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In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure–activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds. [ABSTRACT FROM AUTHOR]

Turfgrass systems hold significant climate change mitigation value, but their management often negates the beneficial effects due to the intense adoption of external inputs. The research objective in this paper was to assess the nitrogen fertilization rate able to maintain the ideal esthetic characteristics of Zoysia turfgrass, reducing the environmental impacts associated with greenhouse gas (GHG) emissions. A two-year open field experiment was conducted. Nitrogen was added to the soil at six rates (0, 50, 100, 150, 200, and 250 kg ha−1). The GHG emissions were monitored using a portable gas analyzer and the static chamber methodology. Cumulative environmental impacts were calculated from the inclusion of CO2, CH4, and, N2O using the Global Warming Potential (GWP). The quality assessment of the turf was assessed through a visual and instrumental approach. Higher CO2 and N2O fluxes were linked to high nitrogen rates, ranging from 83.55 to 87.50 and from 0.046 to 0.047 g N-N2O ha−1 day−1 for 200 and 250 kg N ha−1, respectively. CH4 emissions were not correlated to nitrogen rates. Higher GWP impacts were linked to high N rate treatments. A rate of 100 kg N ha−1 is recommended as the best strategy to reduce GHG emissions while maintaining high turf quality. [ABSTRACT FROM AUTHOR]

A WebGis tool called GoProsit has been developed to support winegrowers in planning a new sustainable vineyard and in the identification of high-quality terroir in Tuscany, Central Italy, by providing various information on soils, climate, hydrological risks, and fertilization. GoProsit, hosted by the web platform GEAPP, is a free, user-friendly, and interactive Geographic Decision Support System (GDSS). Soil data behind the WebGis tool has a 1 ha resolution, achieved by processing the legacy vector-type soil database of the Tuscany Region with the DSMART (Disaggregation and Harmonization of Soil Map Units Through Resampled Classification Trees as supervised classification) algorithm, which disaggregated the map to 297,023 vineyard grid cells. Each grid cell holds climatic and pedologic information, along with physical and chemical features for each horizon of the most probable soil. GoProsit also provides soil maps in image format obtained by georeferencing about 50 historical soil maps (1969–2012). Finally, GoProsit runs and returns the outputs of six models: (a) carbon footprint, (b) potential erosion and maximum vine row length compatible with tolerable erosion, (c) potential water stress, (d) risk of runoff/waterlogging, (e) identification of suitable rootstocks, and (f) nutritional needs before planting. Statistics of the main model results for the investigated area are reported. This promising tool will soon be usable for the whole Italian territory; however, its potential makes it suitable for use in any wine-growing district. [ABSTRACT FROM AUTHOR]

Trichoderma spp. are widely reported to regulate plant growth by improving nutrient uptake, photosynthesis, and abiotic stress tolerance. However, their possible application for bedding plants is little explored, especially when comparing different growing media. Considering that coconut coir dust is finding broader application in the ornamental plants sector as a peat substitute, this work was aimed to test the combination of Trichoderma atroviride AT10 and coconut coir dust on Impatiens walleriana plants. Four treatments were tested as a mix of: (i) two growing media (70:30), peat:perlite or coconut coir dust:perlite; and (ii) the absence or presence of a T. atroviride treatment. At the end of the production cycle, the biomass and ornamental parameters, leaf pigments, nutrient content of the plant tissues, and Trichoderma abundance were assessed. The results revealed that T. atroviride can readily colonize coir, and the same positive effects of inoculum were found in plants grown on both substrates. The biostimulant effect of T. atroviride was observed as an increase in the aboveground biomass, number and weight of flowers, pigments and nutrient concentration, thereby improving the commercial quality of I. walleriana. Thus, T. atroviride has shown its potential in making bedding plant cultivation more sustainable and improving the yield and aesthetic parameters of plants grown on peat and coconut coir dust substrates. [ABSTRACT FROM AUTHOR]

The contribution of animal waste storage on GHG emissions and climate change is a serious issue for agriculture. The carbon emissions that are generated from barns represent a relevant source of emissions that negatively affect the environmental performance measures of livestock production. In this experiment, CO2 and CH4 emissions from different animal wastes, namely, digestate, slurry, and manure, were evaluated both in their original form and with a biochar addition. The emissions were monitored using the static camber methodology and a portable gas analyzer for a 21-day period. The addition of biochar (at a ratio of 2:1 between the substrates and biochar) significantly reduced the emissions of both gases compared to the untreated substrates. Slurry exhibited higher emissions due to its elevated gas emission tendency. The biochar addition reduced CO2 and CH4 emissions by 26% and 21%, respectively, from the slurry. The main effect of the biochar addition was on the digestate, where the emissions decreased by 45% for CO2 and 78% for CH4. Despite a lower tendency to emit carbon-based gases of manure, biochar addition still caused relevant decreases in CO2 (40%) and CH4 (81%) emissions. Biochar reduced the environmental impacts of all treatments, with a GWP reduction of 55% for the digestate, 22% for the slurry, and 44% for the manure. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor (HIF)-1α represents an oxygen-sensitive subunit of HIF transcriptional factor, which is usually degraded in normoxia and stabilized in hypoxia to regulate several target gene expressions. Nevertheless, in the skeletal muscle satellite stem cells (SCs), an oxygen level-independent regulation of HIF-1α has been observed. Although HIF-1α has been highlighted as a SC function regulator, its spatio-temporal expression and role during myogenic progression remain controversial. Herein, using biomolecular, biochemical, morphological and electrophysiological analyses, we analyzed HIF-1α expression, localization and role in differentiating murine C2C12 myoblasts and SCs under normoxia. In addition, we evaluated the role of matrix metalloproteinase (MMP)-9 as an HIF-1α effector, considering that MMP-9 is involved in myogenesis and is an HIF-1α target in different cell types. HIF-1α expression increased after 24/48 h of differentiating culture and tended to decline after 72 h/5 days. Committed and proliferating mononuclear myoblasts exhibited nuclear HIF-1α expression. Differently, the more differentiated elongated and parallel-aligned cells, which are likely ready to fuse with each other, show a mainly cytoplasmic localization of the factor. Multinucleated myotubes displayed both nuclear and cytoplasmic HIF-1α expression. The MMP-9 and MyoD (myogenic activation marker) expression synchronized with that of HIF-1α, increasing after 24 h of differentiation. By means of silencing HIF-1α and MMP-9 by short-interfering RNA and MMP-9 pharmacological inhibition, this study unraveled MMP-9's role as an HIF-1α downstream effector and the fact that the HIF-1α/MMP-9 axis is essential in morpho-functional cell myogenic commitment. [ABSTRACT FROM AUTHOR]

Suicidal behaviors and constructs are putting at risk the accomplishment of Objective 3 of Agenda 2030 for sustainable development in Spanish-speaking countries. The current study's principal objective is to explain the presence of suicidal ideation and deaths by suicide as a result of the COVID-19 pandemic in Spanish-speaking countries based on a review of the scientific literature. The PRISMA model was used as the main method while considering the criteria of periodicity, language, typology, and country in order to choose the 28 articles that were analyzed from the following three databases: SCOPUS, Web of Science, and ProQuest Coronavirus Research Database. Suicidal ideation and death by suicide exhibited a growth trend during the COVID-19 pandemic, including post-pandemic, especially in kids, adolescents, and young women of university age belonging to lower socioeconomic strata and presenting risk factors like living in rural areas, poor mental health, unemployment, and family death due to COVID-19. [ABSTRACT FROM AUTHOR]

A series of new hybrid derivatives 1a–c, 2a–c, 3a–c, 4a–c, 5a–c, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer's disease (AD). These compounds were designed to merge together the trifluoromethyl benzyloxyaminic bioactive moiety, previously identified, with different acids available in nature. The ability of the synthesized compounds to chelate biometals, such as Cu2+, Zn2+ and Fe2+, was studied by UV–Vis spectrometer, and through a preliminary screening their antioxidant activity was evaluated by DPPH. Then, selected compounds were tested by in vitro ABTS free radical method and ex vivo rat brain TBARS assay. Compounds 2a–c, combining the strongest antioxidant and biometal chelators activities, were studied for their ability to contrast Aβ1-40 fibrillization process. Finally, starting from the promising profile obtained for compound 2a, we evaluated if it could be able to induce a positive cross-interaction between transthyretin (TTR) and Aβ in presence and in absence of Cu2+. [ABSTRACT FROM AUTHOR]

The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM), and local cell–cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β (Aβ) peptide is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed to investigate the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time-persistent disassembly of functional astroglial syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of the disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation. [ABSTRACT FROM AUTHOR]

The lower common wheat productivity and quality are major constraints in Afghanistan. The objectives of this study were to (1) quantify the effect of soil and climatic parameters on the yield and quality of common wheat and (2) investigate the response of different wheat varieties to different N and P fertilization rates, to improve the yield and quality of common wheat. Three wheat varieties (DLN7, ZRDN, and KBL13), three phosphorus levels (PL) at 60, 90, and 120 kg P2O5 ha−1, and three nitrogen ratios (NP) at 1:1, 1.25:1, and 1.5:1, respectively, in four locations (L), were evaluated. The higher average grain yield (GY), straw yield (SY), and starch yield (STY) were obtained with DLN7, followed by KBL13 and ZRDN, for all locations. As PL increased, GY, SY, protein yield (PY), and STY significantly increased in all locations. The PL significantly affected protein content (PC), gluten content (GC), and dough strength (W). The NP significantly improved PC, GC, and PY. Starch (ST), STY, and amylopectin (AP) increased significantly with increasing PL. The amylose to AP ratio increased significantly with increasing NP ratios. The findings show that at NP1/PL120, GY, SY, ST, and AP improved significantly, while at NP1.5:1/PL120, PC and GC improved significantly. [ABSTRACT FROM AUTHOR]

Pomegranate fruit (PF) is a fruit rich in nutraceuticals. Nonedible parts of the fruit, especially peels, contain high amounts of bioactive components that have been largely used in traditional medicine, such as the Chinese, Unani, and Ayurvedic ones, for treating several diseases. Polyphenols such as anthocyanins, tannins, flavonoids, phenolic acids, and lignans are the major bioactive molecules present in PF. Therefore, PF is considered a source of natural multifunctional agents that exert simultaneously antioxidant, anti-inflammatory, antitumor, antidiabetic, cardiovascular, and neuroprotective activities. Recently, several studies have reported that the nutraceuticals contained in PF (seed, peel, and juice) have a potential beneficial role in Alzheimer's disease (AD). Research suggests that the neuroprotective effect of PF is mostly due to its potent antioxidant and anti-inflammatory activities which contribute to attenuate the neuroinflammation associated with AD. Despite the numerous works conducted on PF, to date the mechanism by which PF acts in combatting AD is not completely known. Here, we summarize all the recent findings (in vitro and in vivo studies) related to the positive effects that PF and its bioactive components can have in the neurodegeneration processes occurring during AD. Moreover, considering the high biotransformation characteristics of the nutraceuticals present in PF, we propose to consider the chemical structure of its active metabolites as a source of inspiration to design new molecules with the same beneficial effects but less prone to be affected by the metabolic degradation process. [ABSTRACT FROM AUTHOR]

In 2022, the International Council for Harmonisation released draft guidelines Q2(R2) and Q14, intending to specify the development and validation activities that should be carried out during the lifespan of an analytical technique addressed to assess the quality of medicinal products. In the present study, these recommendations were implemented in Capillary Electrophoresis method development for the quality control of a drug product containing trimecaine, by applying Analytical Quality by Design. According to the Analytical Target Profile, the procedure should be able to simultaneously quantify trimecaine and its four impurities, with specified analytical performances. The selected operative mode was Micellar ElectroKinetic Chromatography employing sodium dodecyl sulfate micelles supplemented with dimethyl-β-cyclodextrin, in a phosphate-borate buffer. The Knowledge Space was investigated through a screening matrix encompassing the composition of the background electrolyte and the instrumental settings. The Critical Method Attributes were identified as analysis time, efficiency, and critical resolution values. Response Surface Methodology and Monte Carlo Simulations allowed the definition of the Method Operable Design Region: 21–26 mM phosphate-borate buffer pH 9.50–9.77; 65.0 mM sodium dodecyl sulfate; 0.25–1.29% v/v n-butanol; 21–26 mM dimethyl-β-cyclodextrin; temperature, 22 °C; voltage, 23–29 kV. The method was validated and applied to ampoules drug products. [ABSTRACT FROM AUTHOR]

Background: To evaluate the rates of lumbar puncture (LP) in infants with culture-proven sepsis. Study design: We prospectively enrolled 400 infants with early- or late-onset sepsis due to Group B streptococcus (GBS) or Eschericha coli, diagnosed within 90 days of life. Rates of LP and potential variables associated with LP performance were evaluated. Moreover, cerebrospinal fluid (CSF) characteristics and results of the molecular analysis were investigated. Results: LP was performed in 228/400 (57.0%) infants; 123/228 LPs (53.9%) were performed after antibiotic initiation, hampering the ability to identify the pathogen in the CSF culture. However, polymerase chain reaction increased the probability of positive results of CSF analysis compared to microbiological culture (28/79, 35.4% vs. 14/79, 17.7%, p = 0.001). Severe clinical presentation and GBS infection were associated with higher LP rates. The rate of meningitis was 28.5% (65/228). Conclusions: Rates of LP are low in culture-proven neonatal sepsis and antibiotics are frequently given before LP is carried out. Thus meningitis may be underestimated, and the chances of giving an effective therapy to the newborn are reduced. LP should be performed before the start of antibiotics when there is a clinical suspicion of infection. [ABSTRACT FROM AUTHOR]

The effectiveness of "inadequate" intrapartum antibiotic prophylaxis (IAP administered < 4 h prior to delivery) in preventing early-onset sepsis (EOS) is debated. Italian prospective surveillance cohort data (2003–2022) were used to study the type and duration of IAP according to the timing of symptoms onset of group B streptococcus (GBS) and E. coli culture-confirmed EOS cases. IAP was defined "active" when the pathogen yielded in cultures was susceptible. We identified 263 EOS cases (GBS = 191; E. coli = 72). Among GBS EOS, 25% had received IAP (always active when beta-lactams were administered). Most IAP-exposed neonates with GBS were symptomatic at birth (67%) or remained asymptomatic (25%), regardless of IAP duration. Among E. coli EOS, 60% were IAP-exposed. However, IAP was active in only 8% of cases, and these newborns remained asymptomatic or presented with symptoms prior to 6 h of life. In contrast, most newborns exposed to an "inactive" IAP (52%) developed symptoms from 1 to >48 h of life. The key element to define IAP "adequate" seems the pathogen's antimicrobial susceptibility rather than its duration. Newborns exposed to an active antimicrobial (as frequently occurs with GBS infections), who remain asymptomatic in the first 6 h of life, are likely uninfected. Because E. coli isolates are often unsusceptible to beta-lactam antibiotics, IAP-exposed neonates frequently develop symptoms of EOS after birth, up to 48 h of life and beyond. [ABSTRACT FROM AUTHOR]

Simple Summary: Current evidence supports a negative impact of obesity-associated metabolic dysfunction in several cancers. However, the evidence is still controversial regarding high-grade serous ovarian cancer (HGSOC). In this study, we demonstrated that body composition, particularly the presence of high visceral adiposity (with or without sarcopenia) estimated by aCT scan, is associated with worse survival in HGSOC. As a molecular proxy to CT-scan-based assessment of nutritional status and to identify putative biomarkers of metabolic disorders, we evaluated the expression levels of a set of 425 obesity- and lipid-metabolism-disorder-related genes across 273 tumor samples. We identified two obesity- and lipid-metabolism-related clusters with marked differences in survival and that were associated with molecular features predictive of immune checkpoint blocker response. Finally, we assessed the impact of nutritional/pharmacologic interventions affecting body composition/lipid metabolism on patient survival. We observed that the reduction of visceral adiposity, the increase of muscle mass, and the use of metformin/statins improve survival. Although obesity-associated metabolic disorders have a negative impact on various cancers, such evidence remains controversial for ovarian cancer. Here, we aimed to evaluate the impact of body composition (BC) and metabolism disorders on outcomes in high-grade serous ovarian cancer (HGSOC). Methods: We analyzed clinical/genomic data from two cohorts (PUC n = 123/TCGA-OV n = 415). BC was estimated using the measurement of adiposity/muscle mass by a CT scan. A list of 425 genes linked to obesity/lipid metabolism was used to cluster patients using non-negative matrix factorization. Differential expression, gene set enrichment analyses, and Ecotyper were performed. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival. High adiposity and sarcopenia were associated with worse outcomes. We also found that recovery of a normal BC and drug interventions to correct metabolism disorders had a positive impact on outcomes. Additionally, we showed that immune-cell-depleted microenvironments predominate in HGSOC, which was more evident among the BC types and the obesity/lipid metabolism cluster with worse prognosis. Conclusions: We have demonstrated the relevance of BC and metabolism disorders as determinants of outcomes in HGSOC. We have shone a spotlight on the relevance of incorporating corrective measures addressing these disorders to obtain better results. [ABSTRACT FROM AUTHOR]

Millet is the sixth-highest yielding grain in the world and a staple crop for millions of people. Fermentation was applied in this study to improve the nutritional properties of pearl millet. Three microorganism combinations were tested: Saccharomyces boulardii (FPM1), Saccharomyces cerevisiae plus Campanilactobacillus paralimentarius (FPM2) and Hanseniaspora uvarum plus Fructilactobacillus sanfranciscensis (FPM3). All the fermentation processes led to an increase in minerals. An increase was observed for calcium: 254 ppm in FPM1, 282 ppm in FPM2 and 156 ppm in the unfermented sample. Iron increased in FPM2 and FPM3 (approx. 100 ppm) with respect the unfermented sample (71 ppm). FPM2 and FPM3 resulted in richer total phenols (up to 2.74 mg/g) compared to the unfermented sample (2.24 mg/g). Depending on the microorganisms, it was possible to obtain different oligopeptides with a mass cut off ≤10 kDalton that was not detected in the unfermented sample. FPM2 showed the highest resistant starch content (9.83 g/100 g) and a prebiotic activity on Bifidobacterium breve B632, showing a significant growth at 48 h and 72 h compared to glucose (p < 0.05). Millet fermented with Saccharomyces cerevisiae plus Campanilactobacillus paralimentarius can be proposed as a new food with improved nutritional properties to increase the quality of the diet of people who already use millet as a staple food. [ABSTRACT FROM AUTHOR]

The response of winter wheat (Triticum aestivum L.) to the application of different rates of nitrogen (N) and phosphorus (P) on different agro-climatic zones (ACZs) has not been well studied in Afghanistan. The objectives of this study were to (1) determine the impact of soil and climate on the responses of wheat to N and P fertilization, (2) quantify the specific N and P response of winter wheat for different ACZs, and (3) determine the economical application rates of N and P for farmers for each considered ACZs. This paper evaluates the effects of nitrogen levels (NL) at 35.28, 65, 95, and 120 kg N ha−1 and phosphorus levels (PL) at 0, 50, 70, and 90 kg P2O5 ha−1, respectively, in four locations (L) for two growing seasons (GS), on both yield and quality characteristics of winter wheat. Soil pH was the main environmental parameter affecting straw yield (SY), grain yield (GY), protein content (PC), and protein yield (PY). Winter wheat SY, GY, PC, and PY increased significantly (p < 0.05) with PL rates up to 50 kg P2O5 ha−1 and with NL rates up to 120 kg N ha−1. NL was the most important parameter in determining PC, thus showing potential for further improvement in N management. The highest marginal rate of return was used as an index for the farmers to accept site-specific N and P fertilizer recommendations. [ABSTRACT FROM AUTHOR]

Breast cancer is the first leading tumor in women in terms of incidence worldwide. Seventy percent of cases are estrogen receptor (ER) α-positive. In these malignancies, 17β-estradiol (E2) via ERα increases the levels of neuroglobin (NGB), a compensatory protein that protects cancer cells from stress-induced apoptosis, including chemotherapeutic drug treatment. Our previous data indicate that resveratrol (RSV), a plant-derived polyphenol, prevents E2/ERα-induced NGB accumulation in this cellular context, making E2-dependent breast cancer cells more prone to apoptosis. Unfortunately, RSV is readily metabolized, thus preventing its effectiveness. Here, four different RSV analogs have been developed, and their effect on the ERα/NGB pathway has been compared with RSV conjugated with highly hydrophilic gold nanoparticles as prodrug to evaluate if RSV derivatives maintain the breast cancer cells' susceptibility to the chemotherapeutic drug paclitaxel as the original compound. Results demonstrate that RSV conjugation with gold nanoparticles increases RSV efficacy, with respect to RSV analogues, reducing NGB levels and enhancing the pro-apoptotic action of paclitaxel, even preventing the anti-apoptotic action exerted by E2 treatment on these cells. Overall, RSV conjugation with gold nanoparticles makes this complex a promising agent for medical application in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6), two omega-3 poly-unsaturated fatty acids (PUFAs), are the main components in oil derived from fish and other marine organisms. EPA and DHA are commercially available as dietary supplements and are considered to be very safe and contribute to guaranteeing human health. Studies report that PUFAs have a role in contrasting neurodegenerative processes related to amyloidogenic proteins, such as β-amyloid for AD, α-synuclein in PD, and transthyretin (TTR) in TTR amyloidosis. In this context, we investigated if EPA and DHA can interact directly with TTR, binding inside the thyroxin-binding pockets (T4BP) that contribute to the tetramer stabilization. The data obtained showed that EPA and DHA can contribute to stabilizing the TTR tetramer through interactions with T4BP. [ABSTRACT FROM AUTHOR]

In this work, the ability of several bis-viologen axles to thread a series of heteroditopic tris(N-phenylureido)calix[6]arene wheels to give interwoven supramolecular complexes to the [3]pseudorotaxane type was studied. The unidirectionality of the threading process inside these nonsymmetric wheels allows the formation of highly preorganised [3]pseudorotaxane and [3]rotaxane species in which the macrocycles phenylureido moieties, functionalised with either ester, carboxylic, or hydroxymethyl groups, are facing each other. As verified by NMR and semiempirical computational studies, these latter compounds possess the correct spatial arrangement of their subcomponents, which could lead, in principle, upon proper bridging reaction, to the realisation of upper-to-upper molecular capsules that are based on calix[6]arene derivatives. [ABSTRACT FROM AUTHOR]

Precision fertilization is a promising mitigation strategy to reduce environmental impacts of N-fertilization, but the effective benefits of variable-rate fertilization have not yet been fully demonstrated. We evaluated the short-term response (23 days) of GHGs emissions following variable-rate fertilization on barley. Yields, biomass (grains + straw) and different N-use indicators (N uptake, grain protein concentration, recovery efficiency, physiological efficiency, partial factor productivity of applied nutrient, agronomic efficiency and N surplus) were compared. Four N fertilization treatments were performed: (i) conventional– 150 kg ha−1; (ii) variable with granular fertilizer; (iii) variable with foliar liquid supplement; (iv) no fertilization. According to proximal sensing analysis (Greenseeker Handheld) and crop needs, both variable-rate treatments accounted for 35 kg N ha−1. Cumulative GHGs emissions were not significantly different, leading to the conclusion that the sensor-based N application might not be a GHGs mitigation strategy in current experimental conditions. Results showed that both site-specific fertilizations ensured the maintenance of high yields with a significant N rate reduction (approximately by 75%) and a N use improvement. Variable-rate N fertilization, due to similar yields (~6 tons ha−1) than conventional fertilization and higher protein content in foliar treatment (14%), confirms its effectiveness to manage N during the later phases of growing season. [ABSTRACT FROM AUTHOR]

(1) Background: Any disturbance in the pharmaceutical supply chain (PSC) can disrupt the supply of medicines and affect the efficiency of health systems. Due to shortages in the global pharma supply chain over the past few years and the complex nature of free trade and its limitations when confronted by a major global health and humanitarian crisis, many countries have taken steps to mitigate the risks of disruption, including, for example, recommending the adoption of a plus one diversification approach, increasing safety stock, and nationalizing the medical supply chains. (2) Objective: To scope findings in the academic literature related to decision criteria to guide national policy decisions for the "Partial Nationalization of Pharmaceutical Supply Chain" (PNPSC) from the viewpoints of the three main stakeholders: industry, payers (government and health insurance), and patients. (3) Methods: These consist of a scoping review of the peer-reviewed literature. (4) Results: A total of 115 studies were included. For local manufacturing decisions, five criteria and 15 sub-criteria were identified. Weighting, decision-making, risk assessment, and forecasting were the main data analysis tools applied; (5) Conclusions: The findings could serve as a baseline for constructing PNPSC frameworks after careful adaptation to the local context. [ABSTRACT FROM AUTHOR]

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H2O2 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1. [ABSTRACT FROM AUTHOR]

Capillary electrophoresis (CE) is a potent method for analyzing chiral substances and is commonly used in the enantioseparation and chiral purity control of pharmaceuticals from different matrices. The adoption of Quality by Design (QbD) concepts in analytical method development, optimization and validation is a widespread trend observed in various analytical approaches including chiral CE. The application of Analytical QbD (AQbD) leads to the development of analytical methods based on sound science combined with risk management, and to a well understood process clarifying the influence of method parameters on the analytical output. The Design of Experiments (DoE) method employing chemometric tools is an essential part of QbD-based method development, allowing for the simultaneous evaluation of experimental parameters as well as their interaction. In 2022 the International Council for Harmonization (ICH) released two draft guidelines (ICH Q14 and ICH Q2(R2)) that are intended to encourage more robust analytical procedures. The ICH Q14 guideline intends to harmonize the scientific approaches for analytical procedures' development, while the Q2(R2) document covers the validation principles for the use of analytical procedures including the recent applications that require multivariate statistical analyses. The aim of this review is to provide an overview of the new prospects for chiral CE method development applied for the enantiomeric purity control of pharmaceuticals using AQbD principles. The review also provides an overview of recent research (2012–2022) on the applicability of CE methods in chiral drug impurity profiling. [ABSTRACT FROM AUTHOR]

The potato is the fourth major food crop in the world. Its cultivation can encounter problems, resulting in poor growth and reduced yield. Plant microbiota has shown an ability to increase growth and resistance. However, in the development of effective microbiota manipulation strategies, it is essential to know the effect of environmental variables on microbiota composition and function. Here, we aimed to identify the differential impact of the site of cultivation and plant growth stage on potato rhizosphere microbiota. We performed a 16S rRNA gene amplicon sequencing analysis of rhizospheric soil collected from potato plants grown at four sites in central Italy during two phenological stages. Rhizomicrobiota was mainly composed of members of phyla Acidobacteriota, Actinobacteriota, Chloroflexi, and Proteobacteria and was affected by both the site of cultivation and the plant stages. However, cultivation sites overcome the effect of plant phenological stages. The PiCRUST analysis suggested a high abundance of functions related to the biosynthesis of the siderophore enterobactin. The presence of site-specific taxa and functional profiling of the microbiota could be further exploited in long-term studies to evaluate the possibility of developing biomarkers for traceability of the products and to exploit plant growth-promoting abilities in the native potato microbiota. [ABSTRACT FROM AUTHOR]

Industry 4.0 is pushing forward the need for symbiotic interactions between physical and virtual entities of production environments to realize increasingly flexible and customizable production processes. This holds especially for human–robot collaboration in manufacturing, which needs continuous interaction between humans and robots. The coexistence of human and autonomous robotic agents raises several methodological and technological challenges for the design of effective, safe, and reliable control paradigms. This work proposes the integration of novel technologies from Artificial Intelligence, Control and Augmented Reality to enhance the flexibility and adaptability of collaborative systems. We present the basis to advance the classical human-aware control paradigm in favor of a user-aware control paradigm and thus personalize and adapt the synthesis and execution of collaborative processes following a user-centric approach. We leverage a manufacturing case study to show a possible deployment of the proposed framework in a real-world industrial scenario. [ABSTRACT FROM AUTHOR]

The high nutritional properties of quinoa have resulted in a production increase worldwide. The resistance to environmental stresses renders this crop suitable for sustainable farming systems. Few studies have examined the impact of different agricultural management strategies and its contribution to climate change. In this work, we quantify soil greenhouse gas (GHG) emissions, in terms of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O), and crop productivity (yields and biomass) under conventional (urea) and organic (digestate) fertilization. Significant differences (p < 0.05) in N2O cumulative emissions are reported between digestate (50–100 kg N ha−1), urea (50–100 kg N ha−1) and the control (0 kg N ha−1). Higher cumulative GHG emissions are observed under 100 kg N ha−1 of digestate (337.8 kg C ha−1 CO2 and 0.23 kg N ha−1 for N2O) compared to treatments with lower nitrogen (N) inputs. However, yield and biomass production do not show significant differences (p > 0.05) with increasing nutrient application. Hence, this study opens the discussion about the pros and cons of increasing fertilization to improve yields besides providing agricultural extension workers with additional information to promote sustainable quinoa production worldwide. [ABSTRACT FROM AUTHOR]

Plants are rich in secondary metabolites, which are often useful as a relevant source of nutraceuticals. Quercetin (QUE) is a flavonol aglycone able to bind Transthyretin (TTR), a plasma protein that under pathological conditions can lose its native structure leading to fibrils formation and amyloid diseases onset. Here, the dual nature of five quercetin 3-O-glycosylated flavonol derivatives, isolated from different plant species, such as possible binders of TTR and antioxidants, was investigated. The crystal structure of 3-O-β-D-galactopyranoside in complex with TTR was solved, suggesting that not only quercetin but also its metabolites can contribute to stabilizing the TTR tetramer. [ABSTRACT FROM AUTHOR]

Patient satisfaction after total joint arthroplasties (TJA) represents a key element for the evaluation of surgery success in relation to subjects' needs and expectations. The assessment tools are applied inconsistently throughout the literature, and thus, it is difficult to compare results among different studies. Goodman et al. proposed a standardized questionnaire with strong psychometric properties for the assessment of satisfaction. The present study aims to translate, adapt, and validate the Goodman questionnaire for the Italian population. After translation and back translation, the questionnaire was administrated to 50 patients. Internal consistency, test–retest reliability, floor and ceiling effects, and construct validity were evaluated (correlation with KOOS/HOOS, SF-12 PCS/MCS, EQ-5D). Responsiveness was evaluated with respect to SF-12 PCS improvements. The Italian version of the Goodman score questionnaire demonstrated psychometric properties similar to those of the original version. The translated questionnaire showed good internal consistency (Cronbach's alpha = 0.836) and test–retest reliability (ICC: 0.507). Moderate/strong correlations were observed between the Italian version of the Goodman score and other scores. The score significantly discriminated patients who improved from those who did not improve in SF-12 PCS after treatment. This study provides an adapted and validated Italian version of the Goodman score questionnaire, with psychometric properties similar to those of its original counterpart. [ABSTRACT FROM AUTHOR]

The taxonomic assemblage and functions of the plant bacterial community are strongly influenced by soil and host plant genotype. Crop breeding, especially after the massive use of nitrogen fertilizers which led to varieties responding better to nitrogen fertilization, has implicitly modified the ability of the plant root to recruit an effective bacterial community. Among the priorities for harnessing the plant bacterial community, plant genotype-by-microbiome interactions are stirring attention. Here, we analyzed the effect of plant variety and fertilization on the rhizosphere bacterial community. In particular, we clarified the presence in the bacterial community of a varietal effect of N and P fertilization treatment. 16S rRNA gene amplicon sequence analysis of rhizospheric soil, collected from four wheat varieties grown under four N-P fertilization regimes, and quantification of functional bacterial genes involved in the nitrogen cycle (nifH; amoA; nirK and nosZ) were performed. Results showed that variety played the most important role and that treatments did not affect either bacterial community diversity or bacterial phyla abundance. Variety-specific response of rhizosphere bacterial community was detected, both in relation to taxa (Nitrospira) and metabolic functions. In particular, the changes related to amino acid and aerobic metabolism and abundance of genes involved in the nitrogen cycle (amoA and nosZ), suggested that plant variety may lead to functional changes in the cycling of the plant-assimilable nitrogen. [ABSTRACT FROM AUTHOR]

Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of diabetic complications. Herein we describe a novel series of (E)-benzaldehyde O-benzyl oximes 6a–e, 7a–e, 8a–e, and 9–11 as ALR2 inhibitors endowed with anti-oxidant properties. Inspired by the natural products, the synthesized derivatives are characterized by a different polyhydroxy substitution pattern on their benzaldehyde fragment, which proved crucial for both the enzyme inhibitory activity and the anti-oxidant capacity. Derivatives (E)-2,3,4-trihydroxybenzaldehyde O-(3-methoxybenzyl) oxime (7b) and (E)-2,3,4-trihydroxybenzaldehyde O-(4-methoxybenzyl) oxime (8b) turned out to be the most effective dual-acting products, proving to combine the best ALR2 inhibitory properties with significant anti-oxidant efficacy. [ABSTRACT FROM AUTHOR]

The combination of metallic nanostructures with two-dimensional transition metal dichalcogenides is an efficient way to make the optical properties of the latter more appealing for opto-electronic applications. In this work, we investigate the optical properties of monolayer WS 2 flakes grown by chemical vapour deposition and transferred onto a densely-packed array of plasmonic Au nanoparticles (NPs). The optical response was measured as a function of the thickness of a dielectric spacer intercalated between the two materials and of the system temperature, in the 75–350 K range. We show that a weak interaction is established between WS 2 and Au NPs, leading to temperature- and spacer-thickness-dependent coupling between the localized surface plasmon resonance of Au NPs and the WS 2 exciton. We suggest that the closely-packed morphology of the plasmonic array promotes a high confinement of the electromagnetic field in regions inaccessible by the WS 2 deposited on top. This allows the achievement of direct contact between WS 2 and Au while preserving a strong connotation of the properties of the two materials also in the hybrid system. [ABSTRACT FROM AUTHOR]

Starting from the four component-Dirac equation for free, ballistic electrons with finite mass, driven by a constant d.c. field, we derive a basic model of scalar quantum conductivity, capable of yielding simple analytic forms, also in the presence of magnetic and polarization effects. The classical Drude conductivity is recovered as a limit case. A quantum-mechanical evaluation is provided for parabolic and linear dispersion, as in graphene, recovering currently used expressions as particular cases. Numerical values are compared with the ones from the literature in the case of graphene under d.c. applied field. In particular, the effect of the sample length and field strength on the conductivity are highlighted. [ABSTRACT FROM AUTHOR]

Although photobiomodulation (PBM) has proven promising to treat wounds, the lack of univocal guidelines and of a thorough understanding of light–tissue interactions hampers its mainstream adoption for wound healing promotion. This study compared murine and human fibroblast responses to PBM by red (635 ± 5 nm), near-infrared (NIR, 808 ± 1 nm), and violet-blue (405 ± 5 nm) light (0.4 J/cm2 energy density, 13 mW/cm2 power density). Cell viability was not altered by PBM treatments. Light and confocal laser scanning microscopy and biochemical analyses showed, in red PBM irradiated cells: F-actin assembly reduction, up-regulated expression of Ki67 proliferation marker and of vinculin in focal adhesions, type-1 collagen down-regulation, matrix metalloproteinase-2 and metalloproteinase-9 expression/functionality increase concomitant to their inhibitors (TIMP-1 and TIMP-2) decrease. Violet-blue and even more NIR PBM stimulated collagen expression/deposition and, likely, cell differentiation towards (proto)myofibroblast phenotype. Indeed, these cells exhibited a higher polygonal surface area, stress fiber-like structures, increased vinculin- and phospho-focal adhesion kinase-rich clusters and α-smooth muscle actin. This study may provide the experimental groundwork to support red, NIR, and violet-blue PBM as potential options to promote proliferative and matrix remodeling/maturation phases of wound healing, targeting fibroblasts, and to suggest the use of combined PBM treatments in the wound management setting. [ABSTRACT FROM AUTHOR]

The antifibrotic potential of platelet-rich plasma (PRP) is controversial. This study examined the effects of PRP on in vitro transforming growth factor (TGF)-β1-induced differentiation of fibroblasts into myofibroblasts, the main drivers of fibrosis, and the involvement of vascular endothelial growth factor (VEGF)-A in mediating PRP-induced responses. The impact of PRP alone on fibroblast differentiation was also assessed. Myofibroblastic phenotype was evaluated by confocal fluorescence microscopy and western blotting analyses of α-smooth muscle actin (sma) and type-1 collagen expression, vinculin-rich focal adhesion clustering, and stress fiber assembly. Notch-1, connexin 43, and VEGF-A expression were also analyzed by RT-PCR. PRP negatively regulated fibroblast-myofibroblast transition via VEGF-A/VEGF receptor (VEGFR)-1-mediated inhibition of TGF-β1/Smad3 signaling. Indeed TGF-β1/PRP co-treated fibroblasts showed a robust attenuation of the myofibroblastic phenotype concomitant with a decrease of Smad3 expression levels. The VEGFR-1 inhibition by KRN633 or blocking antibodies, or VEGF-A neutralization in these cells prevented the PRP-promoted effects. Moreover PRP abrogated the TGF-β1-induced reduction of VEGF-A and VEGFR-1 cell expression. The role of VEGF-A signaling in counteracting myofibroblast generation was confirmed by cell treatment with soluble VEGF-A. PRP as single treatment did not induce fibroblast myodifferentiation. This study provides new insights into cellular and molecular mechanisms underpinning PRP antifibrotic action. [ABSTRACT FROM AUTHOR]

Rapid and unplanned urban growth is responsible for the continuous conversion of green or generally natural spaces into artificial surfaces. The high degree of imperviousness modifies the urban microclimate and no studies have quantified its influence on the surface temperature (ST) nearby residential building. This topic represents the aim of this study carried out during summer in different urban zones (densely urbanized or park/rural areas) of Parma (Northern Italy). Daytime and nighttime ASTER images, the local urban cartography and the Italian imperviousness databases were used. A reproducible/replicable framework was implemented named "Building Thermal Functional Area" (BTFA) useful to lead building-proxy thermal analyses by using remote sensing data. For each residential building (n = 8898), the BTFA was assessed and the correspondent ASTER-LST value (ST_BTFA) and the imperviousness density were calculated. Both daytime and nighttime ST_BTFA significantly (p < 0.001) increased when high levels of imperviousness density surrounded the residential buildings. These relationships were mostly consistent during daytime and in densely urbanized areas. ST_BTFA differences between urban and park/rural areas were higher during nighttime (above 1 °C) than daytime (about 0.5 °C). These results could help to identify "urban thermal Hot-Spots" that would benefit most from mitigation actions. [ABSTRACT FROM AUTHOR]

Elucidating the physics of a concentrated suspension of ring polymers, or of an ensemble of ring polymers in a complex environment, is an important outstanding question in polymer physics. Many of the characteristic features of these systems arise due to topological interactions between polymers, or between the polymers and the environment, and it is often challenging to describe this quantitatively. Here we review recent research which suggests that a key role is played by inter-ring threadings (or penetrations), which become more abundant as the ring size increases. As we discuss, the physical consequences of such threadings are far-reaching: for instance, they lead to a topologically-driven glassy behaviour of ring polymer melts under pinning perturbations, while they can also account for the shape of experimentally observed patterns in two-dimensional gel electrophoresis of DNA knots. [ABSTRACT FROM AUTHOR]

By using Langevin dynamics simulations, we study how semiflexible rings that are topologically linked respond tomechanical stretching. We use both constant-force and constant-velocity pulling protocols and map out how the mechanical tension affects observables related to metric quantities such as the longitudinal extension or span, and topology-related ones such as the length of the linked portion. We find that the average extension of linked rings, once divided by that of a single equivalent ring, is nonmonotonic in the applied force. We show that this remarkable feature becomes more prominent as the link complexity is increased, and originates from the different stretching compliance of the linked portion and the rest of the rings' contour. By comparing the results of different pulling protocols, we also establish the best one for telling apart different types of links from their tensile response. [ABSTRACT FROM AUTHOR]

Heatwaves (HWs) are one of the "natural" hazards with the greatest impact worldwide in terms of mortality and economic losses, and their effects may be exacerbated in large urban areas. For these reasons, more detailed analyses of urban HW trends represent a priority that cannot be neglected. In this study, HW trends were investigated during the warmest period of the year (May-September) by using a slightly improved version of the EuroHEAT HW definition applied on long meteorological time-series (36-year period, 1980-2015) collected by weather stations located in the capitals of the 28 European Union member countries. Comparisons between two 18-year sub-periods (1980-1997 vs. 1998-2015) were carried out and a city-specific HW hazard index (HWHI), accounting for the main HW characteristics, was proposed. Most of the capitals revealed significant positive trends of the majority of HW hazard characteristics and substantial HWHI increases were observed during the sub-period 1998-2015, especially in the central-eastern and southeastern cities. Conversely, minor HWHI increases were observed in most of the northern capitals and opposite situations were even observed in several northern and especially southwestern cities. The results of this study represent a support for planning urban HW-related mitigation and adaptation strategies with the priority given to the southeastern cities. [ABSTRACT FROM AUTHOR]

Crop growth and yield are affected by water use during the season: the green water footprint (WF) accounts for rain water, the blue WF for irrigation and the grey WF for diluting agri-chemicals. We calibrated crop yield for FAO's water balance model "Aquacrop" at field level. We collected weather, soil and crop inputs for 45 locations for the period 1992-2012. Calibrated model runs were conducted for wheat, barley, grain maize, oilseed rape, potato and sugar beet. The WF of cereals could be up to 20 times larger than the WF of tuber and root crops; the largest share was attributed to the green WF. The green and blue WF compared favourably with global benchmark values (R2 = 0.64-0.80; d = 0.91-0.95). The variability in the WF of arable crops across different regions in Europe is mainly due to variability in crop yield (cv¯ = 45%) and to a lesser extent to variability in crop water use (cv¯ = 21%). The WF variability between countries (cv¯ = 14%) is lower than the variability between seasons (cv¯ = 22%) and between crops (cv¯ = 46%). Though modelled yields increased up to 50% under sprinkler irrigation, the water footprint still increased between 1% and 25%. Confronted with drainage and runoff, the grey WF tended to overestimate the contribution of nitrogen to the surface and groundwater. The results showed that the water footprint provides a measurable indicator that may support European water governance. [ABSTRACT FROM AUTHOR]

The interaction between the cell membrane and misfolded protein species plays a crucial role in the development of neurodegeneration. This study was designed to clarify the relationship between plasma membrane composition in terms of the differently linked sialic acid (Sia) content and cell susceptibility to toxic and misfolded Aβ-42 peptides. The sialylation status in different cell lines was investigated by lectin histochemistry and confocal immunofluorescence and then correlated with the different propensities to bind amyloid fibrils and with the relative cell susceptibility to amyloid damage. This study reveals that expressions of Sias α2,3 and α2,6 linked to galactose/N-acetyl-galactosamine, and PolySia are positively correlated with Aβ-42-induced cell toxicity. PolySia shows an early strong interaction with amyloid fibrils, favoring their binding to GM1 ganglioside containing α2,3 galactose-linked Sia and a loss of cell viability. Our findings demonstrate that cell lines with a prevailing plastic neuron-like phenotype and high monoSia and PolySia contents are highly susceptible to amyloid Aβ-42 toxicity. This toxicity may involve a change in neuron metabolism and promote a compensative/protective increase in PolySia, which, in turn, could favor amyloid binding to GM1, thus exacerbating cell dysmetabolism and further amyloid aggregation. [ABSTRACT FROM AUTHOR]

Renewable energy communities (RECs) are alternatives toward sustainable production and consumption pathways. In 2020, Italy implemented the EU Directive 2018/2001, defining a common framework for promoting energy from renewable sources. The "Famiglia di Maria", a foundation dealing with social issues in San Giovanni a Teduccio, Napoli (Italy), in collaboration with "Legambiente" and "Con il Sud" Foundations, released the first Solidarity Oriented Renewable Energy Community project in Italy. Therefore, by applying social life cycle assessment (s-LCA) and life cycle assessment (LCA) methodologies, this study aims to: (i) promote the dissemination of RECs in the Italian and European contexts, (ii) suggest REC scenarios for the best social and environmental solutions, and (iii) support the policymakers for sustainable local development. Some key results show that the solidarity-oriented project has already produced mature outcomes about community cohesion. In contrast, technical skills and awareness about environmental issues still need to be further developed and shared among the stakeholders. Finally, social and environmental indicators converge on the self-consumption model as a feasible alternative for energy justice, community empowerment, and economic and market competition independence. [ABSTRACT FROM AUTHOR]

Numerous epidemiological studies have highlighted the positive effects on health of wholegrain bakery products made from 'old' common wheat (Triticum aestivum L.) varieties. However, 'old' common wheat varieties display poor rheological properties, and there is limited information on its free asparagine (ASN) content, the main precursor to acrylamide during the baking process. This paper evaluates the effects of two seeding density levels (SD: 200 and 350 seed m−2), three nitrogen levels (NL: 35, 80 and 135 kg N ha−1), and two sulfur levels (SL: 0 and 6.4 kg S ha−1) towards improving the grain yield (GY), rheological characteristics, and ASN content of 14 'old' common wheat varieties. SL and SD treatments significantly increased GY without decreasing the protein content (PC), while NL significantly increased the PC without affecting GY. The dough strength (W) increased significantly with increasing SL and NL but was significantly reduced with increasing SD. ASN significantly increased by 111% as NL increased from 35 to 135 kg ha−1, while ASN significantly decreased by 85.1% with the SL treatment. The findings show that 135 kg N ha−1 combined with 6.4 kg S ha−1 can improve the technical performance of 'old' wheat wholegrain flours while maintaining the ASN as low as possible. [ABSTRACT FROM AUTHOR]

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent the leading candidate cell in tissue engineering and regenerative medicine. These cells can be easily isolated, expanded in vitro and are capable of providing significant functional benefits after implantation in the damaged muscle tissues. Despite their plasticity, the participation of BM-MSCs to new muscle fiber formation is controversial; in fact, emerging evidence indicates that their therapeutic effects occur without signs of long-term tissue engraftment and involve the paracrine secretion of cytokines and growth factors with multiple effects on the injured tissue, including modulation of inflammation and immune reaction, positive extracellular matrix (ECM) remodeling, angiogenesis and protection from apoptosis. Recently, a new role for BM-MSCs in the stimulation of muscle progenitor cells proliferation has been demonstrated, suggesting the potential ability of these cells to influence the fate of local stem cells and augment the endogenous mechanisms of repair/regeneration in the damaged tissues. [ABSTRACT FROM AUTHOR]