bone marrow stromal cells (hBMSCs) following treatment with primed EVs was evaluated by assessing alkaline phosphatase activity, collagen production and calcium deposition. Triangle pore scaffolds significantly increased osteoblast mineralisation (1.5-fold) when compared to square architectures (P ≤ 0.001). Interestingly, EV yield was also significantly enhanced on these higher permeability structures (P ≤ 0.001), in particular (2.2-fold) for the larger pore structures (1000 µm). Furthermore osteoblast-derived EVs isolated from triangular pore scaffolds significantly increased hBMSCs mineralisation when compared to EVs acquired from square pore scaffolds (1.7-fold) and 2D culture (2.2-fold) (P ≤ 0.001). Coating with nnHA significantly improved osteoblast mineralisation (>2.6-fold) and EV production (4.5-fold) when compared to uncoated scaffolds (P ≤ 0.001). Together, these findings demonstrate the potential of harnessing bone-mimetic culture platforms to enhance the production of pro-regenerative EVs as an acellular tool for bone repair.

Abstract Extracellular vesicles (EVs) are emerging in tissue engineering as promising acellular tools, circumventing many of the limitations associated with cell‐based therapies. Epigenetic regulation through histone deacetylase (HDAC) inhibition has been shown to increase differentiation capacity. Therefore, this study aimed to investigate the potential of augmenting osteoblast epigenetic functionality using the HDAC inhibitor Trichostatin A (TSA) to enhance the therapeutic efficacy of osteoblast‐derived EVs for bone regeneration. TSA was found to substantially alter osteoblast epigenetic function through reduced HDAC activity and increased histone acetylation. Treatment with TSA also significantly enhanced osteoblast alkaline phosphatase activity (1.35‐fold), collagen production (2.8‐fold) and calcium deposition (1.55‐fold) during osteogenic culture (P ≤ 0.001). EVs derived from TSA‐treated osteoblasts (TSA‐EVs) exhibited reduced particle size (1‐05‐fold) (P > 0.05), concentration (1.4‐fold) (P > 0.05) and protein content (1.16‐fold) (P ≤ 0.001) when compared to untreated EVs. TSA‐EVs significantly enhanced the proliferation (1.13‐fold) and migration (1.3‐fold) of human bone marrow stem cells (hBMSCs) when compared to untreated EVs (P ≤ 0.05). Moreover, TSA‐EVs upregulated hBMSCs osteoblast‐related gene and protein expression (ALP, Col1a, BSP1 and OCN) when compared to cells cultured with untreated EVs. Importantly, TSA‐EVs elicited a time‐dose dependent increase in hBMSCs extracellular matrix mineralisation. MicroRNA profiling revealed a set of differentially expressed microRNAs from TSA‐EVs, which were osteogenic‐related. Target prediction demonstrated these microRNAs were involved in regulating pathways such as ‘endocytosis’ and ‘Wnt signalling pathway’. Moreover, proteomics analysis identified the enrichment of proteins involved in transcriptional regulation within TSA‐EVs. Taken together, our findings suggest that altering osteoblasts’ epigenome accelerates their mineralisation and promotes the osteoinductive potency of secreted EVs partly due to the delivery of pro‐osteogenic microRNAs and transcriptional regulating proteins. As such, for the first time we demonstrate the potential to harness epigenetic regulation as a novel engineering approach to enhance EVs therapeutic efficacy for bone repair.

Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs’ potential for bone regeneration has been shown, issues associated with their therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (p ≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (p ≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (p ≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (p ≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration.

Extracellular vesicles (EVs) are emerging as promising nanoscale therapeutics due to their intrinsic role as mediators of intercellular communication, regulating tissue development and homeostasis. The low immunogenicity and natural cell-targeting capabilities of EVs has led to extensive research investigating their potential as novel acellular tools for tissue regeneration or for the diagnosis of pathological conditions. However, the clinical use of EVs has been hindered by issues with yield and heterogeneity. From the modification of parental cells and naturally-derived vesicles to the development of artificial biomimetic nanoparticles or the functionalisation of biomaterials, a multitude of techniques have been employed to augment EVs therapeutic efficacy. This review will explore various engineering strategies that could promote EVs scalability and therapeutic effectiveness beyond their native utility. Herein, we highlight the current state-of-the-art EV-engineering techniques with discussion of opportunities and obstacles for each. This is synthesised into a guide for selecting a suitable strategy to maximise the potential efficacy of EVs as nanoscale therapeutics.

Un échantillonnage systématique des principaux affleurements des séries carbonatées néogènes de Sainte Croix (Iles Vierges) a permis de préciser leur extension stratigraphique. C'est ainsi que la section-type de la formation Kingshill, qui avait été récemment attribuée au Miocène supérieur, est désormais datée du Miocène moyen d'après son riche contenu faunistique en foraminifères planctoniques et nannofossiles calcaires. Les diverses mesures pétrophysiques effectuées dans des niveaux d'environnement de dépôts différents (plate-forme, pente, bassin) tendent à prouver que de bonnes porosités et perméabilités, donc de bons réservoirs, pourraient être trouvées dans des séries de pentes ou de fond de bassins associés à des plates-formes carbonatées. Systematic sampling of the main outcrops of Neogene carbonate series on Saint Croix, Virgin Islands, has enabled their stratigraphic extension to be determined. In this way, the Kingshill formation type section, which has recently been attributed to the late Miocene, is henceforth dated from the middle Miocene according to planktonic foraminifers and calcareous nannofossils. The different petrophysical measurements made in strata originated from different depositional environments (shelf, slope, basin) tend to prove that good porosities and permeabilities, hence good reservoirs, might be found in slope or basin-bottom series associated with carbonate banks.

Fibrotic diseases account for 45% of all deaths in the developed world, and progressive scarring conditions, such as dystrophic epidermolysis bullosa (EB), result in a significant reduction in quality of life. There is thus a need for novel approaches in fibrosis prevention. Herein, it is shown that iota carrageenan, a low‐cost, regulatory approved polysaccharide, is effective at preventing scarring by inhibiting collagen fibrillogenesis, abrogating the transforming growth factor beta 1 (TGFβ1) pathway, and lubricating the epithelium. It is demonstrated that iota carrageenan, and other anionic polysaccharides, can prevent collagen fibril formation, a key step in scar formation. It also binds TGFβ1 to prevent myofibroblast transdifferentiation, evidenced by a significant reduction in both transcription and translation of collagen 1 and alpha smooth muscle actin. Iota carrageenan may be formulated as a microparticle suspension, to allow spraying for even coverage on hard‐to‐reach anatomical sites, like the oral mucosa. This formulation provides good lubrication, to reduce the shear forces that initiate the progressive oral scarring in EB. This study not only provides a novel therapy for fibrosis prevention, but also demonstrates the potential of self‐delivering immunomodulatory polysaccharides as a safe, cost‐effective, and stable platform, which can be more easily translated for clinical benefit. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are a promising cell population for regenerative medicine applications, where paracrine signalling through the extracellular vesicles (EVs) regulates bone tissue homeostasis and development. MSCs are known to reside in low oxygen tension, which promotes osteogenic differentiation via hypoxia-inducible factor-1α activation. Epigenetic reprogramming has emerged as a promising bioengineering strategy to enhance MSC differentiation. Particularly, the process of hypomethylation may enhance osteogenesis through gene activation. Therefore, this study aimed to investigate the synergistic effects of inducing hypomethylation and hypoxia on improving the therapeutic efficacy of EVs derived from human bone marrow MSCs (hBMSCs). The effects of the hypoxia mimetic agent deferoxamine (DFO) and the DNA methyltransferase inhibitor 5-azacytidine (AZT) on hBMSC viability was assessed by quantifying the DNA content. The epigenetic functionality was evaluated by assessing histone acetylation and histone methylation. hBMSC mineralisation was determined by quantifying alkaline phosphate activity, collagen production and calcium deposition. EVs were procured from AZT, DFO or AZT/DFO-treated hBMSCs over a two-week period, with EV size and concentration defined using transmission electron microscopy, nanoflow cytometry and dynamic light scattering. The effects of AZT-EVs, DFO-EVs or AZT/DFO-EVs on the epigenetic functionality and mineralisation of hBMSCs were evaluated. Moreover, the effects of hBMSC-EVs on human umbilical cord vein endothelial cells (HUVECs) angiogenesis was assessed by quantifying pro-angiogenic cytokine release. DFO and AZT caused a time–dose dependent reduction in hBMSC viability. Pre-treatment with AZT, DFO or AZT/DFO augmented the epigenetic functionality of the MSCs through increases in histone acetylation and hypomethylation. AZT, DFO and AZT/DFO pre-treatment significantly enhanced extracellular matrix collagen production and mineralisation in hBMSCs. EVs derived from AZT/DFO-preconditioned hBMSCs (AZT/DFO-EVs) enhanced the hBMSC proliferation, histone acetylation and hypomethylation when compared to EVs derived from AZT-treated, DFO-treated and untreated hBMSCs. Importantly, AZT/DFO-EVs significantly increased osteogenic differentiation and mineralisation of a secondary hBMSC population. Furthermore, AZT/DFO-EVs enhanced the pro-angiogenic cytokine release of HUVECs. Taken together, our findings demonstrate the considerable utility of synergistically inducing hypomethylation and hypoxia to improve the therapeutic efficacy of the MSC-EVs as a cell-free approach for bone regeneration. [ABSTRACT FROM AUTHOR]

Space travel exposes astronauts to several environmental challenges, including microgravity and radiation exposure. To overcome these stressors, the body undergoes various adaptations such as cardiovascular deconditioning, fluid shifts, metabolic changes, and alterations in the state of the bone marrow. Another area of concern is the potential impact of these adaptations on erythrocyte and haemoglobin concentrations, which can lead to what is commonly referred to as space anaemia or microgravity-induced anaemia. It is known that anaemia may result in impaired physical and cognitive performance, making early detection and management crucial for the health and wellbeing of astronauts during extended space missions. However, the effects and mechanisms of space anaemia are not fully understood, and research is underway to determine the extent to which it poses a challenge to astronauts. Further research is needed to clarify the long-term effects of microgravity on the circulatory system and to investigate possible solutions to address spaceflight-induced anaemia. This article reviews the potential link between spaceflight and anaemia, based on existing evidence from simulated studies (e.g., microgravity and radiation studies) and findings from spaceflight studies (e.g., International Space Station and space shuttle missions).

Extracellular vesicles (EVs) are emerging in tissue engineering as promising acellular tools, circumventing many of the limitations associated with cell‐based therapies. Epigenetic regulation through histone deacetylase (HDAC) inhibition has been shown to increase differentiation capacity. Therefore, this study aimed to investigate the potential of augmenting osteoblast epigenetic functionality using the HDAC inhibitor Trichostatin A (TSA) to enhance the therapeutic efficacy of osteoblast‐derived EVs for bone regeneration. TSA was found to substantially alter osteoblast epigenetic function through reduced HDAC activity and increased histone acetylation. Treatment with TSA also significantly enhanced osteoblast alkaline phosphatase activity (1.35‐fold), collagen production (2.8‐fold) and calcium deposition (1.55‐fold) during osteogenic culture (P ≤ 0.001). EVs derived from TSA‐treated osteoblasts (TSA‐EVs) exhibited reduced particle size (1‐05‐fold) (P > 0.05), concentration (1.4‐fold) (P > 0.05) and protein content (1.16‐fold) (P ≤ 0.001) when compared to untreated EVs. TSA‐EVs significantly enhanced the proliferation (1.13‐fold) and migration (1.3‐fold) of human bone marrow stem cells (hBMSCs) when compared to untreated EVs (P ≤ 0.05). Moreover, TSA‐EVs upregulated hBMSCs osteoblast‐related gene and protein expression (ALP, Col1a, BSP1 and OCN) when compared to cells cultured with untreated EVs. Importantly, TSA‐EVs elicited a time‐dose dependent increase in hBMSCs extracellular matrix mineralisation. MicroRNA profiling revealed a set of differentially expressed microRNAs from TSA‐EVs, which were osteogenic‐related. Target prediction demonstrated these microRNAs were involved in regulating pathways such as 'endocytosis' and 'Wnt signalling pathway'. Moreover, proteomics analysis identified the enrichment of proteins involved in transcriptional regulation within TSA‐EVs. Taken together, our findings suggest that altering osteoblasts' epigenome accelerates their mineralisation and promotes the osteoinductive potency of secreted EVs partly due to the delivery of pro‐osteogenic microRNAs and transcriptional regulating proteins. As such, for the first time we demonstrate the potential to harness epigenetic regulation as a novel engineering approach to enhance EVs therapeutic efficacy for bone repair. [ABSTRACT FROM AUTHOR]

The article review of analytical laboratory evidence documenting adulteration and fraud in the international market for elder berry ingredients. Topics include the taxonomy of the main elder species in trade is a matter of debate, the berries of European elder have been used for various purposes since before recorded history, and the archaeological evidence suggests that European elder trees have been cultivated for millennia.

ObjectivesCase Reporting and Surveillance (CRS) are crucial to combat the global spread of the Monkeypox virus (Mpox). To support CRS, the World Health Organization (WHO) has released standardized case definitions for suspected, probable, confirmed, and discarded cases. However, these definitions are often subject to localized adaptations by countries leading to heterogeneity in the collected data. Herein, we compared the differences in Mpox case definitions in 32 countries that collectively reported 96% of the global Mpox caseload.MethodsWe extracted information regarding Mpox case definitions issued by the competent authorities in 32 included countries for suspected, probable, confirmed, and discarded cases. All data were gathered from online public sources.ResultsFor confirmed cases, 18 countries (56%) followed WHO guidelines and tested for Mpox using species specific PCR and/or sequencing. For probable and suspected cases, seven and eight countries, respectively were found to have not released definitions in their national documentations. Furthermore, none of the countries completely matched WHO’s criteria for probable and suspected cases. Overlapping amalgamations of the criteria were frequently noticed. Regarding discarded cases, only 13 countries (41%) reported definitions, with only two countries (6%) having definition consistent with WHO guidelines. For case reporting, 12 countries (38%) were found to report both probable and confirmed cases, in line with WHO requirements.ConclusionThe heterogeneity in case definitions and reporting highlights the pressing need for homogenization in implementation of these guidelines. Homogenization would drastically improve data quality and aid data-scientists, epidemiologists, and clinicians to better understand and model the true disease burden in the society, followed by formulation and implementation of targeted interventions to curb the virus spread.

Abstract The asymmetric access to unreported trans 4-quinolinoxy oxaproline precursors is investigated here in a comparative way by 1,3-dipolar cycloaddition of vinyloxy quinolines with chiral α-alkoxycarbonyl aldonitrones and chiral cyclic surrogates. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

BackgroundIn the context of personalized medicine, screening patients to identify targetable molecular alterations is essential for therapeutic decisions such as inclusion in clinical trials, early access to therapies, or compassionate treatment. The objective of this study was to determine the real-world impact of routine incorporation of FoundationOne analysis in cancers with a poor prognosis and limited treatment options, or in those progressing after at least one course of standard therapy.MethodsA FoundationOneCDx panel for solid tumor or liquid biopsy samples was offered to 204 eligible patients.ResultsSamples from 150 patients were processed for genomic testing, with a data acquisition success rate of 93%. The analysis identified 2419 gene alterations, with a median of 11 alterations per tumor (range, 0–86). The most common or likely pathogenic variants were on TP53, TERT, PI3KCA, CDKN2A/B, KRAS, CCDN1, FGF19, FGF3, and SMAD4. The median tumor mutation burden was three mutations/Mb (range, 0–117) in 143 patients with available data. Of 150 patients with known or likely pathogenic actionable alterations, 13 (8.6%) received matched targeted therapy. Sixty-nine patients underwent Molecular Tumor Board, which resulted in recommendations in 60 cases. Treatment with genotype-directed therapy had no impact on overall survival (13 months vs. 14 months; p = 0.95; hazard ratio = 1.04 (95% confidence interval, 0.48–2.26)].ConclusionsThis study highlights that an organized center with a Multidisciplinary Molecular Tumor Board and an NGS screening system can obtain satisfactory results comparable with those of large centers for including patients in clinical trials.

A biocrude was obtained via the catalytic hydrothermal treatment of lignocellulosic biomass. This was further co-hydroprocessed with Straight Run Gas Oil (SRGO) under desulphurization conditions. Amounts of biocrude of up to 20 wt% could be co-processed, while maintaining a diesel stream density within the specifications contained in the road diesel regulation EN 590. The changes in the diesel properties associated with an increasing amount of biocrude were not a simple linear function of biocrude content. Rather, some positive correlations seem to exist between biocrude and SRGO at low biocrude contents, possibly due to intramolecular hydrogen transfer, yielding a diesel stream with a better quality than would be obtained from simply mixing hydrotreated pure streams in a 80% to 20% ratio. [ABSTRACT FROM AUTHOR]

Highly diastereo- and enantioselective 1,3-dipolar cycloadditions between functional ketonitrones and β-substituted enals are promoted by MacMillan imidazolidinium organocatalysts. A study of the reaction scope shows that high selectivities are conserved if the N-protecting group or the ester function is varied. However, the reaction is sensitive to steric interactions with the C substituent of the nitrone. In all cases, the reaction proceeds with high exo selectivity. In most cases, a third diastereomer, incompatible with a concerted mechanism, was also observed, albeit in minute amounts. DFT calculations suggest that the cycloaddition proceeds in a nonconcerted fashion by an initial oxa-Michael-type addition of the nitrone to the double bond followed by a cyclization. This mechanism explains the formation of the observed minor diastereomers. In addition, the diastereo- and enantioselectivities of the reaction were shown to be intermediately thermodynamically controlled, and the diastereomeric ratio is modulated by the kinetics of iminium hydrolysis. [ABSTRACT FROM AUTHOR]

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An unconventional crude from biomass (biocrude) has been processed to yield a hydrocarbon stream that is not only fully processable in conventional refineries but is already close to the specification of commercial fuels such as transportation diesel. The upgrading of biocrude was carried out with a combination of hydrotreatment and catalytic cracking, yielding middle distillate as the main product. [ABSTRACT FROM AUTHOR]

Bicyclic isoxazolidines displaying one or two quaternary stereocenter(s) were formed starting from functional cyclic ketonitrones equipped with a phenyl glycinol chiral auxiliary. The products were engaged in stereocontrolled 1,3-dipolar cycloaddition reactions with a range of electron-rich and electron-poor dipolarophiles. A new reductive removal of the phenyl glycinol chiral auxiliary was introduced and was shown to afford chemoselectively a quaternary isoxazolidine derivative (of oxaprolinol-type) without cleaving the N-O isoxazolidine bond. Keeping the aldehyde function masked as a cyclic pseudo-acetal, the liberated oxy-amine function was shown to be available for a pseudo-peptide coupling with various N-protected amino acids. The isoxazolidine ring was opened by a reductive N-O bond cleavage, giving a pseudo-dipeptide that was C-terminated with an aldehyde function. [ABSTRACT FROM AUTHOR]

Enantiopure vinyl ethers of Stericol® underwent diastereoselective thermal 1,3 dipolar cycloadditions with N-benzyl, N-benzhydryl, and N-PMB aspartate ester nitrones. Chemoselective N-debenzylation of the resulting cycloadducts afforded diastereomerically and enantiomerically pure crystalline NH-isoxazolidine, the absolute configuration of which was established by X-ray crystallography. N-Protection and N-O cleavage of this isoxazolidine gave enantioenriched quaternary aspartate derivatives bearing functionalized side chains. [ABSTRACT FROM AUTHOR]

In the area north of Lake Kivu, in the western part of the African Rift, deep fractures allow the uptake of gas, especially carbon dioxide, into areas locally called mazuku; in Kiswahili places where a diabolical gas kills people. Generally, mazuku are depressions and / or fronts of lava flows where CO2 accumulates by gravity, forming areas where the air is very rich in CO2 and therefore toxic, even lethal. CO2 is a gas heavier than air, asphyxiating, irritates the eyes, nose and throat, and is lethal at concentrations greater than 15%. Unfortunately many mazuku are located within the perimeter of the city of Goma and in immediate surroundings. The population of Goma believes that the CO2 concentrations have decreased over time in the mazuku, yet four surveys of measurements carried out in the mazuku of the city of Goma show the opposite and it goes up to 70% in some sites. The mazuku are found in the city of Goma, but they are most abundant in the Kituku, Green Lake and Bulengo regions. It is unfortunately on these sites that new housing constructions are oriented, which exposes them to the risk already present, spaces with high concentrations of CO2 are already covered by buildings. This volcanic gas has caused and continues to cause deaths of humans and animals in the affected areas. We propose that warning signs be placed or even replaced in these high-risk zones and information and awareness campaigns on the risks associated with mazuku are also strongly recommended.

Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs' potential for bone regeneration has been shown, issues associated with their therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (p ≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (p ≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (p ≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (p ≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration. [ABSTRACT FROM AUTHOR]

Nicotiana tabacum L. (cv. Xanthi) suspension cultures initially grown in the dark and then exposed to continuous light followed a developmental pattern divided into a lag phase (T0–T2), a growth phase (T3–T9) and a stationary phase (T10–T21). The onset of chloroplast differentiation during the active cell division phase was associated with a rapid chlorophyll synthesis, a high rate of respiratory activity (400 μmol h−1 g−1 dry weight) and a four‐fold increase in soluble protein content compared to that of the initial inoculum. Oxygen evolution was nil until T3. It increased regularly up to a value of 30 μmol h−1 g−1 dry weight at the beginning of the stationary phase, higher values (80 μmol) being reached later in this phase. An inverse relationship between phosphoenolpyruvate carboxylase (PEPCase) and ribulose 1,5‐biphosphate carboxylase (RUBPCase) was shown during cell growth. The PEP‐Case capacity expressed on a soluble protein basis rose from an initial day 0 value of 3.5 μmol to a maximum of 7.0 μmol at T5 and then returned to the initial value during the post‐exponential and stationary phases. In contrast, RUBPCase activity was minimal (0.1 μmol) from T0 to T3 of greening, increasing to a maximum (1.7 to 2.0 μmol) at T8. The 20 fold stimulation of this enzyme capacity was related to a de novo protein synthesis. Immunodiffusion tests revealed the presence of RUBPCase molecules in soluble crude extract of dark-grown cells. The SDS-gel densitometric profile of soluble protein extract from dark-grown cells was qualitatively similar to that obtained with crude extract of green cells. The 56,000 Da polypeptide co-migrating with the large subunit (LSU) of RUBPCase appeared reduced in dark-grown cells compared to the peak height of the same polypeptide present in green cells. In both preparations, the 13,000 Da polypeptide co-migrating with the small subunit (SSU) was equally present. The current hypothesis is that the synthesis of RUBPCase at the time of greening would concern the preferential synthesis of the LSU of the enzyme.

The present study examines the suggestion that in the absence of adequate bile and pancreatic juice, which support the absorption from the gut of long-chain fatty acidsinto lymph, the fatty acids are absorbed directly into the portal blood. Oleic acid (18:l) partitioning between lymph and portal blood was investigated in intact and bile- and pancreatic juice-diverted rats. In a first set of experiments, 18: 1 absorption from the gut into lymph and blood was studied by continuous recovery of the mesenteric lymph for 6 h and mesenteric portal venous blood for 1 h. In a second set of experiments, esterification processes were investigated by study of the mucosal distribution of labelled lipids and by mono- and diacylglycerol acyltransferase (EC 2.3.1.22 and EC 2.3.1.20 respectively) specific activities. In the bile- and pancreatic juice-diverted rats the absorption of labelled 18:l into lymph was significantly reduced during the first 3 h of intraluminal infusion of this substrate. In such rats a compensatory absorption of labelled 18: 1 into mesenteric portal blood was not observed. At 6 h after micellar lipid- mixture infusion, the overload of lipids both in free form and as triacylglycerols persisting in the mucosa paralleled the lower acyltransferase specific activities observed in bile- and pancreatic juice-diverted rats. These studies demonstrate the absence of a previously proposed compensatory absorption of 18: 1 into portal blood when absorption into lymph is impaired by an inadequate supply of bile and pancreatic juice. [ABSTRACT FROM PUBLISHER]

Photoheterotrophic growth of cell suspensions of Nicotiana tabacum L. (cv. Xanthi) in organic culture medium enriched in sucrose (30 g per liter) showed a classical sigmoid growth curve. The cells developed functional chloroplast structures during the exponential growth phase, when their chlorophyll content increased steadily. A limited drop (30%) in the chlorophyll amount and structural changes of the plastids (starch accumulation) were observed during the lag phase. The measurements of photosynthetic capacities (O2 evolution and CO2 fixation) during the growth cycle revealed changes in the photosynthetic ratio (O2/CO2), which was near 1 during the lag and stationary phases and near 2 during exponential growth. During exponential growth there was also a rapid NO3- uptake. Analysis of label distribution among the products of 14CO2 fixation showed that both CO2 assimilation pathways, linked to the ribulose-biphosphate carboxylase (the autotrophic pathway) and to phosphoenolpyruvate carboxylase (the non-autotrophic pathway) were operative with an important increase of the capacity of the tatter during the exponential growth phase. Maximum rate of oxygen evolution, either endogenous or with p-benzoquinone as Hill reagent, as well as the increased CO2 fixation capacity via the non-autotrophic pathway during the exponential phase were concomitant with a high cyanide inhibited O2 uptake. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are emerging as promising nanoscale therapeutics due to their intrinsic role as mediators of intercellular communication, regulating tissue development and homeostasis. The low immunogenicity and natural cell-targeting capabilities of EVs has led to extensive research investigating their potential as novel acellular tools for tissue regeneration or for the diagnosis of pathological conditions. However, the clinical use of EVs has been hindered by issues with yield and heterogeneity. From the modification of parental cells and naturally-derived vesicles to the development of artificial biomimetic nanoparticles or the functionalisation of biomaterials, a multitude of techniques have been employed to augment EVs therapeutic efficacy. This review will explore various engineering strategies that could promote EVs scalability and therapeutic effectiveness beyond their native utility. Herein, we highlight the current state-of-the-art EV-engineering techniques with discussion of opportunities and obstacles for each. This is synthesised into a guide for selecting a suitable strategy to maximise the potential efficacy of EVs as nanoscale therapeutics. [ABSTRACT FROM AUTHOR]

La majorité des adjectifs en EUX du français est dérivée à partir d’un nom comme orag-eux ← orage. Ceux qui ne le sont pas proviennent du latin par emprunt e.g. ligneux < lat lignosus, plus rarement du grec e.g. scléreux. Cette contribution examine un sous ensemble de ces adjectifs dont le nom base dénote un élément du corps (cartilagineux, osseux, tendineux, etc.), ou lié au corps (bronchiteux, cancéreux, migraineux, etc.), avec pour objectif de déterminer la relation sémantique qui s’instaure entre le nom base et le nom recteur. Après avoir établi une classification des adjectifs en fonction de leur nom base (donnée en annexe), nous montrons comment les propriétés sémantiques des noms bases et des noms recteurs déterminent les possibilités interprétatives. Cette analyse est resituée à l’intérieur du traitement plus large des adjectifs en -EUX et montre que les principes interprétatifs généraux à l’œuvre dans la construction de ces adjectifs opèrent dans le domaine de ceux liés au corps. Cette analyse montre surtout que les propriétés sémantiques des noms bases et des noms recteurs déterminent fortement les possibilités interprétatives, et que l’interprétation la moins dépendante de ces propriétés, l’interprétation spatiale, constitue logiquement la plus répandue. Cette étude éclaire, en retour, le classement sémantique des noms.

The article presents information on the synthesis of SF5-substituted isoxazolidines using 1,3-dipolar cycloaddition reactions.