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Argentinean economic reforms introduced in the 1990s were characterized by structural adjustments which increased both job insecurity and barriers to health care. In Córdoba, some individuals found themselves without health coverage. Conversely, many private practices, also in crisis, were forced to close with a resultant loss of heath care jobs. Rather than accepting layoffs, the employees of the private Junin Clinic took over the facility and reorganized it as a cooperative. They wanted both to keep their jobs and to provide affordable health services primarily to the uninsured. We hypothesized that the quality of their clinical jobs would impact on the care they provided. We undertook to examine how changes in the organization of the clinic affected working relations and working conditions . We undertook a descriptive, correlative survey of 25 employees chosen via a multi-stage process to be representative of the clinic. Four percent worked under contract; eighty percent were professionals who split their earning 50/50 with the cooperative. The remaining workers were cooperative members. Fifty percent of those interviewed earned less than the basic minimum wage. Forty-four percent worked alone; the remaining workers were part of teams. Eighty-eight percent felt that their job was appropriate for their level of training. No one reported any occupational accidents. Eighty percent reported satisfactory hygienic conditions in their workplace. While the division of labor at the clinic had not changed since the take over, administrative structures were different. Cooperative decisions are made in large meetings. Since most professionals are not members of the cooperative, they do not participate in these meetings. However, we observed that relations and exchanges among the workers were less hierarchical. This work was undertaken to inform the debate on the relationship between working conditions and the provision of health care. We found that the work environment impacts on health care workers as they try to provide a more equitable form of health care.

Abstract Background Government-led, population-wide initiatives are crucial for advancing the management of hypertension − a leading cause of cardiovascular disease (CVD) morbidity and mortality. An urban population health initiative was conducted against this backdrop, focussing on hypertension in the primary health system in São Paulo, Brazil. Within the frame of the initiative and under the supervision and leadership of the municipal health authorities, a situational analysis was conducted on the needs in hypertension management, marking the first phase of a Design Thinking process. This article describes the situational analysis process and presents the identified elements to be strengthened considering hypertension diagnosis, treatment and control. Methods First, a mixed-methods approach was used, starting with a literature review of municipal hypertension data followed by meetings (N = 20) with the local public health administration to assess health system level components. To investigate activities on hypertension diagnosis, treatment and control, nine primary healthcare units were selected from two districts of São Paulo city– Itaquera and Penha– which received an online form addressed to managers, participated in conversation circles of staff and patients, and underwent shadowing of community health agents. Results Data gave rise to two main outputs: (i) a patient care journey map; and (ii) a matrix summarizing the identified needs at patient, healthcare professional and health system level for diagnosis, treatment and control of hypertension. Patient awareness and knowledge of hypertension was found to be insufficient and its management needs to be improved. For health professionals, disease awareness, technical training, more time dedicated to patients, and simplified guidelines and clinical decision-making tools for hypertension management were identified as principal needs. The situational analysis found that the healthcare systems efficiency might be improved by establishing defined treatment and care delivery goals with a focus on outcomes and implemented through action plans. Conclusions This situational analysis identified several needs related to hypertension control in São Paulo that are in line with global challenges to improve the control of CVD risk factors. Findings were also confirmed locally in an expansion phase of this situational analysis to additional primary care facilities. As a consequence, solutions were designed, promptly taken up and implemented by the municipal health secretariat.

Abstract Europe imports large amounts of soybean that are predominantly used for livestock feed, mainly sourced from Brazil, USA and Argentina. In addition, the demand for GM-free soybean for human consumption is project to increase. Soybean has higher protein quality and digestibility than other legumes, along with high concentrations of isoflavones, phytosterols and minerals that enhance the nutritional value as a human food ingredient. Here, we examine the potential to increase soybean production across Europe for livestock feed and direct human consumption, and review possible effects on the environment and human health. Simulations and field data indicate rainfed soybean yields of 3.1 ± 1.2 t ha−1 from southern UK through to southern Europe (compared to a 3.5 t ha−1 average from North America). Drought-prone southern regions and cooler northern regions require breeding to incorporate stress-tolerance traits. Literature synthesized in this work evidenced soybean properties important to human nutrition, health, and traits related to food processing compared to alternative protein sources. While acknowledging the uncertainties inherent in any modelling exercise, our findings suggest that further integrating soybean into European agriculture could reduce GHG emissions by 37–291 Mt CO2e year−1 and fertiliser N use by 0.6–1.2 Mt year−1, concurrently improving human health and nutrition.

Abstract BackgroundAccurate and timely infectious disease surveillance is pivotal for effective public health responses. An important component of this is the disease surveillance tools used. Understanding views and experiences of users is crucial for informing policy decisions and ensuring the seamless functioning of surveillance systems. ObjectiveIn this study, we aimed to assess the user perceptions of 3 disease surveillance tools used in Côte d’Ivoire, namely, MAGPI, District Health Information Software 2 (DHIS2), and Surveillance Outbreak Response Management and Analysis System (SORMAS), the latter was implemented in 2021 within a pilot scheme. MethodsWe conducted interviews and a web-based survey distributed to users of the 3 surveillance tools. The survey assessed users’ views of the surveillance tools’ usefulness, ease of use, feelings toward the tool, conditions that may influence the use, and other characteristics. The descriptive analysis compared responses from SORMAS, MAGPI, and DHIS2 users, providing a comprehensive evaluation of their experiences. ResultsAmong the 159 respondents who actively use one of the systems, MAGPI was the most widely used surveillance tool among respondents (n=127, 79.9%), followed by DHIS2 (n=108, 67.9%), and SORMAS (n=25, 15.7%). In terms of users’ perceptions, SORMAS, despite its limited implementation, emerged as a tool that allows for data analysis and had the most comprehensive set of functionalities. DHIS2 was appreciated for its frequency of report provision, although users reported occasional IT system failures. MAGPI was recognized for its ease of use but was reported to lack certain functionalities offered by the other surveillance systems. ConclusionsThis study offers valuable insights into the perceptions of disease surveillance tools users in Côte d’Ivoire. While all systems were positively regarded, each exhibited strengths and weaknesses addressing different needs and functionalities. Policy makers and health officials can use these findings to enhance existing tools or consider a unified approach for infectious disease surveillance systems. Understanding users’ perspectives allows them to optimize the choice of surveillance tools, ultimately strengthening public health responses in Côte d’Ivoire and potentially serving as a model for other countries facing similar decisions in their health care systems.

The antifouling booster biocides are frequently studied for toxic effects on the aquatic ecosystems. The present investigation proposes passive silicone rubber samplers as a collection method for biocides, once these methods can concentrate substances in aqueous matrices at very low levels. Through the passive sampler-water partition coefficient (Ksw) and the analyte chemical nature, we can optimize their extraction from the membrane to apply in the sample medium. We used the co-solvent method to determine the Ksw of three third-generation antifouling biocides, chlorothalonil, dichlofluanid, and dichlorooctylisothiazolinone (DCOIT), with log Ksw = 2.24, 4.01, and 2.38, respectively. Improving extraction also led to a recovery range higher than 70%, determinations were carried out by gas chromatography with an electron capture detector. Biocides concentration in seawater samples from Itaqui port (São Marcos Bay, northern Brazil) ranged from 0.058 to 0.72 µg L-1 for chlorothalonil, 0.001 to 0.008 µg L-1 for dichlofluanid, and 0.018 to 0.64 µg L-1 for DCOIT.

The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have therefore investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by NGF identified cases with a significantly shorter median PFS (mPFS; MS: not reached vs 1,4 years, p=0.001; NGF: not reached vs 2 years, p=0.0002) but reaching CR+sCR did not discriminate patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with a mPFS not yet reached vs 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can thus conclude that 1) the standard response categories of the IMWG do not seem to be useful for treatment monitoring in HRsMM patients, 2) MS could be used as a non-invasive, clinical valuable tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference) and 3) similarly to NGF, sequential results of MS are able identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT02415413).

Abstract The genus Flavivirus comprises approximately 80 different viruses. Phylogenetic relationships among its members indicate a clear ecological separation between those viruses transmitted by mosquitoes, ticks, with no known vector, and insect-specific Flaviviruses. The diversity and phylogenetic relationships among insect-specific flaviviruses circulating in the central and northern regions of Argentina were studied by performing molecular detection and characterization of the NS5 protein gene in mosquitoes collected in Córdoba, Chaco and Tucumán provinces. Overall, 68 out of 1776 pools were positive. CxFV, KRV and CFAV circulate in the 3 studied provinces. Several mosquito species (Aedes aegypti, Culex bidens, Cx. dolosus, Cx. interfor, Cx. quinquefasciatus, Cx. saltanensis, Haemagogus spegazzini) were found infected. A wide circulation of CxFV was observed in the central-northern region of Argentina. CxFV strains detected in our study clustered with strains circulating in Santa Fe and Buenos Aires provinces (Argentina), and other countries such as Indonesia, Mexico, Uganda and Taiwan. The presence of these viruses in mosquitoes could play an important role from the public health perspective, because it has been shown that previous CxFV infection can increase or block the infection of the mosquito by other pathogenic flaviviruses.

Abstract Neutrophils play a significant role in sustaining chronic inflammation in Inflammatory Bowel Disease. The intestinal basement membrane acts as a barrier for immunological homeostasis, where the α3 and α4 chains of type IV collagen are expressed on the mucosal surface. We wanted to develop a biomarker reflecting early tissue injury, providing an opportunity for intervention. Two competitive enzyme-linked immunosorbent assays (ELISAs) quantifying human neutrophil elastase (HNE) degraded neo-epitopes of COL4A3 and COL4A4 were developed and investigated in two observational cohorts (n = 161, n = 100). A biomarker of MMP-mediated degradation of COL4A1 (C4M) was used for comparison. In Cohort 1, patients with mild endoscopic ulcerative colitis showed elevated levels of C4A3-HNE compared to those with severe disease. C4M had a strong positive correlation with disease activity. C4A3-HNE/C4M provided superior discrimination between mild and severe endoscopic disease and negatively correlated to disease activity. In Cohort 2, C4A4-HNE and C4A4-HNE/C4M showed similar trends. C4A3-HNE and C4A4-HNE possibly reflect early intestinal tissue injury. Combining the markers with a biomarker of another α-chain of the same collagen provides information on two distinct stages of mucosal damage. These biomarkers may be used to monitor disease flare-up in patients in remission, reducing the need for frequent endoscopic procedures.

This study examined the effects of late sowing, water restrictions, and interannual weather variations on wheat grain yield and quality through field trials in Spain over two growing seasons. Delayed sowing and water scarcity significantly reduced yields, with grain quality mainly affected under rainfed conditions. Early-maturing varieties performed better in these conditions, benefiting from lower temperatures and extended grain-filling periods, leading to higher solar radiation interception, potentially increased photosynthetic activity, and improved yields. These varieties also saved water through reduced total cumulative evapotranspiration from sowing to maturity (ETo TOT), which was advantageous in water-limited environments. In contrast, late-maturing varieties were exposed to higher maximum temperatures during grain filling and experienced greater ETo TOT, leading to lower yields, reduced hectoliter weight, and a lower P/L ratio (tenacity/extensibility). This study highlighted the importance of optimizing temperature exposure and evapotranspiration for improved grain yield and quality, especially under climate change conditions with higher temperatures and water shortages. Notably, it established, for the first time, the importance of phenology on wheat quality of different varieties, suggesting that targeted selection for specific phenology could mitigate the negative impacts of heat stress not only on grain yield but also on grain quality.

One challenge in creating commercial solutions with supervised deep learning is acquiring large, customized labeled datasets. These datasets must often fit within commercial industries’ production times and budgets. There is still a need for target data that allows the model to learn specific characteristics of the target domain. The construction of customized datasets is relevant in imaging waste identification to improve the accuracy and efficiency of models, allowing adaptation to specific conditions. To address this challenge, we propose the EcoMind open-source tool. This tool facilitates waste labeling from user-provided images and empowers local dataset creation and collaborative building with users.

Cytochrome c552 from Wolinella succinogenes is one of the few examples of a low reduction potential class I c-type cytochrome with a mixture of high/low spin state populations observed in its visible spectrum. Analysis of its structural model suggests that the heme is Met/His coordinated and highly solvent-exposed. This supports the hypothesis that it is the solvent accessibility of the propionate groups that controls the reduction potential of this small c-type cytochrome. The visible spectra obtained at different pH values reveal the presence of a protonable group with a pKa of 7.3, which also influences the reduction potential of this small cytochrome c552 (Em0’ of 97 ± 5 mV, pH 7.0) and can be either an H2O/OH− group distantly coordinating the heme iron, or one of the propionate groups. The thermostability of cytochrome c552 was studied by circular dichroism and differential scanning calorimetry, indicating a highly stable protein at pH 5–7 (90°C to 77°C).

Abstract Background The Surveillance Outbreak Response Management and Analysis System (SORMAS) has been implemented for various infectious diseases since 2015. 2020, at the beginning of the COVID-19 pandemic, SORMAS was adapted to SARS-CoV2. Methods We assessed the acceptability and usability of SORMAS and accompanied its implementation in two pilot regions of Côte d’Ivoire (Abidjan 2 and Gbêkê) from July/August 2021 to March 2022. We conducted 136 semi-structured interviews to cover knowledge on COVID-19, information on conventional surveillance systems for disease monitoring including COVID-19, acceptability of SORMAS, and impact of SORMAS on epidemic preparedness and surveillance. Scores before and 6–8 months after implementation were compared. Results SORMAS was implemented in two pilot regions in Côte d’Ivoire. The conventional software for the surveillance of the COVID-19 pandemic by the company MAGPI was maintained in parallel; the additional time needs to enter and manage the data in SORMAS were the main concern. SORMAS acceptance and satisfaction scores were high after the user training, which was prior to implementation, and after 6–8 months of use. The ability of SORMAS to improve COVID-19 preparedness and early detection of cases and contacts was widely acknowledged. To keep the understanding and skills of users up-to-date, regular refresher trainings were requested. The expectation to be able to make decisions based on data produced by SORMAS was high at baseline and the perceived experience after several months of use of the software was very positive. Unfortunately, the link with the laboratories could not be established in the pilot regions, but it is an existing feature of SORMAS that many users were asking for. Following the positive experience using SORMAS for COVID-19, the pilot regions expanded its use for monitoring and management of measles, yellow fever, meningitis, and cholera. Conclusion SORMAS was very well accepted by users and decision makers in the two pilot regions of Côte d’Ivoire and its ability to improve epidemic preparedness and surveillance was acknowledged. If the hurdles of maintenance (tablets, server, and maintaining user skills) are handled sustainably, it can serve as a valid tool to identify, surveil and manage future outbreaks of various infectious diseases in Côte d’Ivoire.

Abstract The fibroblast growth factor (FGF) family regulates various and important aspects of nervous system development, ranging from the well-established roles in neuronal patterning to more recent and exciting functions in axonal growth and synaptogenesis. In addition, FGFs play a critical role in axonal regeneration, particularly after spinal cord injury, confirming their versatile nature in the nervous system. Due to their widespread involvement in neural development, the FGF system also underlies several human neurological disorders. While particular attention has been given to FGFs in a whole-cell context, their effects at the axonal level are in most cases undervalued. Here we discuss the endeavor of the FGF system in axons, we delve into this neuronal subcompartment to provide an original view of this multipurpose family of growth factors in nervous system (dys)function. Video Abstract

This work describes a specialized optical fiber hybrid sensing configuration conceived to monitor internal physical parameters (temperature and pressure) within Li-ion batteries (LiBs) and correlate them with electrochemical performance in operando. The batteries underwent thorough cycling tests under C/3 and C/5 operating rate conditions. Throughout the cycling tests, the optical fiber sensors revealed a compelling correlation between internal and external temperature behavior. Additionally, the application of differential voltage analysis derivative curves during battery operation unveiled insights into the relationship between pressure and temperature changes and the batteries’ electrochemical performance. This optical sensing approach contributes to an understanding of internal LiB dynamics, offering implications for optimizing their performance and safety across diverse applications.

The periodontium is a complex hierarchical structure composed of alveolar bone, periodontal ligament, cementum, and gingiva. Periodontitis is an inflammatory disease that damages and destroys the periodontal tissues supporting the tooth. Periodontal therapies aim to regenerate the lost tissues, yet current treatments lack the integration of multiple structural/biochemical instructive cues to induce a coordinated regeneration, which leads to limited clinical outcomes. Hierarchical biomaterial scaffolds offer the opportunity to recreate the organization and architecture of the periodontium with distinct compartments, providing structural biomimicry that facilitates periodontal regeneration. Various scaffolds have been fabricated and tested preclinically, showing positive regenerative results. This review provides an overview of the recent research on hierarchical scaffolds for periodontal tissue engineering (TE). First, the hierarchical structure of the periodontium is described, covering the limitations of the current treatments used for periodontal regeneration and presenting alternative therapeutic strategies, including scaffolds and biochemical factors. Recent research regarding hierarchical scaffolds is highlighted and discussed, in particular, the scaffold composition, fabrication methods, and results from in vitro/in vivo studies are summarized. Finally, current challenges associated with the application of hierarchical scaffolds for periodontal TE are debated and future research directions are proposed.

Co7Zn7Mn6 is a β-Mn-type alloy belonging to the CoxZnyMnz (x+y+z=20) family that notoriously features a skyrmionic magnetic phase below the ferromagnetic ordering temperature and, in addition, a reentrant spin glass transition at low temperatures. In this work, we have studied the effect of partial substitution of Mn by Fe in the magnetic properties of this alloy. Samples of Co7Zn7Mn6−xFex, 0≤x≤1, were synthesised using the Bridgman–Stockbarger method, and their structure and composition were fully characterised by XRD and EDS. VSM and AC susceptibility measurements show that the partial substitution of Mn by Fe increases TC and the skyrmionic region of the magnetic phase diagram is suppressed for x>0.5. The AC susceptibility behaviour at low temperatures can be ascribed to the presence of a reentrant spin glass state observed for all compositions, with a spin glass freezing temperature, Tg, that shifts to lower temperatures as the Fe content increases.

Acid mine drainage (AMD) is one of the main environmental problems associated with mining activity, whether the mine is operational or abandoned. In this work, several precipitates from this mine drainage generated by the oxidation of sulfide minerals, when exposed to weathering, were used as adsorbents. Such AMD precipitates from abandoned Portuguese mines (AGO, AGO-1, CF, and V9) were compared with two raw materials from Morocco (ClayMA and pyrophyllite) in terms of their efficiency in wastewater treatment. Different analytical techniques, such as XRD diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), N2 adsorption isotherms, and Scanning Electron Microscopy (SEM) with Energy Dispersive X-ray (EDX) were used to characterize these natural materials. The adsorption properties were studied by optimizing different experimental factors, such as type of adsorbent, adsorbent mass, and dye concentration by the Box–Behnken Design model, using methylene blue (MB) and crystal violet (CV) compounds as organic pollutants. The obtained kinetic data were examined using the pseudo-first and pseudo-second order equations, and the equilibrium adsorption data were studied using the Freundlich and Langmuir models. The adsorption behavior of the different adsorbents was perfectly fitted by the pseudo-second order kinetic model and the Langmuir isotherm. The most efficient adsorbent for both dyes was AGO-1 due to the presence of the cellulose molecules, with qm equal to 40.5 and 16.0 mg/g for CV and MB, respectively. This study confirms the possibility of employing AMD precipitates to adsorb organic pollutants in water, providing valuable information for developing future affordable solutions to reduce the wastes associated with mining activity.

After the end-Triassic extinction, parvipelvian ichthyosaurs diversified and became dominant elements of marine ecosystems worldwide. By the Early Jurassic, they achieved a thunniform body plan that persisted for the last 100 m.y.a of their evolution. Diversification and extinctions of thunniform ichthyosaurs, and their swimming performance, have been studied from different perspectives. The transformation of limbs into hydrofoil-like structures for better control and stability during swimming predates thunniform locomotion. Despite their importance as control surfaces, fin evolution among thunnosaurs remains poorly understood. We explore ichthyosaur fin diversity using anatomical networks. Our results indicate that, under a common hydrofoil controller fin, the bone arrangement diversity of the ichthyosaur fin was greater than traditionally assumed. Changes in the connectivity pattern occurred stepwise throughout the Mesozoic. Coupled with other lines of evidence, such as the presence of a ball-and-socket joint at the leading edge of some derived Platypterygiinae, we hypothesize that fin network disparity also mirrored functional disparity likely associated with different capabilities of refined maneuvering. The ball-and-socket articulation indicates that this local point could be acting like a multiaxial intrafin joint changing the angle of attack and thus affecting the maneuverability, similar to the alula of flying birds. Further studies on large samples and quantitative experimental approaches would be worthy to test this hypothesis.

Understanding learners' behavior is the key to the success of any learning process. The more we know about them, the more likely we can personalize learning experiences and provide successful feedback. This paper presents a feedback model implemented in a ubiquitous microlearning environment based on contextual and behavioral information and evaluation results. The model uses SECA rules where the Scenario (S) represents the ubiquitous context variables reflecting the learner behavior during the learning process. The Event (E) identifies the probability that a learner fails or passes its evaluation. Condition (C) evaluates the results of the events. Moreover, Action (A) provides feedback to the learner. The proposal is developed through a controlled experiment whereby a microlearning environment can collect data from a ubiquitous context. The feedback model applies an analytics process to find the best context and behavior variables through different classification models. Those models predict whether a learner could fail, determine evaluation results' causes, and provide feedback. The Random Forest was the model with the best performance. Thus, 94% accuracy, a 97% Recall, a 93% Precision, an F1 score of 95%, and a Jaccard of 91%. Hence, each scenario is defined from a branch of every tree obtained from the Random Forest model personalizing feedback actions applying clustering techniques. Finally, we presented an exemplified set of feedback rules, providing automatic recommendations and improving learner experiences. Thus, the experiment allows analyzing the learner behavior in a ubiquitous microlearning context from a feedback perspective.

Painting materials used in Spanish American Colonial art comprised pigments and binders from European origin as well as those that were already known in pre-Hispanic times. In recent years, we have identified for the first time the mineral atacamite, a basic copper chloride (Cu2Cl(OH)3), in Andean Colonial art pieces (Viceroyalty of Peru, 16th–18th centuries). This work proposes a methodology based on a multitechnical approach to identify and establish the origin (natural or synthetic) of the atacamite pigment in Andean cultural heritage objects. Optical microscopy (OM), scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS), portable X-ray fluorescence spectroscopy (pXRF), attenuated total reflection infrared spectroscopy (FTIR-ATR), micro-Raman spectroscopy, and wide-angle X-ray scattering (WAXS) were applied to analyse green pigments from the altarpiece of the Church of Ancoraimes, atacamite mineral samples from Chile, and atacamite obtained as a secondary product from traditional recipes used to produce verdigris, a copper acetate. Viride salsum by Teófilo Presbítero (SXII) and the Spanish translation by Andrés de Laguna (1566) of “De Materia Médica” from Dioscorides are both texts that include recipes involving the use of metallic copper as a starting material. These studies will contribute to the history of Spanish American Colonial art and to the knowledge on technological capacities and skills in the Andean region during this period.

IntroductionThe inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed.MethodsIn this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues.ResultsWe demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation.DiscussionOverall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

ABSTRACTOsteoporotic-related fractures are among the leading causes of chronic disease morbidity in Europe and in the US. While a significant percentage of fractures can be repaired naturally, in delayed-union and non-union fractures surgical intervention is necessary for proper bone regeneration. Given the current lack of optimized clinical techniques to adequately address this issue, bone tissue engineering (BTE) strategies focusing on the development of scaffolds for temporarily replacing damaged bone and supporting its regeneration process have been gaining interest. The piezoelectric properties of bone, which have an important role in tissue homeostasis and regeneration, have been frequently neglected in the design of BTE scaffolds. Therefore, in this study, we developed novel hydroxyapatite (HAp)-filled osteoinductive and piezoelectric poly(vinylidene fluoride-co-tetrafluoroethylene) (PVDF-TrFE) nanofibers via electrospinning capable of replicating the tissue’s fibrous extracellular matrix (ECM) composition and native piezoelectric properties. The developed PVDF-TrFE/HAp nanofibers had biomimetic collagen fibril-like diameters, as well as enhanced piezoelectric and surface properties, which translated into a better capacity to assist the mineralization process and cell proliferation. The biological cues provided by the HAp nanoparticles enhanced the osteogenic differentiation of seeded human mesenchymal stem/stromal cells (MSCs) as observed by the increased ALP activity, cell-secreted calcium deposition and osteogenic gene expression levels observed for the HAp-containing fibers. Overall, our findings describe the potential of combining PVDF-TrFE and HAp for developing electroactive and osteoinductive nanofibers capable of supporting bone tissue regeneration.