Trophic Effects Research Articles

Osteopontin Rejuvenates Senescent Adipose-Derived Stem Cells and Restores their Bone Tissue Regenerative Function.

The regenerative function of stem cells is compromised when the proportion of senescent stem cells increases with ageing advance. Therefore, combating stem cell senescence is of great importance for stem cell-based tissue engineering in the elderly, but remains largely unexplored. Osteopontin (OPN), a glycosylated phosphoprotein, is one of the key extracellular matrix molecules in bone tissue. OPN activates various signalling pathways and modulates cellular activities, including cell senescence. However, the role of OPN in stem cell senescence remains largely unknown. This study aims to investigate if OPN modulates cell senescence and bone regenerative function in human adipose-derived mesenchymal stem cells (ASCs), and to determine the underlying mechanisms. We first developed a senescent ASC model using serial passaging until passage 10 (P10), in which senescent cells were characterised by reduced proliferation and osteogenic differentiation capacity compared to P4 ASCs. The conditioned medium from P10 ASCs exhibited a diminished trophic effect on human osteoblasts (HOBs), compared to that from P4 ASCs. P10 ASCs on OPN-coated surface showed rejuvenated phenotype and enhanced osteogenic differentiation. The conditioned medium from P10 ASCs on OPN-coating improved trophic effects on HOBs. OPN regulated the morphology of senescent ASCs, transforming them from a more rounded and flattened cell shape to an elongated shape with a smaller area. These findings demonstrated the effects of OPN in restoring senescent ASCs functions, possibly through a mechanism that involves the modulation of cell morphology, indicating that OPN might hold a great potential for rejuvenating senescent stem cells and could potentially open a new venue for regenerating bone tissue in age-related diseases.

Quantifying the δ15N trophic offset in a cold-water scleractinian coral (CWC): implications for the CWC diet and coral δ15N as a marine N cycle proxy

Abstract. The nitrogen (N) isotope composition (δ15N) of cold-water corals is a promising proxy for reconstructing past ocean N cycling, as a strong correlation was found between the δ15N of the organic nitrogen preserved in coral skeletons and the δ15N of particulate organic matter exported from the surface ocean. However, a large offset of 8 ‰–9 ‰ between the δ15N recorded by the coral and that of exported particulate organic matter remains unexplained. The 8 ‰–9 ‰ offset may signal a higher trophic level of coral dietary sources, an unusually large trophic isotope effect or a biosynthetic δ15N offset between the coral's soft tissue and skeletal organic matter, or some combinations of these factors. To understand the origin of the offset and further validate the proxy, we investigated the trophic ecology of the asymbiotic scleractinian cold-water coral Balanophyllia elegans, both in a laboratory setting and in its natural habitat. A long-term incubation experiment of B. elegans fed on an isotopically controlled diet yielded a canonical trophic isotope effect of 3.0 ± 0.1 ‰ between coral soft tissue and the Artemia prey. The trophic isotope effect was not detectably influenced by sustained food limitation. A long N turnover of coral soft tissue, expressed as an e-folding time, of 291 ± 15 d in the well-fed incubations indicates that coral skeleton δ15N is not likely to track subannual (e.g., seasonal) variability in diet δ15N. Specimens of B. elegans from the subtidal zone near San Juan Channel (WA, USA) revealed a modest difference of 1.2 ± 0.6 ‰ between soft tissue and skeletal δ15N. The δ15N of the coral soft tissue was 12.0 ± 0.6 ‰, which was ∼6 ‰ higher than that of suspended organic material that was comprised dominantly of phytoplankton – suggesting that phytoplankton is not the primary component of B. elegans' diet. An analysis of size-fractionated net tow material suggests that B. elegans fed predominantly on a size class of zooplankton ≥500 µm, implicating a two-level trophic transfer between phytoplankton material and coral tissue. These results point to a feeding strategy that may result in an influence of the regional food web structure on the cold-water coral δ15N. This factor should be taken into consideration when applying the proxy to paleo-oceanographic studies of ocean N cycling.

Coherent long-term body-size responses across all Northwest Atlantic herring populations to warming and environmental change despite contrasting harvest and ecological factors.

Body size is a key component of individual fitness and an important factor in the structure and functioning of populations and ecosystems. Disentangling the effects of environmental change, harvest and intra- and inter-specific trophic effects on body size remains challenging for populations in the wild. Herring in the Northwest Atlantic provide a strong basis for evaluating hypotheses related to these drivers given that they have experienced significant warming and harvest over the past century, while also having been exposed to a wide range of other selective constraints across their range. Using data on mean length-at-age 4 for the sixteen principal populations over a period of 53 cohorts (1962-2014), we fitted a series of empirical models for temporal and between-population variation in the response to changes in sea surface temperature. We find evidence for a unified cross-population response in the form of a parabolic function according to which populations in naturally warmer environments have responded more negatively to increasing temperature compared with those in colder locations. Temporal variation in residuals from this function was highly coherent among populations, further suggesting a common response to a large-scale environmental driver. The synchrony observed in this study system, despite strong differences in harvest and ecological histories among populations and over time, clearly indicates a dominant role of environmental change on size-at-age in wild populations, in contrast to commonly reported effects of fishing. This finding has important implications for the management of fisheries as it indicates that a key trait associated with population productivity may be under considerably less short-term management control than currently assumed. Our study, overall, illustrates the need for a comparative approach within species for inferences concerning the many possible effects on body size of natural and anthropogenic drivers in the wild.

Age-Dependent Changes in the Occurrence and Segregation of GABA and Acetylcholine in the Rat Superior Cervical Ganglia.

The occurrence, inhibitory modulation, and trophic effects of GABA have been identified in the peripheral sympathetic nervous system. We have demonstrated that GABA and acetylcholine (ACh) may colocalize in the same axonal varicosities or be segregated into separate ones in the rat superior cervical ganglia (SCG). Neurotransmitter segregation varies with age and the presence of neurotrophic factors. Here, we explored age-dependent changes in the occurrence and segregation of GABA and ACh in rats ranging from 2 weeks old (wo) to 12 months old or older. Using immunohistochemistry, we characterized the expression of L-glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular acetylcholine transporter (VAChT) in the rat SCG at 2, 4, 8, 12 wo and 12 months old or older. Our findings revealed that GAD67 was greater at 2 wo compared with the other ages, whereas VAChT levels were greater at 4 wo than at 12 wo and 12 months old or older. The segregation of these neurotransmitters was more pronounced at 2 and 4 wo. We observed a caudo-rostral gradient of segregation degree at 8 and 12 wo. Data point out that the occurrence and segregation of GABA and ACh exhibit developmental adaptative changes throughout the lifetime of rats. We hypothesize that during the early postnatal period, the increase in GABA and GABA-ACh segregation promotes the release of GABA alone which might play a role in trophic actions.

Experimental archaeological study in China: implications for reconstruction of past manuring and dietary practices indicated by δ15N values of Setaria italica and Panicum miliaceum

Understanding the crop management practices of millet agriculture is pivotal for comprehending the development of Chinese civilization. Recent studies have indicated that organic manuring plays a crucial role in ensuring sustainable millet cultivation on the Loess Plateau. However, uncertainties still exist regarding how manuring practices impact the δ15N values of C4 millets compared to C3 cereals. Furthermore, inadequate information on crop δ15N at archaeological sites has led to controversial interpretations of animal and human diets. In this study, we present new findings from an experimental archaeological research conducted in actual loess farmland in China to explore the potential range of variability in grain δ15N values of millets. Our results demonstrate that animal manure significantly increases Setaria and Panicum grain δ15N values, ranging from 2.7 to 9.3‰. Considering trophic enrichment effects on nitrogen isotopes, humans consuming manured millets may yield values ranging from 5.7 to 12.3‰, suggesting alternative explanations for high δ15N values other than animal protein consumption. Opposite to the general hypothesis, the grain δ15N values are systematically lower than those of leaves. The difference between the values of Setaria and Panicum and the process of manure influencing the grain δ15N values are also discussed. Our study provides novel insights into the nitrogen stable isotopic indicator of millet manuring and will serve to set reconstructions of past manuring and diet practices in northern China on a firmer foundation.

MTOR Regulates Mineralocorticoid Receptor Transcriptional Activity by ULK1-Dependent and -Independent Mechanisms.

The mineralocorticoid receptor (MR) is a transcription factor for genes mediating diverse, cell-specific functions, including trophic effects as well as promoting fluid/electrolyte homeostasis. It was reported that in intercalated cells, phosphorylation of the MR at serine 843 (S843) by Unc-51-like kinase (ULK1) inhibits MR activation and that phosphorylation of ULK1 by mechanistic target of rapamycin (mTOR) inactivates ULK1, and thereby prevents MR inactivation. We extended these findings with studies in M1 mouse cortical collecting duct cells stably expressing the rat MR and a reporter gene. Pharmacological inhibition of ULK1 dose-dependently increased ligand-induced MR transactivation, while ULK1 activation had no effect. Pharmacological inhibition of mTOR and CRISPR/gRNA gene knockdown of rapamycin-sensitive adapter protein of mTOR (Raptor) or rapamycin-insensitive companion of mTOR (Rictor) decreased phosphorylated ULK1 and ligand-induced activation of the MR reporter gene, as well as transcription of endogenous MR-target genes. As predicted, ULK1 inhibition had no effect on aldosterone-mediated transcription in M1 cells with the mutated MR-S843A (alanine cannot be phosphorylated). In contrast, mTOR inhibition dose-dependently decreased transcription in the MR-S843A cells, though not as completely as in cells with the wild-type MR-S843. mTOR, Raptor, and Rictor coprecipitated with the MR and addition of aldosterone increased their phosphorylated, active state. These results suggest that mTOR significantly regulates MR activity in at least 2 ways: by suppressing MR inactivation by ULK1, and by a yet ill-defined mechanism that involves direct association with MR. They also provide new insights into the diverse functions of ULK1 and mTOR, 2 key enzymes that monitor the cell's energy status.

Efficacy of the immediate adipose-derived stromal vascular fraction autograft on functional sensorimotor recovery after spinal cord contusion in rats.

Spinal cord injuries (SCI) lead to functional alteration with important consequences such as motor and sensory disorders. The repair strategies developed to date remain ineffective. The adipose tissue-derived stromal vascular fraction (SVF) is composed of a cocktail of cells with trophic, pro-angiogenic and immunomodulatory effects. Numerous therapeutic benefits were shown for tissue reconstitution, peripheral neuropathy and for the improvement of neurodegenerative diseases. Here, the therapeutic efficacy of SVF on sensorimotor recovery after an acute thoracic spinal cord contusion in adult rats was determined. Male Sprague Dawley rats (n = 45) were divided into 3 groups: SHAM (without SCI and treatment), NaCl (animals with a spinal lesion and receiving a saline injection through the dura mater) and SVF (animals with a spinal lesion and receiving a fraction of fat removed from adipocytes through the dura mater). Some animals were sacrificed 14days after the start of the experiment to determine the inflammatory reaction by measuring the interleukin-1β, interleukin-6 and Tumor Necrosis Factor-α in the lesion area. Other animals were followed once a week for 12weeks to assess functional recovery (postural and locomotor activities, sensorimotor coordination). At the end of this period, spinal reflexivity (rate-dependent depression of the H-reflex) and physiological adjustments (ventilatory response to metabosensitive muscle activation following muscle fatigue) were measured with electrophysiological tools. Compared to non-treated animals, results indicated that the SVF reduced the endogenous inflammation and increased the behavioral recovery in treated animals. Moreover, H-reflex depression and ventilatory adjustments to muscle fatigue were found to be comparable between SHAM and SVF groups. Our results highlight the effectiveness of SVF and its high therapeutic potential to improve sensorimotor functions and to restore the segmental sensorimotor loop and the communication between supra- and sub-lesional spinal cord regions after traumatic contusion.

A global synthesis of predation on bivalves.

Predation is a dominant structuring force in ecological communities. In aquatic environments, predation on bivalves has long been an important focal interaction for ecological study because bivalves have central roles as ecosystem engineers, basal components of food webs, and commercial commodities. Studies of bivalves are common, not only because of bivalves' central roles, but also due to the relative ease of studying predatory effects on this taxonomic group. To understand patterns in the interactions of bivalves and their predators we synthesised data from 52 years of peer-reviewed studies on bivalve predation. Using a systematic search, we compiled 1334 studies from 75 countries, comprising 61 bivalve families (N = 2259), dominated by Mytilidae (29% of bivalves), Veneridae (14%), Ostreidae (8%), Unionidae (7%), and Dreissenidae and Tellinidae (6% each). A total of 2036 predators were studied, with crustaceans the most studied predator group (34% of predators), followed by fishes (24%), molluscs (17%), echinoderms (10%) and birds (6%). The majority of studies (86%) were conducted in marine systems, in part driven by the high commercial value of marine bivalves. Studies in freshwater ecosystems were dominated by non-native bivalves and non-native predator species, which probably reflects the important role of biological invasions affecting freshwater biodiversity. In fact, while 81% of the studied marine bivalve species were native, only 50% of the freshwater species were native to the system. In terms of approach, most studies used predation trials, visual analysis of digested contents and exclusion experiments to assess the effects of predation. These studies reflect that many factors influence bivalve predation depending on the species studied, including (i) species traits (e.g. behaviour, morphology, defence mechanisms), (ii) other biotic interactions (e.g. presence of competitors, parasites or diseases), and (iii) environmental context (e.g. temperature, current velocity, beach exposure, habitat complexity). There is a lack of research on the effects of bivalve predation at the population and community and ecosystem levels (only 7% and 0.5% of studies respectively examined impacts at these levels). At the population level, the available studies demonstrate that predation can decrease bivalve density through consumption or the reduction of recruitment. At the community and ecosystem level, predation can trigger effects that cascade through trophic levels or effects that alter the ecological functions bivalves perform. Given the conservation and commercial importance of many bivalve species, studies of predation should be pursued in the context of global change, particularly climate change, acidification and biological invasions.

Trophic impacts of a rolled‐rye cover crop on the lettuce aphid (Nasonovia ribisnigri) and associated insect fauna in cultivated Histosols

AbstractCultivated peatland (Histosol) in Southern Québec (Canada) is a rapidly declining non‐renewable resource used to grow most Canadian lettuce (Lactuca sativa L., Asteraceae). Rolled‐rye (Secale cereale L., Poaceae) cover crop is one of the conservation practices proposed to reach a more sustainable lettuce production, but the overall impact on the agroecosystem remains poorly studied in Histosols. We assessed multiple effects of rolled‐rye cover crop on the trophic chain associated with the lettuce aphid, Nasonovia ribisnigri (Mosley) (Hemiptera: Aphididae), a major pest of lettuce. During one growing season and through two consecutive lettuce crops, we monitored in situ the impacts of rolled‐rye cover crop on insect fauna and lettuce quality. We used visual scouting and yellow pan traps to assess plant colonization by N. ribisnigri, its natural enemies, and alternative prey. Exclusion cage experiments were also conducted to measure aphid fitness and population growth. Under greenhouse conditions, following cover crop removal, we examined potential lingering effects of rye within the soil on lettuce plants and N. ribisnigri. In situ experiments showed that rolled‐rye cover crop has the potential to inhibit N. ribisnigri field colonization and recruit natural enemies and alternative prey in the first lettuce crop. Rye also reduced aphid fitness as well as lettuce foliar amino acid concentration and weight. For the second lettuce crop, an almost 50% reduction in N. ribisnigri abundance was observed with the use of rolled‐rye cover crop. In greenhouse experiments, no persistent effect of rye was observed on the quality of lettuce grown with soil collected under a cover crop, nor on the fitness of aphids inoculated on these lettuces. This study highlights the diversity of trophic effects rolled‐rye cover crop may have on lettuce production in Histosols and the potential of rolled‐rye cover crop as a cultural practice to reduce aphid populations. Mechanisms at play while underlining agronomic challenges regarding proper rye termination must be further explored to maintain high‐performing lettuce yields.

ADVANCED IN VITRO 3D TISSUE CULTURE MODEL FOR THE ASSESSMENT OF TITANIUM IMPLANT OSTEOINTEGRATION

The use of implant biomaterials for prosthetic reconstructive surgery and osteosynthesis is consolidated in the orthopaedic field, improving the quality of life of patients and allowing for healthy and better ageing. However, there is the lack of advanced innovative methods to investigate the potentialities of smart biomaterials, particularly for the study of local effects of implant and osteointegration. Despite the complex process of osseointegration is difficult to recreate in vitro, the growing challenges in developing alternative models require to set-up and validate new approaches. Aim of the present study is to evaluate an advanced in vitro tissue culture model of osteointegration of titanium implants in human trabecular bone. Cubic samples (1.5×1.5 cm) of trabecular bone were harvested as waste material from hip arthroplasty surgery (CE AVEC 829/2019/Sper/IOR); cylindrical defects (2 mm Ø, 6 mm length) were created, and tissue specimens assigned to the following groups: 1) empty defects- CTR-; 2) defects implanted with a cytotoxic copper pin (Merck cod. 326429)- CTR+; 3) defects implanted with standard titanium pins of 6 µm-rough (ZARE S.r.l) -Ti6. Tissue specimens were cultured in mini rotating bioreactors in standard conditions, weekly assessing viability. At the 8-week-timepoint, immunoenzymatic, microtomographic, histological and histomorphometric analyses were performed. The model was able to simulate the effects of implantation of the materials, showing a drop in viability in CTR+, differently from Ti6 which appears to have a trophic effect on the bone. MicroCT and histological analysis supported the results, with lower BV/TV and Tb.Th values observed in CTR- compared to CTR+ and Ti6 and signs of matrix and bone deposition at the implant site. The collected data suggest the reliability of the tested model which can recreate the osseointegration process in vitro and can therefore be used for preliminary evaluations to reduce and refine in vivo preclinical models.Acknowledgment: This work was supported by Emilia-Romagna Region for the project “Sviluppo di modelli biologici in vitro ed in silico per la valutazione e predizione dell'osteointegrazione di dispositivi medici da impianto nel tessuto osseo”

The Impact of Sex on the Response to Proton Pump Inhibitor Treatment.

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment.

Changes in the Baltic Sea coastal food web: A case study on the invasion of Round goby Neogobius melanostomus (Pallas, 1814)

We used dynamic food web modeling to assess the trophic effects of the increased abundance of the invasive Round goby Neogobius melanostomus (Pallas, 1814) on network flows and trophic levels in the open coastal zone of the south-eastern Baltic Sea. Available data on biomass and diet changes were incorporated in the Ecopath with Ecosim model, which estimated non-available data. Flow changes were related to Round goby predation on Blue mussels Mytilus edulis (Linnaeus, 1758), as well as to its contribution to the diet of piscivorous groups. The model presented changes in Long-tailed duck Clangula hyemalis (Linnaeus, 1758) biomass and consumption and an increase in its trophic level. However, the results showed no changes in the trophic level of other compartments nor average path length, the trophic level of fishery catch or the average trophic level of the community. This demonstrates the network's ability to maintain flows within given input and retain stability under conditions of changes induced by an invasive species. In regards to validating the model results in the representation of the study, trophic levels estimated by the dynamic model strongly correlated to ones calculated from stable nitrogen isotope (δ15N) ratios of consumers.

Neuroprotective effects of Neurotrophin-3 in MPTP-induced zebrafish Parkinson’s disease model

Introduction: Neurotrophin-3 (NT3) is a neuroprotective growth factor that induces the development, maintenance and survival of neurons. This study aims to localize NT3-expressing cells in the adult zebrafish brain and examine the role of NT3 in a zebrafish Parkinson’s disease (PD) model.Methods: Cellular localization of NT3 in adult zebrafish brains was conducted using in situ hybridization. Subsequently, adult zebrafish were injected intraperitoneally with 100 μg/g of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 400 ng/g body weight of recombinant NT3 (rNT3) via intracranial injection 24 h following MPTP injection. The fish were assessed for neurobehavioral, gene expression, immunohistology, and protein analysis on days 3, 5 and 10 post-MPTP injection.Results: Our findings showed that NT3 was extensively expressed throughout the adult zebrafish brain in neurons. Administration of rNT3 has significantly improved locomotor activity, with upregulation of th1, dat, ntf3 and bdnf gene expressions compared to MPTP-induced zebrafish. Dopaminergic neurons were also significantly increased in the zebrafish brain following rNT3 treatment. ELISA analysis reported raised GST and decreased caspase-3 levels on day 3 of assessment. The trophic changes of rNT3, however, decline as the assessment day progresses.Conclusion: This study is the first to examine the role of NT3 in the adult zebrafish PD model. NT3 has remarkable trophic effects in the zebrafish PD model. However, further study is needed to examine the dosage requirements and long-term effects of NT3 in PD.

Use of a Tissue-Targeting Recombinant Human Interleukin-22 Fusion Molecule (F-652) for the Treatment of Advanced Refractory Lower GI Acute Gvhd

Background: Steroid-refractory (SR) gastrointestinal acute GVHD (GI aGVHD) is a serious complication after allogeneic hematopoietic transplantation (allo-HCT), and subsequent lines of treatment following steroid failure are often ineffective. The JAK 1/2 inhibitor ruxolitinib is the only FDA-approved treatment for SR aGVHD, and patients for whom ruxolitinib is not effective or not tolerated have limited therapeutic options and high mortality. Interleukin-22 (IL-22) is a tissue-protective IL-10-family cytokine that has been shown to support intestinal mucosa after damage, directly signaling to the intestinal epithelium and promoting its survival, regeneration, and production of innate antimicrobial molecules. F-652, a recombinant human (rh)IL-22 fusion protein composed of an IL-22 dimer and IgG2 Fc fragment, has recently been studied in a phase 2 trial for patients with newly diagnosed lower GI aGVHD, demonstrating a promising day 28 treatment response rate and improved gut microbial health. Given this, we examined F-652 administration in 3 patients with severe SR GI aGVHD. Methods: Three patients with hematologic malignancies underwent MUD allo-HCT with tacrolimus and methotrexate GVHD prophylaxis ( Table). The patients were initially treated for GI aGVHD with methylprednisolone at a dose of 2 mg/kg/day without response. All patients presented with or progressed to stage 4 gut aGVHD and failed several lines of therapy, including ruxolitinib. All patients also had multiple episodes of bacteremia and at least some degree of GVHD-associated GI bleeding. F-652 treatment was initiated under single-patient-use authorization as the 5 th-7 th line of therapy and was administered at a dose of 45 mcg/kg IV weekly. In vitro cultures suggested that rho kinase inhibition did not interfere with trophic effects of IL-22 on intestinal epithelium, so patients were permitted to continue belumosidil upon F-652 initiation. While there was concern that JAK inhibition could compromise the activity of IL-22, continuation of ruxolitinib was considered on a case-by-case basis. C-reactive protein (CRP) is an acute phase reactant induced by IL-22, and circulating CRP levels served as a pharmacodynamic marker of in vivo biologic activity of F-652. Results: Consistent CRP elevations were observed 3 days after F-652 dosing in patients A and C, both of whom demonstrated a reduction in GVHD symptoms following F-652 treatment. These CRP elevations occurred despite concurrent use of belumosidil in Patient A and ruxolitinib in Patient C. CRP levels increased in Patient B after the first two doses, but not the third ( Figure). By day 28 following F-652 initiation, 2-of-3 patients (A and C) achieved a partial response, with decreased stool output and resolution of GI bleeding. Patient A had experienced 21 episodes of bacteremia prior to initiating rhIL-22 therapy but continued to demonstrate a partial response at day 56 and resolutiuon of bacteremias. Further improvement during the continued treatment (12 total doses) allowed for hospital discharge after 14 months of hospitalization. Patient B received 4 failed lines of therapy beyond ruxolitinib and was experiencing GI bleeding necessitating frequent transfusions prior to F-652 initiation. The symptoms persisted following F-652 treatment, and the patient passed at day 149 post-HCT. Patient C continues on active F-652 treatment and remains in a partial response as of this submission (> 50 days after treatment initiation). Overall, F-652 treatment has been well tolerated, and no significant adverse events attributable to the drug were observed. Conclusions: This is the first report of IL-22 therapy in SR aGVHD. Treatment was well tolerated, and 2-of-3 patients achieved a response following rhIL-22 administration after failing multiple previous therapies. Whereas most treatments for GVHD target immune cells and deepen immunosuppression, IL-22 is understood to act directly upon epithelial cells where it can support tissue recovery, improve barrier function, and promote innate antimicrobial immunity. CRP elevations post-treatment suggest that IL-22 administration may be able to exert these effects even with concurrent use of a JAK inhibitor. Our findings support further development of this approach and provide proof-of-concept for the use of tissue-supportive strategies to enhance the recovery of damaged gastrointestinal mucosa in advanced lower GI aGVHD.

Eutrophication and loss of riparian shading influence food quality and trophic relation in stream food webs

Eutrophication induced by excessive inputs of nutrient is one of the main stressors in aquatic ecosystems. Deforestation in riparian zones alter riparian shading, which together with eutrophication is expected to exert a complex control over stream food webs. We manipulated two levels of riparian shading (open canopy vs. shading canopy) and nutrient supply (ambient vs. nutrient addition) in three headwater streams to investigate the individual and combined effects of eutrophication and loss of riparian shading on carbon sources and nutritional quality of biofilms, and the subsequent trophic effects on macroinvertebrate grazers. Nutrient enrichment increased the autochthonous carbon (i.e., algae especially diatoms) indicated by fatty acid (FA) biomarkers within biofilms and grazers. The nutritional quality indicated by eicosapentaenoic acid (EPA) content of biofilms was increased with nutrient enrichment and more so with the combined effect of an increase in riparian shading, consequently leading to an increase in the nutritional quality, density, and biomass of grazers. In particular, the trophic linkages between biofilms and grazers were mainly influenced by EPA concentration in the biofilms, and strengthened with the combined effects of riparian shading and additional nutrients. Our study emphasizes the nutritional significance of EPA for consumers at higher trophic levels and proposes its potential as an indicator for monitoring the health of aquatic ecosystems.

Small extracellular vesicles from failing heart accelerate tumour growth

Abstract Background Heart failure (HF) is associated with an increased incidence of cancer independently of shared risk factors. The mechanism behind this link is not entirely clear. Purpose We aimed to test the hypothesis that cardiac extracellular vesicles (cEVs) contribute to the link between HF and cancer. In addition, we aimed to determine if heart failure (HF) therapy will reduce the tumour-promoting effects of HF. Methods We used a mouse model of heterotopic lung cancer tumours and post-myocardial infarction (MI) HF. To determine the role of cEVs in tumour growth, we focused on cardiac mesenchymal stromal cells (cMSCs). First, we isolated cMSCs from mice hearts 10d after MI or sham MI and purified cMSC-EVs from the conditioned medium using size exclusion chromatography. Then, we analyzed cMSC-EV characteristics, cargo, and neoplastic effects on lung cancer cells. We also used cMSC-EV transfer to assess EV biodistribution and its effect on tumour growth. Next, we tested the effects of EV depletion on tumour growth. Finally, we used spironolactone to determine if HF therapy would attenuate the harmful interaction between HF and cancer. Results Mice with HF developed larger lung tumours than sham-MI mice during 28 days of follow-up. Failing hearts, particularly cMSCs, produced twice more EVs with neoplastic properties than non-failing hearts (Fig-A). Proteomics analysis revealed unique protein profiles of cMSC-EVs from failing hearts (Fig-B). cMSC-EVs from the failing hearts harbored higher quantities of tumour-promoting cytokines such as periostin, osteopontin, vascular endothelial growth factor, interleukin-6 and tumour necrosis factor-alpha; and tumorigenic microRNAs (miR) such as miR-221 and mir-21. Transfer of labeled cMSC-EVs from the failing heart into the systemic circulation of tumour-bearing mice targeted tumour cells and accelerated tumour growth (Fig-C). Moreover, EV depletion reduced the tumour-promoting effects of HF, and adoptive transfer of cMSC-EVs from failing hearts accelerated tumour growth in mice during systemic EV depletion (Fig-D). Finally, we used spironolactone to determine if HF therapy would inhibit the tumour trophic effects of HF. Spironolactone attenuated LV dilatation and improved global longitudinal strain following MI. Subsequently, spironolactone treatment reduced the number of EVs secreted by cMSCs from failing hearts by 26% and reduced the accelerated tumour growth after MI and HF (Fig E). Notably, spironolactone treatment did not reduce the volume of the tumours in sham-MI mice, indicating that the anti-tumour effects of spironolactone were related to its effects on the faling heart. Conclusions Our results provide new insight into the link between heart failure and cancer. We show, for the first time, that cardiac extracellular vesicles promote tumour growth independently of other secreted factors. Moreover, heart failure therapy reduces the tumour-promoting effects of heart failure.

Long-Term Plant Community Removal Alters Soil Nematode Communities Mainly Through the Trophic Cascading Effects of Fungal Channel

Long-Term Plant Community Removal Alters Soil Nematode Communities Mainly Through the Trophic Cascading Effects of Fungal Channel

The Effects of Chronological Age on the Chondrogenic Potential of Mesenchymal Stromal Cells: A Systematic Review.

Tissue engineering and cell therapy for regenerative medicine have great potential to treat chronic disorders. In musculoskeletal disorders, mesenchymal stromal cells (MSCs) have been identified as a relevant cell type in cell and regenerative strategies due to their multi-lineage potential, although this is likely to be a result of their trophic and immunomodulatory effects on other cells. This PRISMA systematic review aims to assess whether the age of the patient influences the chondrogenic potential of MSCs in regenerative therapy. We identified a total of 3027 studies after performing a search of four databases, including Cochrane, Web of Science, Medline, and PubMed. After applying inclusion and exclusion criteria, a total of 14 papers were identified that were reviewed, assessed, and reported. Cell surface characterization and proliferation, as well as the osteogenic, adipogenic, and chondrogenic differentiation, were investigated as part of the analysis of these studies. Most included studies suggest a clear link between aged donor MSCs and diminished clonogenic and proliferative potential. Our study reveals a heterogeneous and conflicting range of outcomes concerning the chondrogenic, osteogenic, and adipogenic potential of MSCs in relation to age. Further investigations on the in vitro effects of chronological age on the chondrogenic potential of MSCs should follow the outcomes of this systematic review, shedding more light on this complex relationship.

Occurrence of rare earth elements in water, sediment, and freshwater fish of diverse trophic levels and feeding ecology: Insights from the Po river (northwest Italy)

To date, the occurrence of rare earth elements (REEs) in freshwater ecosystems has garnered limited attention in the scientific literature. Furthermore, a dearth of data exists regarding their potential bioaccumulation in freshwater fish. To fill this knowledge gap, we studied REEs concentrations in water, sediment, and fish specimens collected along the Po River (northwest Italy) and calculated biota-sediment accumulation (BSAF) and bioconcentration (BCF) factors, while taking into account fish feeding behavior and trophic level effects on the overall content of total REEs (ƩREEs). The fish communities were composed of native and non-native species. Remarkably low concentrations of REEs (<0.0003 mg/L) were detected in the water samples, indicating REEs insolubility. In contrast, sediment samples were found to be a good sink for REEs, with a higher mean ƩREEs recorded for the samples from the Moncalieri station (70.93 mg/kg). Notably, no significant differences in ƩREEs concentration were observed in the muscle tissue of fish samples from the three stations. The highest mean ƩREEs was recorded in the samples from the Murazzi station (0.027 mg/kg). The BSAF was very low, consistently below the unit, indicating an absence of bioaccumulation in fish muscle from sediment. In contrast, the BCF was high for several REEs, mainly for Sc and Y. While feeding ecology did not appear to affect REEs accumulation in muscle, there was a significant negative relationship between the trophic level and ΣREEs, indicating a trophic dilution of REEs from predator (Silurus glanis) to planktivorous (Alburnus arborella) fish. This study provides baseline concentrations, trophic transfers, and patterns of REEs in a river system. Further studies are needed to understand the transfer of REEs to other biotic components of lotic ecosystems.

SAT028 Beneficial Effect On Intestinal Growth Of A Long-Acting GLP-2 Analog, HM15912, After Treatment Switching From Conventional GLP-2 Drug Or Other Long-Acting GLP-2 Analogs Under Clinical Development In Animal Model

Abstract Disclosure: C. Park: Employee; Self; Hanmi Pharm. Co., Ltd. J. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. E. Park: Employee; Self; Hanmi Pharm. Co., Ltd. H. Kwon: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: Employee; Self; Hanmi Pharm. Co., Ltd. D. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. Y. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. The widespread use of teduglutide, which is only approved GLP-2 analog drug for short bowel syndrome (SBS), may be still limited due to insufficient efficacy and leading to a significant burden for patients by daily administration. Hence, several long-acting GLP-2 analog drugs targeting once a week are currently in clinical development. Here, we investigated that HM15912, a novel long-acting GLP-2 analog, enabled to achieve additional small bowel trophic effect after switching from those existing GLP-2 analogs. To investigate additional intestinotrophic efficacy after switching from teduglutide to HM15912, C57BL/6 mice treated with twice daily administration of teduglutide for 2 weeks were switched to once-weekly administration of HM15912, or continued the typical treatment of teduglutide for the remaining 2 weeks. HM15912 treatment significantly increased wet weight of SI (72.9% over vehicle) compared to teduglutide treated group (39.4% over vehicle) after 2 weeks. After 2 more weeks treatment, while showing the maintained the increased SI weight in teduglutide treated group (58.3% at week 3 and 41.1% at week 4 over vehicle), SI weight was further increased after switching to HM15912 (61.2% at week 3 and 68.5% at week 4 over vehicle). Next, we synthesized GLP-2 analogs to have same sequences with glepaglutide and apraglutide. SD rats treated with every other day administration of these long acting GLP-2 analogs for 2 weeks were switched to HM15912 or continued the typical treatment of them for the remaining 2 weeks. HM15912 treatment significantly increased wet weight of SI compared to weekly GLP-2 analog drug treated groups after 2 weeks (84.4% versus 41.5% or 26.6% over vehicle). After 2 more weeks treatment, while showing the slight increment in SI weight in the long-acting GLP-2 analogs (50.5% and 37.4% over vehicle), SI weight was further increased after switching to HM15912 (82.1% and 90.7% over vehicle, respectively). In line with these results, D-xylose absorption capacity was also significantly increased after switching from existing GLP-2 analogs to HM15912. As a results, HM15912 significantly promoted small intestinal growth than existing GLP-2 analogs even with a less frequent dosing interval of once a week in rodents. A phase 2 clinical study of once-monthly dosing in patients with SBS is ongoing to evaluate the clinical relevance of these findings. Presentation: Saturday, June 17, 2023